5 Pending FDA Decisions in Neurology to Look for in 2023


Take a look at 5 of the most-anticipated FDA pending approvals expected in 2023 that neurological researchers and clinicians should keep an eye out on.

There are several upcoming treatment approvals to come in 2023 ranging from neurological specialties in movement disorders, neuromuscular, headache and migraine, and sleep disorders. As there is so much happening constantly in the clinical drug pipeline, keeping up with the latest approvals might be a challenge.

Here are 5 critical FDA pending approvals with expected data readouts in 2023 that NeurologyLive® will have its eye on.

Friedreich Ataxia: Omaveloxolone (Reata Pharmaceuticals)

Omaveloxone (Reata Pharmaceuticals) is an investigational, oral, once-daily activator of Nrf2 that induces molecular pathways that promote the resolution of inflammation. The therapy has a potential approval data of February 28, 2023, and if approved, would be the first treatment to directly combat the effects of Friedreich ataxia (FA), a rare degenerative neuromuscular disorder. The new drug application (NDA) for the agent was accepted by the FDA in May 2022 and is supported by data from the MOXIe Part 2 trial (NCT02255435) with additional data from the MOXIe Part 1 and MOXIe Extension trials.

In October 2019, data from the phase 2 MOXIe trial of omaveloxolone in patients FA showed a 2.40-point improvement in Friedreich Ataxia Rating Scale (mFARS) score in patients treated with the agent in comparison with placebo.1 Results of the trial were presented at the Muscular Dystrophy Association (MDA) 2022 meeting as well as the MDA-PAS 2021 meeting.

David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine

David R. Lynch, MD, PhD

The trial was a 2-part randomized, placebo-controlled, double-blind study conducted over 48 weeks. Patients treated with omaveloxolone had a statistically significant improvement in mFARS (P =.014). In the treatment group, a mean improvement of -1.55 points in mFARS score from baseline was recorded while those in the placebo group demonstrated a mean worsening of +0.85 points.

“The results of MOXIe represent a truly historic moment for the patients, families, and caregivers that comprise the Friedreich ataxia community,” said Ronald Bartek, president of the Friedreich’s Ataxia Research Alliance, in a statement.1 “We believe the findings announced today bring us closer to our goal of providing an urgently needed therapy to patients with FA.”

Presented at the International Parkinson and Movement Disorders Society (MDS) Virtual Congress 2021, September 17-22, results of the delayed-start study showed continued to show positive effect of treatment with omaveloxolone in patients with FA.2 Lead presenter David R. Lynch, MD, PhD, professor of neurology, University of Pennsylvania Perelman School of Medicine, and colleagues identified a difference in mFARS of –2.18 (±0.96) points between the omaveloxolone and placebo groups at the end of the end of the placebo-controlled MOXIe Part 2. These differences were preserved at the end of the delayed-start period (–2.92 points; ±2.13).

Rett syndrome: Trofinetide (Acadia Pharmaceuticals)

Trofinetide (Acadia Pharmaceutical), formerly known as NNZ-2566, is a novel synthetic analog of the amino‐terminal tripeptide of IGF-1 designed to potentially reduce neuroinflammation and supporting synaptic function. If the agent is approved by the FDA on March 12, 2023, it will become the first approved therapy for Rett syndrome, signifying a major breakthrough. The FDA accepted the NDA for the agent in September 2022, and used data from the phase 3 of the study, which assessed the agent in 187 girls and women with Rett syndrome.

Daniel Glaze, MD, pediatric neurologist at the Baylor College of Medicine, and the director at the Blue Bird Circle Rett Center at Texas Children’s Hospital

Daniel Glaze, MD

In March 2019, findings from a phase 2 study showed that the 200-mg/kg dose of trofinetide displayed a clinically meaningful and statistically significant benefit for a trio of syndrome-specific efficacy measurements in pediatric patients with Rett syndrome.3

“Trofinetide appears to be a very promising drug for the treatment of the core features of Rett syndrome and to address this unmet need. It is an analog of insulin-like growth factor-1 (IGF1) with similar properties to reduce neuroinflammation and support synaptic function, both critical to normal brain development and response to injury, therefore very likely to improve brain functioning in Rett syndrome,” study author Daniel Glaze, MD, pediatric neurologist at the Baylor College of Medicine, and the director at the Blue Bird Circle Rett Center at Texas Children’s Hospital, told NeurologyLive® at the time.

In December 2021, Acadia Pharmaceuticals announced positive topline results from the phase 3 LAVENDER study (NCT04181723) with trofinetide in Rett syndrome.4 The agent met its coprimary efficacy end points in demonstrating statistically significant improvement in the Rett Syndrome Behavior Questionnaire and the Clinical Global Impression of Improvement, comparison with the placebo.

SOD1 ALS: Tofersen (Biogen)

Tofersen (Biogen) is an antisense agent in development for the treatment of SOD1 amyotrophic lateral sclerosis (ALS), currently has a PDUFA date of April 25, 2023, and if approved, could be the first targeted therapy for SOD1-mediated ALS. The FDA accepted the NDA for the therapy in July 2022 and used data from the Phase 3 VALOR study (NCT02623699), and the open label extension (OLE) study as basis for the submission.5

Timothy Miller, MD, PhD, codirector, ALS Center, Washington University School of Medicine in St. Louis

Timothy Miller, MD, PhD

In Septemeber 2022, Biogen announced the findings from its phase 3 VALOR study, the combined analysis of VALOR and its open-label extension (OLE), in the New England Journal of Medicine.6,7 All told, treatment with tofersen was associated with reductions in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), an indirect marker of target engagement, and concentration of neurofilament light (NfL) in plasma over the 28-week randomized component of VALOR.

Ina prespecified combined analysis of VALOR and its OLE, patients who received tofersen at the beginning of VALOR, irrespectively of fast or slow progression, had a smaller numeric decline in the ALS Functional Rating-Revised (ALSFRS-R) score, percentage of predicted slow vital capacity (SVC), and handheld dynamometry mega score at 52 weeks than patients who received the treatment in the open-label extension 28 weeks later.

"I see 3 key take home points from these data. First, tofersen clearly leads to lowering of SOD1 protein, as would be expected. Second there is substantial lowering of neurofilament levels, which I interpret as potentially slowing the underlying disease process. And third, there is a meaningful clinical benefit when looking at the later time points in the open-label extension,” principal investigator Timothy Miller, MD, PhD, codirector of the ALS Center at Washington University School of Medicine in St. Louis, said in a statement.6

Parkinson disease: IPX203 (Amneal Pharmaceuticals)

IPX203 (Amneal Pharmaceuticals) is a novel, oral formulation of carbidopa/levodopa (CD/LD) extended-release capsules intended to treat patients with Parkinson disease (PD). If the drug gets approved by the FDA on June 30, 2023, it may address some of the limitations of the current oral delivery levodopa options. In November 2022, the FDA accepted its NDA for IPX203, which was supported by data from the phase 3 RISE-PD clinical trial (NCT03007888).8,9

Rohit Dhall, MD, MSPH, associate professor of neurology, and director, Neurodegenerative Disorders, University of Arkansas for Medical Sciences

Rohit Dhall, MD, MSPH

“The design of IPX203 provides rapid absorption and prolonged steady concentrations of [levodopa] which lead to sustained pharmacodynamic effect in patients with PD who exhibit motor fluctuations on conventional [immediate-release carbidopa-levodopa] formulations,” Rohit Dhall, MD, MSPH, associate professor of neurology and director of Neurodegenerative Disorders at the University of Arkansas for Medical Sciences, and colleagues wrote. Dhall et al presented the data in a poster at the 2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congress in Washington, DC, June 17-19.

At ATMRD, results from RISE-PD on IPX203 showed that those with PD who were treated with the agent had rapid absorption followed by sustained plasma concentrations, with a maximum serum concentration (Cmax)­ of 2.768 ng/mL (SD, 1.259) in comparison with 2.357 ng/mL (SD, 1.179) for immediate-release carbidopa-levodopa.

"The FDA filing acceptance of IPX203 marks another important milestone for Amneal as we strive to improve the lives and care of people living with Parkinson disease” Gustavo Pesquin, chief commercial officer of Amneal Specialty, said in a statement.8 "We look forward to engaging in conversations with the FDA as we advance the application. We believe the data in our RISE-PD study supports the important benefit IPX203 can offer to this community by providing longer duration of symptom control with the benefit of fewer doses."

Cervical dystonia: DaxibotulinumtoxinA (Revance Therapeutics)

DaxibotulinumtoxinA (Daxxify; Revance Therapeutics) is a novel botulinum toxin type A formulation in clinical development for cervical dystonia. The FDA has scheduled August 19, 2023, as the PDUFA date for the therapy, with promising results from ASPEN-1 (NCT03608397) and also in ASPEN-OLS (NCT03617367) as the basis for the agent’s new biologics license application (sBLA).10,11

Joseph Jankovic, MD, professor of neurology, Distinguished Chair in Movement Disorders, and founder and director, The Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine

Joseph Jankovic, MD

In October 2020, Revance Therapeutics announced that its investigational drug candidate for injection for the treatment of cervical dystonia, daxibotulinumtoxinA, met its primary end point in ASPEN-1, arandomized, placebo-controlled, parallel group clinical trial.10

In both the 125- or 250-unit dose groups of daxibotulinumtoxinA, the therapy met primary end point by demonstrating a clinically meaningful improvement in the signs and symptoms of cervical dystonia, on average, by weeks 4 through 6. The treatment was approved previously as the first and only peptide formulated neuromodulator for the temporary improvement of moderate to severe glabellar lines in adults. In addition, the agent has been evaluated for poststroke spasticity.

"I was delighted to see both the degree and duration of relief that daxibotulinumtoxinA for Injection provided trial subjects in ASPEN-1. Currently, most patients with cervical dystonia visit their physician 3 to 4 times a year for injections, which places a heavy burden on patients’ time and schedule. Often, the treatment effect wears off between injections, significantly impacting the quality of their work and personal lives,” trial investigator Joseph Jankovic, MD, professor of neurology, Distinguished Chair in Movement Disorders, and founder and director of The Parkinson’s Disease Center and Movement Disorders Clinic at Baylor College of Medicine, said in a statement.10

1. Raeta Announces Positive Topline Results from the MOXIe Registrational Trial of Omaveloxolone ir Patients with Friedreich’s Ataxia. News release. Raeta Pharmaceuticals. October 14, 2019. Accessed January 26, 2023. reatapharma.com/press-releases/reata-announces-positive-topline-results-from-the-moxie-registrational-trial-of-omaveloxolone-in-patients-with-friedreichs-ataxia/?releaseyear=2019
2. Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in patients with Friedrich’s ataxia: delayed-start study. Presented at MDS Virtual Congress; September 17-22, 2021. Poster LBA 2.
3. Positive Phase 2 Study Results of Trofinetide in Pediatric Rett Syndrome Published in Neurology, the Medical Journal of the American Academy of Neurology. San Diego, CA; Cincinnati, OH; Melbourne, Australia: ACADIA Pharmaceuticals Inc.; Neuren Pharmaceuticals Limited; Rettsyndrome.org; Published March 27, 2018. Accessed January 26, 2023.
4. Acadia Pharmaceuticals announces positive topline results from the pivotal phase 3 Lavender trial of trofinetide in Rett syndrome. News release. Acadia Pharmaceuticals. December 6, 2021. Accessed December 7, 2021. https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-positive-top-line-results-1
5. Acadia Pharmaceuticals Announces Trofinetide New Drug Application for the Treatment of Rett Syndrome has been Accepted for Filing and Review by US FDA. News release. Acadia Pharmaceuticals. September 12, 2022. Accessed January 26, 2023. https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-trofinetide-new-drug-application-for-the-treatment-of-rett-syndrome-has-been-accepted-for-filing-and-review-by-u-s-fda/
6. The New England Journal of Medicine publishes pivotal tofersen data that show benefits in rare, genetic form of ALS. News release. Biogen. September 21, 2022. Accessed January 26, 2023. https://www.globenewswire.com/news-release/2022/09/21/2520640/0/en/The-New-England-Journal-of-Medicine-Publishes-Pivotal-Tofersen-Data-that-Show-Benefits-in-Rare-Genetic-Form-of-ALS.html
7. Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387:1099-1110. doi:10.1056/NEJMoa2204705
8. Dhall R, Agarwal P, Kilbane C, et al. Design of better levodopa delivery: formulation strategy of OPX203, an investigational extended-release carbidopa-levodopa. Presented at: ATMRD Congress; June 17-19, 2022; Washington, DC.
9. Amneal announces US FDA filing acceptance of new drug application for IPX203 for the treatment of Parkinson disease. News release. November 11, 2022. Accessed January 26, 2023. https://www.businesswire.com/news/home/20221109005842/en/Amneal-Announces-U.S.-FDA-Filing-Acceptance-of-New-Drug-Application-for-IPX203-for-the-Treatment-of-Parkinson%E2%80%99s-Disease
10. 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 January 26, 2023. https://investors.revance.com/news-releases/news-release-details/revance-reports-positive-results-aspen-1-phase-3-trial
11. Revance announces US FDA acceptance of supplemental biologics license application (sBLA) for Daxxify (DaxibotulinumtoxinA-Ianm) for injection for the treatment of cervical dystonia. News release. January 6, 2023. Accessed January 26, 2023. https://investors.revance.com/news-releases/news-release-details/revance-announces-us-fda-acceptance-supplemental-biologics
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