Part 1: Nick Mitrokostas on How COVID-19, FDA Rule Changes Are Shaping the Biosimilar Market

The Center for Biosimilars® (CfB): Hello, I'm Matthew Gavidia. Today on the MJH Life Sciences News Network, The Center for Biosimilars® is pleased to welcome Nicholas K. Mitrokostas, an intellectual property law attorney with Goodwin Proctor in Boston and editor in chief of Big Molecule Watch. Can you just introduce yourself and tell us a little bit about your work?

Mitrokostas Sure, and good morning to everyone. I'm a partner in Goodwin's Boston office. I focus on life sciences litigation. And in particular, I advise companies who are working in the pharmaceutical space with respect to intellectual property matters, and in some cases, regulatory matters. I also have been involved in advising companies and representing them with respect to their biosimilar products.

CfB: [Recently], Pfizer announced its pegfilgrastim biosimilar (Nyvepria) was approved by the FDA. This marks the first biosimilar approval this year. As most of us thought biosimilar momentum would be faster this year, is this a sign of COVID-19's [coronavirus disease 2019] impact or is something else happening?

Mitrokostas: Well, I think we need to put this into context that there have been 28 approvals of biosimilars since the enactment of the BPCIA. Obviously, Pfizer's pegfilgrastim was the first 1 announced in 2020 and then, we had another announcement of an insulin biosimilar from Mylan and Biocon. So, that's number 2. I think there's sort of 2 reasons that we may not have seen more approvals this year, although the year's far from over. One has to do with the fact that we saw the initial wave of biosimilar filings as a result of exclusivity periods that had already expired or we're very near expiry following the enactment of the BPCIA. For those, we have seen a number of filers who have received approval, many of which have launched. I think, now, we're heading into the second wave of molecules that are nearing the end of their exclusivity period.

So, I suspect that we're going to see more filings in the coming year and years. I think the first issue here is that, biosimilar applicants time their filings with respect to when molecules are nearing the end of their exclusivity period from FDA. The second one, obviously, probably has to do in some degree with COVID-19. Everything is obviously functioning much slower than it otherwise would be. But I don't think that these will be the only 2 approvals that we'll see this year.

CfB: The FDA generally doesn't disclose the drug applications it has received but do you have a sense of how robust the pipeline is?

Mitrokostas: While we don't have any guidance from FDA with respect to who has filed and what is pending, there is information that can be gathered from publicly available sources, for example, either earnings calls or SEC [US Securities and Exchange Commission] filings from a number of the publicly listed pharmaceutical companies who are working in this space.

So, we know there are many more files that are under development or have been filed. For example, Mylan announced that its bevacizumab biosimilar was accepted and there's a user fee deadline of December 2020 for that. In addition, Coherus and Bioeq have previously filed a ranibizumab biosimilar. It was withdrawn, but they recently announced that they're going to refile it in the second half of 2020 and Coherus has announced that it will file it’s a-mab [adalimumab] molecule as well. I think we do have a sense from public sources that companies are still very active in the development of biosimilars, are filing them and that there are a number that are still under review with FDA.

CfB: What does the rest of the year look like for biosimilar approvals, do you think?

Mitrokostas: I think we're going to see some more approvals. Maybe I'm being optimistic here, but I do think that FDA will be poised to approve some more biosimilars. I also think we're going to see a number of more filings, given [everything that’s going on] and that people have been describing in their public earnings calls and SEC filings [about] some of the molecules that are nearing their expiration dates. For example, Lucentis (ranibizumab) is reaching the end of its exclusivity pretty soon. Similarly, Eylea (aflibercept) is nearing the end of its exclusivity period and a number of companies have publicly stated that they're working on biosimilar filings for those molecules.

CfB: Meanwhile, we're seeing a number of biosimilars that have been approved but have not yet launched. Wasn't the patent dance process supposed to shorten the time between approval and launch?

Mitrokostas: Well, the patent dance process was intended not necessarily to shorten the time between approval and launch, as much as [help manufacturers] get some clarity in the resolution of patent disputes so that when a product is approved, the biosimilar manufacturer knows whether or not there's patent clearance for them to enter the US market and what the risks are associated with doing so if there isn't. I think the patent dance and the mechanisms that were enacted as part of the BPCIA so far have been successfully achieving that goal in the sense that we have seen a number of these patent disputes resolved either by court decision or settlement during this time period between the filing of the ABLA [accelerated biologics license application] and the approval.

For some of these, obviously, the decision is averse to the ABLA filer or it's a supplement, where the ABLA filer agrees to stay off the market for a certain period of time. For example, for the case of Humira (adalimumab), we know that there are a number of filers who have gotten approval, but through a settlement have agreed not to launch their products until a date in the future. And so, the patent dance actually facilitated those settlements in a way that was contemplated by the BPCIA. So, I think it is essentially achieving the purpose that it was meant to achieve by giving clarity to biosimilar manufacturers as to what the risks are associated with bringing their molecules to the market once they get FDA approval.

CfB: The new approval pathway under the BPCIA gives instant biologic drug license status to products previously approved under the FD&C [Federal Food, Drug, and Cosmetic] Act. Is this the seamless change that the FDA has described?

Mitrokostas: So, I believe you're referring to the "Deemed to be a License" provision under the BPCIA which essentially provided a 10-year window within which products that were previously approved as NDAs [new drug applications]—for example, insulin glargine—would transition 10 years after the enactment of the BPCIA to BLAs, without having to refile the application and get new approval. It also provided a pathway where a biosimilar can come to the market through an ABLA. And since we've passed that March 2020 [transition] date, it has essentially worked the way it was contemplated to work.

Last year, FDA ironed out some of the issues [with the provision] through some guidances. In addition, we saw in Congress's Budget Appropriations Act at the end of last year, some further actions to try to facilitate the approval of biosimilars to some of these molecules. For example, as we talked about short while ago, Mylan [and Biocon], got approval for their insulin glargine product that was originally filed as an ANDA [abbreviated new drug application], because [reference] insulin glargine [Lantus] was approved as an NDA.

In March 2020, that insulin glargine molecule was [transitioned] to be a BLA under the BPCIA. And Congress made clear that ANDAs that were pending, at that time of the transition date, would continue to get reviewed and approved without the need to be refiled as a BLA. That was sort of an issue in question that FDA and stakeholders and others have been weighing into for the last several years with regard to this transition date on what would happen to these pending ANDAs. But, as we saw, there were some clarity to it.

So, from that perspective, there was a seamless transition for the molecules that fell under this "Deemed to be a License" provision. FDA is still addressing the definition of protein, which impacts which of these molecules would fall under the provision, and also the scope of the "Deemed to be a License" provision. But I think, so far, things have been working as they intended.

CfB: What do biosimilar manufacturers need to know about this to make effective decisions about product applications, particularly those for insulins?

Mitrokostas: So, there's been a lot of FDA guidance that has come out around the "Deemed to be a License" provision as well as the manufacturing and development of a biosimilar insulin product. For example, FDA issued guidance about the risks associated with immunogenicity in the development of insulin products [in November 2019]. FDA did that in anticipation of the "Deemed to be a License" transition date [that was approaching] in March 2020.

I think what's clear from all of this is that FDA is obviously interested in seeing robust data from applicants with respect to [making sure their products are] highly similar and [that there are] no clinically meaningful differences [from the reference product, which is] the standard for demonstrating biosimilarity for insulin products. So, developers of these products, I think, are taking that guidance into account and should be advised to speak with FDA about the plan for demonstrating that their biosimilar is highly similar to and shows no clinically meaningful differences from a [reference] insulin product.