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FDA Action Update, October 2022: Submissions, Extensions, and Deferred Action

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.

The FDA took a handful of actions in October 2022, including an extension in amyotrophic lateral sclerosis (ALS), an application submission and a trial pause for the population with Huntington disease (HD), a trial submission in Alzheimer disease (AD) and several other decisions.

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.

Supernus Issued CRL for Continuous Apomorphine Infusion in Parkinson Disease

On October 10, Supernus announced that the FDA issued it a complete response letter (CRL) regarding its new drug application (NDA) submission of the investigational agent SPN-830, a continuous apomorphine infusion pump designed to treat Parkinson disease (PD) motor fluctuations, or OFF episodes.1

In the CRL, the agency noted that it will require additional information and analyses related to the device, including labeling, product quality and manufacturing, device performance, and risk analysis. No additional efficacy or safety clinical studies were requested. The agency also mentioned in the CRL that the application's approval would require inspections that could not be completed because of travel restrictions amid the COVID-19 pandemic. The FDA's initial determination, according to an announcement from Supernus, is that the application amendment will be subject to a 6-month review timeline.

Jack Khattar, president and CEO, Supernus, said in a statement1 that, “SPN-830 remains a key priority for Supernus as there is a need to provide a minimally invasive therapy for PD patients who are experiencing motor fluctuations not adequately controlled with current treatment options. We are committed to PD patients and to working with the FDA to address the CRL issues so that we can put the NDA back on track towards potential US approval.

Tiziana Life Sciences Plans IND for Phase 1 Study of Intranasal Foralumab in Alzheimer Disease

Two days later, on October 12, Tiziana Life Sciences announced that it plans to file an investigational new drug application (IND) to the FDA for a phase 1 study to study intranasal foralumab in AD. The IND is expected to be filed by the third quarter of 2023 upon the completion of requested toxicology studies, with the phase 1 program beginning by the end of 2023.2

"I am thrilled to see the company advancing foralumab into another promising central nervous system (CNS)-related therapeutic area with high unmet need. Intranasal foralumab’s unique action on regulatory T-cells should allow us to study multiple CNS inflammatory pathology indications for this unique drug,” Gabriele Cerrone, executive chairman and interim chief executive officer, Tiziana Life Sciences, said in a statement.2

The decision came after the company received an affirmative response from the FDA on a pre-investigational NDA for the human anti-CD3 monoclonal antibody, formerly known as Nl-0401. Foralumab has been shown to reduce release of key cytokines in healthy volunteers and in patients with Crohn disease. Tiziania had previously submitted a patient application on the potential use of foralumab to improve the success of chimeric antigen receptor T-cell therapy for cancer and other human diseases.

FDA Extends Review Date for ALS Treatment Tofersen

A short time later, on October 17, the FDA announced that it was extending its review of Biogen’s investigational agent tofersen—originally scheduled to be completed by January 25, 2023—pushing the PDUFA date out to April 25, 2023. The drug is designed to treat patients with a SOD1 mutation-mediated ALS. The NDA was originally accepted in July 2022.3

Currently there are no approved therapies for patients with SOD1 mutation ALS, and only a handful of approved therapies for ALS overall. Tofersen is an antisense oligonucleotide, with data from a phase 1 study of healthy volunteers, a phase 1/2 dose ascending study, the pivotal phase 3 VALOR study (NCT02623699), and its open-label extension (OLE), serving as the basis for the NDA.

"We are committed to providing any details the agency needs to complete the review of tofersen,” Priya Singhal, MD, MPH, Head of Global Safety and Regulatory Sciences, and Interim Head of R&D, Biogen, said in a statement.3 "As the review continues, Biogen will maintain the early access program for tofersen."

PTC Therapeutics Pauses Phase 2 Study of PCT518 in Huntington Disease

The next day, on October 18, PTC Therapeutics announced that the US enrollment for the phase 2 PIVOT-HD trial (NCT05358717) of PTC518, a treatment for HD, had been paused. The FDA was seeking more data about the investigational drug, prompting the enrollment halt.4

The study of the oral, small molecule splicing modifier did not halt enrollment at sites in several European countries and in Australia. PTC noted that there have been no treatment-related adverse events (AEs) reported in the study in the US or outside of the US since its initiation in March 2022, adding that it will continue to work with the agency in obtaining the data needed to proceed with the PIVOT-HD trial. PTC noted it is still working toward sharing data from the 12-week portion of the study in the first half of 2023.

A 2-part study, PIVOT-HD consists of an initial 12-week placebo-controlled period that focuses on the pharmacological and pharmacodynamic effect of PTC518, followed by a 9-month placebo-controlled period, during which blood, cerebrospinal fluid, and radiographic biomarker data will be collected. The primary outcome of the study is safety, assessed by number of patients with AEs, and change from baseline in total huntingtin protein at day 85.

FDA Defers Action on AT-GAA Treatment for Pompe Disease

On October 28, the FDA announced that it had deferred action on the biologics license application of cipaglucosidase alfa, an investigational combination therapy for the treatment of late-onset Pompe disease developed by Amicus Therapeutics because of COVID-19-related travel restrictions that did not allow the agency to conduct the required inspection of the WuXi Biologics manufacturing site in China during the review cycle.5

"We are now one step away from the necessary approvals for AT-GAA in the US. We continue to believe this is a question of ‘when’ not ‘if’ AT-GAA will be approved and we will continue to work with great urgency to support the FDA’s completion of the final plant inspection necessary for approval so that this important new treatment option is made available for people living with Pompe disease in the United States," Bradley Campbell, president and chief executive officer, Amicus Therapeutics, said in a statement.5

Amicus noted that the sole reason for the FDA-issued letter was the agency's inability to complete the manufacturing facility inspection, and not because of safety concerns. The FDA has not provided an anticipated action date; however, the agency will be engaged with Amicus to develop plans and logistics for a preapproval inspection plan.

Neurocrine Biosciences Submits sNDA for Valbenazine in the Treatment of Huntington Disease Chorea

Right around the end of October, Neurocrine announced the presentation of new data on its treatment valbenazine, which it is evaluating in the treatment of chorea associated with HD in the phase 3 KINECT-HDstudy (NCT04102579), noting in the same release that it had completed the submission of a suppemental NDA to the FDA for the agent.6

The sNDA was supported by the recently announced data, as well as findings from the ongoing open-label KINECT-HD2 study (NCT04400331). Notably, enrollment in the long-term KINECT-HD2 study is still ongoing, with a target of 158 individuals. Previously, in May 2022, the company announced that valbenazine had received an orphan drug designation from the FDA.

Neurocrine’s chief medical officer, Eiry W. Roberts, MD, said in a statement that "the additional findings of the phase 3 KINECT-HD study presented in this poster demonstrate an improvement in chorea over time, with an increase in responder rates in the [Total Maximal Chorea score] primary end point, and [Clinical Global Impression of Change] and [Patient Global Impression of Change] outcomes by study visit up to week 12.”

1. Supernus Provides Regulatory Update on SPN-830. News release. Supernus. October 10, 2022. Accessed November 8, 2022. https://www.globenewswire.com/news-release/2022/10/10/2531002/19871/en/Supernus-Provides-Regulatory-Update-on-SPN-830.html
2. Tiziana Life Sciences plans to submit IND for phase 1 trial of intranasal foralumab in Alzheimer disease patients. News release. Tiziana Life Sciences. October 12, 2022. Accessed November 8, 2022. https://www.tizianalifesciences.com/news-item?s=2022-10-12-tiziana-life-sciences-plans-to-submit-ind-for-phase-1-trial-of-intranasal-foralumab-in-alzheimers-disease-patients
3. Biogen announces FDA’s 3-month extension of review period for the new drug application for tofersen. News release. Biogen. October 17, 2022. Accessed November 8, 2022. https://www.globenewswire.com/news-release/2022/10/17/2535365/0/en/Biogen-Announces-FDA-s-3-Month-Extension-of-Review-Period-for-the-New-Drug-Application-for-Tofersen.html
4. PTC provides update on ongoing global PIVOT-HD trial of PTC518. News release. October 18, 2022. Accessed November 8, 2022. https://www.biospace.com/article/releases/ptc-provides-update-on-ongoing-global-pivot-hd-trial-for-ptc518/
5. US FDA defers action on filing for AT-GAA in late-onset Pompe disease. News release. Amicus Therapeutics. October 28, 2022. Accessed November 8, 2022. https://www.globenewswire.com/news-release/2022/10/28/2544135/0/en/U-S-FDA-Defers-Action-on-Filing-for-AT-GAA-in-Late-onset-Pompe-Disease.html
6. Neurocrine Biosciences Presents Additional Phase 3 Data for KINECT-HD Study Evaluating Valbenazine for Chorea Associated with Huntington Disease at HSG 2022. News release. Neurocrine. November 3, 2022. Accessed November 8, 2022. https://www.prnewswire.com/news-releases/neurocrine-biosciences-presents-additional-phase-3-data-for-kinect-hd-study-evaluating-valbenazine-for-chorea-associated-with-huntington-disease-at-hsg-2022-301666869.html