Many of our clients are pursuing groundbreaking therapies in disease areas with high unmet medical needs, giving our firm the chance to become intimately familiar with some of the most exciting areas in drug development. One disease area that is receiving a lot of attention is Inflammatory Bowel Disease (IBD), where the disease burden and the need for novel, efficacious therapeutics remain high. Below, we’ll share our thoughts on the current landscape in Ulcerative Colitis (UC), one of the main diseases associated with IBD, and what we’re looking forward to.
Ulcerative Colitis is characterized by recurring episodes of inflammation limited to the mucosal layer of the colon. It commonly involves the rectum and may extend to involve other parts of the colon. The onset of symptoms is usually gradual, with symptoms progressing over several weeks, and can range from mild disease (<4 stools per day) to severe disease (>10 stools per day with severe cramps and continuous bleeding).
Most patients with UC are treated with pharmacological therapy, with the goals of inducing and maintaining endoscopic and clinical remission. The cornerstone treatment for severe UC is anti-tumor necrosis factor (TNF) therapy, including infliximab (Remicade), adalimumab (Humira), and golimumab (Simponi). Unfortunately, these therapies leave much to be desired, with ~10-30% of patients not responding to initial treatment, and ~23-46% of treated patients losing response over time. Additionally, the anti-TNF class has black box warnings for the risk of serious infections and malignancies. However, the treatment landscape is driven largely by payer coverage, and these drugs remain favored due to long-standing physician familiarity and prioritization in formularies. Remicade has faced biosimilar competition since 2016, and Humira and Simponi are expected to lose exclusivity in the US market by 2023 and 2024, respectively. The biosimilar competition will further drive down costs and raise the bar for new market entrants, which will either need to show strong superiority (in both efficacy and safety) or be competitively priced to receive coverage.
Even with the entrance of generics and biosimilars, analysts expect the UC market to expand, fueled by a growing patient caseload and the introduction of pipeline products. Novel pipeline products are expected to diversify the UC market with new mechanisms of action (MOA) and more convenient formulations. JAK inhibitors have been developed as another avenue to induce and retain remission in UC patients. Theravance’s izencitinib recently stalled after clinical readouts indicated it missed primary and secondary efficacy endpoints. Tofacitinib (Xeljanz), however, has been accepted as a convenient small molecule option for patients that can tolerate the JAK inhibitor, and AbbVie is positioning its oral JAK inhibitor, Rinvoq, to be its next-generation product as Humira loses exclusivity. Gilead and Galapagos’s oral JAK inhibitor, Jyseleca, also appears to be clinically promising. Similar to anti-TNFs, though, JAK inhibitors also present serious safety concerns. The FDA issued a complete response letter for Jyseleca in rheumatoid arthritis in 2020, putting the drug’s data package for UC at risk. Similarly, a large post-marketing safety study that evaluated Xeljanz against TNF blockers in patients with rheumatoid arthritis found an increased risk of serious heart-related events such as heart attack, stroke, cancer, blood clots, and death associated with the drug. As a result, the FDA has required a more alarming warning in the label for Xeljanz, with a downstream effect on Eli Lilly’s Olumiant and AbbVie’s Rinvoq.
Because the etiology of UC has not been definitively defined, new treatments focus on suppressing different aspects of the inflammatory response. Beyond JAK inhibitors, other novel MOAs in the UC pipeline include S1P receptor modulators Zeposia (ozanimod, approved 2021) and etrasimod, IL-23 modulator mirikizumab, and TLR-9 modulator Kappaproct (cobitolimod). Results from clinical trials so far show reasonable efficacy and safety, but only modest improvements over established treatments. In order to significantly alter the treatment landscape, more targeted therapies with predictive biomarkers are needed to guide choice of therapy and safely intervene earlier in disease progression. In oncology, tumor phenotyping and precision medicine has advanced rapidly. The same transformative approach is needed in UC, but reliable biomarkers must first be established. Until then, we’ll keep a watchful eye on the 56 drugs in the UC pipeline and eagerly await their results.