FDA Action Update, August 2022: Responses, Extensions, and Approvals


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 August 2022, including some positive data announcements and plans for application submissions, a complete response letter and an application extension, as well a new drug approval and availability, 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.

Alnylam Reports Positive Data on Patisiran in APOLLO-B Trial of ATTR Amyloidosis With Cardiomyopathy

On August 3, Alnylam Pharmaceuticals announced new data from the phase 3 APOLLO-B study (NCT03997383) of patisiran (Onpattro) in patients with transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy, suggesting that the treatment has met both its primary and first secondary end points.1

Notably, in its announcement, Alnylam stated that it plans to use data from the study in a supplemental new drug application (sNDA) to be submitted to the FDA later in 2022. The full results from APOLLO-B are planned to be presented during a late-breaking session of the 18th International Symposium on Amyloidosis on September 8, 2022, in Heidelberg, Germany.

“We are thrilled that APOLLO-B successfully met all its major objectives, which we believe for the first time validates the hypothesis that TTR silencing by an RNAi therapeutic can be an effective approach for treating the cardiomyopathy of ATTR amyloidosis,” Pushkal Garg, MD, chief medical officer, Alnylam, said in a statement.1 “ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world. These patients have limited treatment options, and disease progression is common. As such, we are encouraged to see the potential of patisiran to improve the functional capacity and quality of life of patients living with this fatal, multisystem disease.”

Alnylam Reports Positive Data on Patisiran in APOLLO-B Trial of ATTR Amyloidosis With Cardiomyopathy

FDA Issues Second CRL for Pimavanserin, Now for the Treatment of Alzheimer Disease Psychosis

The following day, August 4, the FDA announced it had issued a complete response letter (CRL) to Acadia Pharmaceuticals for its sNDA for pimavanserin (Nuplazid) in the treatment of hallucinations and delusions in patients with Alzheimer disease (AD) psychosis.2

This CRL, the second Acadia has received for pimavanserin—the first being for its application in dementia-related psychosis—noted that the agency could not approve the application as is, and recommended that Acadia conduct an additional trial in AD psychosis. The FDA did note that while the supportive phase 2 AD psychosis Study-019 (NCT02035553) data were significant, they are limited in their interpretability. Acadia did not state its plans for a resubmission or how it plans to address the FDA's concerns that were included in the CRL.

“We are disappointed with this outcome. The treatment of Alzheimer’s disease psychosis continues to be an area of high unmet need, for which there is no approved therapy,” Steve Davis, chief executive officer, Acadia, said in a statement.2 “We want to express our gratitude to all of the patients, their families and investigators who have participated in our clinical trials."

FDA Issues Second CRL for Pimavanserin, Now for the Treatment of Alzheimer Disease Psychosis

ICER Releases Report Comparing Cost-Effectiveness of ALS Agents Oral Edaravone and AMX0035

Also on August 4, 2022, the Institute for Clinical and Economic Review (ICER) published its revised evidence report assessing the comparative clinical effectiveness and value of 2 treatments for amyotrophic lateral sclerosis (ALS): AMX0035 (Amylyx Pharmaceuticals), an investigational agent, and oral edaravone (Radicava; Mitsubishi Tanabe Pharma), which received FDA approval in May 2022.3,4

The report, reviewed by 4 experts within the field, indicated the incremental cost-effectiveness of oral edaravone far exceeded typical cost-effectiveness threshold across multiple analyses and, if priced similarly to edaravone, the incremental cost-effectiveness of AMX0035 would also far exceed typical thresholds. The health benefit price benchmark (HBPB) for oral edaravone is between $1400 and $3200 annually, and the HBPB for AMX0035 is $9100 to $30,600 annually.

"There is tremendous need for new therapies in ALS,” David Rind, MD, chief medical officer, ICER, said in a statement.3 "Current treatment of this devastating disease is largely focused on supportive care. AMX0035 appears to extend life and modestly slow disease progression, but we expect vigorous debate at the public meeting on the strength of evidence, which hinges largely on the findings from a single trial, particularly given the negative vote by the FDA Advisory Committee."

AMX0035, an oral combination of sodium phenylbutyrate and taurursodiol taken up to twice daily, is under FDA review with an expected decision date by September 29, 2022.

ICER Releases Report Comparing Cost-Effectiveness of ALS Agents Oral Edaravone and AMX0035

FDA Extends Review of Omaveloxolone in Friedreich Ataxia

A few days later, on August 9, the FDA communicated to Reata Pharmaceuticals that it had extended the review period for the company’s NDA for omaveloxolone, an investigational agent for the treatment of Friedreich ataxia, as a result of newly submitted supportive data. The Prescription Drug User Fee Action date was moved 3 months, and is now set for February 28, 2023.5

Reata announced the move in a recent release, noting that it had submitted an updated delayed-start analysis from the phase 2 MOXIe extension study (NCT02255435) that featured a data cut-off of March 2022, propensity-matched analysis of the Clinical Outcome Measures in Friedreich’s Ataxia Study, and an analysis of the relevance of omaveloxolone’s target pathway. The company had submitted these data after a midcycle communication meeting with the FDA, at which time the agency raised concerns about the NDA. The resulting changes warranted a major amendment, and thus, prompted the extension.

“We are pleased with the FDA’s decision to review the new information we recently provided to the Division,” Warren Huff, chief executive officer, Reata, said in a statement.5 “We remain committed to our goal of working with the FDA to secure regulatory approval for omaveloxolone as quickly as possible for patients with this severe disease that has no approved therapies.”

FDA Extends Review of Omaveloxolone in Friedreich Ataxia

BLA Application to Be Submitted for ALS Agent NurOwn Following Phase 3 Statistical Corrections

Later in the month, on August 15, In a company update, BrainStorm Cell Therapeutics announced new clinical analyses that strengthened the phase 3 findings of its NurOwn technology platform for patients with ALS. The erratum will prompt the company to submit a biologics license application (BLA) for the therapeutic, a decision that comes more than a year after the FDA recommended against it.6

In March 2021, following a review of the current clinical phase 3 (NCT03280056) of NurOwn (autologous mesenchymal stromal cells secreting neurotrophic factors cells), the agency concluded that the current level of data did not cross the threshold of substantial evidence to support a BLA.

"The continued analysis and the feedback received from the many scientific presentations of NurOwn'sphase 3 data have uncovered key insights that furthered our understanding of the product mechanism of action and therapeutic potential and strengthened the conclusions of NurOwn's efficacy," Chaim Lebovits, chief executive officer, BrainStorm, said in a statement.6 "After carefully considering these learnings, the totality of the evidence from NurOwn's clinical studies, and the feedback received from key opinion leaders and the broader ALS community, we will submit a biologics license application to the FDA. We intend to provide additional updates upon learning whether the FDA files our BLA submission."

BLA Application to Be Submitted for ALS Agent NurOwn Following Phase 3 Statistical Corrections

Novartis Suspends Phase 2 Study of Huntington Disease Agent Branaplam

On August 24, according to a community update, Novartis temporarily suspended dosing of its phase 2 VIBRANT-HD study (NCT05111249) evaluating its experimental Huntington disease (HD) drug branaplam, citing issues with nerve damage that was reported in treated participants.7

Following a regularly planned data review, an Independent Data Monitoring Committee made the recommendation to stop dosing, which was endorsed by the VIBRANT-HD steering committee, a group made up of medical professionals and community members. In a statement expressing its gratitude for those involved in the program, Novartis noted that it plans on providing updates when more information becomes available in the coming months.

Branaplam, also called LMI070, was developed originally to treat spinal muscular atrophy. In the summer of 2021, Novartis made the decision to stop developing the drug for children with SMA, and to focus its efforts on adults with HD. The decision was supported by data in HD animal models, and early safety trials of branaplam in healthy adults.

Novartis Suspends Phase 2 Study of Huntington Disease Agent Branaplam

FDA Approves Midazolam Autoinjector for Status Epilepticus

On August 30, 2022, the FDA gave the green light to Rafa Laboratories for its 10-mg midazolam autoinjector for the treatment of status epilepticus in adults, making it the first autoinjectable product to be approved by the FDA for this indication, joining other rescue treatments with different routes of administration.8

The midazolam autoinjector is administered into the thigh, and can be done through clothing, without requiring an intravenous line, according to Rafa. It was developed in partnership with the US Department of Defense’s Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, with additional support from the Chemical and Biological Defense Program.

"The usability of the autoinjector has a significant medical advantage in its immediate treatment effect, as well as in reducing long-term damage,” Roy Shay, Head of Emergency Solutions, Rafa, said in a statement.8 “Clinical studies confirmed the correlation between early treatment of status epilepticus and a reduced risk of an ongoing and irreversible neurological damage. This product could assist in saving many lives around the globe."

FDA Approves Midazolam Autoinjector for Status Epilepticus

Sirolimus Topical Gel Available for Facial Angiofibroma Associated With Tuberous Sclerosis Complex

Finally, also on August 30, Nobelpharma America announced that its sirolimus topical gel 0.2% (Hyftor) became commercially available in the United States, after being approved in March 2022 for the treatment of facial angiofibroma associated with tuberous sclerosis complex (TSC) in adults and children ages 6 years and older.9

Sirolimus, the active ingredient in the topical gel agent, is a mammalian target of rapamycin (mTOR) inhibitor. Facial angiofibroma is estimated to occur in approximately 75%-80% of patients with TSC, and without treatment, it can cause significant disfiguration, bleeding, pruritus and erythema. This translates to roughly 40,000 of the 50,000 individuals with TSC in the US.

Yoshiki Kida, president and CEO of Nobelpharma America, said in a statement that, "the US launch of Hyftor is a landmark event for Nobelpharma America. We are proud to bring our first product to the United States TSC community. As we look ahead, we aspire to bring new hope to those living with this rare disease."

Sirolimus Topical Gel Available for Facial Angiofibroma Associated With Tuberous Sclerosis Complex
1. Alnylam Reports Positive Topline Results from APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy. News release. Alnylam. August 3, 2022. Accessed August 31, 2022. https://www.businesswire.com/news/home/20220803005528/en/Alnylam-Reports-Positive-Topline-Results-from-APOLLO-B-Phase-3-Study-of-Patisiran-in-Patients-with-ATTR-Amyloidosis-with-Cardiomyopathy
2. Acadia Pharmaceuticals Receives Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Pimavanserin for the Treatment of Hallucinations and Delusions Associated with Alzheimer’s Disease Psychosis. Acadia Pharmaceuticals. August 4, 2022. Accessed August 31, 2022. https://www.businesswire.com/news/home/20220804006095/en/Acadia-Pharmaceuticals-Receives-Complete-Response-Letter-from-U.S.-FDA-for-Supplemental-New-Drug-Application-for-Pimavanserin-for-the-Treatment-of-Hallucinations-and-Delusions-Associated-with-Alzheimer%E2%80%99s-Disease-Psychosis
3. ICER publishes evidence report on treatments for amyotrophic lateral sclerosis. News release. Institute for Clinical and Economic Review. August 4, 2022. Accessed August 5, 2022. https://icer.org/news-insights/press-releases/icer-publishes-evidence-report-on-treatments-for-amyotrophic-lateral-sclerosis/
4. Makam AN, Suh K, Nikitin D, et al. AMX0035 and Oral Edaravone for ALS; Evidence report. Institute for Clinical and Economic Review. Published August 4, 2022. Accessed August 31, 2022. https://icer.org/wp-content/uploads/2022/02/ICER_ALS_Evidence-Report_080422.pdf
5. Reata Pharmaceuticals Announces Three Month Extension of the Review Period for New Drug Application for Omaveloxolone for the Treatment of Friedreich’s Ataxia. News release. Reata Pharmaceuticals. August 9, 2022. Accessed August 31, 2022. https://www.businesswire.com/news/home/20220809005508/en/Reata-Pharmaceuticals-Announces-Three-Month-Extension-of-the-Review-Period-for-New-Drug-Application-for-Omaveloxolone-for-the-Treatment-of-Friedreich%E2%80%99s-Ataxia
6. BrainStorm Cell Therapeutics announces second quarter 2022 financial results and provides a corporate update. News release. BrainStorm Cell Therapeutics. August 15, 2022. Accessed August 31, 2022. https://ir.brainstorm-cell.com/2022-08-15-BrainStorm-Cell-Therapeutics-Announces-Second-Quarter-2022-Financial-Results-and-Provides-a-Corporate-Update
7. Community update: status of VIBRANT-HD, the study of branaplam/LMI070 in Huntington’s disease. News release. Novartis. August 24, 2022. Accessed August 31, 2022. https://hdsa.org/wp-content/uploads/2022/08/Novartis-FINAL-Community-Letter-8-24-22.pd
8. Rafa Receives FDA Approval for Life-saving Midazolam Autoinjector. News release. Rafa Laboratories. August 30, 2022. Accessed August 31, 2022. https://www.prnewswire.com/news-releases/rafa-receives-fda-approval-for-life-saving-midazolam-autoinjector-301614545.html
9. HYFTOR™ (sirolimus topical gel) 0.2%, the first FDA-approved topical treatment for facial angiofibroma associated with tuberous sclerosis, is now available in the US. News release. Nobelpharma America. August 30, 2022. Accessed August 31, 2022. prnewswire.com/news-releases/hyftor-sirolimus-topical-gel-0-2-the-first-fda-approved-topical-treatment-for-facial-angiofibroma-associated-with-tuberous-sclerosis-is-now-available-in-the-us-301614013.html
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