FDA Accepts NDA for Riluzole Oral Film for ALS

Daniel Barber, MBA, chief strategy and development officer of Aquestive

Daniel Barber, MBA

Aquestive Therapeutics announced that the FDA accepted a new drug application (NDA) for its investigative oral film formulation of riluzole (Exservan) for the treatment of amyotrophic lateral sclerosis (ALS).¹

The treatment was previously granted an orphan drug designation in January 2018; its NDA is supported by a number of studies which sought to confirm its bioequivalence to its reference listed drug, Rilutek, the riluzole formulation marketed by Sanofi.

Daniel Barber, MBA, chief strategy and development officer of Aquestive, noted in a statement that the company is pleased about the FDA’s acceptance of the NDA, “given the needs ALS patients have for treatment advances. ALS, though relatively rare, represents a considerable economic and social burden in the U.S. and globally.”

"Oral films offer great promise to patients who face difficulty swallowing or administering traditional forms of medication. In addition to Exservan, we are also focused on advancing Libervant toward an NDA filing this year. We believe these innovations are important and can help patients interact consistently and compliantly with their medication," he added.

Libervant, a diazepam buccal soluble film, is being developed for the treatment of epilepsy. There is currently a phase 3 trial underway, which is exploring the safety and tolerability of the study drug in doses of 5, 7.5, 10, 12.5, and 15 mg in children, adolescents, and adults with acute repetitive seizures (NCT03428360). Barber spoke with NeurologyLive about the diazepam product at the American Epilepsy Society's 2018 annual meeting.

At the time of the riluzole oral formulation’s orphan drug designation, Keith J. Kendall, chief executive officer of Aquestive, said that the company hopes to bring its oral soluble film to patients by the second half of 2019.²

"Patients suffering from this debilitating neurodegenerative disease often find swallowing to be difficult or impossible,” Kendall said. “To help manage one element of this challenging disease for people with ALS and their caregivers, we developed riluzole OSF to dissolve instantly in the mouth without water, using our proprietary PharmFilm technology."

A number of riluzole formulations have come before the FDA in the last year, with 7 approvals of the therapy worldwide. Most recently, in September 2018, ITF Pharma got the agency’s OK for its oral suspension of the product, marketed as Tiglutick, after being granted both fast track and orphan drug designations. That approval was the first and, as of now, only easy-to-swallow thickened riluzole liquid for ALS. Tiglutick is administered twice daily through an oral syringe.³

In November 2018, the FDA accepted an NDA for BHV-0223, Biohaven’s novel, low-dose Zydis formulation of riluzole that is administered sublingually. In December 2016, it was granted orphan drug designation. That NDA was backed by data from multiple studies and clinical trials that evaluated the bioequivalence of BHV-0223 to riluzole oral tablets as well as its safety and tolerability.⁴

In one of a pair of clinical trials, the original Sanofi formulation showed nonsignificant survival curves in a cohort of 155 patients with ALS when evaluated with the analysis specified in the study protocol (Log rank test, P = .12); however, the difference was found to be significant by another analysis (Wilcoxon test, P = .05). That study also showed an early increase in survival in patients given riluzole. There was also a difference between the treatment groups in the median survival from tracheostomy or death of approximately 90 days among patients who failed treatment during the study. No statistically significant difference in mortality was observed at the end of the study.⁵

In the second study with the original approval, which included 959 patients with ALS, similar results were shown, with a nonstatistically significant difference in survival curves when evaluated by Log-rank test (P = .076), but significant with Wilcoxon test (P = .05). In addition, the results showed an early increase in survival in patients in the treatment groups. Among the patients who failed treatment during the study, there was a difference between the treatment groups in median survival of approximately 60 days.⁵

REFERENCES

1. Aquestive Therapeutics Announces U.S. Food and Drug Administration (FDA) Acceptance of New Drug Application for Riluzole Oral Film for Treatment of ALS [press release]. Warren, NJ: Aquestive Therapeutics; Published April 16, 2019. prnewswire.com/news-releases/aquestive-therapeutics-announces-us-food-and-drug-administration-fda-acceptance-of-new-drug-application-for-riluzole-oral-film-for-treatment-of-als-300832795.html. Accessed April 16, 2019.

2. Aquestive Therapeutics Receives U.S. FDA Orphan Drug Designation for Riluzole Oral Soluble Film to Treat ALS [press release]. Warren, NJ: Aquestive Therapeutics; Published January 31, 2018. aquestive.com/single-news?post=6266. Accessed April 16, 2019.

3. ITF Pharma Announces FDA Approval Of TIGLUTIK™ (Riluzole) Oral Suspension for The Treatment Of Amyotrophic Lateral Sclerosis (ALS) [press release]. Berwyn, PA: ITF Pharma; Published September 6, 2018. prnewswire.com/news-releases/itf-pharma-announces-fda-approval-of-tiglutik-riluzole-oral-suspension-for-the-treatment-of-amyotrophic-lateral-sclerosis-als-300707653.html. Accessed April 16, 2019.

4. Biohaven Announces FDA Acceptance of 505(b)(2) NDA Filing for BHV-0223, a Novel Sublingual Delivery Form of Riluzole for the Treatment of Amyotrophic Lateral Sclerosis (ALS) [news release]. New Haven, Conn.: Biohaven Pharmaceutical Holding Company Ltd.; 2018. prnewswire.com/news-releases/biohaven-announces-fda-acceptance-of-505b2-nda-filing-for-bhv-0223-a-novel-sublingual-delivery-form-of-riluzole-for-the-treatment-of-amyotrophic-lateral-sclerosis-als-300754924.html. Accessed April 16, 2019.

5. Riluzole FDA Label. FDA website. Revised 2008. accessdata.fda.gov/drugsatfda_docs/label/2009/020599s011s012lbl.pdf. Accessed April 16, 2019.