Extrapolating mAbs

What FDA panel's review of Remicade biosimilar means for other biosimilar mAbs

FDA's Arthritis Advisory Committee's discussion and vote to recommend approval of the first biosimilar mAb shows that the mechanism of action of the reference product matters, and companies with biosimilars of mAbs approved for multiple indications based on varying MOAs will need to come armed with ample analytical data to support extrapolation across the different diseases.

On Feb. 9, the panel voted 21-3 to support approval of Celltrion Inc.'s Inflectra (CT-P13), a biosimilar of Remicade infliximab across seven of the eight indications for which the Johnson & Johnson drug is approved: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, ulcerative colitis and adult and pediatric Crohn's disease.

Celltrion is not seeking approval for the Orphan indication of pediatric ulcerative colitis.

The BLA for Inflectra included data from analytical assays, animal models and Phase III data in RA and ankylosing spondylitis.

There was no debate from FDA on whether the company had fulfilled the biosimilar criteria. In its briefing documents and at the meeting, agency reviewers repeatedly stated that Celltrion had demonstrated biosimilarity of Inflectra to Remicade and that the data supported extrapolation to all seven indications.

While Inflectra was not the first biosimilar to be reviewed by an advisory committee - FDA's Oncologic Drugs Advisory Committee reviewed Zarxio filgrastim-sndz from the Sandoz unit of Novartis AG in January 2015 - it was the first mAb to go before an advisory committee.

Because mAbs are inherently more complex than recombinant proteins like filgrastim, with multiple MOAs that determine their efficacy across different indications, the panel's discussion could provide a road map for the at least 31 biosimilar mAbs in Phase III or registration where the reference product is approved for more than one indication (see "mAbs on Deck," page 5).

Panel members struggled with the notion of extrapolating the clinical data in RA to the inflammatory bowel disease (IBD) indications like Crohn's and ulcerative colitis because Remicade's benefit in these latter indications is conferred via a different mechanism than in RA.

They were also concerned that the variability in some of the analytical results could eventually result in manufactured commercial lots that weren't as similar to Remicade, resulting in reduced potency of the biosimilar.

To address the panel's uncertainty over extrapolation, Celltrion presented data from nine analytical assays demonstrating similarity between the MOAs for Remicade and Inflectra. The biotech also outlined its quality control programs and provided preliminary data from an ongoing observational study of Inflectra to treat IBD, which showed similar safety and efficacy.

Inflectra is approved in over 60 countries, including those of the EU.

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