Insulin Exclusivity: How Big Will The Fight Be?

As FDA gears up to turn some NDAs into BLAs, insulins may have the most to lose – or gain, if the agency changes its approach.

Sponsors of insulin products may have the most on the line as FDA gears up to transition some protein drug products that had been approved under the Food, Drug and Cosmetic (FD&C) Act into biologics licensed under the Public Health Service (PHS) Act.

Insulin is a decades-old category, but it remains a lucrative and dynamic market, so the prospect of the regulatory transition, with its potential to lose some exclusivity and force pipeline changes, is likely to put sponsors on edge.

The 2010 legislation that created the biosimilar approval pathway included a section that would transition some products that had been traditionally approved as NDAs and ANDAs and turn them into BLAs. As the 10-year deadline for transitioning products moved closer, industry representatives have called on FDA to explain how it would implement the statute's transition provisions.

However, industry might not like FDA's initial answer about what will happen on the rollover date – March 23, 2020.

In a draft guidance, FDA proposes to implement the "deemed to be a license" provision in Section 7002(e) of the Biologics Price Competition and Innovation Act (BPCIA) such that "applications for biological products that have been approved under Sec. 505 of the FD&C Act will no longer exist" as NDAs or ANDAs, and will be replaced by approved BLAs under Sec. 351(a) or 351(k) "as appropriate."

NDA Exclusivity Lost Is Not BLA Exclusivity Found

Something else that will no longer exist – any non-orphan exclusivity. The FD&C Act's other marketing and labeling exclusivity provisions limit submission or approval of applications under Sec. 505 but not under Sec. 351, FDA said.

The agency concludes that an unexpired period of exclusivity – five-year new chemical entity, three-year Hatch-Waxman, or pediatric – associated with an approved NDA subject to the transition provisions "would cease to have any effect," as of March 23, 2020.

Nothing in the BPCIA suggests that Congress intended to grant products subject to the law's transition provisions the additional 12 years of exclusivity awarded to newly licensed biologics, FDA said.

Since orphan exclusivity is available to both drugs and biologics, this protection would extend beyond the transition date.

Importantly, the agency concludes that sponsors of approved products that transition from NDAs to BLAs cannot take advantage of the BPCIA's 12-year exclusivity for new biologics because they will not have been "first licensed" under 351(a).

"Nothing in the BPCI Act suggests that Congress intended to grant biological products approved under Sec. 505 of the FD&C Act – some of which were approved decades ago – a period of exclusivity upon being deemed to have a license under the PHS Act that would impede biosimilar or interchangeable product competition in several product classes until the year 2032," the agency said.

Industry attorneys said FDA could have interpreted the provision in a way that provides 12-year biologic exclusivity for transition products dating back to original approval under the FD&C Act, rather than eliminating exclusivity entirely.

"I think there was some hope among folks that FDA might do some type of a workaround on the exclusivity front," said Kurt Karst, a director at Hyman Phelps and McNamara in Washington, DC. Instead, "FDA just decided we're going to draw the line here and no exclusivity when the changeover happens."

"I think it's a little bit surprising in the sense that the drug-related exclusivity was just completely terminated at the time of this magic date, said Brian Malkin, senior counsel at McGuireWoods in Washington, DC. "Except for orphan drug exclusivity, you don't have it, it's gone."

Next Steps For Sponsors And Developers

In addition to being in regulatory transition, insulins are in the midst of some market tumult (Also see "Market Snapshot: Under Pressure, Insulin Makers Pin Hopes On New Products" - Pink Sheet, 5 Oct, 2015.). So every scrape of exclusivity will likely be fiercely contested.

So far, sponsors have been mum on what they think of FDA's proposal, but the May 13 comment deadline will likely provide an early indication of which sponsors are most agitated by the potential loss of exclusivity – and which think they might actually be able to convince the agency to give them more exclusivity than they already have by applying the BLA 12 years to their transitioned products.

After the comments, FDA will finalize the guidance and then it will probably be sued.

In the meantime, sponsors with insulin products in the pipeline should start planning to submit them as BLAs. There are almost two dozen products in development in the space (Also see "What’s Yet To Come From Insulin Pipeline" - Pink Sheet, 5 Oct, 2015.).

FDA's guidance includes specific advice for sponsors developing products that are being transitioned, since there may be additional testing requirements for a BLA submission than an NDA (see related story, (Also see "BLAs More Appealing As 'Transition' NDAs, ANDAs Set To Lose Exclusivity" - Pink Sheet, 21 Mar, 2016.)).

The Newer You Are, The Worse It Is

For already-approved insulins, FDA's policy proposal is more meaningful the less time you've been on the market. Eli Lilly & Co./Boehringer Ingelheim GMBH's “biosimilar” type insulin Basaglar (insulin glargine), for example, was approved in December under 505(b)(2) (Also see "FDA Makes It Official With Basaglar Approval For Diabetes" - Pink Sheet, 16 Dec, 2015.).

But the Lantus copycat carries only labeling exclusivity that expires in 2018, and would not be impacted by transition – at least as far as the agency sees it. Lilly, which holds the application, could argue that Basaglar should get 12 years of exclusivity because it's now being licensed as a BLA. Even if it loses that argument, being designated as a biologic could provide an avenue to eventually being designated as interchangeable with Sanofi's Lantus, which could help drive uptake.

Novo Nordisk AS’s Tresiba (insulin degludec), on the other hand, faces more potential downside. It was approved last fall (Also see "Novo’s Business Plan For Tresiba Insulin Includes ‘Moderate’ Price Premium" - Pink Sheet, 5 Oct, 2015.) and carries new chemical entity exclusivity that runs until Sept. 25, 2020, meaning it would lose about four months under FDA's guidance.

Those four months probably aren't critical, since Tresiba has a drug substance patent claim that extends until 2025, and other patents that stretch until 2032. If Novo could convince FDA (or the courts) that it deserves 12 years of exclusivity from the time it first becomes a BLA, it essentially wouldn't have to worry about patent litigation at all.

FDA's guidance could also put a new spin on the idea of a combination product in the space, with pending insulin/GLP-1 products that are now slated to become BLA/NDA combos. Novo's Xultophy, a combo of Tresiba and Victoza (liraglutide), will be reviewed by FDA's Endocrinologic and Metabolic Drugs Advisory Committee on May 24. Sanofi's LixiLan, a combo of Lantus and the investigational drug lixisenatide, will be reviewed the next day.

[Editor's note: This story was updated March 29, 2016 to reflect the revised meeting dates for the Novo and Sanofi products. FDA switched the dates for the two products.]

Xultophy was submitted in September and has a projected user fee date of July 25. LixiLan was submitted in December, but Sanofi has used a priority review voucher to get an August goal date.