Marco Meglio

This article was originally published in NeurologyLive.

The US Food and Drug Administration (FDA) has approved JZP-258 (Xywav) for the treatment of idiopathic 

, making it the first treatment cleared for this indication. The approval was granted to Jazz Pharmaceuticals. 

The combination agent of calcium, magnesium, potassium, and sodium oxybates will be available to patients in the fourth quarter of 2021 following Risk Evaluation and Mitigation Strategies (REMS) implementation.

The company announced the acceptance of its supplemental new drug application (sNDA) for JZP-258 in February, which included data from a positive phase 3 study (NCT03533114) that showed the investigational agent was effective and safe for adults with idiopathic hypersomnia. 

The oral solution received fast track designation from the FDA in September 2020 for this indication, and in December was granted a rolling submission, allowing for the submission of portions of the application as completed.

Idiopathic hypersomnia is a debilitating neurologic sleep disorder characterized by chronic excessive daytime sleepiness (EDS). A majority of physicians in the space have turned to off-label use of wake-promoting therapies typically used in patients with narcolepsy to help address the sleepiness issues.

"We are excited that with today's approval Xywav will become the first and only medicine indicated to treat idiopathic hypersomnia, a unique medical condition that can have significant effects on the lives of those diagnosed with the condition," Bruce Cozadd, chairman and chief executive officer, Jazz Pharmaceuticals, said in a 

 "This milestone exemplifies our patient-focused R&D strategy and internal development capabilities, and underscores oxybate as a key growth opportunity for Jazz. With this launch we will have achieved our goal of five product launches in two years."

The double-blind, multicenter, randomized phase 3 trial featured patients who had EDS associated with idiopathic hypersomnia, and all of those treated with the agent experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores–the primary end point–during the open-label titration period.

A randomized withdrawal portion of the study included 115 patients who were assessed on primary and key secondary end points including Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS). 

Those who received JZP-258 reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. Furthermore, highly statistically significant worsening was observed for those who received placebo compared with JZP-258 for ESS (

Xywav has a Boxed Warning as a central nervous system (CNS) depressant and for its potential for abuse and misuse. The most common adverse reactions, occurring in at least 5% of adults in the phase 3 study, were nausea, headache, dizziness, anxiety, insomnia, decreased appetite, hyperhidrosis, vomiting, diarrhea, dry mouth, parasomnia, somnolence, fatigue, and tremor.

JZP-258 originally received approval for the treatment of cataplexy or EDS in patients 7 years of age or older with narcolepsy in July 2020. The basis of that approval was built on data from a phase 3 double-blind, placebo-controlled, randomized-withdrawal, multicenter study, for which the drug demonstrated statistically significant differences (

 <.0001) in the weekly number of cataplexy attacks and ESS scores compared with placebo.

"Idiopathic hypersomnia can have a significant impact on the social, educational and occupational functioning of people living with the condition. Today's FDA approval is a major milestone for the entire idiopathic hypersomnia community as Xywav becomes the first medicine approved to manage this chronic sleep disorder," Dianne Powell, board chair and chief executive officer, Hypersomnia Foundation, said in a statement.

"Our mission and values have consistently centered around supporting patients and scientific discovery and this announcement truly provides a sense of hope for those living with idiopathic hypersomnia."

Articles

The combination agent breaks ground as the first treatment approved for this indication.

JZP-258 Receives FDA Approval for Idiopathic Hypersomnia

High-dose blarcamesine resulted in a significant improvements in symptom scores for patients with 

The full results from the proof-of-concept phase 2 study of blarcamesine suggests the drug’s impact on increasing sigma-1 receptor (SIGMAR1) mRNA expression corresponded significantly with responses on primary and secondary end points in this patient population.

Anavex Life Sciences noted it plans on submitting these data to the US Food and Drug Administration (FDA) to seek regulatory guidance.

Treatment with blarcamesine, formerly known as ANAVEX 2-73, resulted in significant (

= .035) mRNA expression increase of SIGMAR1, which correlated with clinical efficacy as measured by the Cognitive Drug Research (CDR) system Continuity of Attention (CoA; 

= .029) and CDR system Power of Attention (PoA; 

The correlation also remained true on secondary end points such as Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III (

"This is now the second independent placebo-controlled clinical ANAVEX 2-73 phase 2 study to confirm the predictive biomarker of response established with SIGMAR1 mRNA expression,” Christopher U. Missling, PhD, president and chief executive officer, Anavex, said in a statement. "We believe that the easily accessible predictive biomarker combined with the observed efficacy is a consistent explanation of the efficacy in this second largest CNS indication with unmet medical need. This data further strengthens the foundation of ANAVEX 2-73 as a cross-platform [central nervous system] drug.”

The phase 2 study included 132 patients with PDD randomized 1:1:1 to blarcamesine 30 mg, 50 mg, or placebo for up to 14 weeks. Study participants were allowed to be on a stable regimen of anti-PD medications, including levodopa, dopamine agonists, MAO-B inhibitors, or entacapone.

Those included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score (

By the end of the study period, the MDS-UPDRS total score improved by ­10.98 points in the 50-mg dose group and worsened by 3.53 points in the placebo group, corresponding to a relative improvement of 18.9%. This far exceeds an empirically established cutoff of a 7.1-reduction for detecting meaningful clinical change.

The clinically meaningful improvements observed in patients with PDD suggest that the agent has the capability of slowing and reversing symptoms that progress in PD, an urgent unmet need for this patient population. Notably, blarcamesine did not impair sleep and had a positive effect on rapid eye movement (REM) sleep behavior disorder.

Previously reported data presented at the Clinical Trials on Alzheimer’s Disease (CTAD) 2020 Annual Meeting showed a dose-dependent (

= .003), statistically significant improvement of CDR system Episodic Memory of 42.22 points between 50-mg blarcamesine and placebo. CDR system Episodic Memory has been shown to be highly correlated (70%) with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog).

Patients in the high-dose group also experienced an ADAS-Cog mean change from baseline of –1.9, an 8% mean improvement from baseline to 14 weeks. Investigators documented a 4-point improvement difference of calculated corresponding ADAS-Cog score between the blarcamesine treatment group and the placebo group from baseline to the end of the study period. Anavex is also evaluating blarcamesine in a phase 2b/3 study that features 

The company recently announced that they have exceeded their target enrollment goal of 450 patients, and topline results from the ongoing study are expected to be announced by mid-2022.

Patients included in the high-dose group demonstrated statistically significant improvements compared to placebo for MDS-UPDRS total score.

Blarcamesine Improves Symptoms for Patients with Parkinson Disease Dementia

A new study endeavor will explore US Food and Drug Administration (FDA) approved medications for efficacy in Alzheimer disease.

According to a recent announcement, the National Institutes of Aging (NIA) will be conducting a new innovative study to determine whether medicines currently FDA-approved to treat conditions other than dementia can help prevent or treat Alzheimer disease (AD).

Neurologist Madhav Thambisetty, MD, DPhil, will lead the project in collaboration with researchers at Harvard Medical School, Rutgers University, and Johns Hopkins University School of Medicine, to design a new approach that would be an alternative to traditional drug discovery.

The study, titled Drug Repurposing for Effective Alzheimer’s Medicines (DREAM), will focus on drugs that have already been shown safe and effective for other conditions. The investigators will forego observing data from animal testing models and will instead look at data from large numbers of people who have already been treated with these compounds for other disorders.

Plans for the DREAM study were recently published in 

Alzheimer’s and Dementia: Translational and Clinical Interventions

 Based on abnormal glycolysis as a primary progenitor pathway, researchers hypothesized that there may be greater than 20 related and distinct biochemical pathways that are dysregulated in the AD-related dementia (ADRD) brain. These abnormalities may precede or influence the brain changes that lead to dementia.

To further test this hypothesis, the investigators generated a list of 250 genes that are known to regulate individual reactions within the component pathways of the Alzheimer Disease Aberrant Metabolism (ADAM) network. Using these genetic regulators within the aforementioned dysregulated pathways, 35 FDA-approved drugs were identified as potential repurposing candidates. Of these 35, the team selected 15 drugs as the best candidates for further analysis.

The DREAM study leverages 2 large population-based data sources for pharmacoepidemiologic analyses, the first being the insurance claims data from the Medicare program, and the second is the Clinical Practice Research Datalink (CPRD) GOLD, which is a large United Kingdom primary care database containing de-identified data on nearly 15 million people. Results from the DREAM study could help guide future research, especially if an identified drug appears to reduce the risk or severity of AD and ADRDs.

The hypothesis of repurposing drugs for AD has become increasingly popular in recent years. Cleveland Clinic recently announced that it will conduct a 

, an FDA-approved anti-cancer drug, in early-stage AD or mild cognitive impairment (MCI). That project is comprised of 2 dual studies and is led by Marwan Sabbagh, MD, and Boris Decourt, PhD.

Sabbagh, along with colleagues including Jeffrey Cummings, MD, ScD, who serves as the director emeritus of the Lou Ruvo Center for Brain Health at Cleveland Clinic, and vice chair of the Department of Brian Health at the University of Nevada – Las Vegas, recently published a yearly report on the 

, in which the group noted there was an increase in the number of repurposed agents in the pipeline from 2019 to 2020.4 This datapoint drew Cummings’ attention as a potential area to prioritize.

One [thing that stuck out] was the great increase in the number of repurposed compounds that are in the pipeline. One of the things that alarmed me though was the relatively small number of agents coming into phase 1. We really have to get those drugs out of the lab, out of the animals, and into humans more successfully.”

The investigators generated a list of 250 genes that are known to regulate individual reactions within the component pathways of the Alzheimer Disease Aberrant Metabolism (ADAM) network.

Researchers Look for Potential Treatments for Alzheimer Disease

The US Food and Drug Administration (FDA) has accepted a New Drug Application (NDA) for Idorsia’s daridorexant, an investigational dual orexin receptor antagonist, for the treatment of adult patients with insomnia, according to a recent announcement.

The NDA includes data from a comprehensive clinical and nonclinical developmental program, which demonstrated the efficacy of daridorexant on subjective sleep parameters and an improvement in daytime functioning, while maintaining a favorable safety profile. Idorsia submitted the NDA to the FDA on January 8, 2021 and noted that should they receive approval, daridorexant will launch in the first half of 2022.

"I’m very happy that this first regulatory hurdle is behind us. This was a huge NDA and the team has done an excellent job in preparing the dossier, on which the FDA can judge the properties and merits of daridorexant,” Jean-Paul Clozel, MD, chief executive officer, Idorsia, said in a statement. “We now stand-by to work with the FDA to answer any questions that might arise concerning the effect of daridorexant on sleep, daytime functioning and its safety profile.”

If approved, daridorexant would become the first sleep medication to demonstrate an improvement in sleep and daytime functioning, as measured by the Insomnia Daytime Symptoms and Impacts Questionnaire, while keeping a favorable safety profile in adult and elderly patients.

In April 2020, the company read out data from its first pivotal phase 3 study of daridorexant (NCT03545191), 

. Doses of both 25-mg and 50-mg daridorexant significantly improved sleep onset and sleep maintenance as measured objectively in a sleep lab by polysomnography. Self-reported data from daily diaries also showed the drug’s significant impact on subjective total sleep time, as well.

The double-blind, randomized, placebo-controlled, parallel-group, phase 3 study included 930 adult and elderly patients with insomnia and evaluated treatment with daridorexant over a 3-month period. In addition to improvements in sleep onset and sleep maintenance, treatment with 25-mg and 50-mg daridorexant also significantly improved total sleep time subjectivity (sTST) compared with placebo.

All 3 of these improvements were seen at both the 1- and 3-month timepoints. That study was part of a larger phase 3 registration program that included another phase 3 study and extension study. In July 2020, 

the safety and efficacy of daridorexant was confirmed

 in the publication of a second pivotal phase 3 study.

The latest data demonstrated a statistically significant improvement in sleep maintenance and subjective total sleep time at months 1 and 3 for patients, nearly 40% of whom were 65 or older, who received the 25-mg dose. Additionally, the therapy also demonstrated positive effects on daytime functioning, which were observed in the first phase 3 study as well.

The safety of the drug was consistent across both studies, with treatment-emergent adverse events (TEAEs) reported in 38.2% and 39.3% of patients treated with 10 mg or 25 mg daridorexant compared with 32.7% in the placebo group. The most common TEAEs observed were nasopharyngitis, headache, somnolence, and fatigue. Notably, no cataplexy-like events or next-morning residual effects were reported, and no suicide or self-injurious behavior was observed.

If approved, daridorexant would become the first sleep medication to demonstrate an improvement in sleep and daytime functioning.