Icanbelimod is an orally available, next generation small molecule modulator of the sphingosine-1-phosphate 1 receptor (S1P1), a G-protein coupled receptor (GPCR) that plays a central role in regulating T cell movement and is a validated therapeutic target.
A Phase 2 trial of icanbelimod for the treatment of UC was completed in the second quarter of 2023 and topline results are available from the induction and maintenance period (N=145). A Phase 2 trial to evaluate icanbelimod in CD was initiated but was terminated due to enrollment challenges during the COVID-19 pandemic.
S1P1 mediates the transit of T cells from lymph nodes into circulation and, as a result, the migration of T cells to tissues to release inflammatory mediators.6-10 Icanbelimod causes T cells to internalize S1P1, trapping T cells inside the lymph nodes and preventing them from migrating to sites of inflammation. Icanbelimod has no significant activity for S1P3, a receptor subtype with known safety concerns, and significantly lower potency for S1P4 and S1P5 than S1P1. Additionally, it has high potency and selectivity11 and is designed to be the most potent modulator of the S1P1 drug class, if approved.
Ulcerative colitis (UC) is a common form of inflammatory bowel disease (IBD) that causes chronic inflammation of the large intestine. The Center for Disease Control (CDC) estimates there are 3.1 million U.S. adults with a diagnosis of either Crohn’s disease or ulcerative colitis and as many as 80,000 U.S. children who may have IBD, with most diagnoses made between 15 and 35 years of age.
Current treatment options include systemic corticosteroids and immunosuppressants, injectable biologics and surgery.3 While these treatments provide benefit, significant unmet need remains. We believe that icanbelimod has the potential to improve care outcomes for patients with UC by providing improved safety, efficacy and ease of administration compared with currently available therapies.
Crohn’s disease (CD) is an IBD that causes chronic inflammation of any site in the gastrointestinal tract, but most commonly affects the small intestine and beginning of the large intestine. According to the CDC, 3.1 million U.S. adults have a diagnosis of IBD.1 In North America, CD has a slightly lower prevalence than UC.2
Current treatment options include systemic corticosteroids as first-line therapy and a variety of biologics as second- and third-line therapy.4 There is significant need for orally available therapies that can safely and effectively address unmet need for patients with Crohn’s disease, especially those with severe disease.5
Mechanism of Action
S1P1 mediates the transit of T cells from lymph nodes into circulation and, as a result, the migration of T cells to tissues to release inflammatory mediators.6-10 icanbelimod causes T cells to internalize S1P1, trapping T cells inside the lymph nodes and preventing them from migrating to sites of inflammation. icanbelimod has high potency and selectivity11 and is designed to be the most potent modulator of the S1P1 drug class, if approved. icanbelimod has no significant activity for S1P3, a receptor subtype with known safety concerns, and significantly lower potency for S1P4 and S1P5 than S1P1.
Phase 1 Clinical Data
In a Phase 1 trial in healthy volunteers, dosing of 0.25 mg of CBP-307 in six healthy adults led to a 75% reduction in circulating lymphocytes at day 14. Once daily doses of up to 0.25 mg of CBP-307 were generally well-tolerated. Upon completion of dosing, the levels of lymphocytes returned to baseline within one week. This could minimize the period of being immunocompromised following CBP-307 treatment, potentially reducing the risk of patients developing infections.
Global Phase 2 Clinical Data in Adult Patients with Moderate-to-Severe UC
Two doses of icanbelimod (0.1 mg and 0.2 mg) were evaluated in a randomized, double-blind, placebo-controlled Phase 2 trial in adult patients with moderate-to-severe UC. The trial consisted of an induction period of 12 weeks, followed by a 36 weeks maintanance period. Icanbelimod demonstrated sustained clinical remission through Week 48 in 80% of patients who achieved clinical remission at Week 12 of the induction period, with 67% of patients who completed the 48-week study achieving clinical remission.
In the induction phase, dosing of 0.2 mg of icanbelimod showed a numerical improvement but did not achieve statistical significance. Clinical Remission on adapted Mayo Score and other secondary endpoints achieved statistical significance in the induction phase.
Additionally, the trail provided strong evidence of pharmacodynamic activity of icanbelimod as shown by reduction in lymphocyte counts. Once-daily doses of up to 0.2 mg of icanbelimod were observed to be generally well tolerated throughout the trial.
Current Development Status
Based on the positive data from the completed Phase 2 trial, we are seeking partnerships to advance icanbelimod into a Phase 3 studies for both UC and CD.
Posters & Publications
A randomized, double-blind, placebo-controlled, multiple ascending dose study of the safety, pharmacokinetics and preliminary efficacy of CBP-201 in adult patients with moderate to severe atopic dermatitis (CPB-201AU002)
Presented at the the 29th European Academy of Dermatology and Venereology Congress (EADV), October 29, 2020
- Dahlhamer JM, Zammittie EP, Ward BW, et al. Prevalence of Inflammatory Bowel Disease Among Adults Aged >18 Years – United States, 2015. MMWR. 2016;65(42):1166-1169.
- Hanauer SB. Advances in IBD. Gastroentrerology & Hepatology. 2016;12(11):704-707
- Kobayahsi T, Siegmund B, Le Berre C, et al. Ulcerative Colitis. Nature Reviews: Disease Primers. 2020;6:74.
- Montiel-Martinez MP, Casis-Herce B, Masdeo-Gonzalez, et al. Pharmacologic Therapy for Inflammatory Bowel Disease Refractory to Steroids. Clinical and Experimental Gastroenterology. 2015;8:257-269.
- Crohn’s Disease: Dynamic Market Forecast to 2026 (GlobalData, October, 2018).
- Gilenya US PI. https://www.novartis.us/sites/www.novartis.us/files/gilenya.pdf
- Mayzent US PI. https://www.novartis.us/sites/www.novartis.us/files/mayzent.pdf
- Zeposia US PI. https://packageinserts.bms.com/pi/pi_zeposia.pdf
- Sandborn, W J et al. Ozanimod Induction and Maintenance treatment for Ulcerative Colitis. https://www.nejm.org/doi/full/10.1056/NEJMoa1513248
- Krause, A. et al. Modeling clinical efficacy of the S1P receptor modulator ponesimod in Psoriasis. Journal of Dermatological Science 89 (2018) 136–145
- Connect Biopharma CBP-307 Investigator Brochure (Ed. 5.0). January 2020 [Charter N. Potency and selectivity of CBP-307 on S1P receptors. DiscoveRx Corporation, California, 2015. Study No.: SCB001