Currently, in inflammatory bowel disease (IBD) there is an unmet need for novel oral drug formulations for patients with moderate-to-severe ulcerative colitis (UC ) or Crohn’s disease (CD). Key opinion leaders (KOLs) interviewed by GlobalData in Q2 2020 believe that patients would prefer an oral formulation over the existing subcutaneously or intravenously delivered agents, as there is less concern surrounding immunogenicity and the route of administration is easier. In early June, Bristol-Myers Squibb announced positive topline results from its pivotal Phase III TRUE NORTH trial in 1,012 patients evaluating Zeposia (ozanimod), an oral sphingosine1‐phosphate (S1P), in patients with moderate-to-severe UC. Zeposia demonstrated statistically significant results for induction of clinical remission at weeks 10 and 52. In light of this new information, it is important to determine whether Zeposia can change the treatment paradigm in UC.
Zeposia gained US and EU approval in multiple sclerosis (MS ) in March and May 2020, respectively, and in UC, it has demonstrated a promising efficacy profile in earlier-stage clinical trials. In BMS ’ Phase II TOUCHSTONE trial that assessed the efficacy and safety of Zeposia 1mg in UC at week 8, clinical remission (defined as Mayo score ≤ 2, no subscore >1) was 16.4% with a delta of 10.2% compared to placebo. Should the full TRUE NORTH efficacy and safety dataset show positive results, Zeposia could potentially be the first oral drug to challenge Pfizer ’s Xeljanz (tofacitinib) in UC. However, based on indirect comparisons with Phase II UC trials for Xeljanz and Zeposia, the Xeljanz 10mg dose shows a higher rate of clinical remission than Zeposia at week 8. Of the UC patients who were administered Xeljanz, 48% of patients were in clinical remission at week 8, with a delta of 38% compared to placebo. However, it is difficult to draw definitive conclusions from inter-trial comparisons. Zeposia could gain an advantage in the market over JAK inhibitors because KOLs interviewed by GlobalData remain concerned about Xeljanz’s safety profile due to an increased risk of blood clots in the lungs and in deep veins in patients who are already at high risk. Patients at high risk include those who have had a heart attack or have heart failure, cancer, or inherited blood-clotting disorders.
Although there are safety concerns over Janus kinase (JAK) inhibitors like Xeljanz, there have also been concerns that S1P receptors, such as Novartis ’ Gilenya (fingolimod), can cause slowing of the heart rate in MS patients. However, in a study comparing the safety of Zeposia with Gilenya, two-year risks of adverse events leading to discontinuation such as bradycardia and abnormal enzymes were lower with Zeposia. Furthermore, Zeposia also appears to have a better pharmacodynamic profile than Gilenya and has less long-lasting effects. More long-term data and analysis are required to evaluate Zeposia’s safety profile in UC patients. KOLs interviewed by GlobalData were concerned about the safety profile associated with this mechanism of action. However, upon recent findings, some KOLs stated that they would be happy to use this agent as a first-line treatment for moderate-to-severe UC and CD patients. It is possible that Zeposia could have an impact on the treatment paradigm due to its oral MOA and, if priced competitively, could be used before biologic therapy. However, should further safety signals emerge for ozanimod in UC, the drug may see similar safety restrictions applied, as noted for Xeljanz prescription in the US and EU; thus, this would likely push ozanimod further down the UC treatment algorithm as a potential third- or fourth-line treatment option.
Although there is genuine excitement surrounding Zeposia in the IBD community, there are several unknowns that still need to be resolved. Currently, Zeposia has a high annual cost of therapy in MS, which amounts to almost $86,000 annually. If BMS is to maintain this price point in the IBD markets, this could severely hamper its uptake, as currently, Xeljanz’s annual cost is around $60,000, and the first-line IV-administered biologic, Janssen ’s Remicade (infliximab), is priced at an annual cost of $35,000. To help increase uptake, BMS could use separate branding in IBD; however, this is unlikely, as BMS would want to protect pricing in the MS market. An alternative pricing strategy could be developed if dosage in IBD is different from BMS; currently, Zeposia 0.46mg is being investigated in both CD and UC, as well as the higher 0.92mg dose that is used for MS maintenance therapy. Furthermore, Arena ’s etrasimod, an S1P receptor modulator, and selective JAK inhibitors such as Rinvoq (upadacitinib) and filgotinib, could threaten Zeposia’s position in the market as an oral therapy, so it is imperative that Zeposia is launched before these molecules in order to gain a larger share of the market.