FDA Pushes Back Solriamfetol PDUFA Date for Excessive Sleepiness

December 27, 2018

The agency has decided that a major amendment is needed for the therapy’s NDA and has pushed the PDUFA goal date to March 20, 2019.

Jed Black, MD

Solriamfetol, an investigational agent for the improvement of wakefulness and reduction of excessive daytime sleepiness in adults with narcolepsy or obstructive sleep apnea (OSA), has had its Prescription Drug User Fee Act (PDUFA) goal date extended an additional 3 months, to March 20, 2019.1

According to manufacturer Jazz Pharmaceuticals, during the discussions surrounding the draft labeling, the FDA determined that the New Drug Application (NDA) submission constitutes “a major amendment” to the NDA. In order to provide adequate time for a full review of this submission, the agency has chosen to extend the PDUFA date.

"We appreciate the opportunity to work with the FDA to complete the review process as soon as possible," said Jed Black, MD, the senior vice president of Sleep and CNS Medicine at Jazz Pharmaceuticals and adjunct professor at Stanford University Medical Center’s Stanford Center for Sleep Sciences and Medicine, in a statement. "We are committed to addressing unmet needs in sleep medicine and look forward to offering solriamfetol as a meaningful treatment option for patients living with excessive daytime sleepiness associated with narcolepsy or OSA."

Solriamfetol, a selective dopamine and norepinephrine reuptake inhibitor (DNRI), is also in development for the treatment of excessive sleepiness in adult patients with Parkinson disease. Jazz Pharmaceuticals acquired a license to develop and commercialize solriamfetol from Aerial Biopharma in 2014. It was previously granted an Orphan Drug designation by the FDA for narcolepsy.

Michael Thorpy, MBChB, the director of the Sleep-Wake Disorders Center at Montefiore Medical Center, previously told NeurologyLive that solriamfetol may be a unique medicine in its mechanism of action. He noted that the majority of drugs that improve alertness work through a dopaminergic mechanism, but solriamfetol works through both norepinephrine and dopamine.

“Norepinephrine is an important wake-promoting neurotransmitter,” he said. “Although we don’t know exactly how it’s working, it’s interesting that you’re getting this direct stimulation of wake-promoting neurons through the dopaminergic mechanism, and norepinephrine is important in turning off sleep drive through a nucleus called the ventrolateral preoptic nucleus, also known as a VLPO. There’s a possibility—and we don’t really know this fully—but it may be turning off the drive for sleep as well as stimulating the wake-promoting neurons. So, it may be quite a different effect from other medications that are working predominantly through dopaminergic mechanisms.”

In its clinical trial program, TONES, the therapy showed efficacy compared to placebo in both conditions. In the TONES 5 trial, after approximately 6 months of maintenance treatment, a randomized 2-week placebo-controlled phase was performed. In this phase, there was a -3.7 Least Squares (LS) mean change in Epworth Sleepiness Scale (ESS) with solriamfetol versus placebo (95% CI, -4.80 to -2.65; P <.0001). The mean LS was 1.6 with solriamfetol compared with 5.3 with placebo.

Meanwhile, in the TONES 2 study in patients with narcolepsy, solriamfetol decreased ESS by -3.8 to -6.4 across 3 doses, while the mean change for placebo was -1.6. Mean sleep latency on maintenance of wakefulness test (MWT) was 12.3 minutes at the highest dose of 300 mg, to 4.7 minutes at the lowest dose of 75 mg. For placebo, the mean latency was 2.1 minutes.

In TONES 3, in patients with OSA, the mean sleep latency was 13 minutes at the highest dose of solriamfetol (300 mg) and 4.7 at the lowest (37.5 mg), while in the placebo group, it was 0.2 minutes. The ESS was -7.9 in the highest dose arm and -5.1 with the lowest versus -3.3 with placebo. In TONES 4, also a trial in OSA, the mean sleep latency by MWT was -1.0 minute with solriamfetol compared with -12.1 minutes for placebo. The ESS was -0.1 with solriamfetol versus 4.5 for placebo.

Aside from 4.2% of patients reporting headache, nausea, insomnia, nasopharyngitis, dry mouth, and anxiety in TONES 5, the therapy had little to no serious adverse events (AEs) reported.

In March 2018, Karen Smith, MD, PhD, the executive vice president of research and development and chief medical officer at Jazz Pharmaceuticals, said that Jazz believes solriamfetol will provide a significant option for patients living with excessive sleepiness due to narcolepsy or OSA, and that the company looked forward to working with the FDA during the review process.2

REFERENCES

1. Jazz Pharmaceuticals Receives New PDUFA Goal Date for Solriamfetol for Excessive Daytime Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea [press release]. Dublin, Ireland: Jazz Pharmaceuticals plc; Published December 21, 2018. prnewswire.com/news-releases/jazz-pharmaceuticals-receives-new-pdufa-goal-date-for-solriamfetol-for-excessive-daytime-sleepiness-associated-with-narcolepsy-or-obstructive-sleep-apnea-300770117.html. Accessed December 27, 2018.

2. Jazz Pharmaceuticals Announces FDA Acceptance of NDA for Solriamfetol (JZP-110) for Excessive Sleepiness Associated with Narcolepsy or Obstructive Sleep Apnea [press release]. Dublin, Ireland: Jazz Pharmaceuticals plc; Published March 2, 2018. prnewswire.co.uk/news-releases/jazz-pharmaceuticals-announces-fda-acceptance-of-nda-for-solriamfetol-jzp-110-for-excessive-sleepiness-675650373.html. Accessed December 27, 2018.