It’s Just a Phase: Filgotinib for Moderately to Severely Active Ulcerative Colitis

Gastroenterology & Endoscopy News generally avoids coverage of phase 2 trials. After all, preliminary results frequently fail to meet early expectations, and even promising phase 3 data often fail to bring a drug to market. But that’s not to say that phase 2 findings are irrelevant. They may be the harbinger of exciting developments in the drug pipeline that clinicians should be aware of, or a preview of the future management of a given condition.

With that in mind, we’re launching a new feature called “It’s Just a Phase,” in which we will look at recent phase 2 data in gastroenterology. For our first installment, we’ve chosen studies of the preferential Janus kinase 1 (JAK1) inhibitor filgotinib (Galapagos/Gilead), which is in trials as a potential therapy for the treatment of patients with moderate to severe ulcerative colitis. The findings, from the phase 2b/3 SELECTION Trials, were reported in the Journal of the Canadian Association of Gastroenterology (2021;4[suppl 1]:18-23).

Filgotinib, an oral agent, was tested as induction therapy for patients with moderately to severely active ulcerative colitis who were biologic-naive but failed conventional therapy (Induction Study A) or failed prior biologics (Induction Study B). Patients were randomized 2:2:1 to 200 mg of filgotinib, 100 mg of filgotinib or placebo taken once daily. At week 10, researchers assessed the primary end point (clinical remission), key secondary end points (Mayo score remission, endoscopic remission and histologic remission) and exploratory end points (Mayo score response and endoscopic improvement).

In Study A, which randomized 659 patients, the baseline mean Mayo score was 8.6, and 56% of participants had a Mayo endoscopic subscore of 3. A significantly higher proportion of biologic-naive patients on the 200-mg dose of filgotinib achieved clinical remission compared with placebo and all key secondary end points (Table 1).

In Study B, which included 689 patients, the baseline mean Mayo score was 9.3, and 78% of participants had an endoscopic subscore of 3. Prior treatment failures were anti–tumor necrosis factor agents (86%), vedolizumab (Entyvio, Takeda; 52%) and both therapies (dual refractory; 43%). A significantly higher proportion of biologic-experienced patients on the 200-mg dose of filgotinib achieved clinical remission compared with placebo. In Studies A and B, patients receiving the higher dose of filgotinib were more likely to achieve a Mayo score response and endoscopic improvement compared with those receiving placebo, according to the researchers.

Patients receiving filgotinib and placebo had similar rates of adverse events (AEs), serious AEs and discontinuations due to AEs. In Studies A and B, serious infections were less common with the higher dose of filgotinib (Study A, 0.4% vs. 0.7% vs. 0.7%; Study B, 0.8% vs. 1.4% vs. 1.4%). Herpes zoster occurred in less than 1% in both groups receiving filgotinib.

In the maintenance part of the trial, patients who achieved clinical remission or a Mayo score response after 10 weeks of therapy were rerandomized 2:1 to their induction dose of filgotinib or placebo. Patients randomized to placebo induction continued placebo maintenance, and steroid tapering was mandatory. The primary end point, clinical remission, as well as secondary and exploratory end points were assessed at week 58.

The trial treated 664 patients (93, 270 and 301 from induction with placebo, 100 mg of filgotinib and 200 mg of filgotinib, respectively), and 40% were biologic-experienced. The researchers found that patients receiving either dose of filgotinib were more likely to achieve clinical remission than those receiving placebo (Table 2).

Compared with placebo, patients receiving 200 mg of filgotinib were more likely to achieve key secondary end points, including six-month corticosteroid-free clinical remission, sustained clinical remission, Mayo score remission, endoscopic remission, histologic remission, Mayo score response and endoscopic improvement, the researchers reported. Compared with placebo, patients on either dose of filgotinib were more likely to experience a Mayo score response and endoscopic improvement.

The incidences of all AEs, serious AEs and discontinuations due to AEs were similar across arms. Serious infection (<2%) and herpes zoster (<1%) were infrequent among patients treated with filgotinib. No venous thromboses, including pulmonary embolism, occurred among patients who received the drug.

Experts Weigh In

Brian Feagan, MD, the senior scientific director at Alimentiv Inc. (formerly Robarts Clinical Trials Inc.), and a professor of medicine at Western University, in London, Ontario, said there is a need for more oral agents in ulcerative colitis. Although the oral agent tofacitinib (Xeljanz, Pfizer) was the first JAK inhibitor to be approved for the condition, the drug’s association with flares of herpes zoster is concerning. This side effect appears to be less frequent with filgotinib. “Filgotinib is safe, especially with regards to infection,” Dr. Feagan said.

Currently, no other ulcerative colitis trials are underway for the drug because of reproductive safety concerns that have arisen in animal studies. “The drug has run into issues at the FDA with regard to concern about reproductive toxicology in animals, notwithstanding that it has been on the market in Europe for rheumatoid arthritis,” Dr. Feagan said. “The company is undergoing trials and steps to assure the FDA that it is of a species-specific concern and not a human concern, but that has held up the development of the drug in the United States.”

Aline Charabaty, MD, the assistant clinical director of the Division of Gastroenterology at the Johns Hopkins University School of Medicine, in Baltimore, and clinical director of the IBD Center at Johns Hopkins Sibley Memorial Hospital, in Washington, D.C., said more than 40% of patients with moderate to severe ulcerative colitis do not reach remission with current available therapies. Moreover, a substantial percentage of patients who respond to a therapy will lose this response over time.

“There is an unmet need for effective therapies with different mechanisms of action. An effective oral drug with a good safety profile is a very attractive option for patients in terms of acceptance, convenience and adherence,” said Dr. Charabaty, who was not involved in the SELECTION trials. “JAK inhibition [with tofacitinib] was shown to be effective in controlling inflammation in ulcerative colitis, and with a preferential JAK1 inhibitor we are expecting to combine the JAK inhibition mechanism efficacy with an improved safety. In this study, we see a low rate of serious infection with filgotinib and a low rate of zoster in contrast to the rate of zoster seen with nonselective JAK inhibitors such as tofacitinib, which inhibits JAK1 and JAK3, and where the rate of zoster is 1.5% to 5% depending on the dose used. These studies show that filgotinib is not only an effective option in bio-naive patients, but also effective in the more difficult to treat ulcerative colitis patients with severe endoscopic activity and prior failure of one or two biologics. What is even more exciting is the rate of histological remission in bio-naive [35%] and bio-experienced [20%] patients as early as 10 weeks of therapy.”

—Kate O’Rourke

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Dr. Charabaty reported serving as a consultant to/an advisory board member of AbbVie, Janssen, Pfizer and Takeda. She is a member of the editorial board of Gastroenterology & Endoscopy News. Dr. Feagan reported financial relationships with Galapagos and Gilead.

This article is from the August 2021 print issue.