Expert Perspectives: The Future of Small Molecules in IBD Treatment

Novel trials of improved treatments for patients with active ulcerative colitis (UC) and Crohn disease (CD), hold promise in helping tough-to-treat patients, David Rubin, MD, said in presentation on the future of small molecules at the Advances in Inflammatory Bowel Diseases 2021 virtual meeting on Saturday, March 6, 2021.

Dr Rubin is the chief of Gastroenterology, Hepatology, and Nutrition and the codirector of the Digestive Diseases Center at The University of Chicago.

Dr Rubin explained how new small  molecule therapies can be absorbed through the lining of the small intestine, which evolved into the term “conventional synthetic small molecules,” and includes such  treatments as azathioprine, methotrexate, and cyclosporine. Now there are new, targeted synthetic small molecules such as Janus-kinase (JAK), inhibitors, sphingosine-1-phosphate receptors (S1Ps), and others.

“What we do know about small molecules in inflammatory bowel disease (IBD) is the inflamed bowel can leak proteins and these novel mechanisms are needed,” he said.

“I really think that this is going to represent a paradigm shift in the way that we think about managing IBD. Not just because small molecules are oral and offer convenience, but because of the consideration for mechanisms as well as pK and pD,” said Dr Rubin.

Historically, different small proteins use different JAKs and Signal Transducer and Activator of Transcriptions (STATs). The research utilizing the 4 JAK family members: JAK1, JAK 2, JAK3 and TYK2—partnered with STATs. “If you inhibit Janus kinase enzyme, you’re blocking different pathways. If you have a more selective JAK inhibitor, you might have a slightly different efficacy because you’re only inhibiting some pathways,” Dr Rubin commented.

Some newer therapies include JAK 1 selective inhibitors, including filgotinib for patients with UC and CD as well as rheumatoid arthritis.

Dr Rubin explained the results of various studies, including FITZROY. Showcasing results from phase 2, double-blind, randomized, placebo-controlled trial testing filgotinib 200 mg. Over the course of the trial, 47% of participants receiving filgotinib 200 mg saw clinical remission, compared with the 23% who received a placebo. Furthermore, 59% of patients receiving filgotinib 200 mg saw a clinical response, while 41% saw a clinical response who received the placebo. Lastly, 14% saw endoscopic remission with filgotinib 200mg, as compared to just 7% with the placebo.

“Filgotinib 200mg demonstrated a significant difference in achieving the primary endpoint of clinical remission at week 10 in both the biologic-naïve and biologic-experienced studies,” explained Dr Rubin. “It’s a theme of all of our therapies. By the time patients fail all other treatments and get into clinical trials, they’re less likely to respond to a novel mechanism. This may in fact be because we are selecting out tough-to-treat patients for trials, which I think is most likely the case, but don’t forget the possibility that using other therapies may actually be modifying the immune pathways of these patients, and therefore we might have a biological reason to explain some of this. Nonetheless, you should appreciate the 200 mg dose of Fil was significantly better than the placebo and looked better than the 100 mg dose, and that’s the dose that’s moving forward.”

During the filgotinib SELECTION Trial in UC, 23.8% of patients on filgotinib 100 mg saw clinical remission at week 58, compared to the 13.5% patients on the placebo. During the same study, 37.2% of patients receiving filgotinib 200 mg achieved clinical remission at week 58, vs 11.2 % of those receiving the placebo.

“Filgotinib 200 mg and 100 mg demonstrated a significant difference in achieving clinical remission at week 58 when compared to their matching placebos,” commented Dr Rubin. “It’s fascinating to me that histologic remission was better than endoscopic remission. It could be a matter of how the definitions are being used, or it could be that histologic remission occurs before endo remission, so it may be a more accurate marker of what’s happening in the immune system. It’s an interesting consideration.”

Some adverse events seen in the filgotinib trials include herpes zoster/shingles, while the rest of signal safeties were similar, including no pulmonary embolism outcomes.

Dr Rubin further explained the small molecule therapy upadacitinib trialed in CELEST, a randomized, double-blind, dose-ranging, phase 2 study of 220 patients, as well as in a randomized trial of patients with active UC in U-ACHIEVE study, seeing a 50% response in a tough-to-treat UC population.

“This is clearly an effective therapy,” reported Dr Rubin.

-Angelique Platas

Reference:

Rubin D. Expert perspective: The future of small molecules. Presented at: Advances in Inflammatory Bowel Diseases virtual regional meeting. March 6, 2021