Co-Antibody Therapy Effective in Highly Refractory IBD

The co-antibody therapy JNJ-4804 — a fixed-dose combination of guselkumab (Tremfya) and golimumab (Simponi) — showed clinically meaningful efficacy exceeding that of either drug alone in patients with highly refractory inflammatory bowel disease (IBD), according to two phase IIb trials.

Meanwhile, in the overall study population, the efficacy of high-dose JNJ-4804 was superior to golimumab and numerically greater than guselkumab, researchers reported at the annual Digestive Disease Week (DDW) meeting.

Currently, “we have patients who come into our offices who have been given everything on God’s green earth, and that is the group of patients with the biggest unmet need,” said Maria Abreu, MD, of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai Medical Center in Los Angeles, in an interview with MedPage Today. “We know the next drug we give them is unlikely to work.”

Thus, the question in DUET-CD and DUET-UC evaluating the co-antibody therapy in Crohn’s disease and ulcerative colitis, respectively, was whether the combination delivered at an optimal dose would perform better than each drug alone in a population of patients who were refractory to systemic therapies, including a subpopulation of highly refractory patients.

In both trials, patients were randomized to receive placebo, the tumor necrosis factor (TNF)-alpha inhibitor golimumab, the interleukin-23 inhibitor guselkumab, or JNJ-4804 at one of three doses.

DUET-CD

This trial, which enrolled 693 patients, roughly half of whom had already failed two or more systemic therapies, had co-primary endpoints of clinical remission and endoscopic response.

In the overall population, high-dose JNJ-4804 demonstrated a substantially higher clinical remission rate versus golimumab alone at week 48 (50.8% vs 25.4%, P<0.001), but that gap was much narrower versus guselkumab (42.5%, P=0.171). The same was true for endoscopic response (38.1% vs 19.8% and 33.9%, respectively, P<0.001 and P=0.451).

In the highly refractory subpopulation of patients, there was more of a separation in the number of patients who responded to the combination and those responding to the monotherapies, with 49.2% of patients going into remission with high-dose JNJ-4804 versus 23.1% of those taking golimumab and 27.3% in the guselkumab group.

Endoscopic responses at week 48 among these patients were 33.3%, 12.3%, and 20%, respectively.

“The results from DUET-CD are particularly promising because they show meaningful clinical and endoscopic improvements in patients who have exhausted existing options,” said Bruce E. Sands, MD, MS, of the Icahn School of Medicine at Mount Sinai in New York City, who presented the study at DDW, in a press release.

DUET-UC

In the overall population in DUET-UC, high-dose JNJ-4804 was superior to golimumab alone, with a clinical remission rate of 41% versus 11.5% at 48 weeks (P<0.001), but less so against guselkumab alone (34%, P=0.339).

However, in the highly refractory population, 26.7% went into clinical remission with the combination compared with 2.1% with golimumab and 16% with guselkumab — results that Abreu suggested meant the combination was acting synergistically since there was a clear separation in the number of patients who responded to JNJ-4804 compared with those who responded to the two monotherapies.

“The overall results suggest [JNJ-4804] is really effective in the subset of patients that were on more than two mechanisms of action,” Abreu said. “It seems as if no patient comes to me that hasn’t been on at least two different medication types. So this is a really important need, both for Crohn’s and ulcerative colitis, and I think it would be an advance for the field.”

Sands and Abreu reported that safety events with JNJ-4804 were similar to each of the monotherapies alone. Abreu emphasized that, across groups, the combination did not lead to an increase in infections, “which is kind of the biggest worry that one would have expected immunologically.”

Johnson & Johnson said that with the results of the two studies, it will initiate phase III trials in adults with moderately to severely active Crohn’s disease and ulcerative colitis.

Combinations in Practice

Victor G. Chedid, MD, MS, a gastroenterologist at the Mayo Clinic in Rochester, Minnesota, told MedPage Today that it is not unusual to try combinations in patients with IBD once they’ve exhausted options with individual drugs.

“What I usually see are patients who are in that category of refractory,” said Chedid, who was not involved with either of the DUET trials. “And many a times, we find ourselves trying to get our patients on combination therapy — a JAK inhibitor plus an interleukin-23, or an anti-TNF with an interleukin-23, to try to salvage their colon or their small bowel — to get them in remission when they have had multiple therapies fail them already.”

“So this is something that we have to do — we try, and practice, without that solid clinical trial evidence,” he said.

Thus, Chedid suggested that the value of the DUET studies is that they offer prospective evidence that can support these treatment approaches.

This is particularly important “because in our current state, we appeal to insurance companies to get our patients who have refractory disease, and who are suffering, on combination therapy as the salvage approach, and we have to use retrospective data to help support our appeals with insurance companies,” he noted.