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Narrator: At the intersection of science and clinical experience in IBD, this is Gut Reactions. Settle in, as our host, Dr. David Rubin, brings leading gastroenterologists together for one-on-one conversations. This podcast is brought to you by AbbVie.

Dr. David Rubin: Welcome to the Gut Reactions podcast. I'm your host, Dr. David Rubin, Chief of the section of Gastroenterology, Hepatology, and Nutrition, and Director of the Inflammatory Bowel Disease Center at the University of Chicago. Today, we are fortunate to be joined by Adam, my patient with moderately to severely active ulcerative colitis, who also has experience working with the Crohn's and Colitis Foundation. In this episode, we're going to explore the treatment journey for patients with ulcerative colitis.

Ulcerative colitis, commonly referred to as UC, is a chronic immune condition characterized by inflammation within the large intestine, which means the colon and the rectum. The diagnostic process for ulcerative colitis entails a comprehensive review of physical symptoms, a detailed medical history, and an array of tests which may include blood tests, testing of stool samples, and procedures such as colonoscopies with biopsies.

Diagnosing ulcerative colitis is indeed a complex process and there is no single definitive test to confirm its presence. This complexity is heightened due to the overlapping symptoms with other conditions. That necessitates a thorough approach. Additionally, it's worth noting that the average time to confirm a UC diagnosis can vary depending on individual cases. For some people, it can take a few months and for others up to several years.

Adam, can you provide a brief overview of your history with ulcerative colitis, including how it presented, what your symptoms were, and your overall experience trying to get a diagnosis?

Adam: Absolutely. First off, thanks for having me, Dr. Rubin. I really appreciate it. I'm honored to be here. Yeah, so I was diagnosed when I was nine years old. And my first symptoms really were urgency and increased frequency to need to use the bathroom as well as blood in the stool and all of that. And so, I was taken to my primary care, who is a great doctor. And she got me plugged in with the hospital here pretty quick. And we were able to turn around a diagnosis relatively quickly, which I know isn't always the case with a lot of patients.

Dr. David Rubin: One of the things I often ask my patients about, and I see adult patients with these problems, is when do you think it actually started? Do you recall having symptoms for a while before you brought it to the attention of your parents, or was it pretty obvious?

Adam: I think it was pretty obvious. I know I was having the issues, I was diagnosed fall of 1999. And so, I know I remember having issues in the summer and whatnot. So, I know at least a few months prior to the diagnosis. But yeah, so I think it was months, not years though.

Dr. David Rubin: How did you learn about ulcerative colitis? Did they refer you to some information or was it just what the doctor told you or where did you go?

Adam: So, things turned around pretty quick in getting an appointment with a GI doctor here, and he's phenomenal. But the first thing we did, I remember within the first year, year and a half, was go to a Crohn’s and Colitis Foundation talk in Wisconsin Dells here. And that was kind of where we started. And the Crohn's and Colitis Foundation has a lot of resources where we began. And then our doc filled in the gaps.

Dr. David Rubin: The Crohn's and Colitis Foundation, for those who are less familiar, is a society that actually includes both professionals who take care of people with these conditions and patients. So, it's combined there. And it's obviously a very helpful resource, especially when you're fully newly diagnosed, but as you go through that journey. So, what were you treated with initially? Do you remember?

Adam: Yeah, I was first started on the steroids and the typical 6-MP. But right, it was again in 1999. So the first anti-TNF medications were just about hitting the market. And so I was able to get started on one of those, which helped me immensely, I think.

Dr. David Rubin: So, the management of ulcerative colitis, as in Adam's case, often involves a stepwise approach to treatment, where the diagnosis comes with a prognosis. How severe does the disease look to the doctor who's making the diagnosis, and how sick is the individual? We're still in an era, even now, where we don't necessarily know which treatment's going to be effective. But we do know what the goal of management was. So, Adam, when you started to feel better, what symptom improved first, or do you remember how you felt and when you knew that you were actually responding to those steroids?

Adam: Yeah, I remember just the urgency and frequency of having bowel movements really changed. And then slowly the blood in the stool also improved.

Dr. David Rubin: We think of aminosalicylates as a common therapy, the 5-ASA treatments for moderate colitis. And then we move our way up. If a patient isn't responding to aminosalicylates, we consider the use of corticosteroids, and even, as you mentioned, six mercaptopurine. In the United States, we've really moved away from thiopurines as often. But when these treatments are used, the goal is the same, which is we want people to feel better, and then we want it to last. And recognizing that colitis can be a chronic relapsing and remitting condition.

So, when patients don't respond to these therapies, or when they have a relapse early after starting one of these treatments, it's appropriate that we move on to advanced therapies in UC, which include biological treatments, monoclonal antibodies that target a variety of different proteins, or some of our synthetic targeted small molecules like S1Ps or Janus kinase inhibitors. So Adam, in your journey, tell us about what therapy worked or what didn't and how you made your way all the way to me.

Adam: Yeah, so I think I was just thinking back on all the therapies I've been on, including steroids and whatnot.

I was started on an anti-TNF medication, that I was on for a few more years and got me through high school. And then kind of as school went on and whatnot, I've been on interleukin inhibitors, a JAK inhibitor, mesalamine formulations and steroids, different type of steroids.

Dr. David Rubin: So, which symptoms of yours came back and how did you know that that was going on?

Adam: Yeah, I think the big things would be the urgency and frequency of using the bathroom and then bleeding would start as well. So those are the big first symptoms. Some of these meds that I've been on just never took off.

Dr. David Rubin: Yeah, I have a lot of patients where they have been on one therapy after another that either was a primary failure or the therapy worked for a little while and they lost response, which we call secondary non-response or loss of response and that can really wear on you.

So, in fact, what we've learned has led to an approach in our space called treating to a target. And the targets of treatment are supposed to be proactively pursued as opposed to waiting for somebody to just feel better or waiting for them to not do well. And the whole point of that means that you provide a therapy to a patient with ulcerative colitis and after a defined interval of 6 to 12 weeks, you reassess to see how they're doing both symptomatically as well as more objectively. And the point of treating to a target is that if you're not getting the response you need after an appropriate trial of a therapy, you then will make an adjustment. You discuss with the patient your options. Is it a different dose?

Is it a second therapy added or are you gonna switch treatments altogether? So, there's a well-described and highly discussed consensus statement that's called STRIDE-II. This was a consensus of experts who said that the long-term target for treating ulcerative colitis is endoscopic remission.

And with STRIDE-II, we also talk about histology, which is the biopsies. But the whole point of STRIDE-II is to move us from a treatment strategy that was very reactive, waiting for the patient, like Adam, to call us and say,

"I'm having urgency again and what am I going to do?" So, Adam, as far as your management has gone, and maybe you can even talk about more recently when we've been working together, can you comment on how your management has been a bit more proactive and what measures were used?

Adam: Yeah, I think some of the, well, the big things are always the screening colonoscopies and making sure or surveillance colonoscopies, I should say, in terms of making sure disease is under control. And there are times where I felt great and have gone into a colonoscopy and the scope didn't look great. So, I think that would be one point in terms of the surveillance of the disease and then making adjustments based on that.

Dr. David Rubin: Well, in terms of your own colitis, what have been the measures that we've used to know that you've gotten where you need to go?

Adam: Yeah, so I think one of them is how I'm feeling and how are my symptoms, urgency specifically, frequency of using the bathroom, blood in my stool, and then doing scopes and seeing how it looks and how more recently I think having scopes that look good gives reassurance that we're doing the right thing.

Dr. David Rubin: Stemming from this larger conversation about treatment switches, we’re going to talk next about a treatment option that may help our patients with moderate to severe UC who have failed or who have an intolerance to an anti-TNF.

Narrator:

INDICATION

RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ.

Limitations of Use: RINVOQ is not recommended for use in combination with other Janus kinase (JAK) inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine.

SAFETY CONSIDERATIONS FOR RINVOQ (upadacitinib)

Serious Infections: RINVOQ-treated patients are at increased risk of serious bacterial (including tuberculosis [TB]), fungal, viral, and opportunistic infections leading to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase inhibitor (JAKi) in a study comparing another JAKi with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years with ≥1 CV risk factor.

Malignancies: Malignancies have occurred in RINVOQ-treated patients. A higher rate of lymphomas and lung cancer (in current or past smokers) was observed with another JAKi when compared with TNF blockers in RA patients.

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAKi in a study comparing another JAKi with TNF blockers in RA patients ≥50 years with ≥1 CV risk factor. History of smoking increases risk.

Thromboses: Deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. A higher rate of thrombosis was observed with another JAKi when compared with TNF blockers in RA patients.

Hypersensitivity: RINVOQ is contraindicated in patients with hypersensitivity to RINVOQ or its excipients.

Other Serious Adverse Reactions: Hypersensitivity reactions; gastrointestinal perforations; hypoglycemia in patients with diabetes; laboratory abnormalities; and embryo-fetal toxicity.

Please continue listening and stay tuned for additional Important Safety Information within this podcast.

Dr. David Rubin: When I treat patients with active ulcerative colitis, I always start by saying, "I want you to feel better as soon as possible." Do you want to share a little bit about how your life has progressed since you achieved remission?

Adam: Yeah, and I guess now is probably a good time to say that. So, I'm a gastroenterology fellow in Milwaukee.

Prior to starting RINVOQ, the big symptoms being the fatigue that I was experiencing, the urgency of having to use the bathroom.

Dr. David Rubin: I think that it's a reminder to everybody two things. I think one is how important it is to really understand your patient's treatment goals and match the treatment that they're receiving with those goals. But secondly, it's not a surprise to anybody listening that there's a lot of gastroenterologists who have IBD or whose family members have IBD. So, a lot of people come to this quite honestly because of their personal and family experiences. So we talk a lot about moving along in treatment choices and having a goal treatment, but also what I usually say is trust but verify, meaning when a patient says they're feeling better, especially with colitis, which is somewhat of a noisy symptomatic disease, we of course are very happy, but we want to make sure that they’re actually improved. It's remarkable to remember that some people who say that they're feeling better with colitis will have inflammation if you look with a scope or biopsies or get a stool calprotectin.

So, Adam, we talked a bit about your treatment options when I met you. Can you reflect on how we came to the decision about RINVOQ and what your experience with that therapy was?

Adam: Going into that appointment, I kind of felt like I was at the end of the line. You had presented to me the effects of RINVOQ and despite failure on past anti-TNFs and whatnot that RINVOQ was really a good medication that you've had a lot of success with.

Dr. David Rubin: RINVOQ has a well-studied safety profile. It's backed by over six years of safety data in IBD.

So, it doesn't come without some concerns and education that we share with our patients. During our consultation, I explained to Adam that I understood his concerns about being on a new medicine and what the safety might imply. And I wanted to address these thoroughly. So, I mentioned, RINVOQ has some side effects.

However, I emphasize the importance of weighing those risks against the benefits, of course. It's important for me that they understand that while my primary goal is to effectively manage their UC, I am equally committed to prioritizing their safety. The benefit versus risk conversation between the patient and doctor should be applied to each patient and assessed individually.

Narrator: The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, increased blood cholesterol, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Dr. David Rubin: When we evaluate a patient who has not responded appropriately or who's lost response to therapies, we want to be thoughtful about what was the reason for each of those problems. And another really important prognostic factor is, did the patient ever achieve remission with prior therapies. But in Adam's case, we knew he had done really quite well with anti-TNF earlier in his disease journey, and it made sense that we would be able to try to get him back on track. We also knew that he lost response to an anti-TNF because he developed anti-drug antibodies.

JAK inhibitors like RINVOQ can help provide effective symptom relief and can help achieve remission. So, it's a very good option to consider this in patients who have been on an anti-TNF and either didn't respond at all or who, like Adam, were on an anti-TNF and lost response.

RINVOQ was approved for ulcerative colitis in 2022. After two 8-week, multi-center, double-blind, placebo-controlled ulcerative colitis induction trials, participants on RINVOQ who achieved clinical response at Week 8 with 45 milligrams of RINVOQ were moved into the U-ACHIEVE Maintenance trial. The clinical trials had a primary endpoint of clinical remission, which in these trials means no rectal bleeding, reduced stool frequency, and an endoscopic subscore that's less than or equal to 1 without any friability. And there were a variety of ranked secondary endpoints, which included clinical response based on an adapted Mayo Score, endoscopic improvement and histo-endoscopic mucosal improvement. That means the combination of histology and endoscopy. In the 52-week Maintenance trial, RINVOQ met its primary endpoint, demonstrating clinical remission at Week 52. 42% of the 148 patients on RINVOQ 15 milligrams and 52% of the 154 patients on RINVOQ 30 milligrams achieved clinical remission compared to only 12% of the 149 patients who received placebo. So, Adam, what were the first few weeks of treatment with RINVOQ like?

Adam: I was going down with a buddy from med school to go see somebody else and ended up having an accident in terms of not making it to the bathroom that first day. Prior to starting RINVOQ, I was probably having one to two accidents at least every month.

And I think that was the last accident I had had or incontinence episode, I should say, I had for over a year after that initial two weeks. So, at first when I was first switched, I was like, ah here we go again. But at the same time, I was like, it’s only the first dose. Let’s give it a little time. I think energy really came back with RINVOQ.

Narrator: During the 8-week, double-blind, placebo-controlled Phase 3 clinical studies of 988 patients (473 patients for U-ACHIEVE and 515 patients for U-ACCOMPLISH) with moderately to severely active UC who demonstrated prior treatment failure to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic treatment, researchers assessed the impact of RINVOQ on fatigue, a common symptom for those with ulcerative colitis. Fatigue levels were assessed by change from baseline in FACIT-Fatigue Scale, a validated patient-reported tool.

At Week 8, 59% of patients on RINVOQ experienced clinically meaningful improvement in fatigue, as opposed to 34% of those given a placebo.

These findings suggest that RINVOQ may offer relief from fatigue, providing a potential benefit in managing the overall burden of ulcerative colitis. The effect of RINVOQ to improve fatigue after 8 weeks of induction has not been established.

Dr. David Rubin: Certainly, that rapidity of response in your situation is really nice to hear and it's been described in the clinical trials as well. And also, the ability to avoid steroids because the drug works quickly enough. RINVOQ pivotal trials also evaluated histology by using an endpoint of histo-endoscopic mucosal improvement. And patients who achieved this rigorous endpoint demonstrated both the endoscopic improvement indicated by a Mayo endoscopic subscore of 0 or 1 without any friability and histologic improvement, which was defined as a Geboes score of 3.1 or lower. That score signifies neutrophil infiltration in less than 5% of crypts without crypt destruction and the absence of erosions, ulcerations, or granulation tissue. This is an endpoint that's of great interest in these trials. It's important to note that the relationship between histo-endoscopic mucosal improvement and disease progression or long-term outcomes was not assessed.

Narrator: Endoscopic results are based on a full colonoscopy or flexible sigmoidoscopy, depending on the extent of disease at study entry, and histology results are based on a set of 2 biopsies.

Dr. David Rubin: So RINVOQ also has long-term extension data. The long-term extension study evaluates as-observed data over an extended period. We're combining the results of the initial 52-week Maintenance trial with the long-term extension findings. And we thoroughly examine the two-year data in episodes one and two of this podcast. You should tune into those episodes to learn more, by the way.

So, I think it's really quite important to know that in Adam's case, we have in fact performed endoscopy, and as he referenced, he just had a scope with me recently and it looked better. So, in order to assess if we should continue Adam on RINVOQ, not only did I evaluate those endoscopy results, but in addition, histo-endoscopic improvement that was seen when we did biopsies. With that holistic assessment, the results indicated that he was doing great. And of course, then we continued the treatment. So the drug is approved for maintenance at 30 or 15 milligram.

Narrator: The recommended dosage of RINVOQ for maintenance treatment is 15 mg once daily. A dosage of 30 mg once daily may be considered for patients with refractory, severe or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage. Use the lowest effective dosage needed to maintain response.

Dr. David Rubin: And Adam, what maintenance dose are you on?

Adam: Currently 30 milligrams.

Dr. David Rubin: And the visual evidence from his endoscopy combined with clinical remission tells us that we've achieved that level of control for him. And I really believe that this dual approach enables us to set realistic expectations. And I spend a lot of time with my patients emphasizing the goals of management. So we're all on the same page and we have the same expectations.

I saw a new patient earlier this week, who has ulcerative colitis, she had recently been diagnosed and she had not yet heard about remission. She didn't know what the goal of management was. And that is not what we want. So Adam, what was it like when you got the results from your first endoscopy after you’d been on RINVOQ?

Adam: Yeah, I definitely got choked up and it was definitely an emotional thing.

Dr. David Rubin: I'm so glad you're doing well. So Adam, overall, you have many years of experience living with ulcerative colitis, and now you're actually taking care of people who have IBD.

So, do you have any advice about how to approach someone who's on their way to being diagnosed or maybe newly diagnosed?

Adam: Yeah, I think the biggest thing that I've always been taught is meet the patient where they're at. And I felt like my providers were able to, not only in their limited amount of time in an appointment, able to provide answers, reassurance, and comfort, but also directing patients to appropriate resources like the Crohn's and Colitis Foundation, like other avenues where they can get simplified information. And I think as providers just knowing those resources and utilizing our limited time in clinic with patients that we have to give reassurance and that they're not alone in this is definitely a place to start and then the relationship I think develops after that.

Dr. David Rubin: That's really great, Adam, and I appreciate all your insights and the fact that you've joined us on this Gut Reactions podcast. I want to summarize for our colleagues that we've talked today about the journey people have in being diagnosed and then treated with ulcerative colitis. And Adam and I emphasized the approach that includes understanding the disease and getting the right information, a goal-based strategy emphasizing the need for symptomatic remission, as well as a treat-to-target strategy and understanding how you can be more proactive in managing folks. We talked a bit about different treatment strategies and of course educated you a bit more about RINVOQ.

If you've enjoyed this episode of Gut Reactions and found it educational, you can share it via the share button, email, LinkedIn, or on any of your preferred platforms. Also check out our previous episodes if you want to hear some more. Until next time, this is Gut Reactions.

Narrator:
Please continue listening for additional Important Safety Information.

IMPORTANT SAFETY INFORMATION

SERIOUS INFECTIONS

Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include:

• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent TB infection prior to RINVOQ use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis.
• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MORTALITY

In a large, randomized, postmarketing safety study comparing another Janus kinase (JAK) inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years old with at least one cardiovascular (CV) risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with RINVOQ.

In a large, randomized, postmarketing safety study comparing another JAK inhibitor with TNF blockers in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.

With RINVOQ, consider the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Advise patients to limit sunlight exposure by wearing protective clothing and using sunscreen.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

In a large, randomized, postmarketing study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other CV risk factors. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

THROMBOSIS

Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing study comparing another JAK inhibitor to TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of thrombosis was observed with the JAK inhibitor. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated.

HYPERSENSITIVITY

RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal (GI) perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for GI perforation (e.g., patients with a history of diverticulitis and patients taking NSAIDs or corticosteroids). Promptly evaluate patients presenting with new onset abdominal pain for early identification of GI perforation.

HYPOGLYCEMIA IN PATIENTS WITH DIABETES

Hypoglycemia, including severe hypoglycemia, has been reported following initiation of RINVOQ and other JAK inhibitors in patients with diabetes. During treatment with RINVOQ, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia.

LABORATORY ABNORMALITIES

Neutropenia

Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm³). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm³. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia

Absolute lymphocyte counts (ALC) <500 cells/mm³ were reported in RINVOQ-treated patients. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm³. Evaluate at baseline and thereafter according to routine patient management.

Anemia

Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ-treated patients. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids

Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate patients 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations

Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

EMBRYO-FETAL TOXICITY

Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.

VACCINATION

Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, in agreement with current immunization guidelines.

MEDICATION RESIDUE IN STOOL

Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic or functional GI conditions with shortened GI transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

LACTATION

There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT

RINVOQ is not recommended for use in patients with severe hepatic impairment.

ADVERSE REACTIONS

The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ.

Dosage Forms and Strengths: RINVOQ is available in 15 mg, 30 mg, and 45 mg extended-release tablets.

Visit rxabbvie.com/pdf/rinvoq_pi.pdf for Prescribing Information, including BOXED WARNING, for RINVOQ.

Narrator: At the intersection of science and clinical experience in IBD, this is Gut Reactions. Settle in, as our host, Dr. David Rubin, brings leading gastroenterologists together for one-on-one conversations. This podcast is brought to you by AbbVie.

Dr. David Rubin: Welcome to the Gut Reactions podcast. I'm your host, Dr. David Rubin, Chief of the Section of Gastroenterology, Hepatology, and Nutrition, and Director of the Inflammatory Bowel Disease Center at the University of Chicago. Today, I'll be joined again by Dr. Josh Steinberg to discuss how we identify appropriate patients with moderate to severe ulcerative colitis for their specific treatment options. We'll explore two different treatment options currently available, what factors to consider when assessing these treatments, and when to prescribe them for the best possible treatment outcomes.

Dr. Steinberg is a board-certified gastroenterologist and the Director of Inflammatory Bowel Disease at Gastroenterology of the Rockies, where he serves patients in the Denver and Boulder, Colorado, metropolitan areas. He completed his advanced IBD fellowship with us here at the University of Chicago and his GI fellowship at Georgetown in Washington, DC.

Josh, I'm very happy to have you back with us on Gut Reactions.

Dr. Josh Steinberg: David, thanks so much for having me back. It's a pleasure to come back to Gut Reactions. I really can't wait to start our conversation today.

Dr. David Rubin: Well, we have been trying to schedule this since your first podcast because we had such a good time. So, I'm really glad we all landed on a date today to start having this conversation. So why don't we start with something that I think would be really helpful for our colleagues, a discussion about the objective measures of disease activity. Why are the objective measures so critical in the treatment of ulcerative colitis? Why don't we just ask patients how they're feeling?

Dr. Josh Steinberg: Yeah, this is a really important concept and first we should try and dive into the distinction between what we describe as subjective and objective measures of inflammation. Right? So subjective measures are based on the patient's personal experiences, what they're actually feeling and experiencing from day to day based on self-reported symptoms of what they're going through, like describing the severity of their abdominal pain or how frequent they're having bowel movements or if they're having rectal bleeding or not.

These reports are valuable and they're important to help us guide treatment decisions, but they can be quite varied and influenced by patient perspectives. When you contrast this to objective measures of disease activity, which typically involve concrete data and assessment of inflammatory burden as reflected by diagnostic tools, we're thinking about colonoscopy, biopsies with histopathology, or laboratory results like blood and stool-based testing.

So, these provide a much more standardized and reproducible assessment of disease activity and inflammation. And of course, subjective feedback helps us understand how the patient feels and the symptoms they're experiencing, but it's really the objective measures that provide this concrete data that we really need to help guide our treatment decisions effectively. As you know, there can be this discordance between what the patient is experiencing clinically in terms of their symptoms and what the inflammatory burden as reflected by these objective measures is actually doing.

Dr. David Rubin: How do these objective measures help in managing these challenges?

Dr. Josh Steinberg: So objective measures, including endoscopic assessments and laboratory tests, play a vital role here. For instance, using a colonoscopy or flex sig allows us to visually assess the colonic mucosa and grade the inflammation using various scoring systems, such as the Mayo endoscopic subscore for UC. This helps us determine the severity of the disease and monitor challenges over time. To objectively assess disease activity, we typically use the modified Mayo score or mMS.

Dr. David Rubin: I wanna dive in a little bit and ask you, what are your targets in ulcerative colitis and how do you do it in your practice?

Dr. Josh Steinberg: Yeah, this is important. And we often talk about STRIDE-II that help us kind of frame our treatment paradigm and treatment management for patients. So first we want to talk about short-term goals or short-term targets. And that's typically the clinical targets, right? So, in the setting of UC, we're talking about reduction of rectal bleeding and improvement in stool frequency and urgency and some of the other clinical symptomatic factors.

We talk about intermediate targets. So that's looking at biomarkers, in particular, blood and stool-based tests, right? So, looking at CRP, fecal calprotectin as surrogate markers of inflammation as we start a particular therapy. And then ultimately long-term, what we're really striving towards is objective assessment as based on colonoscopy, right?

So endoscopic outcomes. Trying to achieve endoscopic improvement as demonstrated on a colonoscopy when we're reassessing patients after starting or changing their therapy. So not just the subjective approach, including their improvement in clinical symptoms, obtaining that clinical remission, but really that remission that includes biomarker remission and histologic or endoscopic remission. These are some of the targets that we try to achieve in all of our patients with UC.

Dr. David Rubin: Super helpful. I often say to patients that symptomatic remission is critical, but objective confirmation of disease control is how we make sure it lasts. And when I talked about symptoms, as you've seen, because we work together and I've learned from you as much as I hope you've learned from me, it's about formed stool and the absence of bleeding. But really one of the most important symptoms is also urgency and resolving that particular symptom.

And the astonishing thing, whether it's because patients may normalize their symptoms or whether in fact there really is a disconnect between symptoms and objective findings, is the reality that people who say that they're not having symptoms will still be inflamed if we were to look with a scope or a biomarker. And the implication of that, of course, is that they're more likely then to relapse over time. So that's part of the important messaging regarding combining symptoms and those objective measures.

So, you've made a really good point that really every patient is a bit different and requires this personalized approach, whether we call it treat-to-target or the way you've outlined it. Tell us a little bit more about how you think about the one-size-fits-all or the personal approach to your individual patients with UC.

Dr. Josh Steinberg: Yeah, you know, unfortunately there's really not a one-size-fits-all approach to ulcerative colitis management. Sometimes we try to fit patients in particular boxes when we're thinking about what particular therapy might work best for them. But we really want to take an individualized, patient-centered, patient-first approach for all of our patients. And it's really important that we use all of the tools in our disposal, both from a diagnostic perspective and of course, a disease monitoring perspective.

And then including our medical armamentarium to help determine what treatment is going to work best for them individually. And there's obviously patient characteristics, perhaps contraindications or relative contraindications, underlying risk factors. So, everyone's different.

There's a lot of things that we take into consideration and just really that shared decision-making with the patient at the forefront that we want to take into account when making these decisions together.

Dr. David Rubin: All right, terrific. Now, before we talk about the treatments that are available, we want to distinguish what we've just covered, which is really the pragmatic and clinical practice approach to management with some of the definitions that are used in clinical trials and when we look at data for therapies.

So, Josh, let's set the stage and outline a treatment path for an adult patient who's been recently diagnosed with moderately to severely active ulcerative colitis.

We want people to feel better right away. That makes complete sense, of course. But what are the symptoms you're looking for when you start a patient on a new therapy? And how do you explain it to the patient? What does that first step look like?

Dr. Josh Steinberg: It's an important question, David. So, it's critical, right? That we consider what the patient treatment goals are and that me, as their clinician, and the patient are aligned in their goals and kind of where they're at overall in their journey. So, an important part of this decision-making process involves taking the time to really get to know the patient sitting in front of you, right? And ensuring that we are both equally involved in the decision-making process. As I mentioned before, the shared decision-making is really critical in optimizing a successful outcome.

So, when we understand where the patient's really at in their treatment journey or in their disease journey, we might be able to better understand the individual patient in front of us and what prior treatments might have been effective or ineffective and if they had any potential adverse reactions or side effects from prior treatments that they had previously been on.

We also want to consider the severity of their disease. And we consider severity as this kind of wide-lens, big-picture, longitudinal assessment of the patient's disease burden, as well as the patient's disease activity, right? And then when we have these things in place, we try to weigh the balance of the benefit-risk profile to any particular therapy when we're discussing with the patient. And when we start treatment, we initially focus on addressing symptoms that are really debilitating the patient from day to day.

So, we're talking about rectal bleeding and urgency and frequency. In the short term, we really want these symptoms to start to improve. And once the patients start to feel better, we know that their symptoms can become under better control, which of course is our immediate priority. And we'll get next to our more long-term outcomes as assessed by biomarkers and endoscopic outcomes.

Dr. David Rubin: So as ulcerative colitis is a chronic condition, the treatment plan obviously needs to be assessed over time and monitoring of the disease in terms of early response as well as maintenance of response is part of our management. This obviously depends on how our patients are doing and any changes that occur in their condition or in their age or their body or other physiological changes that occur as well as our new research and treatments that are becoming available. For example, we've been thinking more about biologics as early or first-line options for patients when they're getting started. On the other hand, JAK inhibitors are often considered for adults with moderate to severe UC, who have not responded adequately to anti-TNF therapies. So, Josh, let's outline standard treatment protocols for a patient diagnosed with ulcerative colitis. What are the typical first steps for treatment and how are you doing this?

Dr. Josh Steinberg: Great question, David. So, there is somewhat an order to things. I would typically start them off with a 5-ASA and if necessary, start them on a short course of a corticosteroid. And if we are not able to achieve this response with 5-ASAs alone or with steroids in combination with 5-ASAs, really the next step is gonna be incorporating one of our advanced therapies.

Narrator: Advanced therapies in ulcerative colitis include biologics, S1Ps and JAKs.

Dr. David Rubin: So, depending on how the patient's responding and what their previous medical history tells us, this would involve drugs such as tumor necrosis factor inhibitors or anti-TNFs, integrin receptor antagonists, interleukin inhibitors like the IL-23 inhibitors, or the S1P receptor modulators, and JAK inhibitors. So, let's talk a little bit about anti-TNFs. What can you share with us about that class of therapies, Josh?

Dr. Josh Steinberg: Yeah, of course. So anti-TNF were our first biologic therapies that became available for ulcerative colitis. And while these anti-TNF agents can be effective for many patients with UC, it's important to note that they really don't necessarily work for every single patient. So, patients might experience this primary nonresponse, right? They might never respond at all to that initial anti-TNF agent. And additionally, patients might develop the secondary loss of response over time, which as I mentioned, the patient might do well and then lose that response over time. And this could be due to the development of anti-drug antibodies to the agent that they're on, or sometimes the patient might be underdosed and have subtherapeutic drug levels based on the drug level for the individual agent that they're on.

So, it's really important to consider that patients who did have this primary nonresponse to an anti-TNF probably won't respond very well to another anti-TNF agent if they didn't originally respond favorably initially. So instead, we probably want to consider another class, another mechanism of action of biologic agent or a small molecule agent that the patient previously has not been on that might give them a fair chance of having a beneficial effect in endoscopic improvement long-term.

Dr. David Rubin: I usually divide the primary nonresponders into a couple categories, and I think that you do the same, which is, is this truly a mechanism failure or is this a dose or exposure failure? So, when somebody isn't responding to an anti-TNF, of course, we can consider other biologic agents like the integrin receptor antagonist, or the IL-23 inhibitors. They can, in fact, be used in people who are TNF-naïve or TNF-experienced, but some patients may not respond to those or have a delayed response, and we have to think carefully about where's the drug going when this is occurring.

So, Josh, thinking more broadly, why don't you share an example of a patient profile that would be ideally suited for an advanced therapy in treating their UC?

Dr. Josh Steinberg: Of course. So, I have this patient in mind who does have moderate to severely active ulcerative colitis, and he was diagnosed with left-sided UC about three and half years ago. And when we first met, he was initially treated with steroids and 5-ASAs, but I performed a colonoscopy and he presented with a Mayo score of 2, which just for reference is defined by marked erythema, absent vascular pattern, friability, and the presence of erosions. And this patient, he's a young engineer, he's an active father of two, and he enjoys outdoor activities.

So, there's luckily a lot of therapies that we can start discussing that are advanced treatments in nature that are inclusive of biologics and small molecules that hopefully can get him the chance to get into a remission.

Dr. David Rubin: That's a really great example, Josh, so thanks for sharing that. Could I ask you, do you ever skip 5-ASA and go directly to an advanced therapy, and if so, who might that patient be?

Dr. Josh Steinberg: It's a great question. And the short answer is yes. In patients that really do present with a high or severe inflammatory burden—so, I'm talking about patients who are presenting with extensive colitis with Mayo 3 disease, deep ulcers on colonoscopy, perhaps elevated CRP, perhaps they're anemic, have high platelets, just all signs and symptoms, so to speak, of a high inflammatory burden, where we know that in the broader sense or longer term that the patient has higher risk of a more complicated disease course—in these patients, I would probably bypass a oral 5-ASA and go directly to an advanced therapy for sure. Great question.

Dr. David Rubin: So, what treatment did you land on for your patient with moderate to severe UC?

Dr. Josh Steinberg: So, we have many more treatment options that are available now. And one of them is an interleukin-23 inhibitor, IL-23 agent, from AbbVie that was approved for adult patients with moderate to severely active ulcerative colitis. And that is called SKYRIZI, risankizumab.

Narrator:
INDICATIONS

Ulcerative Colitis: SKYRIZI is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

Crohn's Disease: SKYRIZI is indicated for the treatment of moderately to severely active Crohn's disease in adults.

SAFETY CONSIDERATIONS

SKYRIZI is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of its excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately. SKYRIZI may increase the risk of infection. Instruct patients to report signs or symptoms of clinically important infection during treatment. Should such an infection occur, discontinue SKYRIZI until infection resolves. Evaluate patients for tuberculosis infection prior to initiating treatment with SKYRIZI. Drug-induced liver injury was reported in a patient with Crohn’s disease during induction dosing of SKYRIZI. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks). Interrupt treatment with SKYRIZI if drug-induced liver injury is suspected, until this diagnosis is excluded. Avoid use of live vaccines in SKYRIZI patients.

Please continue listening and stay tuned for additional Important Safety Information for SKYRIZI within this podcast.

Dr. David Rubin: It's really exciting that we have so many treatment options for our patients with ulcerative colitis and I am really happy that we're able to talk about it and share this with our colleagues.

Dr. Josh Steinberg: It really is exciting and the results from these two pivotal clinical trials are promising and we'll dive into those.

So, this INSPIRE Induction study was a Phase 3, randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of SKYRIZI 1200 mg IV at Weeks 0, 4, and 8 versus placebo over 12 weeks in adult patients with moderate to severely active ulcerative colitis. The primary endpoint was clinical remission at Week 12.

The COMMAND maintenance study was a Phase 3 randomized, double-blinded, placebo controlled study to evaluate the efficacy and safety of SKYRIZI 180 milligrams or 360 milligrams subcutaneously versus placebo, up to 52 weeks in adult patients who were clinical responders to one of the three SKYRIZI induction regimens consisting of 600 milligrams, 1200 milligrams, or 1800 milligrams IV in both the Phase 2b study and the Phase 3 INSPIRE study.

Please note though that the 600 milligram and 1800 milligram IV doses are not the FDA-approved induction regimens. The primary endpoint was clinical remission at Week 52.

Narrator: The all-subjects maintenance population includes patients who responded per modified Mayo Score to 1800 mg, 1200 mg, or 600 mg in Phase 2b/3 induction study.

Clinical remission at Week 12 and 52 in UC is defined as stool frequency subscore ≤1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤1 without friability.

Dr. Josh Steinberg: At Week 12, 24% of patients on the SKYRIZI 1200 milligram intravenous infusion achieved clinical remission, compared to 8% of patients on placebo, which is a three-fold delta.

Narrator: At Week 52, in the All Subjects Maintenance Population, 45% of patients receiving SKYRIZI 180 mg subcutaneously achieved clinical remission, based on 179 patients. Additionally, 41% of patients receiving SKYRIZI 360 mg subcutaneously achieved clinical remission, based on 186 patients. In comparison, 26% of patients on placebo achieved clinical remission, based on 182 patients.

Dr. Josh Steinberg: COMMAND also included a pre-specified subgroup analysis inclusive only of patients who responded to the FDA-approved induction dosing of SKYRIZI 1200 milligrams IV. At Week 52, 45% of patients on the subcutaneous injection of SKYRIZI 180 milligram and 50% of patients on the subcutaneous injection of SKYRIZI 360 milligram observed clinical remission compared to 29% of patients on placebo.

Narrator: Patients in the pre-specified subgroup analysis include 90 patients on 180 mg, 92 patients on 360 mg, and 89 patients on placebo.

Advanced therapy–naïve population consisted of 42 patients on 180 mg, 44 patients on 360 mg, and 41 patients on placebo. Advanced therapy–naïve patients include some patients who were exposed to an advanced therapy (biologics, JAK inhibitors, and/or S1P receptor modulators) but did not experience treatment failure.

Dr. Josh Steinberg: Continuing with the findings for advanced therapy–naïve patients at Week 52, the data show promising results for SKYRIZI. Clinical remission was observed in 59% of patients taking the 180 milligram dose and 70% of those on 360 milligram dose compared to the 32% remission rate observed in the placebo group.

Narrator: Limitations of prespecified subgroup analysis: Overall and Advanced Therapy–Naïve patient results discussed are only among patients who responded to the FDA-approved 1200 mg IV induction dose. Excluded are those who received unapproved induction doses (600 mg or 1800 mg). Data were not controlled for multiplicity. No conclusions or statistical inferences can be made.

Dr. David Rubin: Alright Josh, that was a really nice summary and thanks for helping us understand those data. So, when we put this all together to understand it, we have a therapy that has an IV induction that is quite effective, and then we have maintenance dosing of two different subcutaneous doses delivered over time that are both better than placebo.

So, remember, this is also emphasizing what happens when you use this drug as your first advanced therapy.

SKYRIZI also provides patients with the opportunity for endoscopic improvement, which as we've highlighted is a key long-term treatment target in our patients with ulcerative colitis. Endoscopic improvement is defined in pivotal trials for SKYRIZI as the Mayo endoscopic subscore of 0 or 1 without friability. Friability is defined as bleeding with gentle bumping of the scope or the forceps into the mucosa. Endoscopic results are based on a full colonoscopy or flexible sigmoidoscopy that was performed at the discretion of the investigator.

At Week 52, 51% of patients on SKYRIZI 180 milligrams sub-q and 48% of patients on SKYRIZI 360 milligrams sub-q achieved this endoscopic improvement endpoint compared to 31% of patients receiving placebo.

Narrator: In the all subjects maintenance population at Week 52, 51% of 179 patients on SKYRIZI 180 milligrams sub-q and 48% of 186 patients on SKYRIZI 360 milligrams sub-q achieved this endoscopic improvement endpoint compared to 31% of 182 patients receiving placebo. In the 1200 mg prespecified subgroup analysis, 58% of patients who received SKYRIZI 360 mg subcutaneously, and 52% of patients who received 180 mg subcutaneously, observed endoscopic improvement at Week 52, based on 92 patients and 90 patients, respectively. In comparison 36% of patients on placebo observed endoscopic improvement at Week 52, based on 89 patients.

Dr. David Rubin: So, for those patients who responded well to the FDA approved 1200 milligram IV induction doses, about 77% of advanced therapy–naïve, which included some patients who were exposed to an advanced therapy but did not experience treatment failure, continued with the 360 milligram subcutaneous dose and observed endoscopic improvement at Week 52. Even at the lower 180 milligram subcutaneous dose, 62% of these patients observed endoscopic improvement.

Narrator: In the advanced therapy–naïve population, 44 patients on 360 mg and 42 patients on 180 mg observed endoscopic improvement, compared to 34% with 41 patients on placebo.

Limitations of prespecified subgroup analysis: Overall and Advanced Therapy–Naïve patient results discussed are only among patients who responded to the FDA-approved 1200 mg IV induction dose. Excluded are those who received unapproved induction doses (600 mg or 1800 mg). Data were not controlled for multiplicity. No conclusions or statistical inferences can be made.

Dr. Josh Steinberg: I should remind our audience that there are two maintenance dosing options for SKYRIZI, the 180 milligram and the 360 milligram, both of which are given subcutaneously via an on-body injector every eight weeks.

Narrator: Use the lowest effective dose.

Dr. David Rubin: SKYRIZI’s endoscopic outcomes coupled with the clinical remission data demonstrate its efficacy, making it a viable first line advanced therapy treatment option for our patients with moderately to severely active UC.

So, Josh, can you elaborate on the treatment regimen for SKYRIZI? We've gone through this now in the clinical trial data, but how do you actually use this in practice?

Dr. Josh Steinberg: Of course, so we're talking about ulcerative colitis specifically. So, we're talking about starting SKYRIZI. First, we start with the induction dosing, which is three IV doses at 1200 milligrams over the course of eight weeks, which basically is one dose IV every four weeks at Week 0, 4, and 8. And then four weeks after that last induction or infusion therapy, the patients would then be transitioned to the on-body injector, which the patient injects subcutaneously at home once every eight weeks.

Narrator:
Administration Considerations: SKYRIZI is intended for use under the guidance and supervision of a healthcare professional (HCP). SKYRIZI vial for intravenous administration is intended for administration by an HCP. Prior to starting therapy, please refer to the Dosage and Administration section of the Prescribing Information for complete information on how to prepare and administer SKYRIZI. Patients may self-inject SKYRIZI using the on-body injector with prefilled cartridge after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI according to the Instructions for Use.

Dr. David Rubin: So, Josh, can you tell me what specifically made your patient with ulcerative colitis, whom you had spoken about earlier, an ideal candidate for SKYRIZI?

Dr. Josh Steinberg: Of course, so for one thing, he's bio-naïve, right? He's naïve to any advanced treatments. And he initially started, as we talked about, on mesalamine about six months prior, but because he didn't have any meaningful response, we added rectal mesalamine, right? So topical therapy, sometimes on top of oral mesalamine therapy can help improve outcomes. And we also started this patient on the course of oral corticosteroids. And despite all these efforts, he unfortunately continued to struggle.

He still had disease activity with elevated frequency, about five bowel movements or so a day, as well as quite significant rectal bleeding. He overall was defined as having moderate disease as reflected during his endoscopic evaluation, which showed an endoscopic Mayo subscore of 2.

Dr. David Rubin: Thanks so much, Josh. So, it's really exciting to know that SKYRIZI is available for our adult patients with moderate to severe ulcerative colitis.

As we discussed earlier, anti-TNF therapies play a significant role in managing moderate to severe cases of UC. However, some people are primary non-responders. So, it's important to consider alternate options. As I mentioned, oral small molecules offer a different mechanism of action for patients.

One class of small molecules we use in these scenarios are the JAK inhibitors, such as upadacitinib, which has the brand name RINVOQ.

Narrator:
INDICATION

RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ.

Limitations of Use: RINVOQ is not recommended for use in combination with other Janus kinase (JAK) inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine.

SAFETY CONSIDERATIONS FOR RINVOQ (upadacitinib)

Serious Infections: RINVOQ-treated patients are at increased risk of serious bacterial (including tuberculosis [TB]), fungal, viral, and opportunistic infections leading to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase inhibitor (JAKi) in a study comparing another JAKi with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years with ≥1 CV risk factor.

Malignancies: Malignancies have occurred in RINVOQ-treated patients. A higher rate of lymphomas and lung cancer (in current or past smokers) was observed with another JAKi when compared with TNF blockers in RA patients.

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAKi in a study comparing another JAKi with TNF blockers in RA patients ≥50 years with ≥1 CV risk factor. History of smoking increases risk.

Thromboses: Deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. A higher rate of thrombosis was observed with another JAKi when compared with TNF blockers in RA patients.

Hypersensitivity: RINVOQ is contraindicated in patients with hypersensitivity to RINVOQ or its excipients.

Other Serious Adverse Reactions: Hypersensitivity reactions; gastrointestinal perforations; hypoglycemia in patients with diabetes; laboratory abnormalities; and embryo-fetal toxicity.

Please continue listening and stay tuned for additional important safety information for RINVOQ within this podcast.

Dr. David Rubin: I have a patient in mind who I think would be a suitable candidate for RINVOQ. I think that this is an ideal patient for a JAK inhibitor. Similar to your patient, Josh, treatment with 5-ASAs and oral steroids didn't work. She's 22 and has moderately to severely active UC. She was able to control her disease for 12 months with an anti-TNF agent before experiencing breakthrough symptoms, highlighting the challenge you mentioned earlier, Josh. She was experiencing elevated stool frequency, rectal bleeding, and a colonoscopy revealed a Mayo endoscopic subscore of 2 with marked erythema, friability, and erosions, and the lab work confirmed all of this with an elevated fecal calprotectin. Given her prior treatment history and the increased disease activity she was experiencing, it made sense to consider an oral small molecule and specifically, upadacitinib. Knowing that she lost response with an anti-TNF, transitioning her to a treatment option other than a biologic, it made sense. So, she was prescribed RINVOQ once daily and this is a patient who's also of childbearing age, but she's not actively trying to get pregnant, is on contraception, and we had a conversation about that, and that is absolutely appropriate.

It is important to note that RINVOQ is not contraindicated in women of childbearing age, but it's contraindicated in women who are planning imminent pregnancy or who are pregnant or breastfeeding. RINVOQ was approved for ulcerative colitis in 2022. After two 8-week multi-center double-blind placebo-controlled UC induction trials, participants on RINVOQ who achieved clinical response at Week 8 per modified Mayo Score with 45 milligrams of RINVOQ were moved into the U-ACHIEVE maintenance trial where they were randomized to 15 milligrams daily, 30 milligrams daily, or placebo.

Narrator:

RECOMMENDED MAINTENANCE DOSING

The recommended maintenance dosage of RINVOQ is 15 mg once daily. A dose of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dose.

Dr. David Rubin: The clinical trials had a primary endpoint of clinical remission defined as no rectal bleeding, reduced stool frequency, and an endoscopic subscore less than or equal to 1 without friability and a variety of ranked secondary endpoints which included clinical response per the adapted Mayo score, endoscopic improvement, and histo-endoscopic mucosal improvement. So, Josh, tell us how RINVOQ did in meeting its endpoints in these clinical trials.

Dr. Josh Steinberg: Of course. And in fact, RINVOQ achieved all primary and secondary endpoints. Firstly, RINVOQ met its primary endpoint of clinical remission at Week 8 in the induction trials. And then in the 52-week maintenance trial, RINVOQ met its primary endpoint, demonstrating remission at Week 52. 42% of the 148 patients on RINVOQ 15 milligrams and 52% of the 154 patients on RINVOQ 30 milligrams achieved clinical remission, compared to just the 12% of the 149 patients on placebo.

When we look at the secondary endpoints, such as endoscopic improvement, we see that in the U-ACHIEVE maintenance trial, 49% of the 148 patients on RINVOQ 15 milligrams and 62% of the 154 patients on RINVOQ 30 milligrams achieve endoscopic improvement, compared with 14% of the 149 patients receiving placebo. Endoscopic improvement was defined as Mayo endoscopy subscore of 0 or 1 without friability. Endoscopic results were based on a full colonoscopy or flexible sigmoidoscopy depending on the extent of disease at study entry.

Dr. David Rubin: What’s important to consider is where the patients started at the entrance of the induction studies—approximately 70% of patients began as Mayo endoscopic subscore of 3 or severe disease, and 30% as Mayo endoscopic subscore of 2.

In addition to endoscopic improvement, the RINVOQ trials also measured endoscopic remission, defined by a Mayo endoscopic subscore of 0, or normal appearance of the colon. I want to emphasize that, a Mayo endoscopic subscore of 0. At Week 52, approximately a quarter of patients achieved an endoscopic remission on RINVOQ, compared with 6% on placebo.

This is important to our long-term treat-to-target goals and a metric that I aim for with my patients or at least acknowledge to them after I scope them what the positive predictive value is after finding this.

Narrator: 24% of 148 patients on RINVOQ 15 mg, 26% of 154 patients on RINVOQ 30 mg, and 6% of 149 patients on placebo achieved endoscopic remission at Week 52.

Dr. David Rubin: Data are also available for RINVOQ's open-label extension, the U-ACTIVATE study. The long-term extension study evaluates as-observed data over an extended period. We’re combining the results of the initial 52-week Maintenance trial with the long-term extension findings.

Narrator: These patients in OLE were those that completed the U-ACHIEVE maintenance trial and achieved clinical remission per modified Mayo Score at Week 52.

Dr. David Rubin: The long-term extension study evaluates as-observed data over an extended period. The results are promising, especially when we look at the key endpoints we discussed earlier. Endoscopic improvement, clinical remission, and now endoscopic remission.

So, Josh, to get back to our discussion about the Week 52 data, in my practice, as I'm sure is the case in yours, the data suggest that RINVOQ is a proven treatment option for our moderate to severe UC patients who have had intolerance or an inadequate response to anti-TNF. To bring back our patient example, she's an ideal candidate for RINVOQ. She had a history of being treated with an anti-TNF agent and needed relief due to her significant symptoms.

Additionally, she's a young adult. She's not actively trying to get pregnant. She's taking contraception and she does not have any risk factors. So really a perfect person for this. So, Josh, back to you.

Dr. Josh Steinberg: It's a really great point you make, David, and I completely agree. And it's really important that we consider individual patient risk factors when we're trying to determine what might be the most appropriate treatment option in our patients with ulcerative colitis. And like we mentioned before, you always want to try to really individualize this benefit-and-risk discussion to the patient's unique situation based on their disease characteristics, other risk factors and the like. So, for instance, if the patient is elderly and has two or three cardiovascular risk factors, that might warrant perhaps a more cautious approach and might lead me or other providers to reconsider prescribing RINVOQ and maybe consider an alternative option. But that being said, sometimes the most effective treatment is going to be the one that we feel like is going to work best, but we obviously have to take safety into consideration. In our particular patient's case, after carefully weighing the potential benefits and risks, it really became clear that RINVOQ made sense as an option for managing her ulcerative colitis.

Dr. David Rubin: So, Josh, have you found RINVOQ to work well with some of your patients?

Dr. Josh Steinberg: Overall, yes, I really have. It's been the case in my practice that RINVOQ has worked very well for many of my patients with ulcerative colitis. And in particular, my adult patients with moderate to severe UC, I typically transition them to RINVOQ after they've failed just one anti-TNF. I don't really wait and try and cycle them if they had a primary non-response to the first anti-TNF to try to go to another anti-TNF.

Dr. David Rubin: Terrific. Let's talk a little bit more about safety. We want to see patients improve on all levels and we want them to remain safe. And of course, we think about long-term safety when we're using therapies for maintenance. SKYRIZI, as you already covered, is an effective therapy. It has a safety profile established across four indications with approximately nine years of clinical trial experience and has undergone extensive research and follow-up with 34 clinical trials across all those indications.

It's been evaluated in over 8,700 patients globally across all dose levels, providing us with data for more than 26,800 patient-years of clinical trial exposure.

Narrator: Common adverse events for UC patients taking SKYRIZI can include arthralgia, pyrexia, injection site reactions, and rash. Serious adverse events for patients taking SKYRIZI can include infections and hepatic events.

The most common side effects of SKYRIZI in people treated for Crohn’s disease and ulcerative colitis include upper respiratory infections, headache, joint pain, stomach (abdominal) pain, injection site reactions, low red blood cells (anemia), fever, back pain, urinary tract infection, and rash.

Adverse drug reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Please continue listening and stay tuned for additional important safety information for SKYRIZI within this podcast.

Dr. David Rubin: RINVOQ has a well-studied safety profile as well. That being said, discussing the safety of RINVOQ with patients is essential to ensure they are fully informed. During our consultation, I explained, RINVOQ may have side effects.

Narrator: The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, increased blood cholesterol, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Please continue listening and stay tuned for additional important safety information for RINVOQ within this podcast.

Dr. David Rubin: I consistently engage in comprehensive discussions with my patients regarding the potential risks associated with their treatment, and I put it in the context of the risk of inadequately treated disease. It's important for me that they understand that while my primary goal is to effectively manage their UC, I am equally committed to prioritizing their safety. The benefit versus risk conversation between the patient and doctor should be applied to each patient and assessed individually. Not everyone will have the same experience, underscoring the value in this type of discussion with the patient. The patient needs to feel comfortable with what we're recommending. So, we must consider the risk of not treating or under treating the patient and what the other options might be.

We also can decide after we have someone on therapy how they're feeling and reevaluate that risk to benefit by the individual patient. That conversation is dynamic and should occur at different time points during their management. I've had many adult patients with moderate to severe UC achieve clinical remission and after they do so they want to stay on the therapy and we continue to discuss and consider the potential for any side effects.

Dr. Josh Steinberg: That's generally been my patients' experience as well, David. And I really have to say that as a practicing gastroenterologist treating patients with inflammatory bowel disease every single day, it really is so exciting to know that there are more treatment options now than ever for our patients, particularly with moderately to severely active ulcerative colitis.

Dr. David Rubin: So, Josh, we've talked about two different therapies today, SKYRIZI, an IL-23 inhibitor, and RINVOQ, which is a selective JAK-1 inhibitor. Just to summarize, in your practice, how do you decide between those two therapies when you see a new patient with ulcerative colitis?

Dr. Josh Steinberg: I think there's a lot of things that go into consideration when trying to make this decision. But one framework to kind of keep in mind is whether or not this patient in front of you is bio-experienced, particularly anti-TNF experienced or bio-naïve. So, in our patients with UC who are biologic-naïve, an interleukin 23 inhibitor such as SKYRIZI might be a very viable option because we know that we can use it as a first line advanced therapy in this bio-naïve patient.

Now in our bio-experienced patients, right, the more refractory patient that perhaps has previously failed an anti-TNF and we want or need these patients to get better as soon as possible, a small molecule such as RINVOQ, a Janus kinase inhibitor, might be a more favorable approach to take just because we know that we can start therapy and they can have a quite immediate response as we know that the onset of action for a small molecule like RINVOQ is quite rapid.

Dr. David Rubin: So, there's lots of different places where it makes complete sense to use these therapies. And we're hopeful that this conversation is giving some of the folks listening ideas about how to use these drugs more effectively.

Josh, I'm glad we finally found a date to have this conversation and to continue our dialogue about managing IBD. Thank you for joining us and talking about SKYRIZI as a first-line option and RINVOQ as an option after patients have been on anti-TNF.

Dr. Josh Steinberg: Thank you for having me back. It's been an absolute pleasure as per usual. So, David, I'm really looking forward to hearing more from you and learning more from you and your future guests. And thanks again for having me. I hope you have me back for a third time.

Dr. David Rubin: Yeah, we'll see how people evaluate this session and then decide. No, in all seriousness, Josh, it's great having this conversation. So, if you've enjoyed this episode of Gut Reactions and found it educational, you can share it via the share button, email, LinkedIn, or on any of your preferred platforms. Until next time, thank you for joining us on Gut Reactions.

Narrator: Please continue listening for additional important safety information for RINVOQ & SKYRIZI.

INDICATION for RINVOQ (upadacitinib)

RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ.

Limitations of Use: RINVOQ is not recommended for use in combination with other Janus kinase (JAK) inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine.

IMPORTANT SAFETY INFORMATION for RINVOQ (upadacitinib)

SERIOUS INFECTIONS

Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include:

• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent TB infection prior to RINVOQ use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis.
• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MORTALITY

In a large, randomized, postmarketing safety study comparing another Janus kinase (JAK) inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years old with at least one cardiovascular (CV) risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with RINVOQ.

In a large, randomized, postmarketing safety study comparing another JAK inhibitor with TNF blockers in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.

With RINVOQ, consider the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Advise patients to limit sunlight exposure by wearing protective clothing and using sunscreen.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

In a large, randomized, postmarketing study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other CV risk factors. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

THROMBOSIS

Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing study comparing another JAK inhibitor to TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of thrombosis was observed with the JAK inhibitor. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated.

HYPERSENSITIVITY

RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal (GI) perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for GI perforation (e.g., patients with a history of diverticulitis and patients taking NSAIDs or corticosteroids). Promptly evaluate patients presenting with new onset abdominal pain for early identification of GI perforation.

HYPOGLYCEMIA IN PATIENTS WITH DIABETES

Hypoglycemia, including severe hypoglycemia, has been reported following initiation of RINVOQ and other JAK inhibitors in patients with diabetes. During treatment with RINVOQ, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia.

LABORATORY ABNORMALITIES

Neutropenia

Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm³). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm³. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia

Absolute lymphocyte counts (ALC) <500 cells/mm³ were reported in RINVOQ-treated patients. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm³. Evaluate at baseline and thereafter according to routine patient management.

Anemia

Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ-treated patients. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids

Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate patients 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations

Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

EMBRYO-FETAL TOXICITY

Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.

VACCINATION

Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, in agreement with current immunization guidelines.

MEDICATION RESIDUE IN STOOL

Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic or functional GI conditions with shortened GI transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

LACTATION

There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT

RINVOQ is not recommended for use in patients with severe hepatic impairment.

ADVERSE REACTIONS

The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ.

Dosage Forms and Strengths: RINVOQ is available in 15 mg, 30 mg, and 45 mg extended-release tablets.

Visit rxabbvie.com/pdf/rinvoq_pi.pdf for Prescribing Information, including BOXED WARNING, for RINVOQ.

IMPORTANT SAFETY INFORMATION & INDICATIONS for SKYRIZI (risankizumab-rzaa)

INDICATIONS for SKYRIZI (risankizumab-rzaa)

Crohn’s Disease: SKYRIZI is indicated for the treatment of moderately to severely active Crohn’s disease in adults.

Ulcerative Colitis: SKYRIZI is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

IMPORTANT SAFETY INFORMATION for SKYRIZI (risankizumab-rzaa)

Hypersensitivity Reactions

SKYRIZI^® (risankizumab-rzaa) is contraindicated in patients with a history of serious hypersensitivity reaction to risankizumab-rzaa or any of the excipients. Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately.

Infection

SKYRIZI may increase the risk of infection. Do not initiate treatment with SKYRIZI in patients with a clinically important active infection until it resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing SKYRIZI. Instruct patients to seek medical advice if signs or symptoms of clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy, closely monitor and discontinue SKYRIZI until the infection resolves.

Tuberculosis (TB)

Prior to initiating treatment with SKYRIZI, evaluate for TB infection and consider treatment in patients with latent or active TB for whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB.

Hepatotoxicity

Drug-induced liver injury was reported in a patient with Crohn’s disease who was hospitalized for a rash during induction dosing of SKYRIZI. For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline and during induction (12 weeks); monitor thereafter according to routine patient management. Consider an alternate treatment for patients with evidence of liver cirrhosis. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct your patient to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

Immunizations

Avoid use of live vaccines in patients treated with SKYRIZI. Drugs that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating SKYRIZI, complete all age-appropriate vaccinations according to current immunization guidelines.

Adverse Reactions

Most common (>3%) adverse reactions associated with SKYRIZI in Crohn’s disease are upper respiratory infections, headache, and arthralgia in induction, and arthralgia, abdominal pain, injection site reactions, anemia, pyrexia, back pain, arthropathy, and urinary tract infection in maintenance.

Most common (≥3%) adverse reactions associated with SKYRIZI in ulcerative colitis are arthralgia in induction, and arthralgia, pyrexia, injection site reactions, and rash in maintenance.

Lipid Elevations: Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12 in patients treated with SKYRIZI in Crohn’s disease. Lipid elevations observed in patients with ulcerative colitis were similar to those in Crohn’s disease.

Dosage Forms and Strengths: SKYRIZI (risankizumab-rzaa) is available in a 600 mg/10 mL single-dose vial for intravenous infusion and a 180 mg/1.2 mL or 360 mg/2.4 mL single-dose prefilled cartridge with on-body injector.

Visit rxabbvie.com/pdf/skyrizi_pi.pdf for Prescribing Information for SKYRIZI.

Narrator: At the intersection of science and clinical experience in IBD, this is Gut Reactions. Settle in, as our host, Dr. David Rubin, brings leading gastroenterologists together for one-on-one conversations. This podcast is brought to you by AbbVie.

Dr. David Rubin: Welcome to the Gut Reactions podcast. I'm your host, Dr. David Rubin, Chief of the Section of Gastroenterology, Hepatology, and Nutrition and Director of the Inflammatory Bowel Disease Center at the University of Chicago. Today, I'll be joined by Dr. Oriana Damas to discuss objective measures in ulcerative colitis, mucosal healing, and how it can impact the lives of our patients who have moderate to severe ulcerative colitis. We'll also talk about a treatment option that could help your patients achieve mucosal healing.

Oriana Damas is an MD and has her master’s degree in Clinical and Translational Investigation. She's an Associate Professor of Medicine at the University of Miami, where she is also an Inflammatory Bowel Disease Physician Scientist and Director of Translational Studies for their Crohn's and Colitis Center. Her research is focused on understanding environmental and dietary patterns that can influence disease risk and modify IBD outcomes. Her current Career Development Award from the NIH focuses on understanding dietary, genetic, and microbiome factors that lead to gut inflammation in Hispanic patients, which represent an emerging population of IBD. Oriana, I’m so happy to have you here on Gut Reactions.

Dr. Oriana Damas: Thank you, David. It's a pleasure to be here and I'm excited for our conversation.

Dr. David Rubin: Many of our listeners may be familiar with the STRIDE-II recommendations, but to set the stage for our topics today, let's begin with a brief overview. Before STRIDE-II, we had the initial STRIDE recommendations, which were published in 2015 and formalized the idea of treating to a target in inflammatory bowel disease. The original STRIDE recommendations on treatment targets included patient-reported outcomes, such as rectal bleeding and stool frequency, as well as objective measures of disease control with a focus on endoscopy. Since STRIDE launched, new data came out that led to the STRIDE-II.

STRIDE-II recommends short-term, intermediate, and long-term targets in the treatment of IBD. As the timeframe for reaching these targets increases, the measures become increasingly objective. As a member of the International Organization for the Study of IBD committee that was responsible for drafting these recommendations, a key insight that led to STRIDE-II was the desire to achieve long-term outcomes for our patients. Oriana, would you share with our listeners the STRIDE-II targets and how they align with your real-world management of IBD patients? For this episode of the podcast, we’ll keep the conversation focused on moderate to severe ulcerative colitis.

Dr. Oriana Damas: Sure. So, I think it's important to recognize that why were the STRIDE-II targets developed in the first place? I think there's increased recognition that we shouldn't just focus on symptom improvement. We should also look for more significant metrics that really correlate with improved outcomes for patients. And those are both biomarker improvement and, in the long term, endoscopic and maybe even histologic improvement.

And so, that's really why the STRIDE-II criteria were developed in the first place. As a short-term target, the STRIDE-II signals symptomatic response as being the first short-term target for providers and for patients. And what does that mean? Specifically, it means a decrease in rectal bleeding for ulcerative colitis, as well as a decrease in the stool frequency, followed by actual symptomatic remission, which generally means no blood in the stool and normal stool frequency.

As an intermediate target, then STRIDE-II recommends the biomarker measures. It's that fecal calprotectin and the C-reactive protein in the blood. We want to normalize both of those metrics and we want to assess that as an intermediate target in between symptomatic improvement, which is a short-term target, and the long-term target, which is endoscopic/histologic improvement.

So, in my clinical experience, biomarkers can be helpful measures to assess underlying inflammation and also to assess whether your patient is responding to that therapy in an objective measure. So, I would normally recommend completing biomarker evaluation in parallel with your clinical follow-up. So that really depends on whether your patients are really symptomatic when you first meet them or whether they're somewhat controlled on steroids and you're starting them on that medication.

So, I use the level of acuity to decide when I bring those patients back. So typically, if they're very active and I'm concerned that I need this drug to really start acting right away, if not, they may end up in the hospital, for example, I try to have them seen much sooner in our follow-up appointments, typically at the 6- to 8-week mark.

And I also check a fecal calprotectin, again, that measure of biomarker activity, which is an intermediate target for STRIDE-II. And I'll typically check that around six to eight weeks as well.

If I find that patients are relatively stable, then I'll schedule a follow-up appointment at around a 12-week mark. In that moment, I will also ask patients to do a stool sample typically a week or so before their appointment at 12 weeks in order to assess what their fecal calprotectin is at that point in time. Much later on, if I find that there is in fact both clinical, right, that short-term target, and intermediate target improvements with fecal calprotectin, then I'm reassured and I'll have the patient come back at around five months or so.

Dr. David Rubin: Oriana, can you share with our listeners the long-term targets identified in STRIDE-II and your clinical experience with them?

Dr. Oriana Damas: So, for long-term targets, STRIDE-II identifies endoscopic healing as a preferred long-term treatment target in IBD. In ulcerative colitis, endoscopic healing is generally defined as achieving a Mayo endoscopy subscore of 0 or 1, which is normal or mild disease. The STRIDE-II recommendations note how a score of 0 is associated with superior disease outcomes. And the end goal, right, the long-term target as per STRIDE-II criteria and what I follow in my clinical practice, is that if patients are improving both symptomatically and biochemically, I'll plan to do a colonoscopy at around 8 to 12 months to really hit that target, which is what we know has the best outcomes possible, which is endoscopic healing. This gives me visible evidence of disease control, and this is what is supported in all the studies looking at treatment outcomes.

Endoscopic healing is a critical treatment goal for my UC patients. In my practice, around 8 to 12 months depending on disease severity, but no later than typically a year after initiating therapy, I'll have the patient back for a colonoscopy where I look for improvement of the appearance of the mucosa. When I see a patient improve to normal or mild disease, this gives me visible evidence of disease control.

And I think that's where the STRIDE-II criteria really add value to clinical practice because they tell us, don't just check clinical symptoms, make sure that you are also achieving biochemical and endoscopic healing as well.

Dr. David Rubin: Yeah, I say to patients, I want you to feel better right away because that'll improve your quality of life. But if we want it to last, we want to look for objective measures that we're controlling the disease process. So feeling better means decreased stool frequency, elimination of bleeding, of course, but also elimination of urgency.

And then we start talking about how we would assess whether the disease is under control, looking at labs and, of course, endoscopic improvement as well. So, I think that this makes good sense, but it's important to make sure your patients know where you're going and that we're on the same page. Building on our conversation of long-term UC treatment targets, let's dive deeper into the topic of mucosal healing. Over recent years, the definition of mucosal healing in ulcerative colitis has evolved to include both endoscopic and histologic results. In fact, STRIDE-II includes histologic activity as an aspirational therapeutic target in UC. When used in conjunction with endoscopic healing, it can represent a deeper level of healing. Evidence suggests that achieving histological remission in conjunction with endoscopic healing is associated with improved patient outcomes such as long-term remission, a reduced need for surgery, and a lower risk of cancer. Before we go further, I think we do need to acknowledge that there are multiple indices used to assess histologic activity, and there's not currently one standard definition of histologic remission. Oriana, how are you incorporating histology into your practice to evaluate disease control, if you're doing it at all?

Dr. Oriana Damas: In addition to endoscopy, which is a key part of ongoing management, I commonly perform biopsies to assess for histologic assessment again around that 8- to 12-month mark. And this will be read by our central lab or GI pathologist. So, in my practice, I have found that it can be a helpful predictor of future relapse. I typically take biopsies at different segments, as it provides a roadmap for disease activity. Often there is a parallel and correlation between endoscopic outcomes and histologic findings. I'll tell you that, histologic activity, we still don't have very clear data on what to do with it as far as the research studies and the treatment targets. When I have found it to be particularly helpful is when I grade an endoscopic score as a Mayo 1 and it ends up being a little bit more severe disease on histology. In that case, I may consider doing a different management option based on the biopsy results.

Dr. David Rubin: I do the same. Are you changing treatments if the patient doesn't achieve histologic remission, though?

Dr. Oriana Damas: I wouldn't change treatment just based on achievement or lack of achievement, I should say, of histologic remission, because our data does not support that yet. And so, you know, I think if a patient has a Mayo score of 0 or a Mayo score of 1, feels great, has completely normal laboratory values, including biochemical markers of inflammation, but on the biopsies, there's still some mildly active disease, I really do not think that at this point, we should be trying to be more aggressive with the treatment pattern for patients if, in my mind, they've already achieved endoscopic improvement and a good outcome overall.

Dr. David Rubin: In my practice, I take a similar approach with using it as more of a holistic component of assessing disease control in conjunction with an endoscopy. In the STRIDE-II recommendations, histological healing is not yet a formal target for a few reasons, including the difficulty to achieve it, a lack of consensus around what a standard measurement index should be, and of course, cost reasons. That said, it's interesting to see that recent clinical trials are incorporating composite endoscopic and histologic endpoints as secondary endpoints. The clinical trials may use different names and criteria for their endpoints, such as histologic endoscopic mucosal improvement or endoscopic histologic mucosal improvement, so it's important for us to understand what a trial's endpoint is measuring so we can appropriately interpret the result.

So, Oriana, how do you consider histologic and endoscopic outcomes when you're evaluating the different treatments for UC?

Dr. Oriana Damas: So, when evaluating ulcerative colitis therapies, objective evidence can be an important component of my holistic treatment decision. So for every patient, I'm weighing the risks, the benefits of the treatment, their treatment history, and their current presentation. So when evaluating clinical trial results, endoscopic results are important. I need to know the drug can work beyond symptom control to really address underlying inflammation.

Stringent endpoints that include histology, like histo-endoscopic mucosal improvement, are also valuable. And while I'm not using histologic evidence on its own to make a treatment switch decision, as we mentioned earlier, a drug achieving stringent endpoints within its clinical trials can give me increased confidence on the therapy's long-term efficacy profile.

Narrator:

INDICATION

RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ.

Limitations of Use: RINVOQ is not recommended for use in combination with other Janus kinase (JAK) inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine.

SAFETY CONSIDERATIONS

Serious Infections: RINVOQ-treated patients are at increased risk of serious bacterial (including tuberculosis [TB]), fungal, viral, and opportunistic infections leading to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase inhibitor (JAKi) in a study comparing another JAKi with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years with ≥1 CV risk factor.

Malignancies: Malignancies have occurred in RINVOQ-treated patients. A higher rate of lymphomas and lung cancer (in current or past smokers) was observed with another JAKi when compared with TNF blockers in RA patients.

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAKi in a study comparing another JAKi with TNF blockers in RA patients ≥50 years with ≥1 CV risk factor. History of smoking increases risk.

Thromboses: Deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. A higher rate of thrombosis was observed with another JAKi when compared with TNF blockers in RA patients.

Hypersensitivity: RINVOQ is contraindicated in patients with hypersensitivity to RINVOQ or its excipients.

Other Serious Adverse Reactions: Hypersensitivity reactions; gastrointestinal perforations; hypoglycemia in patients with diabetes; laboratory abnormalities; and embryo-fetal toxicity.

Please continue listening and stay tuned for additional Important Safety Information within this podcast.

Dr. David Rubin: Turning our attention to RINVOQ, this is a treatment that you and I both have experience prescribing, going back to the clinical trials.

RINVOQ had two, 8-week, multicenter, double-blind, placebo-controlled UC induction trials. Participants on RINVOQ who achieved clinical response at Week 8 with 45 mg of RINVOQ were moved into the U-ACHIEVE Maintenance trial.

The clinical trials had a primary endpoint of clinical remission—defined as no rectal bleeding, reduced stool frequency, and an endoscopic subscore of 1 or less without friability—and ranked secondary endpoints, which included clinical response per an adapted Mayo score, endoscopic improvement, and histologic-endoscopic mucosal improvement.

Oriana, tell us how RINVOQ ultimately did against its primary endpoints.

Dr. Oriana Damas: RINVOQ achieved all primary and secondary endpoints. RINVOQ met its primary endpoints of clinical remission at Week 8 in the induction trials, delivering powerful rates compared to placebo. In the 52-week Maintenance trial, RINVOQ met its primary endpoint, demonstrating durable remission at Week 52. 42% of the 148 patients on RINVOQ 15 mg, and 52% of the 154 patients on RINVOQ 30 mg, achieved clinical remission, compared to 12% of the 149 patients on placebo.

Dr. David Rubin: In the U-ACHIEVE Maintenance trial, 49% of the 148 patients on RINVOQ 15 mg and 62% of the 154 patients on RINVOQ 30 mg achieved endoscopic improvement, compared with 14% of the 149 patients receiving placebo.

What’s important to consider is where the patients started at the entrance of the induction studies—approximately 70% of patients began as Mayo endoscopic subscore of 3 or severe disease, and 30% as Mayo endoscopic subscore of 2.

Dr. Oriana Damas: In addition, data is also available for RINVOQ’s open label extension, the U-ACTIVATE study.

Narrator: In an open-label extension (OLE), there is a potential for enrichment of the long-term data in the remaining patient populations since patients who are unable to tolerate or do not respond to the drug often drop out.

In an as-observed analysis, missing data were excluded from calculations from that visit, which may increase the percent of responders. All observed data were used regardless of premature discontinuation of study drug or initiation of concomitant medications. The same patient may not have a response at each time point.

Dr. Oriana Damas: All patients who completed the Maintenance trial were eligible for the open-label extension trial. The RINVOQ 15-mg arm includes patients who were in remission at the completion of the U-ACHIEVE Maintenance trial and taking continuous RINVOQ 15 mg. The 30-mg arm includes both patients who were in remission and patients who were not in remission from the Maintenance trial regardless of remission status.

Narrator: The interim analysis includes 101 patients on continuous RINVOQ 15 mg and 175 patients on RINVOQ continuous 30 mg, following the U-ACHIEVE maintenance trial.

Dr. Oriana Damas: At Week 48, Week 100 overall, 82% of patients on continuous RINVOQ 15 mg and 78% of patients on continuous RINVOQ 30 mg observed endoscopic improvement.

The difference in remission status upon entrance to the U-ACTIVATE open-label long-term extension may explain the difference in efficacy between the 15- and 30-mg arms.

Dr. David Rubin: In addition to endoscopic improvement, the RINVOQ trials also measured endoscopic remission, defined by a subscore of 0 or a normal appearance of the colon. At Week 52, approximately a quarter of patients achieved endoscopic remission on RINVOQ compared with 6% on placebo. At Week 100 overall, 55% of patients on RINVOQ 15 mg and 51% on RINVOQ 30 mg achieved endoscopic remission.

Oriana, seeing these endoscopic data from the RINVOQ clinical trials, in your personal experience, do you find results are similar?

Dr. Oriana Damas: So, I prescribe the 30-mg dose of RINVOQ once daily for patients with refractory, severe or extensive disease, and I have found that RINVOQ is an efficacious medicine that achieves endoscopic outcomes. When my RINVOQ patients are experiencing sustained symptom relief, we’re then able to do an endoscopy and confirm that they’re showing minimal signs of disease activity.

From its induction trials, through its Maintenance trial, we see that RINVOQ delivered significant endoscopic improvement compared to placebo.

Dr. David Rubin: The RINVOQ trials also assessed histology, using the endpoint of histo-endoscopic mucosal improvement. Patients who achieved this stringent endpoint achieved both endoscopic improvement with a Mayo subscore of 0 or 1 without friability and histologic improvement with a Geboes score less than or equal to 3.1, indicating neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue.

Now, we should note that the relationship between histo-endoscopic mucosal improvement to disease progression and long-term outcomes was not evaluated. That said, at Week 8, results from the U-ACHIEVE and U-ACCOMPLISH induction studies showed a powerful treatment difference, with one in three RINVOQ patients demonstrating visible improvement in the colon lining and decreased histologic inflammatory activity, as measured by the Geboes Index score.

At Week 52, 35% of patients on RINVOQ 15 mg and 50% of patients on RINVOQ 30 mg achieved histo-endoscopic mucosal improvement, with 12% on placebo achieving the same endpoint. Endoscopic results are based on a full colonoscopy or flexible sigmoidoscopy, depending on the extent of disease at study entry. And histology results are based on a set of two biopsies.

Dr. Oriana Damas: Now, that data really stands out to me. I mean, half of the 30-mg cohort was able to achieve both endoscopic and histologic improvement? That signals to me that RINVOQ is an efficacious medicine that has demonstrated the ability to not only deliver clinical remission, but meets important endpoints and adjunctive healing measures, playing a key role in our pursuit of controlled disease.

I have personally witnessed endoscopic and histologic improvement with RINVOQ.

Dr. David Rubin: Overall, my impression of RINVOQ remains that it is a proven treatment option for our moderate to severe UC patients and aligns with the STRIDE-II recommendations. I have patients who have been on RINVOQ for over 2 years, and these data also reflect what I am seeing in my practice.

Thank you so much, Oriana, for taking the time today to discuss the objective outcomes and the concept of healing for our patients with ulcerative colitis. I know we both look forward to seeing treatment options for UC continue to expand.

Dr. Oriana Damas: [Closing remarks and acknowledgment] It was an absolute pleasure, and I hope that we hear more and learn more from your future guests.

Dr. David Rubin: If you’ve enjoyed this episode of Gut Reactions and found it educational, you can share it via the share button, email, LinkedIn, or on any of your preferred platforms. Until next time, this is Gut Reactions.

Narrator:

Please continue listening and stay tuned for additional Important Safety Information.

IMPORTANT SAFETY INFORMATION

SERIOUS INFECTIONS

Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include:

• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent TB infection prior to RINVOQ use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis.
• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MORTALITY

In a large, randomized, postmarketing safety study comparing another Janus kinase (JAK) inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years old with at least one cardiovascular (CV) risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with RINVOQ.

In a large, randomized, postmarketing safety study comparing another JAK inhibitor with TNF blockers in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.

With RINVOQ, consider the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Advise patients to limit sunlight exposure by wearing protective clothing and using sunscreen.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

In a large, randomized, postmarketing study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other CV risk factors. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

THROMBOSIS

Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing study comparing another JAK inhibitor to TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of thrombosis was observed with the JAK inhibitor. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated.

HYPERSENSITIVITY

RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal (GI) perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for GI perforation (e.g., patients with a history of diverticulitis and patients taking NSAIDs or corticosteroids). Promptly evaluate patients presenting with new onset abdominal pain for early identification of GI perforation.

HYPOGLYCEMIA IN PATIENTS WITH DIABETES

Hypoglycemia, including severe hypoglycemia, has been reported following initiation of RINVOQ and other JAK inhibitors in patients with diabetes. During treatment with RINVOQ, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia.

LABORATORY ABNORMALITIES

Neutropenia

Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm³). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm³. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia

Absolute lymphocyte counts (ALC) <500 cells/mm³ were reported in RINVOQ-treated patients. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm³. Evaluate at baseline and thereafter according to routine patient management.

Anemia

Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ-treated patients. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids

Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate patients 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations

Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

EMBRYO-FETAL TOXICITY

Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.

VACCINATION

Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, in agreement with current immunization guidelines.

MEDICATION RESIDUE IN STOOL

Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic or functional GI conditions with shortened GI transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

LACTATION

There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT

RINVOQ is not recommended for use in patients with severe hepatic impairment.

ADVERSE REACTIONS

The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ.

Dosage Forms and Strengths: RINVOQ is available in 15 mg, 30 mg, and 45 mg extended-release tablets.

Visit rxabbvie.com/pdf/rinvoq_pi.pdf for Prescribing Information, including BOXED WARNING, for RINVOQ.

Narrator: At the intersection of science and clinical experience in IBD, this is Gut Reactions. Settle in, as our host, Dr. David Rubin, brings leading gastroenterologists together for one-on-one conversations. This podcast is brought to you by AbbVie.

Dr. David Rubin: Welcome to the Gut Reactions podcast. I'm your host, Dr. David Rubin, Chief of the Section of Gastroenterology, Hepatology, and Nutrition at the University of Chicago, where I'm also the Director of our Inflammatory Bowel Disease Center.

I'm delighted to be joined today by Dr. Joshua M. Steinberg, who is a board-certified gastroenterologist and director of IBD at Gastroenterology of the Rockies, a large GI practice serving patients in Denver and the Boulder, Colorado, metropolitan areas. He's also part of the SCL Intermountain Healthcare Network. Wow, that's a mouthful, Josh.

But more importantly, he's an adjunct clinical instructor at the University of Colorado School of Medicine. And Josh and I, out of full disclosure, worked together because he did an advanced fellowship year in IBD at the University of Chicago after he did his regular fellowship at Georgetown. So hi, Josh. How are you doing? Welcome to Gut Reactions.

Dr. Josh Steinberg: Hi David, thanks so much for having me. I'm excited to be here.

Dr. David Rubin: All right, well, we're gonna make sure that you haven't forgotten what we taught you here. So that's part of this. That's the secondary agenda to our podcast today.

Dr. Josh Steinberg: A little pop quiz.

Dr. David Rubin: That'll come later.

Anyway, in our last episode, we talked a lot about treatment targets, and I had a wonderful conversation with Dr. Oriana Damas. But today we're gonna continue the discussion by exploring next steps when patients are not meeting their treatment goals.

Dr. David Rubin: Many moderate to severe patients with UC may not adequately respond to an anti-TNF or other treatments, as we all know, and loss of response can present either as primary or secondary loss of response to that anti-TNF. Just as a reminder to our colleagues, primary loss of response occurs when a patient isn't experiencing an adequate response after starting the therapy. In this case, we're talking about anti-TNFs, and this is usually noticed within the initial weeks or months of starting that therapy. Secondary loss of response, or what I call secondary non-response, occurs when a patient initially responds well to the anti-TNF. They may even experience complete remission, but over time, they have either attenuation, where they're losing response, but still having some response when they get their dose, or complete loss of response. And that can happen within months after starting treatment to years later. So, Josh, tell us a little bit about how you define disease control before we get into sort of the non-responder. Just talk to us about what do you think about when you're starting a patient on therapy to know that it's working, and how do you explain that to your patients?

Dr. Josh Steinberg: It's an important question, David. Disease control is all about addressing the inflammation associated with ulcerative colitis to ensure the symptoms as well as the endoscopic response remain managed. So, in my practice, achieving disease control and a satisfactory treatment response goes well beyond symptom relief. It's about reaching and maintaining clinical remission where symptoms like bleeding are significantly reduced, but we also want to see a reduction in Mayo endoscopic subscores. So steroid-free remission, of course, is also an important disease control target for patients with UC, since it helps prevent the long-term complications associated with steroid use, but also provides an alternative treatment strategy for those who cannot tolerate steroids. To ensure the authenticity of these improvements, we closely monitor biomarkers. We look at blood tests like CRP, C-reactive protein, as well as fecal calprotectin, and of course we utilize endoscopic measures.

This comprehensive approach to effectively manage the underlying inflammation can lead to better symptom control.

Dr. David Rubin: And that, of course, is very similar to what I do, not surprisingly. And I would also just say that for the patient, I make sure they understand that our goal is remission and that our goal is for them to be stable in remission and to do well. It's interesting because it often comes up when a patient says, am I going to be on this the rest of my life? And I always say, well, let's first make sure the therapy is working.

And then secondly, let's make sure it works as long as we need it until we have something better. And I think it's safe and fair to bring that up and to say that to patients. So, Josh, for patients who demonstrate an initial response to therapy, let's say they're doing okay, what do you do in terms of your ongoing monitoring of these patients to know that they're continuing to respond? What do you choose and how often do you do it?

Dr. Josh Steinberg: So, typically I advise a monitoring schedule that involves regular check-ins. I want to see my patients frequently, especially in the beginning. We're going to schedule visits more frequently every three to six months, if not sooner, to closely track the progress and ensure that response to the therapy is sustained.

Dr. David Rubin: And you mentioned calprotectin already, but do you incorporate that?

Dr. Josh Steinberg: Yeah, calprotectin of course, a noninvasive surrogate marker for inflammation. We're going to use that more frequently. Obviously, this is not as invasive as a colonoscopy. It would be tough sell for our patients to do a colonoscopy every three, four or six months. So, I use that in conjunction with the endoscopic response.

Dr. David Rubin: Yeah, I completely agree. It needs to be benchmarked. And we also, of course, have to remember that sometimes patients don't even want to handle their stool, which is one of the limitations of that test. And there are reasons that it can be falsely positive as well as falsely negative, although that's less common in colitis.

So, Josh, in your experience, what are some of the ways that inadequate responders present to you in clinical practice?

Dr. Josh Steinberg: Yeah, so inadequate responders in clinical practice present in many ways. So, one common scenario is when patients are presenting with breakthrough symptoms, despite their treatments. So, diarrhea, increased stool frequency, rectal bleeding, abdominal pain, rectal urgency. All these symptoms can persist or even worsen as the current therapy is unable to control their inflammation causing these symptoms. Additionally, if a patient finds it difficult to taper off of steroids without their symptoms firing up again, that's really another indication that the disease is not well controlled. Steroids of course are a useful tool, but we don't want to rely on steroids for an extended period of time. Another situation is when patients have symptoms that improve with treatment initially, but when we look at the objective measures, including biomarkers like calprotectin or CRP, we find that there's still underlying inflammation that needs to be addressed. And this tells me that the drug is losing its efficacy and the patient might be at risk for flaring and further ulcerative colitis complications.

Dr. David Rubin: So, Josh, this is obviously a very important conversation, in part because we now have so many different treatment options in ulcerative colitis, and we would like to know when to use them. We also need to know when one therapy isn't working and when to make these decisions. And I'm really glad that you brought up the steroid issue. A patient who's responding to steroids, but when they drop below a certain dose, they have immediate return of their symptoms, or when they've been off steroids for some period of time, they have a relapse and need the steroids again—because this is clearly an indication that the steroid-sparing maintenance therapy is not doing its job. And we have to keep that in mind as an important marker of non-response among all the other things that you nicely identified.

And we also need to communicate to patients that if they're having breakthrough, if they're not in stable, controlled remission, we need to know about it and we need to think carefully about what we're going to do. So, as you've seen when you worked with me, I routinely ask patients, “Do you have any breakthrough symptoms in anticipation of the next dose of your medicine?” And that's when they tell us about whether they're really doing as well as we hope.

So, Josh, why don't we talk a little bit about the common symptoms that give us a clue that patients may be losing response. When we ask them about how they're doing, what do we hear from them that tells us we should be assessing this more carefully?

Dr. Josh Steinberg: Absolutely. I would say bloody stool is probably the most common symptom and my top reason for concern, followed by diarrhea or increased stool frequency. So, patients may miss or not report rectal bleeding to us directly, since it's not maybe as impactful to them as stool frequency, but blood in the stool could really indicate ongoing inflammation that's not being adequately controlled. When the disease is not controlled, patients can experience a range of symptoms, including weight loss, loss of appetite, and all these symptoms can really seriously impact a patient's day-to-day activities, whether it's their hobbies, their work schedule, parenting duties, and the like. So that’s a really important aspect that we want to take control of when we are starting patients on therapy for their ulcerative colitis.

Dr. David Rubin: So, Josh, do you have any hobbies?

Dr. Josh Steinberg: No hobbies, just work. I'm just kidding. I am a father of two. I like to go out with my kids. We spend a lot of time outside in Colorado where I'm at currently. And yeah, in my free time, I love to travel when I get the chance.

Dr. David Rubin: There you go. And, you know, obviously traveling with ulcerative colitis is a big problem if the disease is active. People can't plan a long trip, they can't be in a car without knowing where the next restroom stop might be, and certainly being on a plane. Certainly, if you're in a middle seat or a window seat, you can imagine how someone with uncontrolled colitis can feel and how nervous they are about those types of experiences. So, it does really, truly affect quality of life in major ways.

So, let's talk a little bit about patients' hesitancy to openly discuss all their symptoms during a maintenance appointment. And that can lead to misunderstanding or later loss of control to the point where they get much sicker. So what questions are you asking to try to bring this out when you're talking to the patients?

Dr. Josh Steinberg: So typically, many patients who are in an active flare, they will be direct about sharing their symptoms, but many are not. So, I'll ask the typical common symptom questions, “rectal bleeding, how many stools per day? Are you having urgency? Are you waking up at night to have a bowel movement?” But I'll also ask other questions to really understand how they're functioning in their daily life to understand their disease burden specifically. So, for example, “Are you doing what you want and need to be doing in your daily life? Are you going to work? Are you able to,” if you're a, you know, 20-year-old college student, “make it to class?” If you're a 45-year-old mother of two, “Are you able to take your kids to school and spend time with your family?” Many patients will not be forthcoming in some of their symptoms and how it's really affecting them.

And of course, all of the symptoms and disability that might come with ulcerative colitis can seriously affect a patient's mental and psychosocial health. So, all these things we want to consider and address during a clinic visit.

Dr. David Rubin: I heard someone once say that what they ask patients is, “What are they unable to do because of their current state of their colitis?” And I think that that's a good open-ended question that gets at some of this as well. And because often the patient is compensating for many different ways of their daily existence and avoiding certain behaviors or have changed where they work or how they get to work in the morning or what they're able to do to take care of their kids. And I think that that can be a really helpful way to do this.

And as you know, from working with me, the five questions I always ask patients with colitis is, “Are you having formed stool? Are you sleeping through the night without bowel movements? Do you see blood in your stool? Do you have urgency?” And, “Are you able to pass gas without fear of leaking?” And when a patient is unable to answer those questions properly, we know that they're probably not in symptomatic remission. I also then emphasize to them, even though they're feeling better in some cases, it might not be enough. And we want to make sure we get them where they need to be and that they're going to be able to function at the level they want to. And that includes going to school, taking care of their family, being able to work, being able to travel unencumbered.

So, after you've asked some of these questions, what objective measures do you use? Does it depend on the patient? Does it depend on their disease? Or how do you think about this and what do you use?

Dr. Josh Steinberg: Sure, so assessing disease is getting easier as we have labs that are noninvasive and fairly accurate in predicting endoscopic activity. As we mentioned earlier, the key ones are C-reactive protein and fecal calprotectin. The latter, of course, offers us advantageous sensitivity over the other biomarkers, meaning we can get a more accurate read on disease activity. Now, some patients may exhibit anemia and low platelets, not mounting a reliable CRP level.

For these patients, measuring albumin levels can help provide biomarker data in determining appropriate treatment strategies. Proactively, biomarkers are helpful during routine follow-ups to catch potential issues early, regardless of symptom recording.

Dr. David Rubin: Hey Josh, let's bring this to life for our listeners. Can you describe one of your patients who recently demonstrated signs of inadequate response and needed a treatment switch? It may be a reach, because I'm sure all your patients are in remission, but maybe you can think of one. [Laughs]

Dr. Josh Steinberg: Of course, I'd wish all my patients were in remission, but as you know, we're dealing with a really complicated disease with ulcerative colitis. And many of my patients will respond, but many will lose response. So, of several examples I can think of, one was a young person who had done relatively well on an anti-TNF treatment. He responded initially and he did have a loss of response. He had worsening rectal bleeding, stool frequency, clearly elevated inflammatory markers in the stool with his calprotectin. And we knew we needed to make a switch because even though this patient had an initial response, clearly, they had a secondary loss of response to this treatment.

Dr. David Rubin: Josh, once it's been determined that a patient might benefit from switching to another therapy, how do you actually have that conversation? Because a lot of times what happens is a patient is finally trying a new therapy or has been on a therapy that was working and there's a lot of inertia to move to a new treatment or to a different treatment as well as all the fear and uncertainty of whether it's gonna work. So, tell me a little bit about how you approach those patients and how you discuss making a treatment switch.

Dr. Josh Steinberg: So, it's an important question. And this whole concept of shared decision-making with our patients is really critical. And you have to really get to the patient's level. And patients might differ in terms of their understanding of their disease and of their understanding of the disease treatment options. Cause as we know, there's many options available more so than there were five years ago, let alone 10 or 20 years ago. So, we want to use our patient's understanding to really help make that decision together. And listen, I'm sensitive to a patient's kind of thought or notion that they're doing better, right? But what does better really mean, right? Are they able to go out and see their friends and family and do all the things they want to be doing? You know, is their new normal having eight to 10 bowel movements a day as opposed to 15 to 20, which sure by the numbers might be an improvement, but we know we can do better.

Dr. David Rubin: I think that's a really good approach. One of the things that I say to patients as well is I remind them that chronic inflammation in their body can affect their health in general. So, getting by with active symptoms because the patient's been able to manage their job or their workplace or be closer to a bathroom is not necessarily something that is okay in many other ways that they need to be aware about.

I also agree completely that we have to work with the patient to make these decisions so that we're all on the same page. And sometimes it takes multiple attempts. A patient may want to try the therapy they're on a little bit longer. They wanna just give it a chance. And I think that that's okay as long as we define what that means and when it's going to occur. In other words, we don't want patients to continue trying something that's clearly not working.

On the other hand, we want them to feel comfortable enough that they did do what they wanted to try, at least for a bit, before we move on to something else. And that's the give and take of being a clinician and having these conversations. Earlier today, I had a conversation with a patient who happened to be on an anti-TNF therapy that had worked for a long time, and now it's not working. And he's about to get on an airplane and travel across the country for a business trip and wanted to know what he should do now and what he should do when he gets home to try and get it under control.

And he was obviously reluctant to make a big switch in his therapy because he'd had such great success for so long with his current treatment. And we went through all the different possibilities and options and he's gonna be thinking about those. And when he gets back, we'll see how he's feeling, and I think he'll be more likely to move forward. I think that having a patient with active disease is an easier conversation than when we find somebody who feels improved or even well, but we see inflammation that wasn't expected.

Dr. Josh Steinberg: I agree with you, and I try to really lean into that whole component of clinical remission and endoscopic remission because if we're not able to achieve those targets, we know what patients won't do as well long-term. So, you know, often I tell patients perfect can be the enemy of good, but in these circumstances, we know that we can truly do better. So, although I'm sensitive to, you know, a patient's own particular interests and maintaining their particular treatment that they're on, I want them to know that we have options that they can do better on potentially.

Dr. David Rubin: Yeah, I think that that's a really important point. And I'll also really emphasize the importance to know that we're gonna take this one step at a time, right? And that if this therapy doesn't do what we need, we're gonna try something else. But explaining to the patient the real cost of living with active inflammation.

And sometimes it's more than they even are acknowledging, not just in what they're willing to say, but in terms of how much they've normalized the way they're living or they've adjusted their lifestyle to accomplish what they need to accomplish or try to accomplish living with active ulcerative colitis. And until they get to this point where they realize what remission is supposed to be and how they should feel, they often are not aware that they could actually have a much better existence if they make the right treatment switch. And so, I do think that these conversations are difficult.

And it's often a very challenging time for us to move a patient through to a new treatment. But we also need to remember that this can happen over multiple conversations or multiple clinic visits and that we can do this with baby steps. What I say is let's try the therapy and see if it even works before we get too far down the road about discussing how long you're gonna stay on it. And I think that that's all part of helping somebody feel comfortable and confident in what we're doing.

And the last thing I'll say, and what I've taught the fellows, and I often remind my colleagues, is that when a patient isn't willing to do something that you're recommending, I think it's completely appropriate to suggest they get another opinion. And I think that that is a very helpful way either to reinforce what you're already saying or to provide the patient with the humility that they might hear from another expert and then feel more comfortable with what you've been recommending. So, I do think that that's another approach to some of these challenging interactions.

Ultimately though, when they feel better and they're in stable remission, the risk to benefit ratio in terms of their tolerance for the therapy completely changes. It's a completely new conversation after they're actually feeling better.

Dr. Josh Steinberg: I agree with you and many patients will tell me, you know, whether it's three months, six months after starting a new treatment that they wish they kind of made that decision earlier to make that change because they felt so comfortable feeling better—right?—but not well, that it was hard for them to make that decision. So, once they finally get over that hump and hopefully are doing better on a newer therapy, patients are super grateful and doing incomparably better. And it makes us as physicians feel wonderful that we're able to get them to that point.

Dr. David Rubin: I say to patients that it's my job to help evaluate their condition and to make recommendations and to educate them and then ultimately to respect their decisions. And I work with them to try to get to these points.

So, Josh, stemming from this larger conversation about treatment switches, we’re going to talk next about a treatment option that may help our patients with moderate to severe UC who have failed or who have an intolerance to an anti-TNF. Patients should be educated on the importance of controlling their disease progression, and the risks and benefits of this therapy, which is, upadacitinib, or RINVOQ.

Clinical trials for RINVOQ have proved that patients can achieve durable remission. Following Important Safety Information about RINVOQ, we’ll look at its comprehensive data and share our personal experience prescribing it to our anti-TNF patients who’ve had an inadequate response.

Narrator:

INDICATION

RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response or intolerance to one or more tumor necrosis factor (TNF) blockers. If TNF blockers are clinically inadvisable, patients should have received at least one approved systemic therapy prior to use of RINVOQ.

Limitations of Use: RINVOQ is not recommended for use in combination with other Janus kinase (JAK) inhibitors, biological therapies for UC, or with potent immunosuppressants such as azathioprine and cyclosporine.

SAFETY CONSIDERATIONS

Serious Infections: RINVOQ-treated patients are at increased risk of serious bacterial (including tuberculosis [TB]), fungal, viral, and opportunistic infections leading to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase inhibitor (JAKi) in a study comparing another JAKi with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years with ≥1 CV risk factor.

Malignancies: Malignancies have occurred in RINVOQ-treated patients. A higher rate of lymphomas and lung cancer (in current or past smokers) was observed with another JAKi when compared with TNF blockers in RA patients.

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAKi in a study comparing another JAKi with TNF blockers in RA patients ≥50 years with ≥1 CV risk factor. History of smoking increases risk.

Thromboses: Deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. A higher rate of thrombosis was observed with another JAKi when compared with TNF blockers in RA patients.

Hypersensitivity: RINVOQ is contraindicated in patients with hypersensitivity to RINVOQ or its excipients.

Other Serious Adverse Reactions: Hypersensitivity reactions; gastrointestinal perforations; hypoglycemia in patients with diabetes; laboratory abnormalities; and embryo-fetal toxicity.

Please continue listening and stay tuned for additional Important Safety Information within this podcast.

Dr. David Rubin: RINVOQ had two 8-week multi-center double-blind placebo-controlled induction trials in ulcerative colitis and met its primary endpoint of clinical remission. Participants on RINVOQ who achieved clinical response at Week 8 with 45 mg of RINVOQ were moved into the U-ACHIEVE maintenance trial. The clinical trials had a primary endpoint of clinical remission, which was defined as no rectal bleeding, reduced stool frequency, and an endoscopic subscore of less than or equal to 1 without friability.

It also had ranked secondary endpoints, which included clinical response per the adapted Mayo score, endoscopic improvement, and histo-endoscopic mucosal improvement. All primary and secondary endpoints were achieved.

In clinical trials, RINVOQ provided rapid relief of rectal bleeding and stool frequency as early as Week 2. The ranked secondary endpoint of clinical response per partial modified Mayo score is a composite of the Mayo stool frequency and rectal bleeding subscores and is defined as a decrease in total score more than or equal to 30% and more than or equal to one point from baseline and a decrease in rectal bleeding subscore more than or equal to 1 or a rectal bleeding subscore of 0 or 1.

In the U-ACHIEVE induction trial at Week 2, 60% of the 319 patients on RINVOQ 45 milligrams achieved clinical response compared to only 27% of the 154 patients on placebo, measured by a decrease in rectal bleeding and stool frequency. Pretty remarkable.

Dr. Josh Steinberg: I agree. And so, what I see within that data is that it addresses the fact that patients want to feel better quickly.

Dr. David Rubin: What I say to patients when I start this therapy is that they should expect to feel well quickly in most cases, and this is something that they can expect to notice within the first couple weeks.

Dr. Josh Steinberg: Yeah, after response, however, both patients and clinicians are looking for and value a durable remission.

Dr. David Rubin: So that's what we'll discuss next. Following the 8-week induction trials, the subsequent 52-week U-ACHIEVE maintenance trial randomized the induction responders to receive either placebo, RINVOQ 15 milligrams or RINVOQ 30 milligrams once daily.

In the 52-week maintenance trial, RINVOQ met its primary endpoint, demonstrating durable remission at Week 52. 42% of the 148 patients on RINVOQ 15 milligrams and 52% of the 154 patients on RINVOQ 30 milligrams achieved clinical remission, compared to 12% of the 149 patients on placebo. A dose of 30 milligrams once daily may be considered for patients with refractory, severe, or extensive disease. And you should discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dose.

Data are also available for RINVOQ's open-label extension, the U-ACTIVATE study. In an open-label extension, there is a potential for enrichment of the long-term data in the remaining patient populations, since patients who are unable to tolerate or who do not respond to the drug often drop out. In an as-observed analysis, missing visit data were excluded from calculations for that visit, which may increase the percentage of responders. All observed data was used regardless of premature discontinuation of study drug or initiation of concomitant medications. The same patient may not have a response at each time point. All patients who completed the maintenance trial were eligible for the open-label extension trial. The RINVOQ 15-milligram arm includes patients who were in remission at the completion of the U-ACHIEVE maintenance trial and taking continuous RINVOQ 15 milligrams.

The 30-milligram arm includes both patients who were in remission and patients who were not in remission from the maintenance trial regardless of remission status. The interim analysis includes 87 patients on continuous RINVOQ 15 milligrams and 151 patients on RINVOQ continuous 30 milligrams following the U-ACHIEVE maintenance trial.

Dr. David Rubin: At Week 100, 78% of 87 patients on continuous RINVOQ 15 milligrams and 69% of 151 patients on continuous RINVOQ 30 milligrams achieved clinical remission on RINVOQ. The difference in remission status upon entrance to the U-ACTIVATE open-label extension may explain the difference in efficacy between the 15- and 30-milligram arms.

Narrator: Week 100 mentioned previously is intended to mean Week 48 of open-label extension, OLE, and Week 100 overall.

Dr. David Rubin: So, I think it was helpful to review the clinical trial data, but let’s hear from you about how it matches your clinical experience. And I'll tell you that in my clinical experience, I've had similar results and we've been really pleased with seeing how this can be an effective option for our patients with moderate to severe UC.

So, Josh, I know you've prescribed RINVOQ for some of your patients. Do you think that your results match what we saw in the clinical trials?

Dr. Josh Steinberg: David, I have to say I'm quite impressed with RINVOQ’s clinical trial results, not just in terms of the clinical remission data, but especially the endoscopic response and remission data too. And again, we're talking about an oral small molecule, a once-daily pill, that really has the potential to help some of our patients who have been refractory or intolerant to anti-TNF agents and get them feeling better. And we know per the data and the clinical trials that they can get feeling better quite soon, right? Within two weeks. And that really does match my personal experience. We often talk about this concept of a steroid-free remission and staying off steroids long term is of utmost importance for us and for our patients. And in the RINVOQ clinical trials, which did look at steroid-free remission as a ranked secondary endpoint, this endpoint was achieved. So, I'm quite pleased with the clinical trial. And again, in my personal clinical experience and I know amongst the clinical experience of my colleagues, I would say that largely my personal experience does match the clinical trial results.

So, I've had patients start on RINVOQ with a broad spectrum of disease activity. So, in patients with more severe disease, those patients who were on anti-TNF agents, that we couldn't get them into a durable remission. And I've also had more moderate activity patients that I've started on RINVOQ who were refractory or intolerant to our anti-TNFs. And in general, I've had success with my patients who I started on RINVOQ in both the short and long term, now that I've been using it for the last year and a half or so since it was initially approved.

Dr. David Rubin: You know, I think it's really important to recognize that it has steroid-sparing effects and met that secondary endpoint, but I also want to remind everyone that 60% or more of the patients that were in the clinical trials were not even on steroids on entry. So, we can also avoid steroids completely, which is something I think we should be doing more of, especially if we can get them on therapy quickly.

So, Josh, previously you shared a story about one of your patients who had an inadequate response to their anti-TNF. Can you tell us a little bit more about what your treatment decision was in that situation and the outcome of the switch?

Dr. Josh Steinberg: Definitely. So, I encountered a patient with UC who faced breakthrough symptoms despite being on an anti-TNF agent. And the patient's treatment history comprised of various mesalamine formulations orally and rectally, corticosteroids, immunomodulators. But unfortunately, their symptoms did persist, causing significant distress for the patient and their family. These symptoms included frequent bloody diarrhea, abdominal pain, weight loss, leading to a notable decline in their overall well-being.

So, recognizing these challenges posed by the inadequate response to an anti-TNF therapy, we did explore alternative options. And following a comprehensive discussion, we decided to transition the patient to RINVOQ, given its potential efficacy in cases where anti-TNFs were ineffective. The patient was successfully able to achieve clinical remission without the need for steroids using RINVOQ.

And I recently scoped the patient and I was so pleased to see that he did have endoscopic improvement.

Dr. David Rubin: Why did you think RINVOQ was the right option for your patient?

Dr. Josh Steinberg: So, based on the data from RINVOQ and my personal experience, I knew it was a great option and valued the rapid relief and durable remission.

Dr. David Rubin: So, in your practice, who do you think is the appropriate patient to receive RINVOQ, and who would not be appropriate to receive RINVOQ?

Dr. Josh Steinberg: For all medications, it's important to weigh the benefits and the risks for the individual patient when making a treatment decision. I also consider the risk of uncontrolled disease. And once I've identified a potential patient for RINVOQ, I confirm that the patient has had an inadequate response to an anti-TNF agent, and I perform tuberculosis tests, blood work including a CBC, hepatitis screen, hepatic function, and I confirm a negative pregnancy status before starting treatment. Patients who experience a prior anti-TNF failure further back in their treatment history are also candidates and important to keep in mind. We don't want to dismiss a potentially therapeutic treatment just because someone isn't actively failing or not tolerating an anti-TNF, especially if they're having a poor experience with their current therapy.

So, I consider cardiovascular and venous thromboembolism risk factors. Patients over 65 with a history of a cardiac event will give increased concern, so it is crucial to conduct risk stratification of patients before initiating treatment. While having a cardiovascular condition is not considered a contraindication, it is essential to carefully evaluate the risks and benefits specific to each individual patient.

Being a woman of childbearing age is not a contraindication for RINVOQ and may be an appropriate treatment option if it was deemed so. However, I don't consider RINVOQ for women who are pregnant or actively planning for a pregnancy.

For more information on the safety profile of RINVOQ including long-term safety data, I do encourage you to visit the RINVOQ website for Healthcare Providers or contact your local representative.

Dr. David Rubin: So, I think, Josh, that you've outlined some very important points. First of all, the choice of the right patient for this therapy and who we should be thinking about. And in general, I think this is an excellent option for our patients with moderate to severe UC after they've been exposed to an anti-TNF if it's not working or they're not tolerating that therapy. I would also add that I wouldn't use it in a woman who was pregnant, but I would certainly treat a woman who was of childbearing age, and I think that that's completely appropriate and reasonable.

I want to thank Dr. Josh Steinberg for taking the time today to assess when there is an inadequate response and evaluate the need to transition treatments for patients with moderate to severe UC, how to include the patient in the conversation, and discussing RINVOQ as a treatment option. I look forward to seeing treatment options for patients with moderate to severe UC continue to expand and certainly to help our colleagues understand when they should use them.

Dr. Josh Steinberg: David, thank you so much. This was an absolute pleasure. And I really hope that we hear more from you and from your future guests in the Gut Reactions podcast.

Narrator:

Please continue listening and stay tuned for additional Important Safety Information.

IMPORTANT SAFETY INFORMATION

SERIOUS INFECTIONS

Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include:

• Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent TB infection prior to RINVOQ use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis.
• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MORTALITY

In a large, randomized, postmarketing safety study comparing another Janus kinase (JAK) inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years old with at least one cardiovascular (CV) risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ.

MALIGNANCIES

Lymphoma and other malignancies have been observed in patients treated with RINVOQ.

In a large, randomized, postmarketing safety study comparing another JAK inhibitor with TNF blockers in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.

With RINVOQ, consider the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Advise patients to limit sunlight exposure by wearing protective clothing and using sunscreen.

MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE)

In a large, randomized, postmarketing study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of MACE (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other CV risk factors. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

THROMBOSIS

Thromboses, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing study comparing another JAK inhibitor to TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of thrombosis was observed with the JAK inhibitor. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated.

HYPERSENSITIVITY

RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

GASTROINTESTINAL PERFORATIONS

Gastrointestinal (GI) perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for GI perforation (e.g., patients with a history of diverticulitis and patients taking NSAIDs or corticosteroids). Promptly evaluate patients presenting with new onset abdominal pain for early identification of GI perforation.

HYPOGLYCEMIA IN PATIENTS WITH DIABETES

Hypoglycemia, including severe hypoglycemia, has been reported following initiation of RINVOQ and other JAK inhibitors in patients with diabetes. During treatment with RINVOQ, consider increased monitoring of blood glucose as clinically indicated in patients with diabetes. Advise patients with diabetes to notify their healthcare provider if they develop signs or symptoms of hypoglycemia.

LABORATORY ABNORMALITIES

Neutropenia

Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm³). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm³. Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia

Absolute lymphocyte counts (ALC) <500 cells/mm³ were reported in RINVOQ-treated patients. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm³. Evaluate at baseline and thereafter according to routine patient management.

Anemia

Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ-treated patients. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids

Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate patients 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations

Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

EMBRYO-FETAL TOXICITY

Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ.

VACCINATION

Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy. Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including prophylactic varicella zoster or herpes zoster vaccinations, in agreement with current immunization guidelines.

MEDICATION RESIDUE IN STOOL

Reports of medication residue in stool or ostomy output have occurred in patients taking RINVOQ. Most reports described anatomic or functional GI conditions with shortened GI transit times. Instruct patients to contact their healthcare provider if medication residue is observed repeatedly. Monitor patients clinically and consider alternative treatment if there is an inadequate therapeutic response.

LACTATION

There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT

RINVOQ is not recommended for use in patients with severe hepatic impairment.

ADVERSE REACTIONS

The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, peripheral edema, increased blood creatine phosphokinase, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, rash, and anemia.

Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ.

Dosage Forms and Strengths: RINVOQ is available in 15 mg, 30 mg, and 45 mg extended-release tablets.

Visit rxabbvie.com/pdf/rinvoq_pi.pdf for Prescribing Information, including BOXED WARNING, for RINVOQ.