乌鸦传媒

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CHICAGO -- The possibility that the biosimilar form of infliximab sold as Inflectra can be used interchangeably with the original version, Remicade, looks to be coming closer to reality with several studies reported here.

Three trials presented at Digestive Disease Week (DDW) 2017, two of which specifically tested outcomes in patients switching from Remicade to the biosimilar version, and each conducted in different countries and involving different patient populations, all showed no significant differences in any efficacy or safety endpoint. These included clinical and biomarker effects, pharmacokinetics, adverse events, and development of anti-drug antibodies.

But DDW attendees expressed concerns that the patients included in these studies were a selected population, and that therefore the possibility that clinically significant neutralizing antibodies could develop in real-world patients couldn't be excluded.

Several biosimilars -- biologic drugs developed as copies of pioneering drugs but not exactly identical -- including Inflectra are now on the U.S. market, but none have been approved to be used interchangeably with the original agents. To win that type of label, companies must perform a different and more elaborate set of trials to confirm that efficacy and safety don't differ when patients switch back and forth.

The "back and forth" aspect was not tested in any of the studies reported here, but rather just evaluated patients stabilized on Remicade who then switched to the biosimilar infliximab, known generically as infliximab-dybb.

Three Trials

First to the podium at DDW was Young Ho Kim of Sungkyunkwan University School of Medicine, Seoul, South Korea, who reported a phase III trial of 214 patients new to infliximab randomized to receive either the original or the biosimilar version (thus, not a switching study per se).

This was a relatively short-term trial, with the primary endpoint -- achievement of CDAI-70 (70% score reduction on the Crohn's Disease Activity Index) -- evaluated at 6 weeks although the blinded treatment and assessments continued to week 30.

Kim said there were no differences on the primary endpoint or on dozens of secondary endpoints including CDAI scores at later time points, achievement of remission, freedom from supplemental steroids, levels of calprotectin and C-reactive protein, patient-reported global status, maximal and trough serum drug concentrations, and levels of anti-drug antibodies through week 30. Rates of adverse events were also similar and of a type expected for these agents.

Up next were the two studies of patients who switched from the original infliximab to the biosimilar. Kristin K. Joergensen, of Akershus University Hospital, in Loerenskog, Norway, reported results from the yearlong NOR-SWITCH trial, conducted in 24 centers across Norway and enrolling 482 patients with any of the conditions for which infliximab is approved. These included Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriasis, and psoriatic arthritis.

Clinical outcomes were assessed using standard instruments for each of the conditions. For Crohn's disease, this was the Harvey-Bradshaw Index; for ulcerative colitis it was Partial Mayo Score. The primary endpoint, assessed at week 52, was the proportion of patients showing significant clinical worsening on the relevant score (e.g., ≥4 points on the HBI; ≥3 points on the Mayo scale). Other endpoints reported were changes in scores from baseline at various intermediate time points, rates of remission, and adverse events.

Patients in the study had been on infliximab for at least 3 years (mean 7).

As in Kim's study, Joergensen's group found no significant differences in any measure, meeting prespecified criteria for non-inferiority of biosimilar infliximab versus the original drug. She did note that there appeared to be a higher rate of clinical worsening at week 52 for Inflectra than with Remicade that approached statistical significance (36.5% versus 21.2%). But there was no such difference in rates of clinical remission, and Joergensen said the trial was not powered to test noninferiority for individual conditions.

Toward that point, Joergensen noted that about half of the overall sample had inflammatory bowel disease (155 Crohn's, 93 ulcerative colitis), with the remainder spread among the other conditions.

She also reported, like Kim, that there was no difference in rates of anti-drug antibodies.

The third presentation came from a group in the Netherlands, also testing the switch from Remicade to the biosimilar. Reported by Anne Samira Strik, of Academic Medical Center in Amsterdam, it was a small, open-label study with mainly pharmacokinetic and biomarker endpoints.

Strik's group enrolled 61 patients who had been on stable doses of original infliximab (duration not reported) with HBI scores of no more than 4. The primary endpoint was 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 the biosimilar after 8 and 16 weeks (measured just prior to the next schedule dose).

Mean ratio of post-switch to baseline drug concentration was 107.6% at week 8 (90% CI 100.7%-114.9%) and 109.6% at week 16 (90% CI 99.7%-120.6%), Strik said. Non-inferiority was set at a mean 15% difference, which was easily met by the biosimilar.

As in the other studies, there was no difference in adverse effects, and rates of anti-drug antibodies did not change after the switch, she reported.

Results Questioned

Both Joergensen and Strik faced multiple questions from audience members about the robustness of their findings on neutralizing antibodies.

One pointed out that only one direction of switching was addressed in these studies, from Remicade to Inflectra. "We don't know what the immunogenicity will be with multiple switching," i.e., moving the other direction and perhaps back again, he said.

Another noted that if patients in these studies had long experience with infliximab, individuals prone to develop anti-drug antibodies wouldn't be enrolled, because "it would have happened already" and they would have been taken off the drug. He suggested the data reported here wouldn't apply to patients new to either version of the drug.

Kim's data did shed some light on the risk of neutralizing antibodies in new users of the biosimilar. Overall, about 40% of both groups in the trial showed some evidence of anti-drug antibodies at week 30, but quantitative analysis showed that in nearly all of those, titers were considered low.

It's not certain whether or when the South Korean firm that developed the biosimilar, Celltrion, or any of its marketing partners (Pfizer in the U.S.) will formally seek approval for interchangeability with Remicade, although their support of these studies suggest it as a goal (Kim's study was funded by Celltrion and Strik's by the Dutch distributor, Mundipharma; Joergensen's had no commercial funding). Neither firm could be reached immediately for comment.

In her talk here, Joergensen agreed with attendee comments about anti-drug antibodies, and said additional studies were needed to investigate multi-directional switching.