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Upadacitinib shows mucosal healing in UC biologic failures, responders
SAN DIEGO — A new JAK inhibitor, upadacitinib, produced dose-dependent results in moderate-to-severe ulcerative colitis despite previous biologic failures, according to two presentations during Digestive Disease Week.
“Induction treatment with upadacitinib (AbbVie) at 30 and 45 mg once daily consistently demonstrated significant improvement in endoscopic and histologic outcomes compared to placebo,” William J. Sandborn, MD, of the University of California San Diego, said during his presentation. “The composite definition of mucosal healing was achieved at week 8 with the highest rate observed in the 45 mg once daily dose in this patient population with moderately-to-severely active ulcerative colitis, 75% of whom had failed anti-TNF blockers.”
Sandborn and Remo Panaccione, MD, FRCPC, from the University of Calgary, presented results from the double-blind, placebo-controlled, dose-ranging study. In this study, participants received one of four doses of upadacitinib (7.5 mg, n = 47; 15 mg, n = 49; 30 mg, n = 52; or 45 mg, n = 56) or placebo (n = 46). Each group comprised patients with moderate-to-severe ulcerative colitis and previously demonstrated inadequate response or intolerance to corticosteroids, immunosuppressants or biologics.
Sandborn presented the endpoints of clinical remission, clinical response, endoscopic improvement, endoscopic remission and histologic improvement at week 8. While Panaccione broke out the results by previous biologic response.
“In this current analysis of the efficacy comparing the bio-IR and non-bio-IR subpopulations, for both the primary and key secondary efficacy endpoints measured at week 8, ... upadacitinib displayed a dose response in both groups with the highest rate observed in the 45 mg once daily treatment arm in the majority of the endpoints. The efficacy in the non-bio-IR population ... was consistently numerically greater than in the bio-IR population.”
Clinical response, remission
Looking at clinical remission overall at week 8, Sandborn showed that placebo produced no clinical remission while the 15 mg group had 14.3% remission and the 30 mg group had 13.5% (both P < .05 vs. placebo); The 45 mg group showed 19.6% clinical remission overall (P < .01 vs. placebo). In the biologic-intolerant patients, the results were not clinically significant, though all treatment groups did show some improvement while placebo showed none. Looking at patients who were not biologic-intolerant, 45.9% of the 45 mg group achieved clinical remission (P < .05 vs. placebo).
Clinical response at week 8 showed a similar trend. Overall, each treatment group showed significant improvement compared with placebo, with 29.3% of the 7.5 mg group (P < .05 vs. placebo) showing response while 44.9% of the 15 mg group, 44.2% of the 30 mg group and 50% of the 45 mg group (all P < .001 vs. placebo) also showed response. A similar trend was seen in the group with inadequate response, loss of response or intolerance to biologic therapies (bio-IR) while in those who did not fall into those categories (non-bio-IR), the significance was in the higher-dose groups with 83.3% of the 30 mg group and 78.6% of the 45 mg group (P < .05 vs. placebo) showing response.
Endoscopic response, remission
Endoscopic results at week 8 also demonstrated the efficacy of upadacitinib, Sandborn showed. Endoscopic improvement was seen in all treatment groups – ranging from 14.9% of the 7.5 mg group (P < .05) to 35.7% of the 45 mg group (P < .001) – compared with just 2.2% of the placebo group. In the bio-IR groups, the three higher doses showed significant impact: 25% of the 15 mg group and 20% of the 30 mg group (P < .01 for both) and 26.2% of the 45 mg group (P < .001). Though all treatment groups showed endoscopic improvement in the non-bio-IR subset, only the 45 mg group reached significance with 64.3% (P < .01).
No patients in the placebo group reached endoscopic remission in the 8 weeks of study, but, 9.6% of the 30 mg group (P < .05) and 17.9% of the 45 mg group (P < .001) did show remission. There were no significant results in the bio-IR group, but the non-bio-IR group produced remissions in all treatment groups, with the only significant results in 35.7% of the 45 mg group (P < .05).
Histologic improvement, mucosal healing
Histologic improvement at week 8 was seen in all treatment groups: 31.9% of the 7.5 mg group (P < .01); 51% of the 15 mg group; 44.2% of the 30 mg group and 48.2% of the 45 mg group (P < .001 for all). Panaccione reported that the three highest doses showed histologic improvement in the bio-IR group (41.7% of the 15 mg group and 37.5% of the 30 mg group, P < .01; 47.6% in the 45 mg group, P < .001). All three treatment doses showed histologic improvement in the non-bio-IR group, ranging from 50% in the 45 mg group (P < .01) to 76.9% in the 15 mg group (P < .001).
Histologic remission results also pointed toward a dose-dependent response, Sandborn said. In the placebo group, 2.2% entered remission, compared with 12.8% in the 7.5 mg group, 22.4% in the 15 mg group (P < .01), 30.8% in the 30 mg group (P < .001) and 41.1% in the 45 mg group (P < .001).
Lastly, Sandborn presented results on a prespecified mucosal healing definition composed of endoscopic subscore of 0 and Geboes score of less than 2.
“This is a really stringent endpoint. It means normal endoscopic finding and no neutrophils on the biopsies,” Sandborn said.
With this definition, no patients in the placebo group met the endpoint and the dose-dependent results were again present with the 30 mg group showing 5.8% with mucosal healing and the 45 mg group with 14.3% attaining the goal (P < .05 for both).
Safety results
Panaccione explained that the overall rates of adverse events and those leading to discontinuation of participation were lower in the upadacitinib group than in the placebo group.
“Upadacitinib displayed significantly greater efficacy in the overall population compared with placebo and was generally well tolerated in patients with moderately to severely active ulcerative colitis,” Panaccione said. “We must remember, though that these are small numbers in both groups and the findings need to be confirmed in larger phase 3 studies, which are ongoing.” – by Katrina Altersitz
Reference:
Panaccione R, et al. Abstract 799. Presented at: Digestive Disease Week; May 18-21, 2019; San Diego.
Sandborn WS, et al. Abstract 800. Presented at: Digestive Disease Week; May 18-21, 2019; San Diego.
Disclosures: Panaccione reports financial relationships with AbbVie, Allergan, Celgene, Eli Lily, Ferring, Gilead, Janssen, Pfizer and Takeda. Sandborn reports financial relationships with AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Cosmo, Escalier Biosceinces, Oppilan, Otuska, Pfizer and Precision IBD.
Perspective
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Tofacitinib (Xeljanz, Pfizer) is a JAK inhibitor approved for the treatment of moderate-to-severe ulcerative colitis based on phase 3 trials that demonstrated clinical responses, clinical remissions and mucosal improvement in both TNF naive and TNF exposed patients. There is a dose-response with tofacitinib both for clinical efficacy and side effects, and as we have seen with biologic therapies bio-naive patients are more likely to respond than patients who failed prior biological therapy.
At DDW, Sandborn and Pannacionne presented data from a dose-ranging induction study of upadacitinib (AbbVie), a novel “more selective” JAK inhibitor evaluated in similar population patients with moderate-to-severe ulcerative colitis refractory to corticosteroids, immunosuppressants or biologics. After 8 weeks of dosing with either 7.5 mg, 15 mg, 30 mg, 45 mg or placebo, there appeared to be a dose-response compared with placebo for endpoints of clinical response, clinical remission, endoscopic improvement and histologic improvement. As has been seen previously, trends in achieving all endpoints were better for bio-naive patients.
While further development of tofacitinib is not going forward in Crohn’s disease, both upadacitinib and filgotinib (Gilead, Galapagos NV) are moving forward in phase 3 clinical trials in both ulcerative colitis and Crohn’s disease. We do not have comparative efficacy or safety data for different classes of JAK inhibitors in inflammatory bowel disease although all have evidence of dose-related immunosuppression.