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FDA Action Update, November 2023: Acceptance, Clearance, and Hold
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Catch up on any of the neurology news headlines you may have missed over the course of November 2023, compiled all into one place by the NeurologyLive® team.
The FDA was busy in November 2023, making a number of decisions on potential new therapeutic agents including acceptance of resubmission, clearance of a clinical trial, granting a meeting, declining lift of clinical trial hold, issuing a warning, extending review time, and placing a clinical hold.
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 Accepts Supurnus’ Resubmitted NDA for SPN-830 Apomorphine Infusion Device
Earlier in the month, on November 2, the FDA accepted Supernus Pharmaceuticals’ resubmitted new drug application (NDA) for SPN-830, an apomorphine infusion device designed for the treatment of OFF episodes in patients with Parkinson disease (PD). The FDA is expected to reach a decision on whether to approve the therapy by April 5, 2024, the scheduled PDUFA date.1
"We are pleased with the FDA’s acceptance of our NDA resubmission for SPN-830 and look forward to continuing to work with them during their review," Jack Khattar, president and chief executive officer at Supernus, said in a statement.1 "SPN-830 is an important product candidate which, if approved by the FDA, represents a novel and less invasive treatment option for patients with PD."
SPN-830 is an experimental under-the-skin continuous infusion therapy for reducing motor fluctuations in patients with PD between doses of standard levodopa-based therapy. The phase 3 TOLEDO study (NCT02006121), a double-blind, randomized, multicenter trial, served as the supportive data for the NDA. In the study, treatment with SPN-830 resulted in –1.89 hours per day better OFF time for treated patients vs those on placebo, with reductions observed within 1 week of initiating therapy.2
FDA Clears Phase 2 Study of CAR T-Cell Therapy KYV-101 in Myasthenia Gravis
A couple of weeks later, on November 17, Kyverna Therapeutics announced that the FDA has cleared its investigational new drug (IND) application for KYV-101, a fully human CD19 chimeric antigen receptor (CAR) T-cell therapy, to be assessed in a phase 2 study of patients with myasthenia gravis (MG), an autoimmune disorder.3
"We have seen firsthand the transformative effects of KYV-101 in MG patients treated with the investigational therapy in our clinic,” Aiden Haghikia, director of the department of neurology at Otto-von-Guericke University in Magdeburg, Germany, said in a statement.3 "I welcome the FDA's decision and look forward to more clinical data to further our knowledge about CAR T-cell therapy in patients with severe neurological autoimmune diseases."
CAR T cells have been seen as a versatile new class of effective, molecularly precise therapy. Dubbed KYSA-6, the phase 2 study will continue to assess the efficacy and safety of KYV-101, an autologous agent, in patients with MG. In its release, Kyverna did not include much details on the design of the trial but that it expands on the current pipeline, which includes the ongoing US-based phase 1 KYSA-1 study and the phase 1/2 KYSA-3 trial in Germany, which feature patients with active lupus nephritis.
FDA Grants Meeting With BrainStorm Cell Therapeutics on ALS Therapy NurOwn
A few days later, on November 20, the FDA granted BrainStorm Cell Therapeutics a meeting to discuss NurOwn, the company’s investigational stromal cell therapy, and its regulatory path forward as a treatment for patients with mild to moderate amyotrophic lateral sclerosis (ALS). The meeting is set to take place on December 6, 2023, and the company stated that it plans to discuss a Special Protocol Assessment (SPA) with the agency for the overall protocol design of a potential confirmatory phase 3 trial.4
"We are pleased that the FDA has granted this expedited in-person meeting to discuss the best path forward for NurOwn for ALS. Our proposed plan is to conduct a confirmatory phase 3b trial and it is important that we are aligned with the agency on the expected requirements for resubmitting a biologics license application (BLA),” Chaim Lebovits, president and chief executive officer of BrainStorm Cell Therapeutics, said in a statement.4 “We believe that reaching an agreement through a SPA on the overall protocol design and the adequacy to address the requirements for marketing approval will be a key step to position the company for success and to potentially derisk the program. We are grateful for the FDA's support and quick response in granting this meeting as we remain committed to our goal of making NurOwn available to the ALS community."
In September 2023, the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee voted 17-1-1 (17 No; 1 Yes; 1 Abstain) that the current data on NurOwn was not sufficient in demonstrating efficacy as a treatment for patients with mild to moderate ALS. Throughout the meeting, members of the committee raised concerns about the efficacy and manufacturing of the product, including its mechanisms of action. NurOwn, a technology platform of autologous mesenchymal stromal cells secreting neurotrophic factors cells (MSC-NTF), was supported by several clinical studies.5
FDA Declines to Lift Clinical Hold on Entrada Therapeutics’ ENTR-601-44 in Duchenne Muscular Dystrophy
A couple of days later, on November 22, the FDA declined to lift the clinical hold on Entrada Therapeutics' IND application for the phase 1 clinical trial of ENTR-601-44 in Duchenne muscular dystrophy (DMD) despite the company providing additional information to the agency.6 The company noted that the information submitted to the FDA at least supported the initiation of a United Kingdom-based phase 1 clinical trial of ENTR-601-44 among healthy volunteers, which was announced months ago.
In December 2022, the FDA placed a clinical hold on the IND for ENTR-601-44.3 At the time, the agency indicated they would provide an official clinical hold letter to Entrada in 30 days and the company planned to share additional updates pending further communications with the FDA. ENTR-601-44, an exon 44 skipping oligonucleotide developed with Entrada’s Endosomal Escape Vehicle (EEV) platform, aims to target the underlying genetic cause of DMD to allow muscle cells to produce functional dystrophin. For context, roughly 7.5% of the DMD population are considered exon 44 skipping amenable.
“We are disappointed that the U.S. clinical hold has not been lifted, especially given the strength of the data package submitted to the FDA. It’s important to emphasize that the ongoing ENTR-601-44 development program continues to progress, with ENTR-601-44-101 clinical data expected in the second half of 2024. We will re-engage the FDA to discuss next steps in due course,” Dipal Doshi, president and chief executive officer at Entrada Therapeutics, said in a statement.6
FDA Warns of Serious Adverse Effects for Using Levetiracetam and Clobazam in Epilepsy
A few days later, on November 28, the FDA issued a warning for the use of antiseizure medicines levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam) and clobazam (Onfi, Sympazan), which can cause drug reaction with eosinophilia and systemic symptoms (DRESS), a rare but serious adverse effect.7
The reaction may start as a rash but can quickly progress, resulting in injury to internal organs, the need for hospitalization, and even death. As a result, the FDA is requiring new warnings about this risk to be added to the prescribing information and patient medication guides for these medicines.
In the cumulative review of these therapies, the FDA observed several reports of serious cases of DRESS in pediatric patients and adults globally. According to the data submitted to the FDA and in the medical literature, 32 patients treated with levetiracetam and 10 patients treated with clobazam reported DRESS. The majority of patients in these cases required hospitalization and received medical treatments. Notably, 2 of the patients treated with levetiracetam died. Data on most of the cases reported that DRESS symptoms improved when the medicines were discontinued. Thus, the FDA had reasonable evidence that levetiracetam and clobazam were the cause of DRESS in these reports.
FDA Extends Review Time for Italfarmaco’s Duchenne Agent Givinostat
On the same day, November 28, the FDA informed Italfarmaco it had extended the review process for the company's investigational agent givinostat, with a new scheduled PDUFA of March 21, 2024. Givinostat, a proprietary histone deacetylase (HDAC) inhibitor, is currently in development as a treatment for DMD, a severe neuromuscular genetic disease.8
The FDA accepted the NDA submission for givinostat earlier this year, with data from the phase 3 EPIDYS trial (NCT02851797) as the supporting evidence. Givinostat is designed to inhibit HDACs, which are enzymes that prevent gene translation by changing the 3-dimensional folding of DNA in the cell. In the latest update, Italfarmaco noted that the agency needs more time to review the application, but that there was no issues with the data submitted.
EPIDYS, a randomized, double-blind, placebo-controlled, multicenter study, included 179 ambulant male individuals who were randomly assigned 2:1 to either oral givinostat or placebo for an 18-month treatment period. Of these, 120 boys formed the target population. At the conclusion of the study, results showed a slower decline in givinostat-treated patients on the primary end point of climbing 4 stairs in comparison with placebo (difference, 1.78 seconds; P = .0345).
FDA Places Clinical Hold on Roche’s BTK Inhibitor Fenebrutinib for Multiple Sclerosis
A couple of days later, on November 30, the FDA placed a clinical hold on the development program for fenebrutinib (Roche), an investigational oral, reversible, and noncovalent Bruton tyrosine kinase (BTK) inhibitor in development for patients with multiple sclerosis (MS).9
The decision was based on 2 recent cases of hepatic transaminase elevations in conjunction with elevated bilirubin suggestive of drug-induced liver injury that was documented in the blinded phase 3 FENhance studies of relapsing MS. Both patients were asymptomatic and had elevations returned to normal levels following the discontinuation of fenebrutinib.
As a result of the hold, new enrollment for the FENhance 1 trial (NCT04586023) in the US will be paused, while enrollment in countries outside of the US will continue. Participants in the US who received fenebrutinib for more than 70 days will continue treatment in all studies, which comprise the ongoing, fully enrolled FENhance 2 (NCT045586010) and FENtrepid trial (NCT04544449). Roche noted that only a small number of participants in the US who received the treatment for 70 days or less will discontinue treatment.
REFERENCES
1. Supernus announces SPN-830 apomorphine infusion device NDA accepted for review by FDA. News release. November 2, 2023. Accessed December 6, 2023. https://ir.supernus.com/news-releases/news-release-details/supernus-announces-spn-830-apomorphine-infusion-device-nda
2. Katzenschlager R, Poewe W, Rascol O, et al. Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomized, placebo-controlled trial. Lancet Neurol. 2018;17(9):749-759. doi:10.1016/S1474-4422(18)30239-4
3. Kyverna Therapeutics announces FDA clearance of phase 2 IND for KYV-101, a fully human CD19 CAR T-cell therapy to treat myasthenia gravis. News release. Kyverna Therapeutics. November 13, 2023. Accessed December 6, 2023. https://www.prnewswire.com/news-releases/kyverna-therapeutics-announces-fda-clearance-of-phase-2-ind-for-kyv-101-a-fully-human-cd19-car-t-cell-therapy-to-treat-myasthenia-gravis-301986135.html
4. BrainStorm Cell Therapeutics Announces In-Person Meeting with the FDA to Discuss Confirmatory Phase 3 Trial for NurOwn® in ALS. News Release. BrainStorm Cell Therapeutics. Published November 20, 2023. Accessed December 6, 2023. https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-in-person-meeting-with-the-fda-to-discuss-confirmatory-phase-3-trial-for-nurown-in-als-301993513.html
5. FDA Cellular, Tissue, and Gene Therapies Advisory Committee Hearing. September 27, 2023. Accessed December 6, 2023.
6. Entrada Therapeutics Announces Updates on ENTR-601-44 in Duchenne Muscular Dystrophy. News Release. Entrada Therapeutics. Published November 22, 2023. Accessed December 6, 2023. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-announces-updates-entr-601-44-duchenne
7. FDA warns of rare but serious drug reaction to the antiseizure medicines levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam) and clobazam (Onfi, Sympazan). Published November 28, 2023. Accessed December 6, 2023. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-rare-serious-drug-reaction-antiseizure-medicines-levetiracetam-keppra-keppra-xr-elepsia-xr
8. Italfarmaco group announces new PDUFA date for givinostat DMD NDA. News release. November 29, 2023. Accessed December 6, 2023. https://finance.yahoo.com/news/italfarmaco-group-announces-pdufa-date-100000954.html
9. Fenebrutinib multiple sclerosis clinical trial program update. News release. Genentech/Roche. November 30, 2023. Accessed December 6, 2023. https://www.gene.com/media/statements/ps_113023
