In the last several months, three separate new drug applications for asthma and COPD therapies have been rejected by the FDA with a CRL; both Mylan and Hikma/Vectura’s generic versions of Advair were rejected, and Sunovion’s nebulized glycopyrrolate also failed to secure approval. Some sources have speculated that the generics were impacted by a citizen’s petition filed by Sandoz asking that specific bioequivalence criteria be met before any generic Advair is approved. Several therapies have already faced hurdles calibrating their dosage before finally securing approval, and it is likely that dosing will continue to be a preoccupation of the FDA when evaluating new inhaled therapies. Additionally, lung deposition is a significant concern for both surveyed and interviewed pulmonologists and respiratory nurse practitioners, and matching the inhalation device to the needs of a patient is critical to maximize the benefit of their medication.

 

 

The first instance of dosing holding up an approval goes back to Spiriva (tiotropium), which is currently available in two devices with three different dosages. The Spiriva HandiHaler, a capsule type dry powder inhaler (DPI), has long been a market leader for COPD and is offered at 18 mcgs per puff, to be taken as two puffs once daily. This device is not ideal for all patients, and interviewed practitioners note that “more severe COPD patients can be cachexic or generally weak, and can't create the inspiratory effect that is needed with DPIs.” This problem led Boehringer Ingelheim to develop the Respimat device, a novel soft-mist inhaler (SMI) that delivers a plume of medication. However, during development the company had to adjust the dose of tiotropium downward from 10 mcg to 5 mcg, finding that patients had a strong response to smaller doses of tiotropium delivered in the Respimat (clinicaltrials.gov NCT00239473 and NCT00240435, accessed June 27, 2017). The final approved was granted for 2.5 mcg or 1.25 mcg per puff, dosed as two puffs once daily.

 

The approval of glycopyrronium (Seebri) also hinged on the dosage, and most significantly, held up the launch of the fixed-dose combination (FDC) of indacaterol/glycopyrronium (Utibron) in the United States, where it is the fourth-to-market among the five long-acting beta2 agonist/long-acting muscarinic antagonists (LABA/LAMAs). Although this drug has a robust clinical trial package and will likely remain the sales leader in the EU5, the delayed launch and lower dosing in the United States prompted DRG to forecast it will have the lowest sales of the five LABA/LAMA FDCs that will be available in this market. In the Phase II dose-ranging studies, glycopyrronium monotherapy was tested at doses up to 200 mcg once-daily (clinicaltrials.gov NCT00510510, accessed June 27, 2017). In the EU, both Seebri and Utibron (called Ultibro) were ultimately approved to deliver 44 mcg of glycopyrronium once-daily in a capsule type DPI. However, some European pulmonologists would have preferred a twice-daily dose, as one German pulmonologist says “Even a very high dose of glycopyrronium is still less effective in the evening; glycopyrronium should be a twice daily medication. Naturally, you can prolong the duration of the effect if you heighten the dose, but it’s not the optimum way.” In the United States both the mono- and combination therapies deliver only 15.6 mcg. Additionally, the U.S. approvals are for one puff taken twice daily, while in the EU these medications are dosed as one puff once daily. However, these therapies still suffer from the drawbacks of a DPI for patients who are not able to inhale hard enough to achieve good lung deposition.

 

 

As a consequence, there is some interest in developing an alternative formulation of glycopyrronium. This therapy, SUN-101, is being developed in a novel proprietary nebulizer called the eFLOW. If the eFLOW is approved and can be dosed more quickly than traditional nebulizers, it is likely to have a substantial payoff; as one nurse practitioner notes, “Physicians and patients would love a nebulizer that was smaller and took less time to dose.” Interestingly, the original dose finding studies went to even higher doses than for the DPI, up to 1000 mcg, even though nebulizers are often perceived to deliver superior lung deposition, which would intuitively require a lower dose of medication (clinicaltrials.gov NCT02951312, accessed June 27, 2017). The dose was brought down in later studies, and the final Phase III trials included in the FDA submission included only 50 and 25 mcg doses (clinicaltrials.gov NCT02347761, accessed June 27, 2017). However, this submission was met with a CRL (Sunovion press release, May 26, 2017). This response does not require additional clinical trials, but additional details have not been released; while the exact issue triggering the CRL is not known, it is possible that dosing or device are holding up this approval.

 

The dosing picture becomes even more complicated when considering generic version of GlaxoSmithKline’s blockbuster drug Advair. The original metered-dose inhaler (MDI) was dosed at 21 mcg salmeterol, while fluticasone propionate ranges from 45-130 mcg. The salmeterol dose delivered in the Diskus DPI more than doubles to 50 mcg, with fluticasone propionate ranging from 100-500 mcg. This DPI was developed as an alternative for patients since “the sequencing of the steps tends to be difficult for patients; they must remember to exhale before they inhale and actuate the inhaler right after the exhalation while they start to inhale,” as noted by an interviewed respiratory nurse practitioner. However, the dosing differences were likely necessary to compensate for drug being deposited in the back of the throat rather than being propelled further into the airway in the MDI device.

 

Currently, only one generic version of Advair has become available; Teva’s branded generic was launched in Q2 of 2017. This generic likely succeeded in being first to market because it offers the same drug in a difference device at a different dose, allowing Teva to bypass studies showing it is substitutable with the brand. The AirDuo RespiClick DPI offers salmeterol at 14 mcg, while fluticasone propionate ranges from 55-242 mcg. This overlaps and bridges the doses for both Advair’s Diskus and MDI, supplementing the choices pulmonologists have to tailor both the drug, device, and dosage to a particular patient. At this time, both Mylan and Hikma/Vectura have received a CRL for their AB-rated, or substitutable, generic of Advair. It remains unclear what bioequivalence standard will be required to secure this AB rating; only draft guidance for salmeterol/fluticasone propionate FDCs is currently available. Interestingly, when Sandoz filed a citizen’s petition highlighting questions about bioequivalence, the FDA denied it without comment. However, the timing of the denial coincided with the rejection of Mylan’s ANDA, the first for an AB-rated generic Advair, raising questions about the impact of this letter on the FDA’s CRL. These delays may result in a big payday for Teva, whose authorized generic version of their own AirDuo is offered at a significant discount.

 

These examples highlight the significance of dosing when new drugs are seeking FDA approval and the impact of device factors on the final doses made available. Lung deposition, device type, and other factors impact both pulmonologists’ perception of drug quality and their prescribing decisions. Dosing will remain an important consideration when making prescribing decisions, especially as more drugs become available in multiple devices, with one Advair generic already available and others in development and Spiriva and Symbicort expected to face generic competitors in the United States by 2020. This proliferation of drug/device combinations will allow physicians to select a formulation, both drug and device, that best fits the needs of a particular patient.

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