FDA Action Update, August 2023: Approvals, Clearances, and Designations

The FDA was busy in August 2023, making a number of decisions on potential new therapeutic agents including issuing a complete response letter, granting traditional approval, and clearing a clinical trial, 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, xxx.

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

Ceribell’s Status Epilepticus Software Receives FDA Clearance With CMS NTAP Coverage Included

Earlier in the month, on August 3, the FDA granted 510(k) clearance to Ceribell’s new software, ClarityPro, for the diagnosis of electrographic status epilepticus (ESE) in adults over the age of 18, becoming the first such tool available.¹ Subsequently, the US Centers for Medicare and Medicaid Services (CMS) gave new technology add-on payment (NTAP) for ClarityPro for up to $913.90 per eligible Medicare patient case.

This point-of-care EEG system delivers real-time seizure monitoring with around-the-clock alerts, enabling more precise treatment of patients with suspected non-convulsive seizures. The only such device to diagnose ESE according to the American Clinical Neurophysiology Society definition of ESE, ClarityPro utilizes a machine learning algorithm to analyze EEG signals and generate bedside alerts.

"These decisions from the FDA and CMS are further validation that Ceribell's clinical impact is significant for patients," Jane Chao, PhD, co-founder and chief executive officer at Ceribell, said in a statement.¹ "This dedicated reimbursement from CMS will also expand access to this vital technology to more Americans, especially seniors and critically ill patients who are more likely to suffer from neurological illnesses."

FDA Accepts New Drug Application for Long-Acting Form of Glatiramer Acetate

On August 7, the FDA accepted Viatris and Mapi Pharma’s new drug application (NDA) for its investigational agent GA Depot, a long-acting, once-monthly glatiramer acetate solution for the treatment of patients with relapsing forms of multiple sclerosis (MS). The agency is expected to have a decision on the therapy by March 8, 2024.²

The NDA was supported by data from a phase 3, multinational, double-blind, placebo-controlled study (NCT04121221) in which treatment with GA Depot resulted in a 30% statistically significant reduction of annualized relapsing rate relative to placebo (P = .0066). The trial featured 1016 patients who were randomly assigned to 40 mg of GA Depot or placebo, via intramuscular injection, once every 4 weeks for a total of 13 doses. Findings from the study were strengthened by MRI end points as well.³

"The NDA filing acceptance for GA Depot is yet another example of our continuous commitment to look for opportunities to enhance existing therapies and innovation to support unmet medical needs,” Rajiv Malik, president at Viatris, said in a statement.² "Our application is backed by Phase 3 efficacy and safety data, and we believe, when approved, GA Depot could improve patient experience through fewer injections, greater tolerability and increased compliance. This milestone gives us further confidence in the strength of our GA Depot clinical program, and we look forward to continuing to work closely with FDA to bring access to this important complex medicine to patients."

FDA Approves Expanded Indication of DaxibotulinumtoxinA to Treat Cervical Dystonia

A few days after, on July 14, the FDA approved Revance’s daxibotulinumtoxinA-Ianm (Daxxify) for the treatment of cervical dystonia in adults, expanding its previous label as a therapy for the temporary improvement of moderate to severe glabellar lines. Powered by Peptide Exchange Technology, it became the first and only peptide-formulated, long-lasting neuromodulator for patients with cervical dystonia.⁴

"We are very pleased to see the expansion of the Daxxify label to include our first therapeutic indication, unlocking a new market opportunity for Daxxify following the product’s recent launch in the aesthetics market. Further, we believe FDA approval represents a significant advancement in the treatment of cervical dystonia,” Mark J. Foley, the chief executive officer of Revance, said in a statement.⁴ "Daxxify's differentiated efficacy, duration, and safety profile can help physicians deliver long-lasting symptom relief to patients suffering from cervical dystonia, while also helping payers address the total cost of care for this population."

The expanded indication was based on results from the phase 3 ASPEN trial (NCT03608397) and its open-label study (OLS; NCT03617367), which included 382 patients and 1240 treatments over an 88-week time span. In ASPEN-1 both the 125- and 250-unit dose groups of daxibotulinumtoxinA met the primary end point of clinically meaningful improvement in the signs and symptoms of cervical dystonia, on average, by weeks 4 and 6. In this randomized, placebo-controlled, parallel-group study, the 125- and 250-unit treatment groups showed improvements of 12.7 and 10.9 points, respectively, on Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) vs the placebo group, which recorded changes of 4.3 (P <.001 and P = .0006, respectively).⁵

Exon 44 Skipping Agent AOC 1044 Granted FDA Orphan Drug Designation for Duchenne Muscular Dystrophy

A day after, on August 15, the FDA granted orphan drug designation to Avidity Biosciences’ AOC 1044, an investigational therapy in development for the treatment of Duchenne muscular dystrophy (DMD) in patients with mutations amenable to exon 44 skipping (DMD44).⁶ The therapy is currently being assessed in the phase 1/2 EXPLORE44 trial (NCT05670730) with results from the healthy volunteer portion of the trial expected to come in the fourth quarter of 2023.

AOC 1044, a proprietary monoclonal antibody, binds the transferrin receptor 1 conjugated with a phosphorodiamidate morpholino oligomers (PMOs) targeting exon 44. In a preclinical model using the therapy, a murine active AOC created durable exon skipping and functional dystrophin protein in skeletal muscle and heart tissue after a single intravenous dose. Earlier this year, the agent received FDA fast track designation for the treatment of DMD44, further validating its the potential in this patient population.⁷

“It is very encouraging to receive FDA fast track designation as it further validates the potential of AOC 1044 to target the underlying cause of DMD44 and the importance of bringing people living with this devastating disease an effective treatment option. This recognition also means that now all three of our clinical-stage programs have Fast Track status, further reinforcing our efforts to make a profound difference in people's lives," Steve Hughes, MD, chief medical officer at Avidity said in a statement at the time.⁷ "We will continue to work closely with the FDA as we advance AOC 1044 and look forward to the anticipated data readout from the healthy volunteer portion of our phase 1/2 EXPLORE44 clinical trial later this year."

FDA Clears IND to Test Intranasal Foralumab in Alzheimer Disease

On the same day, August 15, the FDA cleared the investigational new drug (IND) application to evaluate Tiziana Life Sciences’ intranasal agent foralumab, a fully human intranasal anti-CD3 monoclonal antibody, as a treatment for Alzheimer disease (AD).⁸ Foralumab might be a promising therapy for AD since it targets the underlying disease pathology through attacking the neuroinflammation caused because by the collection of toxic proteins in the brain.

"The IND clearance is a significant milestone for Tiziana that highlights the strength and the therapeutic potential of foralumab. We are deeply committed to advancing the field of neurodegenerative diseases and bringing much-needed relief to patients suffering from Alzheimer's with a novel therapeutic approach,” Gabriele Cerrone, Chairman, acting CEO and founder of Tiziana Life Sciences said in a statement.⁸ “We are thrilled to have reached this critical juncture and are eager to move forward with the necessary trials to evaluate the effectiveness of foralumab in Alzheimer’s disease in combination with an FDA approved therapy or as a single agent."

In October 2022, the company announced plans to file the IND to the FDA for a phase 1 study assessing intranasal foralumab in AD following an affirmative response from the FDA on its pre-investigational new drug application. Foralumab, formerly known as Nl-0401, has been shown to reduce release of key cytokines in healthy volunteers and in patients with Crohn disease. A patient IND application for foralumab to improve the success of chimeric antigen receptor T-cells therapy for cancer and other human diseases has also been submitted.

FDA Approves Neurocrine Biosciences’ Valbenazine for Huntington Disease Chorea

On August 18, the FDA approved an expanded indication for Neurocrine Biosciences’ therapy valbenazine (Ingrezza) to include the treatment of chorea associated with Huntington disease (HD). With the decision, the therapy became the only selective vesicular monoamine transporter 2 inhibitor approved for the condition, offering an effective starting dosage that can be adjusted according to response and tolerability with no complex titration.⁹

Data from the phase 3 KINECT-HD study (NCT04102579), a double-blind trial, and its ongoing open-label extension, KINECT-HD2 (NCT04400331), served as the basis for the approval. Similar in design, each study featured adults aged 18 to 75 years who had been diagnosed with either manifest HD or motor manifest HD who have sufficient chorea symptoms. In KINECT-HD, the agent met its primary end point, demonstrating a statistically significant placebo-adjusted reduction in the Unified Huntington’s Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score of 3.2 units (P <.00001) from baseline to weeks 10 and 12.¹⁰

"Clinical results that led to this important approval showed reduction in the severity of chorea as early as two weeks after starting Ingrezza at an initial dose of 40 mg, with consistently greater improvements versus placebo seen at all subsequent visits," principal investigator Erin Furr Stimming, MD, FAAN, FANA, a professor of neurology at McGovern Medical School of UTHealth Houston said in a statement.⁹ "Data also demonstrated Ingrezza was generally well tolerated and showed clinically meaningful improvement in adults with chorea associated with HD."

FDA Approves Sandoz’s Natalizumab-sztn as First Biosimilar for Multiple Sclerosis

On August 24, the FDA approved Sandoz's and Polpharma Biologics' injection treatment natalizumab-sztn (Tyruko; formerly known as PB006), the first biosimilar to the approved formulation of natalizumab (Tysabri; Biogen) for the treatment of adults with relapsing forms of MS.¹¹ With its indication, the therapy can be utilized for patients with clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.

Additionally, the biosimilar is indicated for inducing and maintaining clinical response and remission in adults with moderately to severely active Crohn disease (CD) who also have evidence of inflammation and have had an inadequate response or inability to tolerate conventional therapies and inhibitors of tumor necrosis factor.

“Biosimilar medications offer additional effective treatment options that have the potential to increase access for people living with relapsing forms of multiple sclerosis,” Paul R. Lee, MD, PhD, director of the Division of Neurology II in the FDA Center for Drug Evaluation and Research, said in a statement.¹¹ “Today’s approval could have a meaningful impact for patients managing their disease.”

FDA Grants Fast Track Designation to TSHA-102 as Potential Rett Syndrome Therapy

On the same day, August 24, the FDA granted Fast Track Designation to Taysha Gene Therapies’ TSHA-102, an adeno-associated virus (AAV) vector gene transfer therapy, for the treatment of Rett syndrome.¹² The gene therapy utilizes a novel miRNA-Responsive Auto-Regulatory Element (miRARE) platform designed to regulate cellular MECP2 expression, otherwise known as the root genetic cause of Rett syndrome.

Currently, the agent is being investigated in the Canadian-based REVEAL phase 1/2 trial (NCT05606614) of adult patients with Rett syndrome. The company also recently announced that the FDA has cleared its investigational new drug application for the agent to be assessed in pediatric patients with the condition and expects to dose the first pediatric patient in the first quarter of 2024.

“We are pleased to receive FTD from the FDA, which underscores the significant unmet medical need in patients with Rett syndrome and the potential of TSHA-102 to serve as a meaningful treatment option,” Sukumar Nagendran, MD, president and head of R&D at Taysha said in a statement.¹² “Initial data from the first adult patient in Canada with severe disease dosed with TSHA-102 is encouraging, and we expect to dose the second patient in our ongoing REVEAL phase 1/2 adult trial in the current quarter. We look forward to expanding the clinical evaluation to earlier stages of disease progression following recent FDA clearance to initiate clinical development of TSHA-102 in pediatric patients in the United States.”

REFERENCES
1. Ceribell recieves FDA 510(k) clearance and CMS NTAP reimbursement for New ClarityPro Software with electrographic status epilepticus diagnostic indication. Ceribell. August 3, 2023. Accessed September 1, 2023. https://www.prnewswire.com/news-releases/ceribell-receives-fda-510k-clearance-and-cms-ntap-reimbursement-for-new-claritypro-software-with-electrographic-status-epilepticus-diagnostic-indication
2. Viatris and Mapi Pharma announce FDA acceptance of new drug application filing for GA Depot for the treatment of relapsing forms of multiple sclerosis. Viatris. August 7, 2023. Accessed September 1, 2023. https://www.prnewswire.com/news-releases/viatris-and-mapi-pharma-announce-fda-acceptance-of-new-drug-application-filing-for-ga-depot-for-the-treatment-of-relapsing-forms-of-multiple-sclerosis
3. Miller AE, Popper L, Berger JR, et al. Results of a Phase III, Multinational, Double Blind, Placebo-Controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis to Assess the Efficacy, Safety and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks. Presented at ACTRIMS Forum 2023; February 23-25; San Diego, California. Abstract P087.
4. US FDA approves first therapeutic indication for Revance’s DAXXIFY (daxibotulinumtoxinA-Ianm) for injection for the treatment of cervical dystonia. August 14, 2023. Accessed September 1, 2023. https://investors.revance.com/news-releases/news-release-details/us-fda-approves-first-therapeutic-indication-revances-daxxifyr
5. Revance reports positive results from ASPEN-1 phase 3 trial of daxibotulinumtoxinA for injection in cervical dystonia. News release. Revance Therapeutics. October 14, 2020. Accessed September 1, 2023. https://investors.revance.com/news-releases/news-release-details/revance-reports-positive-results-aspen-1-phase-3-trial
6. Avidity Biosciences Receives FDA Orphan Drug Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy in People with Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published August 15, 2023. Accessed September 1, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-receives-fda-orphan-drug-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-in-people-with-mutations-amenable-to-exon-44-skipping
7. Avidity Biosciences Granted FDA Fast Track Designation for AOC 1044 for Treatment of Duchenne Muscular Dystrophy Mutations Amenable to Exon 44 Skipping. News Release. Avidity Biosciences. Published April 24, 2023. Accessed September 1, 2023. https://www.prnewswire.com/news-releases/avidity-biosciences-granted-fda-fast-track-designation-for-aoc-1044-for-treatment-of-duchenne-muscular-dystrophy-mutations-amenable-to-exon-44-skipping-301804651.html
8. Tiziana Life Sciences Announces FDA IND Clearance of Intranasal Foralumab for the Treatment of Alzheimer’s Disease. News Release. Published August 15, 2023. Accessed September 1, 2023. https://www.tizianalifesciences.com/news-item?s=2023-08-15-tiziana-life-sciences-announces-fda-ind-clearance-of-intranasal-foralumab-for-the-treatment-of-alzheimers-disease
9. Neurocrine Biosciences Announces FDA Approval of INGREZZA® (valbenazine) Capsules for the Treatment of Chorea Associated With Huntington's Disease. News Release. Neurocrine Biosciences. Published August 18, 2023. Accessed September 1, 2023.
10. Stimming EF, Claassen DO, Kayson E, et al. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-HD): a phase 3, randomized, double-blind, placebo-controlled trial. Lancet Neurol. 2023;22:494-504
11. FDA Approves First Biosimilar to Treat Multiple Sclerosis. News release. FDA. August 24, 2023. Accessed September 1, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-biosimilar-treat-multiple-sclerosis
12. Taysha Gene Therapies Announces Fast Track Designation Granted by U.S. FDA for TSHA-102 in Rett Syndrome. News Release. Taysha Gene Therapies. Published August 24, 2023. Accessed September 1, 2023. https://ir.tayshagtx.com/news-releases/news-release-details/taysha-gene-therapies-announces-fast-track-designation-granted