Mission: Remission — Patient Need For Durable Treatment Informs J&J's Ulcerative Colitis Trial

A conversation with David M. Lee, MD, Ph.D., global therapeutic area head, immunology, Johnson & Johnson Innovative Medicine

Nearly half a million Americans have been diagnosed with ulcerative colitis (UC), and its prevalence has been on the rise. So, the recent supplemental Biologics License Application (sBLA) submission by J&J for its TREMFYA (guselkumab) is likely a welcome one for patients living with UC who, even with treatment, are still experiencing its debilitating symptoms.

What’s key with the TREMFYA advancement is the drug’s history of treating other immune-mediated diseases, plaque psoriasis (PsO) and psoriatic arthritis (PsA). In this interview, J&J Global Therapeutic Area Head, Immunology, David M. Lee, MD, Ph.D., talks about the progression from treating PsO and PsA to UC, the importance of integrating patient needs into the trial’s design, and the quest for a durable treatment that lends itself to total remission.

TREMFYA is currently approved for the treatment of adults with moderate to severe PsO and for the treatment of adult patients with active PsA. Explain the process by which J&J IM discovered it could also prove beneficial for adults with moderately to severely active ulcerative colitis.

Millions of Americans have chronic immune-mediated diseases, including severe PsO, PsA, and inflammatory bowel disease (IBD). While we recognize these as different diseases, they share a common inflammatory driver of disease, and therefore a single biologic treatment can treat these multiple diseases.

For background, TREMFYA (guselkumab) is a dual-acting IL-23 that blocks IL-23 and binds to CD64, a receptor on cells that produce IL-23.  IL-23 is a cytokine secreted by activated monocyte/macrophages and dendritic cells that is known to be a driver of immune-mediated diseases including IBD.

In delving into our insights with TREMFYA, we realized it has a dual mechanism. In addition to binding the inflammatory mediator IL-23, it also binds to another molecule called CD64, which is on the surface of the IL-23-expressing inflammatory cells. So, this puts TREMFYA on the cell that's making the IL-23, allowing it to capture the IL-23 at the source of inflammation, and that's within the tissues. So, sometimes we say, “Tissue is the issue,” and that's one of the drivers of the advancements TREMFYA will bring.

We see it having greater potency in these inflamed tissues. We also see that it enables a subcutaneous dosing approach, both in induction and maintenance, in addition to offering patients an unparalleled potential for lasting remission with durable responses and a great safety profile.

We were also informed by our Stelara (ustekinumab) program. Stelara targets a common molecular subunit called P40 that gets both IL-23 and IL-12, and it's approved for Crohn's disease (CD) and UC. In contrast, TREMFYA is selective for IL-23. It was the insights from the selective targeting of IL-23 that we learned in PsO and PsA that showed us the next-generation advances with TREMFYA; they were a major part of the rationale that informed our choice to go into CD and UC.

You recently stated that “many people living with ulcerative colitis still experience inadequate response to or do not tolerate existing therapies.” How are each of those states defined, and how does that influence whether J&J IM would pursue a therapy for such a condition?

It means that they continue to have persistent, debilitating symptoms, such as increased bowel movements or rectal bleeding, and other terrible symptoms that go along with UC and bowel disease. Now, there are different kinds of inadequate response. Some patients don't respond to a therapy up front — that's what we call a primary non-responder — and we just don't see a meaningful improvement with a therapy. For others, they may initially have a response, but then they experience a secondary loss of response - this unfortunately happens for a significant portion of patients. The third bucket is what we call intolerance, where a patient doesn't stay on a drug because they get a side effect and/or a reaction, and therefore they must stop.

These are major areas of inadequate response, and we are not satisfied until everyone's in remission. Remission is our mission.

TREMFYA was studied in QUASAR, a randomized, double-blind, placebo-controlled, parallel group, multicenter, seamless Phase 2b/3 program. How did the J&J team determine this particular trial design and methodology as the most appropriate for gleaning meaningful results?

Each of those descriptors has significant meaning, and each plays a part in our fit-for-purpose approach to demonstrating the efficacy and safety of TREMFYA for patients with UC. This trial is really three separate studies contained within a single protocol. The first was a Phase 2b dose-ranging induction study, showing that we have the efficacy to continue. Then, we had a Phase 3 induction study. So, we proceeded from Phase 2b, got the dose into a Phase 3 portion, and then extended that induction Phase 3 into a Phase 3 maintenance study, because it's not good enough to get just an initial response. Our goal is durable, safe remission.

Now, the reason we chose this fit-for-purpose approach is that it’s operationally seamless and incorporates the dose ranging and then the pivotal study showing induction in maintenance in a method that allows a rapid transition from Phase 2 to Phase 3. At one level this increases overall efficiency, and at another level it brings the medicine to patients faster.

I would also underscore the QUASAR program design incorporates a range of efficacy assessments, including symptoms, endoscopy, histology, and patient-reported outcomes focused on quality of life and fatigue.  These assessments define holistically the efficacy that UC patients experience with TREMFYA.

When considering the patient experience during trial design, what patient needs must be considered and addressed? Are there are any accommodations or considerations specific to a patient population living with UC?

It's so important that we not only understand the unmet need that I've already described but we also understand the patient experience in our clinical trials and design them in a way that is fit-for-purpose and convenient for them.

QUASAR was one of our first studies to have IBD patients participate in a simulated study that let us test drive, if you will, and provide input to the final study design. And that's something that we've started routinely incorporating into all of our trial designs — getting that first test drive with these simulations with patients so we understand what their needs are as we're going into these large operational studies.

We are letting them see the questions, getting their feedback, and understanding where their concerns are. And in addition, one of the things we learned with QUASAR was the impact on patients receiving the placebo, so we provided the opportunity for patients who were randomized to placebo to later cross over into the TREMFYA arm if they met certain criteria.

The other thing that rose to the forefront was the number and types of assessments — how much work is it for patients? We carefully considered the things we must measure while generating as little burden as possible. Finally, while we established a defined period of formal primary endpoint for the maintenance phase, we also incorporated a long-term extension so patients could continue on the study drug, meeting certain criteria after the formal study period had ended.

But I’m also focused on the importance of durable response. So, for all those patients, what does remission mean? It means restoring health for them holistically. Again, really focusing on the maintenance phase, and our ability to document that past the 48-week primary endpoint, is where the bar is essentially set. We're very much indexing on that higher bar efficacy that is durable and sustained in the maintenance phase.

Were there any learnings from the original TREMFYA trials that you brought into this trial design or protocol?

We are proud of our iterative learning, and we pay a lot of attention to and build on the experience and learnings from all our clinical programs. I see two dimensions here. On the one hand, we learned a lot about the pharmacology of TREMFYA from the other approvals. We do have to prove the specific dosing and other elements of the pathology in IBD, but we did enter with a lot of information from PsO and PsA on both pharmacology as well as safety in those populations. The other dimension is that we built on our experience in IBD, and we have other drugs approved for IBD; the learnings from those are also incorporated in the QUASAR study.

Leading up to J&J IM’s submission of its supplemental BLA for TREMFYA for the treatment of adults with UC, what conversations or consultations occurred with the FDA to improve the likelihood of its approval?

Interactions with health authorities are incredibly important as we design and then go to prosecute our global studies. And it's not just the FDA; we take a global perspective for health authorities. We engage and work closely with them in the Phase 2 and Phase 3 processes, and we don't enter these large studies without a significant degree of assurance that we're on the same page as the health authorities about how we're approaching the studies and how we’ll measure success.

Now, it's not just efficacy; I would underscore there's a depth to that conversation. It includes a big index on safety and also topics that are on the nonclinical side and the manufacturing side of the drug. And, we're certainly building on the rich foundation we have with the psoriasis and psoriatic arthritis submissions and interactions with the health authorities.

About The Expert:

David M. Lee, MD, Ph.D., is global therapeutic area head, immunology, for Johnson & Johnson Innovative Medicine (J&J IM), where he leads a team focused on end-to-end pipeline and a portfolio of treatments for immune-mediated disease. Under his leadership, immunology researchers are working to build on the success of their current portfolio, which includes STELARA (ustekinumab) and TREMFYA (guselkumab).

Prior to joining Johnson & Johnson in 2018, David he served as global head, immunology, inflammation, and infectious disease discovery and translation area for Roche and, prior to that, as global head of autoimmunity, dermatology, and transplant translational medicine at the Novartis Institutes for BioMedical Research. He is also an active author and speaker and has completed more than 80 peer-reviewed publications, book chapters, and more than 100 lectures/seminars.

Before transitioning to the pharmaceutical industry, David was a faculty member at Brigham and Women’s Hospital/Harvard Medical School. David earned his undergraduate degree at Stanford University and subsequently earned his MD and Ph.D. in microbiology/immunology from the Duke University School of Medicine.