Three studies presented at Digestive Disease Week (DDW) 2017 in Chicago suggest the possibility that the infliximab biosimilar, Inflectra, can be used interchangeably with the reference drug Remicade. Two of the trials presented outcomes in patients switching from Remicade to the biosimilar version, and all 3 showed no significant differences in any efficacy and safety endpoints. These included clinical and biomarker effects, pharmacokinetics, adverse events, and development of anti-drug antibodies. The trials involved different patient populations.
None of the biosimilars currently approved in the United States have been designated as interchangeable with the reference agents. In order to demonstrate interchangeability, the FDA requires drug sponsors to present data from so-called switching studies. While none of the 3 studies presented at DDW 2017 were switching studies, they evaluated patients stabilized on Remicade who then switched to Inflectra, which was approved in the United States in early 2016.
The first trial, described by Young Ho Kim of Sungkyunkwan University School of Medicine in Seoul, South Korea, was a phase 3 study of 214 patients new to infliximab, randomized to either the reference drug or the biosimilar. The primary endpoint was a 70% reduction on the Crohn’s Disease Activity Index at 6 weeks (although blinded treatment and assessments will continue to week 30). Researchers noted no differences on primary endpoint or dozens of secondary endpoints, including achievement of remission, freedom from supplemental steroids, and levels of anti-drug antibodies through week 30. Rates of adverse events were similar.
The second and third studies followed patients who switched from Remicade to the Inflectra. The first of these, reported by Kristin K. Joergensen of Akershus University Hospital in Loerenskog, Norway, presented results from the year-long NOR-SWITCH trial conducted in 24 centers across Norway. The study enrolled 482 patients who had any of the approved indications for Remicade: Crohn’s disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis.
The primary endpoint, assessed at week 52, was the proportion of patients showing significant clinical worsening on the relevant scores for each condition. Patients in the study had been on infliximab for at least 3 years (mean, 7 years). There were no significant differences in any measure, meeting pre-specified criteria for non-inferiority of biosimilar infliximab versus the original drug. There did appear to be a significantly higher rate of clinical worsening at week 52 for Inflectra compared with Remicade (36.5% vs 21.2%), but rates of clinical remission were similar. The trial was not powered to test non-inferiority for individual conditions, and there was no difference in the rates of anti-drug antibodies.
The third study—a small, open-label trial, presented by Anne Samira Strik of the Academic Medical Center in Amsterdam—mainly reported on pharmacokinetic and biomarker endpoints. The study was conducted in 61 patients who had been stable on doses of Remicade, with Harvey-Bradshaw index scores of no more than 4 points. The primary endpoint was a change from baseline in trough drug concentration in each patient, comparing the level of Remicade just before receiving the first dose of Inflectra with the level of biosimilar after 8 and 16 weeks. The biosimilar demonstrated non-inferiority with Remicade. There were no differences in adverse events, and rates of anti-drug antibodies did not change after the switch.
Meeting attendees questioned the strength of the studies’ findings on anti-drug antibodies. They pointed out that the studies only addressed a 1-way switch from Remicade to Inflectra and thus it is not known what the immunogenicity will be with multiple switching. Some were concerned that the patient populations in the studies were “selected”—for example, if patients had longer experience with infliximab, those prone to developing anti-drug antibodies wouldn’t be enrolled because they would have already developed the antibodies and would have been taken off the drug. Thus, they said, it could not be ruled out that clinically significant neutralizing antibodies could develop in real-world patients. Joergensen agreed that additional studies are needed to investigate multidirectional switching.
Celltrion, sponsor of the biosimilar infliximab, funded Kim’s study, and some of his coauthors were employees of Celltrion. Joergensen disclosed no relevant relationships with industry. Strik’s study was funded by Mundipharma International, and some coauthors were company employees.