Bristol Myers Squibb's S1P Receptor Modulator Zeposia (Ozanimod) Demonstrates Significant Efficacy in Phase 3 Trial for Moderate to Severe Ulcerative Colitis

Recently, Bristol-Myers Squibb (BMS) announced that its oral S1P receptor modulator, Zeposia (ozanimod), met both primary endpoints in a pivotal Phase 3 clinical trial evaluating adult patients with moderately to severely active ulcerative colitis (UC). Compared with placebo, Zeposia significantly increased the proportion of patients achieving clinical remission at Week 10 of the induction phase (18.4% vs. 6.0%; p<0.0001) and at Week 52 of the maintenance phase (37.0% vs. 18.5%; p<0.0001). The company noted that this is the first S1P receptor modulator to demonstrate clinical benefit for patients with UC in a Phase 3 clinical trial.

Unmet Medical Needs in Patients with Inflammatory Bowel Disease

Ulcerative colitis is a chronic inflammatory bowel disease (IBD) characterized by an abnormal, persistent immune response that causes sustained inflammation and ulceration of the mucosa in the colon or rectum. Patient symptoms include bloody stools, severe diarrhea, and frequent abdominal pain. Ulcerative colitis significantly impacts patients’ quality of life, affecting physical functioning, social and emotional well-being, and work capacity. Many patients exhibit an inadequate response or no response at all to currently available treatments. It is estimated that approximately 12.6 million people worldwide suffer from IBD; besides ulcerative colitis, another common form of IBD is Crohn’s disease.

Currently, treatments for inflammatory bowel disease (IBD) include various biologics targeting tumor necrosis factor (TNF) and interleukin (IL) signaling pathways, as well as oral inhibitors targeting the Janus kinase (JAK) signaling pathway. However, antibody-based biologic agents typically require administration via subcutaneous or intravenous injection and may gradually lose efficacy due to immune responses against the antibodies in patients. JAK inhibitors may be intolerable for some patients because they can inhibit multiple signaling pathways mediated by the JAK family of proteins.

"The New Battlefield" of Next-Generation S1P Receptor Modulators

When Zeposia (ozanimod) is mentioned, the first thing that comes to mind is likely that “it is a medication for treating multiple sclerosis (MS).” Indeed, Zeposia received approval from the U.S. Food and Drug Administration (FDA) in March this year for the treatment of adult patients with relapsing forms of multiple sclerosis. Zeposia is an oral sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. As a class of therapeutics, S1P receptor modulators have achieved considerable success in the treatment of MS. Novartis’s fingolimod was first approved by the FDA in 2010 for the treatment of MS. Subsequently, the company’s next-generation S1P receptor modulator, siponimod, was also approved in 2019. Janssen’s S1P1 receptor modulator, ponesimod, is currently under review by the U.S. FDA and is expected to gain approval for the treatment of MS next year. These drugs work by binding to S1P receptors on the surface of lymphocytes, thereby preventing lymphocytes from exiting lymph nodes and reducing immune system attacks on the myelin sheath that protects nerves.

In IBD, the attack of immune cells on the intestinal mucosa is also one of the important reasons for chronic inflammation. By targeting S1P receptors, Zeposia may block the migration of lymphocytes to the intestinal mucosa, thereby reducing the inflammatory response.

Image source: Bristol-Myers Squibb official website

In the multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial named True North, patients with moderately to severely active ulcerative colitis who had an inadequate response to prior therapy were randomly assigned to receive treatment with Zeposia or placebo. During the induction phase, a total of 645 patients were randomized to receive Zeposia (n=429) or placebo (n=216), with 94% and 89% of patients, respectively, completing the induction period. During the maintenance phase, 457 patients were re-randomized to receive maintenance treatment with Zeposia (n=230) or placebo (n=227). Among these, 80% of patients receiving Zeposia and 54.6% of those receiving placebo completed the study.

Trial results demonstrated that Zeposia not only met the primary endpoint, but also achieved multiple key secondary endpoints, including clinical response, endoscopic improvement, and mucosal healing at Week 10 of the induction phase and Week 52 of the maintenance phase. For example, a significantly higher proportion of patients in the Zeposia treatment group achieved clinical response compared to the placebo group at both Week 10 (47.8% vs. 25.9%, p<0.0001) and Week 52 (60.0% vs. 41.0%, p<0.0001).

“The results achieved by Zeposia in the True North clinical trial represent a significant milestone for patients with ulcerative colitis, many of whom have had an inadequate response or no response to currently available therapies,” said Dr. Mary Beth Harler, Head of Immunology and Fibrosis Development at Bristol-Myers Squibb. “We look forward to working with regulatory authorities to bring Zeposia to this patient population and remain committed to pursuing new scientific advancements to help deliver transformative medicines for patients with gastrointestinal diseases.” In addition to treating ulcerative colitis, Bristol-Myers Squibb is conducting the Phase 3 YELLOWSTONE clinical trial, which aims to evaluate the efficacy and safety of Zeposia in the treatment of moderate-to-severe active Crohn’s disease.

Phase 3 Clinical Trial of Innovative S1P Receptor Modulator for the Treatment of UC Patients Has Been Launched in China

Other biopharmaceutical companies are also developing selective S1P receptor modulators for the treatment of various immune-mediated and inflammatory diseases. For example, etrasimod, developed by Arena Pharmaceuticals, is a next-generation oral S1P modulator that selectively binds to S1P receptors 1, 4, and 5, potentially offering an improved efficacy/safety profile. This investigational therapy is currently being evaluated in clinical trials for the treatment of ulcerative colitis (UC), Crohn’s disease, atopic dermatitis, and alopecia areata. Everest Medicines, which recently completed its initial public offering on the Hong Kong Stock Exchange, has secured the development rights for etrasimod in Greater China. In China, the Phase 3 clinical trial of this investigational drug for the treatment of patients with UC has entered the patient enrollment stage.

Image Source: Everest Medicines Official Website

We wish for the smooth development of the new generation of S1P receptor modulators, which will not only provide oral treatment options with a novel mechanism of action for patients with ulcerative colitis but also benefit more patients with immune-mediated and inflammatory diseases.

References:

[1] Bristol Myers Squibb Presents Positive Late-Breaking Data from Phase 3 True North Trial Evaluating Zeposia (ozanimod) in Adult Patients with Moderate to Severe Ulcerative Colitis. Retrieved October 10, 2020, from https://www.businesswire.com/news/home/20201010005029/en

[2] ETRASIMOD. Retrieved October 11, 2020, from https://www.arenapharm.com/pipeline/etrasimod/#

[3] Pipeline. Retrieved October 11, 2020, from https://www.everestmedicines.com/Pipeline.aspx

▽Follow [WuXi AppTecDe】WeChat Official Account