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FDA Action Update, July 2022: Application Acceptances, Approvals, and Clinical Holds

Catch up on any of the neurology news headlines you may have missed over the course of the last month, compiled all into one place by the NeurologyLive® team.

Several FDA actions took place over the course of July 2022, including several approvals—including one tentative—as well as a clinical hold and an announcement of the reconvening of an advisory committee for ongoing trials of investigational therapies, among others.

With all the treatments that have progressed through the pipeline of clinical development, the NeurologyLive® team has been hard at work covering all the agency movements to make sure you are up to date on the latest news in neurology. To give you a chance to catch up on any of the headlines you may have missed over the course of the last month, we’ve compiled all the updates into one place. The coverage includes the latest FDA approvals, new designations, submissions and resubmissions, and clinical trial initiations and holds.

Click the read more buttons for more detail and information about each update.

FDA Advisory Committee Agrees to Reconvene for Decision on ALS Treatment AMX0035

On July 5, the FDA announced that its Peripheral and Central Nervous System Drugs Advisory Committee is planning to reconvene on September 7, 2022, to discuss the new drug application (NDA) for Amylyx Pharmaceuticals's AMX0035, an investigational agent in review for amyotrophic lateral sclerosis (ALS) treatment. The new meeting is set just a few weeks before the scheduled September 29, 2022, PDUFA date.1

This second-time meeting of the panel will also feature a conversation assessing whether AMX0035 demonstrated a significant enough efficacy in the phase 2 CENTAUR study (NCT03127514) and open-label extension, which serve as the foundation of the NDA. AMX0035 is an orally administered fixed-dose coformulation of sodium phenylbutyrate-taurursodiol, and originally had a PDUFA target action date of June 29, 2022, which was then pushed back early that month to September 29, 2022, to allow more time for the FDA to review data.2 In March, the AdComm panel voted 6–4 (6 no; 4 yes; 0 abstain) that the data included in the NDA did not adequately establish AMX0035 as an effective treatment for ALS, with several members citing concerns over the trial’s conduct and robustness of the data.

"We remain engaged with the FDA to advance AMX0035 through the review process as efficiently as possible,” Tammy Sarnelli, Global Head of Regulatory Affairs, Amylyx, said in a statement.1 "We are pleased that the members of the advisory panel will review additional analyses from our clinical studies, including recently published analyses, supporting the previously reported functional and overall survival benefit for AMX0035. As we have heard from the ALS community, there is a crucial need for new and effective treatments in ALS, and our team will continue to work around the clock to advance treatments for ALS in the US."

FDA Accepts BLA for Lecanemab in Alzheimer Disease, Sets PDUFA Date for January 2023

The following day, July 6, the FDA announced that it had accepted and granted priority review to Eisai and Biogen’s biologics license application (BLA) of lecanemab (BAN2401), an investigational agent to treat mild cognitive impairment (MCI) because of Alzheimer disease (AD). The submission was also given a Prescription Drug User Fee Act (PDUFA) action date, set for January 6, 2023.3

The investigational therapy's BLA was submitted under the accelerated approval pathway—the same pathway that aducanumab (Aduhelm) was approved under in 2021—with supporting data from the phase 2b proof-of-concept clinical trial known as Study 201 (NCT01767311). The agency noted it will consider and review results from the ongoing phase 3 Clarity AD study (NCT03887455) as complimentary data to aid in the verification of the clinical benefit of lecanemab, after approval. Dependent upon the results of Clarity AD, Eisai will submit for traditional approval of lecanemab to the FDA before the end of the first quarter in 2023.

Lecanemab is an antiamyloid beta (Aß) protofibril antibody designed to neutralize and eliminate soluble toxic Aß aggregates that are thought to contribute to the neurodegenerative process in AD. Study 201 was a Bayesian design clinical trial that randomly assigned 856 patients with early AD with a confirmed presence of amyloid pathology to lecanemab at multiple doses or placebo, identifying 10 mg/kg biweekly as the effective dose achieving at least 90% of the maximum treatment effect.

FDA Places Clinical Hold on Phase 2/3 ReMEDy2 Trial of DM199 in Acute Ischemic Stroke

Also on July 6, 2022, DiaMedica Therapeutics announced that the FDA had placed a clinical hold on the company’s ongoing phase 2/3 ReMEDy2 trial (NCT05065216) of its investigational treatment for acute ischemic stroke, known as DM199.4

The hold was initiated after 3 serious adverse events (AEs) were reported to the agency—at which time recruitment was also paused by DiaMedica—related to clinically significant, transient hypotension. These AEs occurred following initiation of the intravenous (IV) dose of DM199, and blood pressure levels of all 3 individuals recovered to their baseline levels within minutes after the infusion was halted. DM199 is a recombinant form of human tissue kallikrein-1 (KLK1), and in September 2021, the FDA granted it fast-track designation for the treatment of acute ischemic stroke.

“Patient safety is very important as we plan and conduct our clinical studies. Patient blood pressure is easily and routinely monitored in stroke patients which is why our study sites were able to quickly identify the issue and immediately stop the dosing of DM199, after which the patients then recovered within minutes and suffered no injuries. We are committed to working diligently with the FDA to resolve this issue and resume the trial as soon as reasonably practicable,” Kirsten Gruis, MD, chief medical officer, DiaMedica, said in a statement.4

SciSparc to Submit IND for Phase 2b Trial of Cannabis-Derived Therapy in Tourette Syndrome

A few days later, on July 8, SciSparc announced it had begun its submission process for an investigational new drug application (IND) for a phase 2b trial to evaluate its cannabis-derived agent, SCI-110, in patients with Tourette Syndrome (TS). As part of the submission, the company is looking to expand the trial and include a site in the US.5

The newly announced phase 2b trial stems from results of a previously conducted phase 2a trial, which showed that treatment using SCI-110 led to a 21% reduction of tic symptoms across a sample of patients with medically refractory TS. Additionally, the agent was proven to be safe, with no concerning AEs, and improved patients’ tic symptoms over time on the Yale Global Tic Severity Scale.

The news came shortly after an announcement from the company that it successfully completed the development of the formulation to be used in the multinational phase 2b study.6 SCI-110, currently in development for other indications, such as obstructive sleep apnea and Alzheimer disease (AD) agitation, contains a combination of dronabinol, an FDA-approved synthetic form of tetrahydrocannabinol (THC), with endocannabinoid palmitoylethanolamide (PEA).

Zonisamide Oral Suspension FDA-Approved for Partial Seizures in Epilepsy

Later in the month, on July 18, the FDA cleared a new oral suspension of zonisamide from Azurity Pharmaceuticals, marketed as Zonisade, for the treatment of partial seizures in adults and pediatrics aged 16 years and older with epilepsy.7 Designed as a carbonic anhydrase inhibitor, the efficacy and tolerability of the oral suspension had been previously established in 3 double-blind, placebo-controlled, multicenter trials.

"The provider community continues to seek reliable formulations of medicines that may reduce the epilepsy patient and caregiver burden and help improve treatment adherence,” James Wheless, MD, chair, Pediatric Neurology, University of Tennessee Health Science Center, said in a statement. “Zonisade addresses an important unmet need in patients who have difficulty swallowing or who are unable or unwilling to take tablets."

The recommended initial dose of zonisamide is 100 mg daily, although dosage may be increased to 100 mg daily every 2 weeks, based on clinical response and tolerability, to 400 mg daily. Those who tolerate a 400-mg daily dose and require further reduction of seizures may increase their dosage to a maximum of 600 mg daily. Additionally, the drug is contraindicated in patients who have demonstrated hypersensitivity to sulfonamides or zonisamide.

FT218 Receives Tentative Approval for EDS, Cataplexy in Adults With Narcolepsy

The next day, July 19, 2022, the FDA gave tentative approval to Avadel Pharmaceuticals for its extended-release oral suspension formulation of sodium oxybate, marketed as Lumryz, for the treatment of excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy.8 Previously, the therapy was known as FT218.

The NDA was supported by data from the phase 3 REST-ON study (NCT02720744), which was held under a special protocol assessment agreement with the FDA. The study met all 3 of its primary end points of change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacks within the 6-, 7.5-, and 9-g groups.

“We have reached a critical milestone, as tentative approval confirms the safety profile and clinical efficacy of Lumryz for adults with narcolepsy,” Greg Divis, chief executive officer at Avadel Pharmaceuticals, said in a statement.8 “Tentative approval is an important regulatory step forward and indicates Lumryz could potentially be granted final approval in 11 months or less. We believe once-at-bedtime Lumryz offers the opportunity to positively transform the lives of oxybate-eligible patients living with narcolepsy. Our extensive market research indicates Avadel is well-positioned to capture a significant share of the oxybate-eligible patient population which we estimate to be in excess of 30,000 patients. We are pursuing all options to accelerate final approval on or before June 2023 and prepare for commercial launch.”

FDA Clears Rapid Hyperdensity Tool for Inclusion in RapidAI Platform for Neurovascular Conditions

On July 21, 2022, the agency cleared a new tool for RapidAI’s neurovascular artificial intelligence (AI) platform, called Rapid Hyperdensity, as part of the clinical decision support and patient workflow. The tool allows for quick assessment of injury severity among those with traumatic brain injury and brain hemorrhages, with a goal of improving and speeding up patient care decisions.9

Rapid Hyperdensity uses noncontrast CT scans to evaluate the hyperdense tissue volume during the identification and assessment of intracerebral hemorrhage. In the hospital and mobile stroke unit settings, the Rapid Hyperdensity tool can provide additional contextual data to help inform triage and transfer decisions, which have been an area of focus in the clinical care of stroke and neurovascular conditions.

"As a neurosurgeon who treats many patients with intracranial hemorrhage (ICH), I am very excited for the recently approved Rapid Hyperdensity product that builds on the well-established RapidAI stroke platform,” Alejandro M. Spiotta, MD, director, Neuroendovascular Surgery Division, Medical University of South Carolina, said in a statement.9 “Detection of ICH via AI can save lives by helping to speed up diagnosis and accelerate [the] transfer to the best physician and hospital that can take care of the patient. With the addition of automatic hyperdense volume measurement, physicians can more easily track volume over time and help quickly identify which patients may require an intervention. This is an exciting time for those of us treating ICH."

ALS Therapy Tofersen Has NDA Accepted by FDA, Granted Priority Review

Finally, on July 26, Ionis Pharmaceuticals announced that the FDA had accepted its NDA for tofersen, an investigational antisense medicine being evaluated for the treatment of superoxide dismutase 1 (SOD1) ALS. Additionally, the agency assigned the treatment priority review and set a PDUFA date of January 25, 2023.10

Ionis will be seeking approval under the accelerated approval pathway based on data that showed changes in neurofilament. The NDA included data from a phase 1 study of healthy volunteers, a phase 1/2 dose ascending study, and the phase 3 VALOR study (NCT02623699) and its open-label extension. In VALOR, the most recently reported study, treatment with tofersen resulted in reductions in neurofilament light, accompanied by trends toward reduced disease progression and reductions in SOD1 protein in patients with SOD1 ALS.

"Acceptance of the new drug application for tofersen is a monumental milestone, not just for Ionis but for all people with SOD1 ALS, their families and healthcare professionals battling this devastating disease. To them we extend our deepest gratitude. Their courage has been instrumental to the achievement of this goal," C. Frank Bennett, PhD, executive vice president, chief scientific officer, and franchise leader for neurological programs, Ionis, said in a statement. "We also want to thank Biogen for their commitment to advancing tofersen, which, if approved, will be the first treatment that targets a genetic cause of ALS. Acceptance of the NDA for tofersen further strengthens Ionis' platform strategy to target all forms of ALS and central nervous system disorders more broadly."

REFERENCES
1. Amylyx Pharmaceuticals announces FDA plan to reconvene advisory committee to review AMX0035 NDA for the treatment of ALS on September 7, 2022. News release. Amylyx Pharmaceuticals. July 5, 2022. Accessed July 6, 2022. https://www.businesswire.com/news/home/20220704005425/en/Amylyx-Pharmaceuticals-Announces-FDA-Plan-to-Reconvene-Advisory-Committee-to-Review-AMX0035-NDA-for-the-Treatment-of-ALS-on-September-7-2022
2. Amylyx Pharmaceuticals Receives Notification of PDUFA Date Extension for AMX0035 for the Treatment of ALS. News release. Amylyx. June 3, 2022. Accessed July 6, 2022. https://finance.yahoo.com/news/amylyx-pharmaceuticals-receives-notification-pdufa-110000354.html
3. The FDA accepts BLA and grants priority review for lecanemab for treatment of early Alzheimer disease under the accelerated approval pathway. News release. Biogen / Eisai. July 6, 2022. Accessed July 6, 2022. https://www.biospace.com/article/releases/the-fda-accepts-bla-and-grants-priority-review-for-lecanemab-for-treatment-of-early-alzheimer-s-disease-under-the-accelerated-approval-pathway/
4. DiaMedica Therapeutics Announces Clinical Hold of its Phase 2/3 ReMEDy2 Clinical Trial for DM199. News release. DiaMedica. July 6, 2022. Accessed July 8, 2022. https://www.diamedica.com/investors/press-releases/detail/1646/diamedica-therapeutics-announces-clinical-hold-of-its-phase
5. SciSparc announces expanding its clinical operations to include a US site towards its phase 2b trial with its proprietary SCI-110 for the treatment of Tourette Syndrome. News release, SciSparc. July 8, 2022. Accessed July 13, 2022. https://www.biospace.com/article/releases/scisparc-announces-expanding-its-clinical-operations-to-include-a-u-s-site-towards-its-phase-iib-trial-with-its-proprietary-sci-110-for-the-treatment-of-tourette-syndrome/
6. SciSparc advances its phase 2b clinical trial in patients with Tourette syndrome with its proprietary drug candidate SC-110. News release. SciSparc. January 18, 2022. Accessed July 13, 2022. https://www.prnewswire.com/news-releases/scisparc-advances-its-phase-iib-clinical-trial-in-patients-with-tourette-syndrome-with-its-proprietary-drug-candidate-sci-110-301462718.html
7. Azurity Pharmaceuticals, INC. announces FDA approval of Zonisade (zonisamide oral suspension). News release. Azurity Pharmaceuticals. July 18, 2022. Accessed July 18, 2022. https://www.prnewswire.com/news-releases/azurity-pharmaceuticals-inc-announces-fda-approval-of-zonisade-zonisamide-oral-suspension-301587834.html
8. Avadel Pharmaceuticals Announces Tentative Approval of LUMRYZ™ (sodium oxybate) extended-release oral suspension. News release. Avadel. July 19, 2022. Accessed July 20, 2022. https://www.globenewswire.com/news-release/2022/07/19/2481626/0/en/Avadel-Pharmaceuticals-Announces-Tentative-Approval-of-LUMRYZ-sodium-oxybate-extended-release-oral-suspension.html
9. RapidAI Receives FDA Clearance for Rapid Hyperdensity. News release. RapidAI. July 21, 2022. Accessed July 21, 2022. https://www.rapidai.com/press-release/rapid-hyperdensity
10. Ionis announces that FDA accepts new drug application and grants priority review of tofersen for a rare, genetic form of ALS. News release. Ionis. July 26, 2022. Accessed July 26, 2022. https://www.prnewswire.com/news-releases/ionis-announces-that-fda-accepts-new-drug-application-and-grants-priority-review-of-tofersen-for-a-rare-genetic-form-of-als-301592936.html