TNF-α inhibitors have historically been the prized thoroughbreds in the race to dominate position in the ulcerative colitis (UC) market as the preferred treatment for patients with more severe disease and unresponsive to conventional therapies. More recently, however, there has been a rapidly-increasing number of new entries to the late-stage UC stable. This surge in development is fueled, in part, by both an attractive market size (of nearly $4 billion) and a limited number of alternative treatment options available for TNF-α refractory patients. Takeda’s Entyvio, with a new mechanism of action for UC, trotted out to the track in 2014 as the first new breed to challenge the triple crown of TNF-α inhibitors. This alternative option has now raised the bar for new agents hoping to enter the winner’s circle; they will need to offer additional benefits beyond simply a novel mechanism of action. Three prominent owners: Pfizer, Roche/Genentech, and Celgene, are saddling up with their respective late-stage stallions, Xeljanz (tofacitinib), etrolizumab, and ozanimod. Each agent offers a unique set of advantages and disadvantages, so which one can take the trophy? Let’s examine the contenders:

Frontrunner

Pfizer’s Xeljanz, an oral Jak 1/3 inhibitor is first out of the gate and closest to approval amongst the myriad agents in the pipeline for UC. Initial results from the induction phase of its pivotal Phase III OCTAVE program met primary end point goals, giving it a distinct advantage in this race as the frontrunner. In addition to offering a novel mechanism of action in UC, Xeljanz has the potential to be the first oral formulated option targeted to the moderate to severe patient population, a feature that is highly attractive to both patients and physicians. As one U.S. gastroenterologist comments, “Well, of course an oral pill is attractive. Not having to pay for an infusion, not having to pay for the set-up, not having the person have to take two, three hours of their workday to go to an infusion center to get a drug, is a great advantage.” Xeljanz is also the only one of the three compounds discussed here that is pursuing an expanded indication, having received approval from the FDA for RA in 2012. However, this agent may be considered a wild stallion; an extensive side-effect profile and serious safety concerns led to a black box warning on its label for use in RA. In addition, the drug has received multiple negative opinions from the EMA’s CHMP due to an unfavorable view of Xeljanz’s risk: benefit profile, citing similar concerns over the drug’s safety, but this horse is not out of the RA race yet, and the effort to receive marketing authorization for RA in that region is ongoing. More recently, the FDA rejected Pfizer’s application for Xeljanz to enter the psoriasis race because of lingering safety concerns and mixed efficacy results. Pfizer has yet to provide any long-term data for Xeljanz in UC, and until such data are available, the safety profile that has been consistently reported in trials for other indications will continue to cast a shadow over this horse’s potential success in UC. The maintenance phase of the OCTAVE trials is expected to complete by the second half of 2016, providing a much anticipated piece of news in the near future. If proven effective, the advantage of the first oral agent for moderate to severe UC may allow Xeljanz to take off down the track, however, the added weight of its less than favorable safety profile may end up slowing this horse down.

Risk Taker

Roche/Genentech has big plans for their up and comer etrolizumab, which has a similar mechanism of action to Entyvio—which exclusively inhibits the α4β7integrin—a feature that can be perceived as an advantage in one context (the target achieved approval status), and a disadvantage in another (second to market in its class). However, etrolizumab’s additional inhibition of αE offers an alternative mechanism that differentiates this young colt from Entyvio. Etrolizumab is also formulated as a subcutaneous injection as opposed to Entyvio’s IV formulation, a feature that would be novel to this class and analogous to the second-to-market TNF-α inhibitor Humira, which offers a subcutaneous alternative to Remicade’s IV delivery. Despite Remicade’s head-start in the UC race (approved in 2005 versus 2012 for Humira), Humira has done quite well in making up ground for market share. This is likely due, in part, to the perceived convenience advantage a subcutaneous injection offers. Whether etrolizumab can follow a similar path in uptake relative to Entyvio, or take the inside track, remains to be determined, with any shortfalls not due to a lack of effort. Etrolizumab’s training program is the most extensive for UC to date. It is comprised of five Phase III trials that includes two parallel induction studies pitting etrolizumab head-to-head against a leading favorite Humira. These warm-up races are the first of their kind in UC, creating a high risk, high reward scenario that will be enticing to follow as pivotal data are released. In addition, etrolizumab is adding another piece of flare to its repertoire, through the development of a companion diagnostic tool to assess which patients would be most likely to benefit from riding etrolizumab. As a German physician who follows etrolizumab comments: “Co-developing a biomarker is very smart. It indicates that this can be useful and I believe every company who wants to survive in the future has to do that.” Success in these trials—differentiating etrolizumab from current competitors—could allow etrolizumab to pull away in the race; however, inability to demonstrate any meaningful separation will likely force etrolizumab to have to come from behind as other contenders round the corner.

Silent Type

Celgene’s ozanimod, nicknamed “Hotel California,” is an oral modulator of the S1P receptor, with selective targeting of the S1P1 and S1P5 subunits. Developed as a second-generation S1P-R modulator to compete in the MS race with Novartis’ first-generation philly Gilenya, ozanimod has somewhat quietly forged its way onto the pivotal stage in UC. As an S1P-R modulator, ozanimod also falls into the category of drugs designed to reduce lymphocyte trafficking, albeit in an alternative fashion from etrolizumab or Entyvio. In the Phase II RADIANCE study for MS published in The Lancet, patients receiving ozanimod demonstrated a reduction from their baseline hourly heart rate of less than two BPM under first-dose monitoring (a required feature for Gilenya’s use) and no increased incidence of atrioventricular blocks. However, trial evidence suggests that some patients may still be prone to elevated liver aminotransferase levels of at least three times the normal level. In UC, where reporting of serious adverse events does not typically include cardiac events, inclusion of a cardiac safety profile adds an extra obstacle in addition to more-typical observations, such as infection or worsening of disease, that puts ozanimod at a slight disadvantage heading into the race. On the other hand, ozanimod would offer a once-daily oral regimen, trumping Xeljanz’s twice-daily schedule as well as the SC and IV offerings of current biologics, giving an advantage to ozanimod among this group of competitors. The Phase III program for ozanimod in UC is fairly subtle, as it will examine a single primary end point (i.e., percentage of patients in clinical remission after the induction and maintenance periods). Information on common secondary end points such as mucosal healing is not provided, however, reporting of these data will be necessary to bring this contender to the front of the pack.

And They’re Off…

As of May 5, 2016, all three owners have shown off their respective contender’s performances in highly-respected, peer-reviewed journals; results from Phase II studies were published in the NEJM for Xeljanz and ozanimod, data for etrolizumab were published in The Lancet. Although data from these trials cannot be compared directly, an indirect comparison of patient characteristics using historical champion Remicade’s performance in its pivotal ACT trial runs as a reference suggests that patients from these trials were fairly uniform (see Figure 1).

Figure 1

Figure 1. Average patient characteristics at baseline of the ACT I & ACT II trials (infliximab) and Phase II trials for Xeljanz, etrolizumab, and ozanimod.

Efficacy on select UC metrics important to physicians (clinical remission and mucosal healing) suggests that Xeljanz may be in a comfortable lead (see Figure 2), however, the Phase II trial runs for Xeljanz did not employ the same centrally-read scoring strategy that etrolizumab and ozanimod used in their Phase II programs.

figure 2

Figure 2. Indirect comparison of key end point data presented in ACT I & ACT II (infliximab) and Phase II trials for Xeljanz, etrolizumab, and ozanimod.

This centrally-read scoring strategy was, however, employed in the Phase III OCTAVE program for Xeljanz, and reported efficacy for the agent now appears more similar to that of other contenders (see Figure 3).

Figure 3

Figure 3. Indirect comparison of key end point data presented in ACT I & ACT II (infliximab), OCTAVE induction studies (Xeljanz), and Phase II trials for etrolizumab and ozanimod.

As these competitors round the corner, it is still too early to determine which of these contenders will take the trophy. Owners have placed their bets, and as the dust settles and the results come in, we might just have a photo finish.

 

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