Among the nine pipeline agents for ulcerative colitis (UC), there are three anti-IL-23s, two Janus kinase (JAK) inhibitors, two anti-integrins, and two sphingosine-1-phosphate (S1P) receptor modulators.
The anti-IL-23s are AbbVie’s Skyrizi (risankizumab), Eli Lilly’s mirikizumab, and J&J’s Tremfya (guselkumab). IL-23 is a heterodimeric cytokine composed of two subunits, p40 and p19. By specifically targeting the p19 subunit, an IL-23 inhibitor blocks the high-affinity binding of IL-23 to IL-23R, inhibiting the JAK/STAT signaling pathway. Due to the favorable safety profile of IL-23 inhibitors, there is a possibility of combining this class of drugs with other biologics. There is some evidence that suggests that refractoriness to anti-TNF inhibitors may be triggered by upregulation of the IL-23 pathway, and this is being explored in the Phase IIa VEGA trial that is studying Tremfya and Simponi as a combination in moderate to severe UC (J&J, NCT03662542). Furthermore, data from other indications, such as psoriasis, suggest that IL-23 inhibitors may be a better option than J&J’s Stelara, as Skyrizi was proven to be more effective than the IL-12/IL-23 inhibitor. In the same indication, non-responders to Stelara displayed benefit when given Tremfya. More head-to-head trials are needed in UC to prove whether similar outcomes can be replicated in this disease. Key opinion leaders (KOLs) interviewed by GlobalData have been very positive about the effect of IL-23 inhibitors compared with Stelara.
Another novel mechanism of action (MOA) that could have an impact in UC is the S1P receptors. The cell-surface-associated S1P1 receptor plays an important role in lymphocyte trafficking from lymphoid organs. S1P1 receptor agonists induce the internalization and degradation of the S1P1 receptor. This makes B and T lymphocytes incapable of migrating from secondary lymphoid organs. The net effect is a reversible reduction in the number of circulating lymphocytes in the blood. There have been concerns that S1P receptor modulators, such as Novartis’ Gilenya (fingolimod), can cause slowing of the heart rate in multiple sclerosis (MS) patients. The non-selective MOA of Gilenya may explain some of the adverse events reported with the use of this drug, such as atrioventricular blocks. However, selective S1P receptor modulators such as BMS’ Zeposia (ozanimod; targets S1P1 and S1P5) and Arena’s etrasimod (targets S1P1, S1P4 and S1P5) may improve the safety of this class of drugs. However, more long-term analysis is required to ensure that the selectivity of S1P modulators translates into a better safety profile, and many KOLs interviewed by GlobalData were concerned about the safety profile associated with this MOA.
JAK-1 inhibitors such as AbbVie’s Rinvoq (upadacitinib) and Gilead/Galapagos’ Jyseleca (filgotinib) are aiming to join Pfizer’s Xeljanz (tofacitinib) in the treatment paradigm. These drugs prevent the upregulation of cytokines, IL-6 signals, and many cellular processes. In biochemical assays, Rinvoq has been proven to be more selective for JAK-1 than for JAK-2 and JAK-3. This enhanced selectivity may offer a better safety profile than Xeljanz, which has been reported to have an increased risk of blood clots in the lungs and in deep veins in patients who are already at high risk. Nonetheless, KOLs interviewed by GlobalData are still very concerned about JAK inhibitors as a class and its prospects within the treatment algorithm.
Figure 1 shows the competitive landscape for the UC pipeline agents.
Figure 1: Competitive Assessment of the Late-Stage Pipeline Agents that GlobalData Expects to Be Licensed for the Treatment of ulcerative colitis During the Forecast Period.