Risankizumab appears to be effective in treating the symptoms of moderate to severe Crohn’s disease relatively quickly and to benefit patients who failed prior biologic therapies, according to post hoc analyses of several trials.

Risankizumab (Skyrizi, AbbVie) has been shown to be well tolerated and superior to placebo for inducing and maintaining clinical remission and endoscopic response in people with moderate to severe Crohn’s disease, noted Ryan Ungaro, MD, an associate professor of medicine at the Icahn School of Medicine at Mount Sinai, in New York City. “But for most patients,” Dr. Ungaro added, “fast resolution of symptoms—abdominal pain and increased stool frequency being two of the most burdensome—is an important goal of therapy.”

To assess the effectiveness of risankizumab therapy on these two symptoms, Dr. Ungaro and his co-investigators conducted a post hoc analysis of the risankizumab phase 3 clinical trial program (ADVANCE and MOTIVATE induction trials and (FORTIFY maintenance trial), collecting patient-reported outcomes on clinical symptoms.

“During the screening period, patients were provided with an electronic diary with which to record Crohn’s-related symptoms throughout the study,” Dr. Ungaro said.

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Patients recorded information daily, and the investigators reviewed the diaries at each study visit, calculating the seven-day average stool frequency and abdominal pain scores. The latter were rated from 0 to 3, with 0 being no pain and 3 being severe pain.

Presenting the findings at the 2022 annual meeting of the American College of Gastroenterology (abstract 37/S713), Dr. Ungaro said, “At induction, the majority of patients had an abdominal pain score of 2 or more and a stool frequency mean of around 6.” At maintenance week 0—the end of induction week 12—most patients had an abdominal pain score of 1 or less and a mean stool frequency score of approximately 2.

Significantly more patients given the 600-mg dose of risankizumab than placebo-treated patients reported improvements from baseline in stool frequency and abdominal pain scores at weeks 4, 8 and 12.

During the maintenance trial, which compared 360 and 180 mg of subcutaneous risankizumab and placebo, both doses of the agent were better than placebo at reducing abdominal pain scores at weeks 32 through 52.

“For stool frequency, the higher dose of risankizumab was superior to placebo at week 40 through 52 but not statistically different from the lower dose,” Dr. Ungaro said.

At week 52, the end of maintenance, both doses were superior to placebo in achieving a pain score of 0 and stool frequency score of less than 1, “but only the 360-mg dose was statistically significantly superior to placebo in stool frequency score and for the composite of no abdominal pain and resolution of stool frequency,” Dr. Ungaro said.

Dr. Ungaro noted that the correlation between symptom improvement and endoscopic outcomes was weak after induction and moderate during maintenance. “I think this really underscores the importance of having objective measures for disease activity.”

David Dulaney, MD, a gastroenterologist and an assistant professor of medicine at Brooks Army Medical Center, in San Antonio, found risankizumab‘s effects on stool frequency within four weeks and abdominal pain at eight weeks encouraging. “When starting patients on therapies for Crohn’s disease, a question I am commonly asked is, ‘When will I start to feel better?’ This [study] aims to answer that question exactly for these common symptoms.”

Efficacy After Multiple Biologic Failures

Another post hoc analysis presented at the meeting looked at the efficacy of risankizumab in patients who had failed one, two, or three or more prior biologics (abstract 39/S715).

Evaluating Risankizumab Reinduction

A second induction with risankizumab can effectively treat some patients who did not achieve clinical response after an initial 12-week induction period with the agent.

In the phase 3 ADVANCE and MOTIVATE induction trials of risankizumab, patients who did not achieve clinical remission at week 12 were kept blinded and offered a second induction. It was “reinduction, essentially, and evaluation at week 24,” said investigator Marla Dubinsky, who reported the week 52 efficacy and safety results on patients who underwent 24 weeks of induction therapy at the ACG meeting (abstract 38/S714).

Dr. Dubinsky noted that the end point of 52 weeks occurred after the 24-week induction period, “so this is a full year of maintenance therapy after reinduction.”

Most of the patients who underwent reinduction achieved clinical remission with 180- or 360-mg doses of risankizumab, and many experienced endoscopic response. “The patients who received 360 mg did somewhat better when it came to endoscopic end points, so I think evaluating the more robust end points will be important when we’re deciding maintenance dosing,” Dr. Dubinsky said.

Although it’s not yet certain what the optimal maintenance therapy will be, it is clear that patients who are withdrawn into a placebo arm experience a return of ulcers. “Even though these patients may have still had a durable response when they went into the withdrawal arm at week 12 of the original trial, and their clinical symptoms don’t come back as quickly, you see endoscopic activity. This shows us that withdrawal of this drug will not be the right thing to do in patients,” Dr. Dubinsky said.

“These findings underscore the additional benefit of initiating maintenance dosing after IV induction even in patients who were initial nonresponders,” she added. “Basically, don’t give up after the IV. It looks like if you can convert them to subcutaneous, you may get patients who need a little longer on this drug. And risankizumab was well tolerated, with no new safety risks identified.”

Commenting on the study, David Dulaney, MD, a gastroenterologist and an assistant professor of medicine at Brooks Army Medical Center, in San Antonio, said clinicians need to know if they can expect clinical improvements in patients who do not respond during induction. “When treating IBD, we consider clinical response and remission to be a very important treatment target. This [study] is particularly noteworthy because it provides evidence that risankizumab might be efficacious in patients who do not achieve a clinical response in the induction phase of therapy.”

—M.J.S.

Dr. Dubinsky reported financial relationships with AbbVie, Arena, BI, BMS, Celgene, Gilead, Janssen, Lilly, Pfizer, Prometheus, Roche, Takeda, Trellus and UCB. Dr. Dulaney reported no relevant financial disclosures.

“The more biologics a patient had failed, the longer their disease duration. As expected, some disease activity scores, such as CDAI [Crohn’s Disease Activity Index] and fecal calprotectin [with] CRP [C-reactive protein] tended to be higher in patients who had failed more biologics,” said investigator Marc Ferrante, MD, PhD, a professor of medicine at University Hospitals Leuven, in Belgium.

At baseline 48%, 25% and 27% of patients had failed one, two, or three or more biologics, respectively; 6%, 27% and 75% had prior vedolizumab (Entyvio, Takeda) exposure, and 2%, 12% and 59% had prior ustekinumab (Stelara, Janssen) exposure. Ninety percent of patients who had failed one biologic and all who had failed two or more were refractory to anti–tumor necrosis factor therapy.

During the induction trials (ADVANCE and MOTIVATE), clinical remission and endoscopic response were highest in patients who received 600 mg of risankizumab across all subgroups, with greater efficacy generally observed in those who failed fewer biologics.

During the maintenance trial (FORTIFY), endoscopic remission and response were again higher across all subgroups in patients receiving either dose of risankizumab versus placebo, with significantly higher achievement of deep remission and ulcer-free endoscopy in those taking 360 mg of risankizumab.

“I think it’s clear that risankizumab is efficacious and well tolerated in Crohn’s patients, despite the number of prior biologics they had failed,” Dr. Ferrante said.

“At week 52, a numerically greater proportion of patients previously failing two or more biologics achieved endoscopic end points with the higher maintenance dose. Although we cannot say a lot about [ustekinumab] due to the small patient numbers, I think that in the [ustekinumab]-experienced patients there seem to be some patients who do benefit from risankizumab,” he said.

Encouraging Results

Dr. Dulaney found the results of statistically significant improvement across all subgroups during the induction phase encouraging, suggesting that risankizumab might be useful in patients with refractory Crohn’s disease.

“Furthermore, this analysis was done in such a way that each portion of the current STRIDE-II recommendations was assessed with response and remission for both clinical and endoscopic end points,” he added. “Although further research will be needed to determine the sustainability of the response/remission achieved in these trials, the results ... will be useful for biologic positioning.”

—Monica J. Smith

Dr. Dulaney reported no relevant financial disclosures. Dr. Ferrante reported financial relationships with AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Celltrion, EG, Falk, Ferring, Janssen, Lamepro, Lilly, Medtronic, Merck, Pfizer, Regeneron, Samsung, Sandoz, Takeda, ThermoFisher, Truvion and Viatris. Dr. Ungaro reported financial relationships with AbbVie, Bristol Myers Squibb, Janssen, Lilly, Pfizer and Takeda.

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This article is from the May 2023 print issue.