FT218 – Avadel’s lead investigational asset

Sodium Oxybate is currently the only drug approved for the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients suffering from narcolepsy.

Avadel’s FT218 is an investigational, once-nightly, extended-release, formulation of sodium oxybate designed to treat excessive daytime sleepiness (EDS) and cataplexy in patients suffering from narcolepsy.

Once-nightly FT218 has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of narcolepsy. The designation was granted on the plausible hypothesis that once-nightly FT218 may be clinically superior to a formulation of sodium oxybate that is already approved by the FDA for the same indication. In particular, once-nightly FT218 may be safer due to ramifications associated with the dosing regimen of the previously-approved, twice-nightly product. The twice-nightly sodium oxybate market is currently valued at an estimated annualized rate of $1.7 billion1. Avadel’s market research leads it to believe that FT218, if approved by the FDA, has the potential to take a significant share of this market. Avadel has patent protection until at least mid-2037.

FT218 is currently being studied in the pivotal REST-ON study (Randomized study Evaluating the efficacy and SafeTy of a Once Nightly formulation of sodium oxybate), a double-blind, randomized, placebo-controlled Phase 3 trial to assess the efficacy and safety in the treatment of excessive daytime sleepiness and cataplexy in patients suffering from narcolepsy. The REST-ON study completed patient enrollment (a total of 212 patients) in December 2019. The last patient last visit (LPLV) is expected to occur by the end of the first quarter of 2020, with topline data expected in the second quarter of 2020. To find out more about the REST-ON study, please visit the clinical trial website.

Published FT218 Data:

In June 2019, Avadel presented pharmacokinetic (PK) data in healthy volunteers for FT218 at the 33rd Annual Meeting of the Associated Professional Sleep Societies. These data include a head-to-head pilot PK comparison of three prototypes of FT218 to twice-nightly sodium oxybate at 4.5 g and dose proportionality of FT218 across three doses (4.5g, 6g and 9-g).

In the pilot PK study, the 4.5g dosage of FT218 (prototype 2) demonstrated lower overall peak plasma concentrations (Cmax),similar total exposures (AUC), and similar morning plasma levels (C8H) compared to twice-nightly (i.e. 2.25g x 2) sodium oxybate in a head-to-head study. See poster presentation here.

Figure 1: plasma levels of FT218 single dose versus twice-nightly dosing

In a dose proportionality study, FT218 was dose proportional for Cmax and higher than dose proportional for AUC. See poster presentation here.

Figure 2: FT218 plasma concentration time curves for rising doses from 4.5g to 9g per night

In September 2109 at the World Sleep 2019 Congress, leading sleep expert, Dr. Michael Thorpy, Director of the Sleep-Wake Disorders Center at the Montefiore Medical Center, presented PK data for FT218 from four Phase 1 studies: two head-to-head studies comparing once-nightly FT218 at 4.5g and 6g of to 4.5g and 6g (divided into two equal doses) of twice-nightly sodium oxybate, one evaluating the food effect of FT218, and the last one determining the dose proportionality of FT218. According to Dr. Thorpy, “The totality of the pharmacokinetic data from these four Phase 1 studies demonstrates that Avadel has developed a formulation of sodium oxybate that exhibits a pharmacokinetic profile desirable for once-nightly dosing.” The slides from Dr. Thorpy’s presentation can be viewed here.

In total, the data demonstrated:

  • Once-nightly FT218 at 4.5g and 6 g demonstrated:
    • A lower overall Cmax and equivalent exposure to twice-nightly sodium oxybate IR
    • Similar morning plasma levels (C8h) and variability to twice-nightly sodium oxybate IR
  • For FT218, Cmax was dose proportional and AUC was slightly higher than dose proportional
  • In the Fed state, as expected, both AUC and Cmax of FT218 were lower than in the Fasted State
  • Up to the 9 g dose level, FT218 was generally well tolerated and the safety profile appeared comparable to twice-nightly sodium oxybate IR at the 4.5g and 6 g dose levels

In addition, more information on narcolepsy can be found by visiting http://www.narcolepsynetwork.com/.