AbbVie’s next-generation Crohn’s disease combination candidate has beaten Skyrizi in a midphase clinical trial.
Skyrizi is a powerhouse product, generating $10 billion for AbbVie over the first half of the year. Yet, while the IL-23 antagonist is a clinical and commercial success, the Big Pharma spotted a weakness in the drug’s mechanism. Evidence of α4β7-driven inflammation despite IL-23 inhibition led the company to assess the effects of adding the α4β7 inhibitor trosunilimab to Skyrizi.
AbbVie randomized 300 people with moderate-to-severe Crohn’s to receive Skyrizi, trosunilimab or the two treatments in combination. At Week 12, 30.2% of patients treated with the drug combination, code-named ABBV-466, met the primary endpoint of endoscopic remission. The remission rates in the Skyrizi and trosunilimab monotherapy cohorts were 21.3% and 18.0%, respectively.
The ABBV-466 rate is higher than in AbbVie’s phase 3 trials of Skyrizi in Crohn’s, which reported (PDF) endoscopic remission in 24% and 19% of patients, respectively. Differences between the studies complicate cross-trial comparisons.
In the Skyrizi-trosunilimab trial, 75% of patients had failed at least one advanced therapy, while the remaining 25% were biologic-naïve. In contrast, the phase 3 Skyrizi study with the 24% remission rate included some biologic-naïve patients, while the rate was 18% in patients with prior biological failure alone. Meanwhile, the Skyrizi trial with the 19% remission rate only included patients with prior biological failure.
The type of drugs patients tried before entering trials was also different. In the Skyrizi-trosunilimab trial, 9.3% of patients with prior biological failure had tried an IL-23 therapy, such as Skyrizi, and 12% had tried a JAK inhibitor. AbbVie’s Rinvoq, the first FDA-approved JAK inhibitor for moderate-to-severe Crohn’s, came to market after the company completed the Skyrizi monotherapy trials.
AbbVie’s phase 2 data suggest advantages to the dual-targeting approach in today's heavily pretreated populations. The company linked ABBV-466 to colonic epithelial repair and barrier restoration at Week 12. By Week 24, AbbVie saw tissue remodeling and metabolic changes in ABBV-466 patients that were generally not observed in either monotherapy arm.
Rates of serious adverse events were similar across the three cohorts. The most common adverse events in the ABBV-466 and trosunilimab arms were Crohn’s disease and nausea, according to the release. The most common adverse events in the Skyrizi monotherapy arm were Crohn's disease and joint pain.
AbbVie began a larger phase 2 study of the drug combination in July. The 2,000-patient trial features two substudies, one of which is assessing ABBV-466 in patients with moderate-to-severe Crohn’s or ulcerative colitis. The pharma's Chief Scientific Officer Roopal Thakkar, M.D., commented on the trial on an earnings call in July, noting how it could trigger further development of a Skyrizi-trosunilimab coformulation.
“We don't have an intention to wait until the end,” Thakkar said. “We will take a couple of interim snapshots and if we see, for example, the higher dose of [trosunilimab] is supporting higher efficacy, then we would start making plans to move into phase 3 with that combination.”
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