Speculation around generic LABA/ICS (long-acting beta2 agonist/inhaled corticosteroid) combinations in the United States has been going on for years. Finally on Wednesday, one day after its GDUFA (generic drug user free act) date, Mylan announced that they received a complete response letter (CRL) from the FDA, rejecting their initial bid to be the first substitutable generic version of GlaxoSmithKline’s Advair in the United States. This has implications beyond just Mylan and GSK, as Hikma and Vectura’s version is also waiting for a decision, with a GDUFA date of May 10. In addition, Sandoz filed a Citizen’s Petition in October 2016 to delay the approval of Mylan’s version, presumably in an attempt to stall the approvals until development of their own generic can catch up; although it was rejected by the FDA, the points raised may have played some part in the FDA’s recent decision on Mylan’s version.

What does the CRL mean for GSK? Obviously, in the short term, GSK has no substitutable generic competition in the United States and will continue to take advantage of this situation, whether through Advair prescriptions or encouraging patients to switch onto its once-daily follow-up LABA/ICS, Breo. Indeed, stock values increased for the company on Wednesday following the CRL news. However, a branded-generic is already approved (see below) and a substitutable generic is coming. Mylan, and any other competitors who follow, did not spend all the time and money developing their own version of Advair’s Diskus to throw in the towel now. Conversations between the FDA and generic manufacturers will likely continue until one company can put together the desired package. The mere potential for generic formulations of Advair to launch has already had a significant impact on the respiratory market landscape in the United States. GSK has been proactive, providing payers with substantial price cuts on its drugs in recent years to sustain formulary placement, including a final deal with payers a few weeks ago to lock in their formulary positions through the end of 2018, a measure to ward off the presumed incoming generics. Thus, despite the outgoing CEO’s confidence that generics would be hard-pressed to succeed in the U.S. market, GSK has clearly been preparing for the worst. With payer contracts locked through 2018, they are likely to switch focus to promoting Breo, Anoro, Incruse, and Arnuity, all delivered via their favored Ellipta dry-powder inhaler, as well as Nucala and accepting Advair’s fade into the sunset.

What does it mean for Mylan? In the short-term, Mylan’s share price has understandably dropped. Mylan was deemed by some analysts to have a fairly solid filing for their generic, given their numerous interactions with the FDA throughout the process; many predicted the FDA’s ruling would come after the March 28 GDUFA date but would still result in a first-round approval. In 2013, when draft guidance for a generic salmeterol/fluticasone propionate was first released, the FDA’s guidance was considered to be lenient, easier to achieve than anticipated. However, it turns out that the relatively low bar set forth by the FDA was not so easy to surmount after all. So far, Mylan has been tight-lipped about the content of the CRL and their path moving forward. I would expect them to make any necessary adjustments and re-file – whether that occurs in 2017 or beyond. The U.S. LABA/ICS market is too lucrative to pass up – and generic versions in Europe have been successful in making small inroads despite more branded competitors and tighter price regulations. Even taking a few percentage points of share away from Advair could result in noteworthy sales for Mylan, making continuing to strive for U.S. approval worthwhile.

What does it mean for other competitors developing their own substitutable salmeterol/fluticasone propionate, including Hikma, Vectura, and Sandoz? This one depends on your perspective: the glass half-full view is that the door is open for one of these companies to have the first substitutable generic; the glass half-empty view is that no manufacturer should assume their drug will get approved easily with the FDA taking a rigorous examination of Mylan’s application. Sandoz is likely in the better position here. Given that Hikma and Vectura’s review is well underway, there’s not much they can do but wait to receive the FDA’s decision in another month or so and then respond accordingly if they also were to receive a CRL. Sandoz, being further behind in development, can adapt and pivot their filing strategy if necessary when we get the full details of Mylan’s CRL and the FDA’s decision of Hikma/Vectura’s application. It would certainly be interesting to see a three- or four-horse race in another year or two.

What does it mean for Teva? Teva has the designation of having the first (and only, to date) generic Advair, AirDuo RespiClick, approved earlier this year. The catch is that AirDuo is not a substitutable generic, meaning that it contains the same molecules as Advair delivered in a proprietary device (Teva’s RespiClick) rather than a copycat of Advair’s Diskus. This non-substitutable status also means that if a physician prescribes “Advair” or “salmeterol/fluticasone propionate,” AirDuo cannot necessarily be automatically substituted. If Mylan’s denial is a premonition of what is to come for Hikma and Vectura in May, does that mean Teva is the only approved generic for the foreseeable future? Teva has yet to launch their version, but their RespiClick device has received positive feedback from physicians in Europe, where the dry-powder inhaler is known as the Spiromax. If they can effectively promote their inhaler, there may be an opportunity here for Teva to take some of Advair’s share before any substitutable generics launch and to solidify a place in the LABA/ICS market, which may be the only way that Teva could see notable sales from a branded-generic version in the presence of substitutable generics. For their sake, I hope Teva’s delayed launch means they are revving up their sales and marketing force to promote AirDuo.

Any way you slice it, it’s exciting that we’re finally starting to see some progress as to whether anyone can successfully launch a substitutable generic Advair in the United States. If and when the first version does launch, DRG’s respiratory team will be tracking its launch closely…but we’re not holding our breaths on this one just yet.

How Glympse Bio oversubscribed their Series B funding amidst the pandemic

View Now