FDA Action Update, January 2022: Approvals, Acceptances, Clinical Holds

A number of FDA actions took place in January 2022, including an approval for adults with insomnia, a number of treatment application acceptances for various neuromuscular disorders, and a few clinical holds placed on trials in Alzheimer and Parkinson disease.

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.

FDA Approves Daridorexant for Insomnia Treatment

On January 10, 2022, the FDA approved daridorexant (Quviviq; Idorsia), for the treatment of insomnia in adults. The dual orexin receptor antagonist, which has been recommended as a controlled substance by the FDA, is expected to be available in May 2022 following scheduling by the US Drug Enforcement Administration.¹

The basis for the decision came from a clinical program that included 1854 adults across 160 clinical trial sites. Data showed that treatment with daridorexant 25- and 50-mg resulted in significant improvement compared with placebo on objective measures of sleep onset and sleep maintenance, as well as patient-reported total sleep time. Designed to block the binding of the wake-promoting neuropeptides orexins to address overactive wakefulness, daridorexant showed statistically significant improvement in sleep and daytime functioning, as measured by the Insomnia Daytime Symptoms and Impacts Questionnaire, while keeping a favorable safety profile in adult and elderly patients through 2 phase 3 clinical trials, Study 1 (NCT03545191) and Study 2 (NCT03575104).

Martine Clozel, MD, chief scientific officer, Idorsia, said in a statement at the time, "After more than 20 years of research and a progressive understanding of the role of orexin in sleep-wake balance and of the potential of orexin receptor antagonism, we designed daridorexant to help address several issues people with insomnia face. Daridorexant properties include a potent inhibition of both orexin receptors, a rapid absorption for sleep onset, and a pharmacokinetic profile such that around 80% of daridorexant has been eliminated after a night of sleep to help minimize residual effects."

Application Accepted for Oral Edaravone in Amyotrophic Lateral Sclerosis

On January 12, Mitsubishi Tanabe Pharma America (MTPA) announced that the FDA had accepted a new drug application (NDA) for its investigational oral formulation of edaravone (MT-1186) for the treatment of amyotrophic lateral sclerosis (ALS). The Prescription Drug User Fee Action date was set for May 12, 2022, with the application being accepted for priority review.²

The intravenous (IV) formulation of edaravone (Radicava; MTPA) was approved by the FDA for treatment of ALS in May 2017, with the investigational oral formulation developed to have a similar clinical profile. A series of phase 1 studies comparing the oral formulation and IV formulation of edaravone were completed by MTPA in 2019. A phase 3 clinical trial (NCT04165824) has also been initiated to evaluate the safety and tolerability of the oral formulation, enrolling 185 patients with ALS at 50 different sites in the US, Canada, Europe, and Japan. The safety extension study of the trial (NCT04577404) is also underway to evaluate the long-term safety and tolerability of oral edaravone for up to 96 weeks. 

“At MTPA, we thrive on tackling the toughest challenges and are focused on addressing the unmet needs of the ALS community, which is illustrated by our ongoing development program for edaravone," Atsushi Fujimoto, president, MTPA, said in a statement at the time.2 "Our top priority is to help ensure ALS patients have flexibility with treatment and formulation options that are right for their specific needs. We look forward to working with the FDA in the coming months to bring this new formulation to patients as soon as possible.”

FDA Places Clinical Hold on IND for DNL919 in Alzheimer Disease

On January 13, the FDA placed a clinical hold on the investigational new drug (IND) application for DNL919, an antibody transport vehicle (ATV) designed to activate the TREM2 protein and normalize microglial function in patients with Alzheimer disease (AD), Denali Therapeutics recently announced.³ Just 2 days earlier, Denali announced that Takeda Pharmaceutical Company would be exercising its option to codevelop and cocommercialize the treatment for patients with AD.

An official clinical hold letter was expected to be provided by the FDA within 30 days after the agency notified the company about the hold on January 12, 2022, via email. Updates will be provided following that discussion with the FDA, Denali said in a statement.

When compared with a non-ATV TREM2 antibody, DNL919 demonstrated enhanced brain uptake and improved pharmacodynamic response, according to animal model data. Prior to the clinical hold, Denali had planned to initiate first-in-human clinical trials in the first half of 2022, with human safety and biomarker data available in the second half of 2022. These results were also expected to include the effect of DNL919 on colony-stimulating factor 1 receptor in cerebrospinal fluid (CSF), which is a key indicator of TREM2 pathway engagement.⁴

Phase 2 Trial of Sodium Oligomannate in Parkinson Disease Greenlit by FDA

The FDA accepted an IND application from Green Valley Pharmaceuticals’ and has allowed the company to proceed with its phase 2 trial assessing sodium oligomannate (GV-971), an agent approved in China for AD, in a global cohort of patients with early-stage Parkinson disease (PD).⁵

The multicenter trial will include approximately 300 patients with early-stage PD who will be randomized to either sodium oligomannate or placebo for a 36-week period. Following that, patients may enter into a nonrandomized, 36-week, open-label extension for further testing. No information was provided as to when the study would begin. After receiving fast track designation, China’s National Medical Products Administration approved sodium oligomannate for the treatment of mild-to-moderate AD and improving cognitive function on November 2, 2019. The drug is currently only approved in China, although several studies, including a notable phase 3 trial, have demonstrated its significant benefits.

Sodium oligomannate is a seaweed-based oral compound derived from marine brown algae that is designed to promote a healthy gut microbiome. It specifically targets the gut-brain axis—the interplay between the nerve cells governing the intestines and those in the brain—and works to reduce inflammation by reconditioning the gut microbiota and inhibiting the abnormal balance of the byproducts of gut microbiota metabolism.

Partial Clinical Hold Placed on Multidose Clinical Trials of YTX-7739 in Parkinson Disease

Just a few days later, on January 19, Yumanity Therapeutics announced that the FDA placed a partial clinical hold on multidose clinical trials of YTX-7739, a disease-modifying therapy for the treatment of PD, in response to the company’s IND application, which was submitted in December 2021.⁶

The hold suspended the initiation of multiple dose trials of the treatment in the US until questions from the FDA have been addressed, with Yumanity anticipating additional details from the FDA in the days following the notice. Previously, YTX-7739 was assessed in healthy patients, with results reported from 14- and 28-day multiple dosing studies, as well as in patients with PD in a 28-day multiple-dose clinical study. The treatment is designed to penetrate the blood-brain barrier (BBB), then inhibiting the activity of stearoyl-CoA desaturase (SCD), a novel target. By inhibiting SCD, YTX-7739 controls and upstream process in the α-synuclein pathological cascade, and in preclinical cellular and animal models, it has been shown to rescue or prevent toxicity, according to Yumanity.

In February of last year, Yumanity provided updates for the development of YTX-7739, namely the results of a single ascending dose (SAD) study, the completion of enrollment in a multiple ascending dose (MAD) study, as well as the initiation of a phase 1b study. Ultimately, the SAD study identified no safety concerns, and the treatment was considered well-tolerated. Most AEs were deemed mild or moderate in severity. In tandem with a favorable pharmacokinetic profile in the fed state, the half-life of the therapy supports the notion that low daily doses administered with food can sustain the targeted range of drug exposure.

Risdiplam Gets Priority Review for Presymptomatic SMA in Babies Under 2 Months

A supplemental NDA for risdiplam (Evrysdi; PTC Therapeutics) was granted priority review by the FDA for treatment of presymptomatic babies under 2 months of age with spinal muscular atrophy (SMA) on January 25, 2022. The treatment is currently used to treat SMA in adults and children 2 months of age and older, and if approved, risdiplam would become the first medicine administered at home for presymptomatic babies with SMA.⁷

“Treating very young babies with Evrysdi before SMA symptoms arise may help them to achieve milestones such as standing and walking within timeframes typical of healthy infants,” Levi Garraway, MD, PhD, chief medical officer, and head of Global Product Development, Genentech, said in a statement at the time. “Extending treatment access for the youngest members of the SMA community is crucial and we look forward to working with the FDA on this application.”

The submission incorporates interim data from the RAINBOWFISH study (NCT03779334), which suggest that following 12 months of treatment with risdiplam, a majority of presymptomatic babies met key milestones of healthy babies, including sitting, standing, and walking, in addition to maintaining the ability to swallow. Data were presented at the World Muscle Society (WMS) Virtual Congress 2021, September 20-24. The RAINBOWFISH study included 5 babies, all of whom maintained the ability to swallow and feed exclusively orally after 12 months of treatment. Additionally, after 12 months, 4 out of 5 babies (80%) receiving risdiplam were able to stand and walk independently, in accordance with the established windows for health children from the World Health Organization.⁸

REFERENCES
1. Idorsia receives US FDA approval of Quiviviq (daridorexant) 25 and 50 mg for the treatment of adults with insomnia. News release. Idorsia. January 10, 2022. Accessed February 2, 2022. https://www.biospace.com/article/releases/idorsia-receives-us-fda-approval-of-quviviq-daridorexant-25-and-50-mg-for-the-treatment-of-adults-with-insomnia/?s=85
2. Mitsubishi Tanabe Pharma America announces FDA acceptance of new drug application (NDA) for oral edaravone formulation for the treatment of ALS. News release. Mitsubishi Tanabe Pharma America, Inc. January 12, 2022. Accessed February 2, 2022. https://www.prnewswire.com/news-releases/mitsubishi-tanabe-pharma-america-announces-fda-acceptance-of-new-drug-application-nda-for-oral-edaravone-formulation-for-the-treatment-of-als-301459460.html
3. Denali Therapeutics announces FDA clinical hold on DNL919 investigational new drug (IND) application. News release. Denali Therapeutics. January 13, 2022. Accessed February 2, 2022. https://www.biospace.com/article/releases/denali-therapeutics-announces-fda-clinical-hold-on-dnl919-investigational-new-drug-ind-application/
4. Denali Therapeutics announces progression and expansion of broad therapeutic portfolio for neurodegeneration and expected key milestones in 2022. News release. Denali Therapeutics. January 10, 2022. Accessed February 2, 2022. https://www.biospace.com/article/releases/denali-therapeutics-announces-progression-and-expansion-of-broad-therapeutic-portfolio-for-neurodegeneration-and-expected-key-milestones-in-2022/
5. Green Valley obtains IND approval from US FDA for sodium oligomannate’s global phase 2 clinical trial in treating Parkinson disease. News release. Green Valley Pharmaceuticals. January 17, 2022. Accessed February 2, 2022. https://www.prnewswire.com/news-releases/green-valley-obtains-ind-approval-from-us-fda-for-sodium-oligomannates-global-phase-ii-clinical-trial-in-treating-parkinsons-disease-301461838.html
6. Yumanity reports partial clinical hold by US FDA on multidose clinical trials for YTX-7739. News release. Yumanity Therapeutics. January 19, 2022. Accessed February 2, 2022. https://www.biospace.com/article/releases/yumanity-reports-partial-clinical-hold-by-u-s-fda-on-multidose-clinical-trials-for-ytx-7739-/
7. Genentech’s Evrysdi (risdiplam) granted FDA priority review for treatment of presymptomatic babies under 2 months of age with spinal muscular atrophy (SMA). News release. Genentech. January 25, 2022. Accessed February 2, 2022. https://www.biospace.com/article/releases/genentech-s-evrysdi-risdiplam-granted-fda-priority-review-for-treatment-of-pre-symptomatic-babies-under-2-months-of-age-with-spinal-muscular-atrophy-sma-/
8. Roche presents new data at World Muscle Society (WMS) 2021 highlighting new advances for people living with rare neuromuscular disorders. News release. Roche. September 24, 2021. Accessed February 2, 2022. https://www.roche.com/media/releases/med-cor-2021-09-24.htm