Jeremy Gale, vice president and clinical portfolio leader of Pfizer’s inflammation and immunology research unit, focuses on early clinical development in gastroenterology and inflammatory bowel disease (IBD). IBD, a chronic condition affecting the gastrointestinal tract, includes both Crohn’s disease (CD) and ulcerative colitis (UC) and requires long-term management and close monitoring. While the past two decades have seen a rise in monoclonal antibodies targeting specific cytokines (like anti-tumor necrosis factor agents), many patients experience limited responses, side effects, or need to discontinue these medications.
“There are about 2.4 million patients with IBD in the United States, and their symptoms are pretty profound with diagnosis rates increasing,” said Gale.
For years, Pfizer contributed to the fight against IBD by developing a class of molecules known as Janus kinase (JAK) inhibitors. The JAK pathway is crucial in transmitting signals from various pro-inflammatory cytokines directly involved in gut inflammation, potentially underlying IBD development (1). Pfizer has recently completed two Phase 2 clinical trials for a combined kinase inhibitor therapy targeting moderate to severe CD and UC (2,3). This treatment involves the combination of ritlecitinib, a JAK3 and tyrosine kinase (TK) inhibitor and brepocitinib, a TYK2 and JAK1 inhibitor. For patients with active IBD, JAK inhibitors offer an alternative to conventional strategies, which have been the mainstay of IBD treatment for the past 20 years.
How did you begin studying IBD?
Pfizer has been in the IBD space for a long time, and we've had successful clinical development programs. In IBD, the barrier function inside the gut is compromised, which leads to alarm signals that penetrate the intestine. There is then an overcharged immune response likely resulting from a genetic predisposition in many people. There is a supercharged immune response to the insult from the inside. We're trying to target molecules upstream of the inflammatory pathways by using JAK inhibitors and anti-cytokine-type approaches.
How did Pfizer start work with JAK inhibitors for IBD?
Pfizer has led the JAK pharmacology area for well over a decade. That program ultimately yielded tofacitinib, a drug approved for several indications, including UC. That established the first JAK inhibitor benefit in a patient population. Within inflammation research, we came up with a second generation of JAK inhibitors, ritlecitinib, and realized that JAK appeared to be an essential mechanism in IBD. To understand the benefits, we wanted to go above and beyond the current standard of care in that patient population with these molecules. Ritlecitinib is one of the most exciting members of that family of drugs. It was a perfect storm, and I was tasked with leading a team to develop that molecule for many indications, including IBD.
How are kinase inhibitors different from traditional first-line treatments for IBD?
Historically, patients were treated with oral steroids, which can't be given chronically due to side effects. Old-fashioned oral immunosuppressants can be used chronically but have some nasty side effects as well. The idea of an advanced therapy was dominated by biologics such as anti-cytokine inhibitors. Now, we can go even further by targeting the production of these cytokines themselves using JAK inhibitors.
The data was even better than we'd hoped for because it's a notoriously difficult disease to get a strong clinical signal.
- Jeremy Gale, Pfizer
We now know that cytokines play an essential role in inflammatory processes in the walls of the intestine, especially in IBD. One beautiful element is the selectivity of JAK inhibitors. They don’t inhibit good anti-inflammatory cytokines like interleukin (IL)-10 and IL-27, which are immunomodulatory in a positive way. This changes how we can think about treating this disease from a fundamental approach.
Does this type of treatment slow down the progression of the disease, or is it a cure?
Honestly, we don't know if we have a cure. Do we have something that can alter disease progression? That would have to be measured. The small, short studies that we conduct in Phase 2 are not designed to address those sorts of questions. Those studies would come next. Patients with IBD want to avoid surgery and also the effects on their daily lives, such as bleeding and pain. We studied many aspects of the disease over the short term and, to some extent, over the longer term. The CD study was a year-long one; the UC study was six months long. There could be some benefit in long-term symptom control, but we must investigate further.
What significant hurdles or challenges did you encounter during the clinical Phase of development?
The biggest challenge was patient recruitment. IBD is not a rare disease, but it's not a super common disease, which is good news from a patient perspective. There were some barriers to finding patients willing and able to participate in an early-Phase clinical trial, especially since the drug had yet to prove efficacious. We need to understand its long-term tolerance and safety fully. That's a barrier for some people to participate in a trial. With a disease that comes and goes, there's a timeline that a patient must be on for their current medication schedule. Taking them off these can be pretty difficult.
How did you feel about the positive results you got from your Phase 2 trials?
I was incredibly excited. It had been a long haul. A lot of people have done work over several years, both scientists at Pfizer and the patients who were involved. The data was even better than we'd hoped for. It's a notoriously difficult disease to get a solid clinical signal, and there's a lot of failure in this area. All the endpoints moved strongly in the right direction. Symptoms looked positive on endoscopy and histology. The team was delighted.
What is the most rewarding part about working in this pipeline at Pfizer?
I've been in this company for a long time and in the industry for 37 years. I'm as excited today coming into work as I was at the beginning. It's partly because this industry is an incredibly rewarding ecosystem to work in as we discover new things. I know it's very simplistic to say that, but I have no one day that is ever the same as another. I am discovering or doing new things and trying to think in novel ways to address our challenges in human medicine. It's that combination of cutting-edge science, doing new things, and discovering new things to help put new drugs into the hands of patients. How could that ever be boring?
This interview has been condensed and edited for clarity.
References
- Honap, S. et al. JAK inhibitors for inflammatory bowel disease: recent advances. Frontline Gastroenterol 15, 59–69 (2024).
- Vermeire, S. et al. OP09 Oral ritlecitinib and brepocitinib in patients with moderate to severe active Crohn’s Disease: Data from the PIZZICATO umbrella study. JCC 18, i16 (2024).
- Sandborn, W. J. et al. Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study. CGH 21, 2616-2628.e7 (2023).
