This year’s Digestive Disease Week meeting took place in Chicago, IL from May 6th to May 9th. This annual event provides the setting for physicians, industry, and academia to come together to discuss all topics gastrointestinal (GI)-related, and beyond. Among the news from this year’s meeting that was of particular interest to DRG were trial results from several mid- and late-stage emerging therapies in the ulcerative colitis (UC) and/or Crohn’s disease (CD) pipelines. What follows is a (small) selection of key data presentations that caught our attention:

 

Pfizer’s Xeljanza Janus activated kinase (Jak)-1/3 inhibitor—offers impressive Phase III maintenance data (OCTAVE-Sustain) in UC1: Detailed Phase III maintenance data first presented at the European Crohn’s and Colitis Organization (ECCO) meeting in February, had a second showing during the DDW abstract sessions. According to results from this study, which enrolled patients from either the OCTAVE 1 or 2 induction studies, treatment with Xeljanz (5 mg or 10 mg, BID) resulted in a statistically significant improvement over placebo on the trial’s primary end point (clinical remission), and a number of secondary outcomes (e.g., mucosal healing, clinical response). Impressively, 23.2% and 29.5% of patients, placebo-adjusted, receiving 5-mg and 10-mg Xeljanz BID, respectively achieved clinical remission at 52 weeks. Worth noting, these percentages appear to be higher than those reported for the sales-leading TNF-alpha inhibitors (i.e., Remicade and Humira) during their late-phase UC trials; however, importantly, this was not a direct comparator trial and not a perfect apples-to-apples comparison, as the trial designs and definition of remission vary.

 

Of course, Xeljanz’s efficacy improvements were not without their safety shortcomings. In particular, the rates of infections (general) and herpes zoster were higher in Xeljanz-treated patients than those receiving placebo. The 5-mg and 10-mg BID doses of Xeljanz were associated with infection rates of 35.9% and 39.8% respectively, compared with 24.2% for placebo. Similarly, 5.1% of patients receiving Xeljanz 10-mg BID developed a Herpes zoster infection compared with only 1.5% of 5-mg BID-treated patients and 0.5% of placebo-treated patients. While perhaps numerically not alarming, given the road blocks previously faced for psoriasis (the FDA declined Pfizer’s sNDA for psoriasis and issued a CRL in 2015, which we believe may have been driven by safety concerns), even a slight risk for infection could give physicians—and regulators—pause. Experts interviewed following the ECCO and DDW conference also note that the drug’s potential negative impact on lipid levels (total cholesterol, low-density lipoprotein, and high-density lipoprotein) is another side effect of concern.

 

Nevertheless, Xeljanz’s impressive maintenance data, together with its induction data put it well on track to become the first oral agent—and the first agent in its class—to be approved for moderate to severe UC. Experts interviewed by DRG offer enthusiasm regarding this agent’s novel mechanism of action and oral formulation. However, many also express caution regarding the drug’s safety profile, and, like us, they eagerly await long-term safety data from the ongoing open-label extension study. We will continue to closely track Xeljanz’s path to approval in our Ulcerative Colitis | Disease Landscape & Forecast | G7 offering; we’ll also be exploring physician and payer receptivity to the agent in our upcoming Ulcerative Colitis & Crohn’s Disease | Access and Reimbursement | US report, publishing later this year.

 

AbbVie’s upadacitinib (ABT-494), a Jak-1 selective inhibitor, shows signs of promise in TNF-alpha refractory CD3: AbbVie is also hoping to hit the ‘jak’pot with its oral, Jak-1 selective agent, upadacitinib, which is in development for a range of immune indications, including UC and CD. Although efficacy data presented during the late-breaking abstract session at DDW were largely positive (e.g., treatment with the 24 mg dose QD and BID resulted in a statistically significantly improvement over placebo on endoscopic remission), the study drug—all doses—did fail to separate from placebo on the trial’s other co-primary end point (clinical remission). Still, significant efficacy for select doses was reported for secondary outcome measures (e.g., clinical response, modified clinical remission), and overall, experts—and investors—appear to view these data quite positively. Perhaps in part because this trial shows promising efficacy among the more difficult to treat moderate to severe CD patients (i.e., those with an inadequate response/intolerance to TNF-alpha agents). AbbVie, too, appears quite happy with the data, and plans to advance upadacitinib into Phase III development for CD.

 

AbbVie/Boehringer Ingelheim’s risankizumab, a novel interleukin (IL)-23 blocker, is well tolerated, and induces and maintains clinical remission in moderate-to-severe CD4: AbbVie/Boehringer Ingelheim’s risankizumab shares a mechanism of action similar to that of Janssen’s Stelara—a biologic recently approved for CD—and appears to have a similar dosing schedule (IV induction, SC maintenance); however, risankizumab targets interleukin (IL)-23 only (by comparison, Stelara is an IL-12 and IL-23 inhibitor). Phase II data from an open-label study indicate suggest that risankizumab was more effective at inducing both clinical and endoscopic remission at 12 weeks compared with placebo (as assessed during the first treatment period of the study: 12-week double-blind IV induction period). The study drug was also effective at maintaining clinical remission—in those who had achieved clinical remission during the induction phase—to week 52 (as assessed during the 26-week open label maintenance period). Phase III trials in CD are poised to being, and together with interviewed experts, we eagerly data from robust, Phase III studies.

 

We have to wonder: As both Remicade and Humira face biosimilar competition, will we continue to see Janssen and AbbVie compete for a share of the IBD space, this time in the market for IL-23 inhibitors, as Stelara and risankizumab fight for a similar group of patients. With upadacitinib also chugging along quite nicely in development for a host of immune indications, including UC and CD, AbbVie may very well be positioned to maintain—or regain—its foothold in the IBD markets.

 

TiGenix/Takeda’s Cx-601 demonstrates sustained efficacy for complex perianal fistulas in CD for up to one year following a single administration5: Stem-cell treatments are an exciting, novel area of development for IBD, and experts interviewed by DRG are cautiously optimistic about their potential in niche CD populations. According to trial results presented at DDW, treatment with a single injection of Cx-601 (one of two stem-cell therapies in late-stage development for CD) at study start resulted in a significantly greater percentage of patients achieving clinical and combined remission at week 52 post-dose compared with placebo. Cx-601’s target patient population (CD patients with perianal fistulas) is among the least well-served with available treatment options, and experts interviewed are hopeful that this agent will demonstrate robust efficacy in this difficult-to-treat population. However, experts temper their enthusiasm by expressing safety concerns with using stem-cell therapies, given the paucity of clinical data and limited experience with cellular therapies in CD to date, and reservations regarding the anticipated high cost and inconvenient delivery of such therapies. Still, if approved, Cx-601 will offer a much-needed treatment option for those CD patients suffering from severe perianal fistulas.

 

 

For further detailed analyses on the CD and UC markets please see: DRG’s Crohn’s Disease | Disease Landscape & Forecast | G7 and Ulcerative Colitis | Disease Landscape & Forecast | G7 offerings.

 

 

References:

  1. William J. Sandborn, et al. Efficacy and safety of oral tofacitinib as maintenance therapy in patients with moderate to severe ulcerative colitis: results from a phase 3 randomized controlled trial. Presentation Number: 1080.

 

  1. William J. Sandborn, et al. Histological remission is predictive of improved clinical outcomes in patients with ulcerative colitis: results from the touchstone ole. Presentation number: su1922.

 

  1. William J. Sandborn, et al Safety and efficacy of abt-494 (upadacitinib), an oral jak1 inhibitor, as induction therapy in patients with crohn’s disease: results from celest. Presentation number: 874h.

 

  1. Brian g. Feagan, et al. Efficacy and safety of open-label maintenance therapy with subcutaneous risankizumab in patients with moderate-to-severe Crohn’s disease. Presentation number: 874l.

 

  1. Julian Panés, et al. Cx601, allogeneic expanded adipose-derived mesenchymal stem cells (easc), for complex perianal fistulas in Crohn's disease: long-term results from a phase iii randomized controlled trial. Presentation Number: 985.

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