For Ulcerative Colitis, Two First-In-Class Candidates and an Interleukin-23 Competition

Ulcerative colitis and Crohn’s disease are the two most common inflammatory bowel diseases. Ulcerative colitis is characterized by chronic inflammation and ulceration of the colon mucus membrane, resulting in symptoms such as bloody diarrhea, abdominal pain and cramping, bowel urgency and weight loss. In the United States, ulcerative colitis accounts for more than $4 billion in annual medical costs.

There is no cure for this chronic condition, and treatment goals focus on inducing and maintaining remission. Conventional treatments include 5-aminosalicylates (5-ASAs), such as mesalamine and sulfasalazine, and glucocorticoids. In more severe cases, biologics, such as the tumor necrosis factor-alpha (TNF-alpha) blockers Remicade (infliximab), Humira (adalimumab) and Simponi (golimumab), and the integrin receptor antagonist Entyvio (vedolizumab), may be used. More recently, the Janus kinase (JAK) inhibitors Xeljanz (tofacitinib) and Rinvoq (upadacitinib) were approved for use in moderate to severe cases.

Even with this growing armamentarium, a large proportion of patients do not respond to treatment, or the treatments stop working. According to the Crohn’s and Colitis Foundation of America, less than half of people living with ulcerative colitis are in remission each year. Several pharmaceutical companies have recognized the need for the development of treatments with alternative mechanisms of action.

Two firsts

Two potential first-in-class agents are currently in phase 3 trials for the treatment of moderate to severe ulcerative colitis.

Cobitolimod is being developed by InDex Pharmaceuticals, based in Stockholm, Sweden. This drug candidate is a DNA-based oligonucleotide and Toll-like receptor 9 (TLR9) agonist. TLRs play a key role in maintaining intestinal homeostasis and mediating interactions among microbiota typically present in the gut and immune responses. In ulcerative colitis, abnormal TLR function has been associated with increased mucosal inflammation. Activation of TLR9 by cobitolimod induces the production of interleukin (IL)-10 by macrophages and T cells and is thought to reduce inflammation and promote colon healing. Cobitolimod, which is administered locally as a rectal enema, is expected to have limited immune-related side effects due to decreased systemic absorption.

In the CONDUCT phase 2b trial, cobitolimod was more effective than placebo at inducing clinical remission after six weeks of treatment in patients with moderate to severe, left-sided ulcerative colitis. Based on these encouraging results, InDex began recruiting volunteers for a phase 3 version of CONCLUDE. The trial is designed to include about 440 patients from over 30 countries. The primary endpoint will be clinical remission after six weeks of treatment. A secondary endpoint is the efficacy of maintenance treatment in inducing or maintaining clinical remission at 52 weeks. CONCLUDE will evaluate dosing at 250 mg every three weeks, which was used in the CONDUCT trial, and a higher every-three-weeks dosage of 500 mg. The study is expected to be completed by December 2024.

Obefazimod is another possible first-in-class class for ulcerative colitis. The drug is an orally administered micro-RNA-124 (miR-124) upregulator that inhibits the production of inflammatory modulators involved in ulcerative colitis. In a phase 2b trial, obefazimod met the primary endpoint of a statistically significant reduction in Modified Mayo Endoscopic Score after eight weeks of once-daily dosing. Obefazimod was also effective in patients who had been previously treated with JAK inhibitors or other biologics.

After these encouraging results, Abivax, the French company developing the drug, launched the ABTECT phase 3 program evaluating the safety and efficacy of obefazimod in inducing clinical remission in patients with moderate to severe ulcerative colitis who have not responded or responded poorly to conventional or advanced ulcerative treatments. Results are anticipated in May 2024.

Three-way race

Meanwhile, three companies are in a race to be the first one to develop an IL-23 inhibitor monoclonal antibody for moderate to severe ulcerative colitis. AbbVie is developing Skyrizi (risankizumab); Janssen Pharmaceuticals, Tremfya (guselkumab); and Eli Lilly and Company, mirikizumab.

Mirikizumab’s phase 3
LUCENT-2 study was completed, and results were presented in May 2022 at the Digestive Disease Week conference. The trial included patients with ulcerative colitis who had responded to a previous 12-week induction mirikizumab treatment. Results showed that about one-half of the participants achieved and maintained clinical remission at one year compared with one-quarter in the placebo group. Secondary endpoints, including reduced bowel urgency, were also met.

In early 2022, the company submitted a biologics license application to the FDA for approval and a marketing authorization application for approval in the European Union. Decisions are expected later this year.

AbbVie’s Skyrizi, which is already approved by the FDA for the treatment of Crohn’s disease, psoriatic arthritis and psoriasis, is not far behind. The company is now seeking an added indication for the treatment of ulcerative colitis. The drug is currently in a phase 3 trial, which has an enrollment goal of nearly 1,000 participants with ulcerative colitis who responded to Skyrizi induction treatment in a prior study. The primary outcome is remission at 52 weeks. Secondary endpoints are discontinuation of corticosteroids, lack of bowel urgency and mucosal healing.

Janssen’s Tremfya, currently approved for psoriatic arthritis and psoriasis, is in the phase 3 ASTRO study for the treatment of moderately to severely active ulcerative colitis. The previous phase 2b QUASAR Induction Study 1 saw an overall clinical response rate of around 80% at week 12 or 24 of Tremfya treatment in adults with moderately to severely active disease. Participants had inadequate response or were intolerant to conventional or advanced therapies.

Results from the phase 2b study were presented in October 2022 at the American College of Gastroenterology Annual Scientific Meeting. Study author and presenter Bruce E. Sands, M.D., M.S., at Mount Sinai Hospital in New York and the Dr. Burrill B. Crohn Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai, said in a news release that outcomes from the QUASAR study will provide insights that “may help advance the treatment landscape and are a step forward for the many adult patients who remain in need of adequate treatment options.”

Intravenous to subcutaneous

Takeda Pharmaceutical Company is the maker of Entyvio (vedolizumab) intravenous injection, a monoclonal antibody approved for the treatment of moderately to severely active ulcerative colitis and Crohn’s disease. The company has developed a subcutaneous (SC) form of the product and is seeking FDA approval for maintenance therapy in adults with moderate to severe ulcerative colitis.

Entyvio SC is currently approved in several countries, including Switzerland, Australia, Canada, and those in the European Union. A complete response letter from the FDA in 2019 has delayed approval in the U.S. According to Takeda, the FDA was concerned about the labeling and design of the device, not clinical or study issues. If approved, the subcutaneous formulation will allow for self-administered treatment at home, reducing costs and other burdens associated with healthcare facility visits.

Rosanna Sutherby, Pharm.D., is an independent medical writer and community pharmacist in High Point, North Carolina, and a regular contributor to Managed Healthcare Executive ®.