January 24, 2024
2 min read
The FDA’s approval of Zymfentra in fall 2023 offers patients the “flexibility” of a subcutaneous therapy option for moderately to severely active ulcerative colitis and Crohn’s disease, Stephen B. Hanauer, MD, told Healio in an interview.
The agency based its decision on data from the randomized, double-blind, phase 3 LIBERTY UC and LIBERTY CD trials, which assessed the efficacy and safety of Zymfentra (Celltrion, infliximab-dyyb) as maintenance therapy following induction of IV infliximab over 54 weeks. In both trials, Zymfentra was superior to placebo in achieving the primary endpoints of clinical remission and endoscopic response.
“The trials with Zymfentra are very reassuring because despite sustained levels, which are positive, we did not see any unexpected side effects or toxicity related to subcutaneous infliximab compared with placebo-treated patients,” Hanauer, the Clifford Joseph Barborka Professor of Medicine at Northwestern University Feinberg School of Medicine, said. “It gives patients an option for either IV infusions, which some patients do prefer, or subcutaneous dosing, which most patients prefer due to its flexibility, and it can be performed at home.”
Hanauer discussed what the FDA approval means for patient care and how Zymfentra fits into the growing pipeline of treatments for inflammatory bowel disease.
Healio: What comes next after this FDA approval of Zymfentra?
Hanauer: It is an evolving story, because first comes the approval and then the launch of the drug. It is not yet available to our patients, but we expect it to be in late first quarter of 2024.
Healio: How could this affect patients with UC and Crohn’s disease?
Hanauer: First, it is going to give patients another option. Patients who have been on infliximab, either the originator or biosimilar, have had to receive IV infusions, both for induction and maintenance. What we have learned is that even though infliximab is highly effective in both UC and Crohn’s disease, there are several remaining controversies, despite infliximab being available since 1998 as Remicade (Janssen) and recently as a biosimilar. Most controversies include whether patients need immunomodulatory agents to improve their efficacy.
About 50% of patients who start on an anti-TNF blocker are off the drug by the end of the year and that means that there are several things going on, such as loss of response. The IV infusions may make patients more susceptible to loss of response due to their less sustained bioavailability of the drug.
The LIBERTY CD and LIBERTY UC trials demonstrated that subcutaneous infliximab administration has sustained drug levels better. Therefore, we are looking forward to seeing some comparative effectiveness between subcutaneous maintenance with Zymfentra vs. IV maintenance with other infliximab formulations.
Healio: How will Zymfentra fit in with the growing IBD pipeline?
Hanauer: We have very few head-to-head trials in IBD and no head-to-head trials vs. infliximab. We have seen head-to-head trials vs. Humira (adalimumab, AbbVie), against Entyvio (vedolizumab, Takeda Pharmaceuticals) in UC and compared with Stelara (ustekinumab, Janssen) in Crohn’s disease. In one head-to-head trial, Stelara was compared with Skyrizi (risankizumab, AbbVie) in patients with Crohn’s disease who were exposed to biologics.
What we need to see is a head-to-head study of IV vs. subcutaneous infliximab in the maintenance phase. My suspicion is that the subcutaneous formulation is going to sustain remission better than the IV formulation, partly because one of the advantages is higher sustained blood levels. With IV infusions, we get high initial levels and then lower trough levels. Those low trough levels lead to poor outcomes, including loss of response at the end of the infusion cycle and development of anti-drug antibodies. After each IV infusion, the antibodies accumulate.
With subcutaneous administration we see antibodies, but they are sublimated because of the sustained blood levels with infliximab.