FDA Action Update, September 2023: Approvals, Hold Lifted, and Clearance

The FDA was busy in September 2023, making a number of decisions on potential new therapeutic agents including granting approvals, updating a label, issuing complete response letters, granting a clearance, and lifting a clinical trial hold, among other actions.

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 details and information about each update.

FDA Issues Ravulizumab Complete Response Letter for NMOSD, Citing Needed Changes to REMS Program

Eariler in the month, on September 6, the FDA issued a complete response letter (CRL) to AstraZeneca for the supplemental biologics license application (sBLA) of ravulizumab (Ultomiris) as a potential treatment for patients with neuromyelitis optica spectrum disorder (NMOSD). In its response, the agency did not raise concerns about the provided evidence for the therapy, rather it requested modifications to enhance the Risk Evaluation and Mitigation Strategy (REMS) program.¹

According to an announcement from the company, the requested modifications are in reference to validate patients’ meningococcal vaccination status or prophylactic administration of antibodies prior to receiving treatment. AstraZeneca is expected to work with the FDA to determine the next steps for the REMS modifications and will not need any additional analysis or reanalysis of the phase 3 CHAMPION-NMOSD study (NCT04201262), the supporting trial for ravulizumab’s sBLA. Ravulizumab remains an approved treatment for patients with NMOSD in the European Union, Japan, and other countries.

In CHAMPION-NMOSD, ravulizumab, a long-acting C5 complement inhibitor, met its primary end point of time to first on-trial relapse, with no relapses observed in 58 patients with anti-aquaporin-4 NMOSD over a 73-week treatment period. Previously approved as a medication for myasthenia gravis (gMG), the therapy demonstrated statistically significant and clinically meaningful reductions in the risk of relapse compared with those on placebo from the external PREVENT trial (NCT01892345), a phase 3 study that evaluated eculizumab (Soliris; Alexion), an FDA-approved treatment for NMOSD.²

FDA Updates Label for Psychosis Medication Pimavanserin

Later, on September 18, the FDA updated the packaging label for pimavanserin (Nuplazid; Acadia Pharmaceuticals), an approved therapy for Parkinson disease psychosis (PDP), to clarify that the medication may be used for patients with PDP with or without dementia.³

Pimavanserin, originally approved in a tablet form, became the first medication marketed for the treatment of hallucinations and delusions associated with psychosis in patients with PD in 2016. With the new updated label, the agency restated in the Clinical Studies section that the phase 3 study that supported its approval included patients with PDP with or without dementia. Although no risk information was changed, the therapy’s boxed warning language was further clarified to include patients with PDP who also have dementia.

"This update makes it clear that NUPLAZID can be prescribed to treat patients with Parkinson’s disease psychosis, with or without dementia,” Jeffrey Cummings, MD, ScD, director of the Chambers-Grundy Center for Transformative Neuroscience, University of Nevada, Las Vegas, said in a statement.³ "As a prescriber, I believe that this clarification to the Boxed Warning language will help healthcare providers better identify appropriate candidates with Parkinson’s disease psychosis for treatment with Nuplazid."

FDA Approves AI-Incorporated Alzheimer Detection Software AIRAscore

One day after, on September 19, the FDA granted 510(k) clearance to AIRAmed for AIRAscore, a deep learning and artificial intelligence (AI)-incorporated medical image management and processing tool designed to detect Alzheimer disease (AD) and other related dementias at the earliest point. AIRAscore, which has been commercially available in Europe for 4 years, will be available for purchase in the US in the first quarter of 2024.⁴

With AIRAscore, clinicians are able to objectively assess MRI brain scans of patients in a quick manner and compare them with a large reference population, corrected for head size, age, and sex. The technology provides absolute values of volumes of tissues, including information on different lobes and limbic structures. Through this, clinicians can identify brain volumes that are not age appropriate, further aiding in the differentiation of other dementia forms and movement disorders.

"For so long, we’ve been limited to reading a patient’s MRI to detect Alzheimer’s and other dementias. However, we know from several studies that patients with these brain diseases suffer from subtle brain volume loss early in their disease course that cannot be observed with the human eye," Tobias Lindig, MD, founder and managing director, AIRAmed, and specialist in both radiology and neurology, University Hospital Tubingen, said in a statement.⁴ "With AIRAscore, we are now offering physicians a highly precise, quantitative tool for the rapid detection of areas with a brain volume below the normal range."

FDA Approves HoneyNaps’ Artificial Intelligence Sleep Disorder Diagnosis Software

A week later, on September 25, the FDA approved HoneyNaps’ SOMNUM artificial intelligence (AI) sleep disease analysis algorithm, the first AI solution designed for diagnosing sleep disorders.⁵

SOMNUM, supported by eXplainable Medical AI technology, utilizes deep learning-based AI to conduct a real-time analysis of vast volumes of multi-channel/time series biosignals. The technology is believed to surpass conventional video image reading systems for biosignals, according to the company. HoneyNaps also noted that this technology is setting a new standard for accuracy and transparency in the field.

"Like the AlphaGo case, which defeated humanity, this FDA approval is a very important event and a turning point in the field of sleep medicine in Korea. In the future, AI reading technology for biosignals is expected to play a very important role, similar to AI autonomous driving technology in cars. Furthermore, with the continuous improvement of biosignals AI reading technology, it will be possible to detect or predict some cardiovascular, neurological, and muscular diseases beyond the diagnosis of sleep disorders,” Ji Ho Choi, MD, PhD, head of the Center for Sleep Medicine at Soonchunhyang University Bucheon Hospital in Korea, said in a statement.⁵

FDA Advisory Committee Downvotes Mesenchymal Stem Cell Approach NurOwn as Potential ALS Therapy

A couple of days after, on Septemebr 27, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted that current data on NurOwn, BrainStorm Cell Therapeutics’ stromal cell therapy, is not sufficient in demonstrating efficacy as a treatment for patients with mild to moderate amyotrophic lateral sclerosis (ALS). The agency is expected to make a final decision on the treatment by its scheduled PDUFA date of December 8, 2023.⁶

At the conclusion of the hearing, the committee voted 17-1-1 (17 No; 1 Yes; 1 Abstain) that the evidence presented did not adequately establish NurOwn as an effective treatment. Throughout the meeting, members of the committee raised concerns about the efficacy and manufacturing of the product, including its mechanisms of action. NurOwn, an investigational product, is a technology platform of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF).⁶

In the FDA’s presentation, the agency concluded that MSC-NTF showed no efficacy compared with placebo on primary and all key secondary end points in the main phase 3 study used, and that exploratory and post-hoc subgroup analyses cannot provide substantial evidence of effectiveness. In one part of their response, the agency claimed that BrainStorm tried to “rescue” the failed study by exploring various subgroups. Above all, the subgroup analyses could not be considered reliable because of factors such as high risk of obtaining false positive results, lack of control for multiple hypothesis testing, and breaking randomization.

FDA Lifts Hold on IND for Phase 3 Trial of Ataxia Agent EryDex

A day after, on September 28, the FDA lifted its clinical hold on the investigational new drug application (IND) for Quince Therapeutics agent EryDex, a unique autologous drug/device combination agent in development for patients with ataxia-telangiectasia (A-T). The company will now proceed with its phase 3 NEAT trial assessing the safety and efficacy of the therapeutic in A-T, with a potential new drug application submission at the end of 2025, pending positive results.⁷

EryDex is an automated outpatient bedside technology to ex-vivo encapsulate dexamethasone sodium phosphate (DSP) into patient’s red blood cells, which are then re-infused, allowing for the circulation of controlled, slow release, low doses of dexamethasone over the subsequent several weeks following treatment. To date, the therapy has gained orphan drug designation for the treatment of A-T both from the FDA and European Medicines Agency. EryDex is part of a larger technology platform, the EryDex System, that is capable of expansion to other drugs or biologics, including enzyme replacement therapy.

"We are pleased with the FDA’s decision to lift the partial clinical hold related to EryDel’s lead asset, EryDex. We look forward to completing the clinical and regulatory activities necessary to advance EryDex into the Phase 3 NEAT study – with patient enrollment beginning as soon as the second quarter of 2024,” Dirk Thye, MD, chief executive officer, Quince, said in a statement.⁷ "Notably, this pivotal trial will be conducted under a Special Protocol Assessment (SPA) that has already been reviewed with the FDA, which should allow for the submission of a New Drug Application (NDA) following completion of this single study, assuming positive results."

FDA Approves Cipaglucosidase Alfa and Miglustat as First Two-Component Therapy for Pompe Disease

On the same day, Septemebre 28, the FDA approved Amicus Therapeutics’ combination of cipaglucosidase alfa-atga (Pombiliti) and miglustat (Opfolda) as the first and only 2-component treatment for patients with late-onset Pompe disease (LOPD).⁸ This new therapy, which was already previously approved in the European Union and United Kingdom, is indicated for adults with the disease weighing at least 40 kg and who are not improving on their current enzyme replacement therapy (ERT).

The design of the 2-component therapy is unique. Cipaglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme naturally expressed with high levels of bis-Mannose 6-Phosphate, designed for increased uptake into muscle cells. Once in the cell, this enzyme can be properly processed into its most active and mature form to break down glycogen, while the second part, miglustat, stabilizes the enzyme in the blood.

"The Pompe community continues to face unmet need and limited treatment options,” Tahseen Mazaffar, MD, director of the division of neuromuscular diseases in the department of neurology at the School of Medicine at UC Irvine, said in a statement.⁸ “This two-component therapy is an important new treatment for those adults living with late-onset Pompe disease and not improving on current therapies. I am encouraged by the evidence generated over many years of clinical research studying this therapy for ERT-experienced patients living with late-onset Pompe disease.”

REFERENCES
1. Update on US regulatory review of Ultomiris in NMOSD. News release. AstraZeneca. September 6, 2023. Accessed October 9, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/update-on-us-review-of-ultomiris-for-nmosd.html
2. Ultomiris met primary end point in CHAMPION-NMOSD phase 3 trial in adults with neuromyeltis optica spectrum disorder. News release. AstraZeneca. May 5, 2022. Accessed October 9, 2023. https://www.astrazeneca.com/media-centre/press-releases/2022/ultomiris-nmosd-ph-iii-trial-met-primary-endpoint.html
3. Acadia Pharmaceuticals announces label update for Nuplazid (pimavanserin). News release. September 18, 2023. Accessed October 9, 2023. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-label-update-for-nuplazid-pimavanserin/
4. AIRAmed recieves FDA 510(k) clearance for its AIRAscore brain volumetry software. News release. September 19, 2023. Accessed October 9, 2023. https://www.businesswire.com/news/home/20230919787530/en/AIRAmed-Receives-FDA-510-k-Clearance-for-Its-AIRAscore-Brain-Volumetry-Software
5. HoneyNaps Receives U.S. FDA Approval for Groundbreaking AI Sleep Disorder Diagnosis Software. News Release. Published September 25, 2023. Accessed October 9, 2023. https://prnmedia.prnewswire.com/news-releases/honeynaps-receives-us-fda-approval-for-groundbreaking-ai-sleep-disorder-diagnosis-software
6. FDA Cellular, Tissue, and Gene Therapies Advisory Committee Hearing. September 27, 2023. Accessed October 9, 2023.
7. US FDA partial clinical hold lifted on IND for EryDel’s lead phase 3 asset EryDex for the treatment of ataxia-telangiectasia. News release. Quince Therapeutics. September 28, 2023. Accessed October 9, 2023. https://ir.quincetx.com/news-releases/news-release-details/us-fda-partial-clinical-hold-lifted-ind-erydels-lead-phase-3
8. Amicus Therapeutics announces FDA approval and launch of new treatment for Pompe disease. News release. September 28, 2023. Accessed October 9, 2023. https://www.globenewswire.com/news-release/2023/09/28/2751407/15991/en/Amicus-Therapeutics-Announces-FDA-Approval-and-Launch-of-New-Treatment-for-Pompe-Disease.html