Biosimilar Advisory Committee Features Actual Debate About Biosimilarity

FDA says problem with protein misfolding with Sandoz' Enbrel biosimilar candidate unlikely to generate unique toxicity issues in extrapolated indications.

The path down the biosimilar approval pathway has been a bumpy one for FDA's advisory committees, with many advisors expressing discomfort with the very idea of relying on analytic similarity as the basis of approval even as FDA has worked to ensure that only the most robust applications reach the panel review stage.

But the Arthritis Advisory Committee's July 13 review of Sandoz Inc.'s GP2015, which references Amgen Inc.'s tumor necrosis factor blocker Enbrel (etanercept), was in many ways a watershed because the agency's outside experts not only embraced the biosimilarity concept but also debated the technical merits of the application in depth.

Uncertainty about the analytical characterization of Sandoz's proposed biosimilar etanercept product nearly created an extrapolation problem for the firm as the committee discussed whether protein misfolding questions were enough uncertainty to think twice about approving the product for all of Enbrel's indications.

Sandoz's GP2015, which references Amgen Inc.'s tumor necrosis factor blocker Enbrel (etanercept), is seeking all of the indications approved for Enbrel: rheumatoid arthritis, polyarticular juvenile idiopathic arthritis in patients two years and older, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis in patients 18 and older.

Sandoz only conducted a clinical study of the product in plaque psoriasis.

It was one of only a few issues that loomed during what was a mostly smooth advisory committee session.

Yihong Ye, a senior investigator at the National Institute of Diabetes, Digestive and Kidney Diseases, who's expertise was in protein quality control, said it is unclear whether the misfolded protein in GP2015 will cause toxicity problems.

"The question here is whether the long-term administration of the products into patients with that kind of misfolding is going to have any adverse effects in disease situations that have not been tested," Ye said.

"I think there's a gap there as to if we want to extrapolate the applications into other diseases. I think we should be more cautious with that."

Indication extrapolation is an important concept for biosimilar sponsors, in part because it limits the necessary clinical studies for approval.

But it remains a concern for some patient groups and other stakeholders, who want more information about whether a biosimilar will behave like its reference product in the indications that are not studied. (Also see "Biosimilars Education Needs To Come From Industry, Not FDA, NACDS Says" - Pink Sheet, 23 Feb, 2016.)

Committee members still voted unanimously, 20-0, that the totality of the evidence supported approval of the product for all of Enbrel's indications.

The GP2015 meeting was the second consecutive day the advisory committee considered a biosimilar application. On July 12, it unanimously recommended that the totality of evidence supported approval of Amgen's ABP 501, a proposed biosimilar of AbbVie Inc.'s TNF-inhibitor Humira (adalimumab), despite confusion about some aspects of biosimilar development. (Also see "Amgen's Humira Biosimilar Gains Nod From Panel Perplexed By Regulatory Pathway" - Pink Sheet, 12 Jul, 2016.)

FDA had noted in its committee briefing documents that initial testing of GP2015 raised a characterization issue due to a finding that it was not statistically equivalent to US-approved Enbrel. Sandoz had to design another model to resolve the issue and established that its product was in fact equivalent. (Also see "Sandoz Steers Enbrel Biosimilar Away From Equivalence Quandary With Reanalysis" - Pink Sheet, 11 Jul, 2016.)

GP2015-Only Toxicity Issue Unlikely, FDA Says

Similar protein misfolding problems also have been seen with Enbrel, FDA said. But Ye countered that Amgen confirmed that related adverse events did not emerge with Enbrel.

"The reference product used in all those diseases has been tested for each of the cases, whereas Sandoz is trying to extrapolate the [indications] based on testing in one clinical situation and they want to extrapolate that into other situations," Ye said. "They don't have data on that."

FDA used Enbrel's history to argue that Sandoz did not need to repeat that testing with GP2015.

Steven Kozlowski, director of the Office of Pharmaceutical Quality's Office of Biotechnology Products, said the many production lots that Sandoz analyzed found the issue and that it occurred in similar ways between the two products.

He also said that expecting a different result unique to an indication for which GP2015 was not studied is unlikely.

"I understand the point that maybe this is misfolded a little differently than that even though there's less and that might be disease-specific, but that seems very unlikely to sort of be misfolded in a different way that wasn't detected by all these assays and would only play out in other indications," Kozlowski said.

Ye ultimately agreed that the data was robust and that toxicity was less likely.

The exchange is the type of conversation FDA has been hoping to see more of during biosimilar advisory committee meetings.

Kozlowski said previously that the agency want to direct committee discussions more toward analytical characterization issues rather than clinical data. (Also see "Biosimilar Advisory Committees Will Focus Less On Clinical Data" - Pink Sheet, 25 Jan, 2016.)

Sandoz On Track For Second 351(k) Win

The GP2015 review appears to be behind. The goal date was in June, based on the application filing date.

Despite the apparent delay, Sandoz still is on track to become the first sponsor with two approved biosimilars in the US.

Its Zarxio (filgrastim-sndz), a biosimilar of Amgen's Neupogen (filgrastim) was the first biosimilar to be approved in the US and is the only one currently on the market. (Also see " US FDA's inaugural biosimilar review bumpier than first appeared " - Pink Sheet, 15 Jun, 2015.)

Sandoz also has a pending biosimilar application for pegfilgrastim, which references Amgen's Neulasta, but it also appears to be delayed. (Also see "Pending Biosimilars" - Pink Sheet, 7 Mar, 2016.)