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FDA Action Update, October 2021: Submissions and Delays

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.

A number of FDA actions took place in October 2021, including application submissions for a number of hopeful therapies for Alzheimer disease (AD), as well as the delay of an anticipated sleep disorder agent.

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.

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

Ublituximab Biologics License Application Submitted for Relapsing MS

In early October, TG Therapeutics submitted a biologics license application (BLA) to the FDA for the use of ublituximab as treatment for patients with relapsing forms of multiple sclerosis. The agent, an investigational glycoengineered anti-CD20 monoclonal antibody, was evaluated in 2 independent, identical, phase 3, randomized, global, multicenter, double-blinded, active-controlled trials, ULTIMATE 1 (NCT03277261) and ULTIMATE 2 (NCT03277248), which compared the efficacy of the treatment with teriflunomide (Aubagio; Sanofi).1

Results from both trials were announced earlier in June 2021, at the 7th Congress of the European Academy of Neurology, with investigators concluding that ublituximab met its primary end point in significantly reducing annualized relapse rate and MRI parameters over a 96-week period, when compared to teriflunomide (P <.005 in each trial).1-3

Michael S. Weiss, chairman and CEO, TG Therapeutics, said in a statement that the submission “marks a major milestone for us, being our first submission of a marketing application for an autoimmune indication and rounds out our near-term US regulatory submissions.” He added that the company believes that “ublituximab has the potential to offer an important new treatment option for these patients, and we look forward to working closely with the FDA on this submission. We want to thank the patients and their families, as well as the physicians and their research teams, who participated in our ULTIMATE 1 and 2 trials.”

Gantenerumab Gets Breakthrough Designation for Alzheimer Disease

A little later in month of October, the FDA awarded Genentech and Roche’s a breakthrough therapy designation for their investigational antiamyloid-ß (Aß) antibody agent, gantenerumab, in the treatment of individuals with AD. If eventually approved, it would be the first subcutaneous medicine for the treatment of patients with AD.4

The decision was made based on the data from the ongoing SCarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608) open-label extension trials. Thus far, they have shown that the therapy significantly reduced brain amyloid plaques. Investigators then used those findings to optimize the design of 2 ongoing parallel, placebo-controlled, randomized phase 3 studies, dubbed GRADUATE 1 (NCT03444870) and GRADUATE 2 (NCT03443973). The trials include more than 2000 participants and are evaluating the safety and efficacy of the therapy an early AD population, with a monthly target dose of 1020 mg. The company will release data from both studies in the second half of 2022.

Levi Garraway, MD, PhD, chief medical officer, and head, Global Product Development, Roche, said in a statement, that "for more than a decade, we’ve been committed to advancing the science of Alzheimer’s as well as our investigational medicine gantenerumab, and we look forward to delivering a comprehensive and robust data set that furthers our collective understanding of this devastating disease.” Garraway continued by saying that the designation “reinforces our confidence in gantenerumab.”

FDA Announces NDA Review for FT218 in Narcolepsy Still Ongoing

Shortly after the gantenerumab news, the FDA announced that the new drug application (NDA) for Avadel Pharmaceutical’s investigational agent FT218, a once-nightly sodium oxybate formulation for treatment of excessive daytime sleepiness and cataplexy in adults with narcolepsy, was still under review and the decision would be pushed back.5

The submission had been accepted by the FDA in February 2021, with aPrescription Drug Use Fee Act action date of October 15, 2021. The application was supported by positive data from the phase 3 REST-ON study (NCT02720744), which was held under a special protocol assessment agreement with the FDA, and included a total of 222 patients with narcolepsy, all of whom were 16 years or older. Patients were randomized 1:1 to receive uptitration doses of 4.5 g, 6 g, 7.5 g, and 9 g of FT218 or placebo over the course of a 3-week screening period, a 13-week treatment period, and a 1-week follow-up period. The study met all 3 of its primary end points, which were change from baseline in mean sleep latency on the Maintenance of Wakefulness test, Clinical Global Impression Improvement, and weekly cataplexy attacked within the 6-, 7.5-, and 9-g group. Patient randomization was stratified by narcolepsy type 1 or type 2.6

Greg Divis, CEO, Avadel, said in a statement that the company had “addressed all questions received to date” and was “confident that the package we have submitted satisfies all of the FDA’s requests.” At that point, Divis added, Avadel had not been informed of deficiencies in the application. “Once-at-bedtime FT218 has the potential to truly impact the way people with narcolepsy are able to live their lives and we are dedicated to making this important therapy available to patients as quickly as possible,” he said.

Eli Lilly Initiates Rolling Submission for Donanemab in Early Alzheimer Disease

At the end of October 2021, Eli Lilly announced that it had initiated a rolling submission of a BLA for donanemab, an investigational antibody therapy, to the FDA for accelerated approval in early AD. The company also announced plans to conduct the TRAILBLAZER-ALZ 4 study, a phase 3 head-to-head trial comparing donanemab to the newest approved agent, in early AD.7

Lilly announced in June that the FDA had granted breakthrough therapy designation for donanemab, alongside its plan to submit the BLA, backed by data from the phase 2 TRAILBLAZER-ALZ study, which showed that when compared to placebo, donanemab slowed the progression of AD. The phase 2 trial evaluated the efficacy and safety of the agent in 272 patients with early-stage, symptomatic AD, and its data showed a 32% slower decline on Integrated Alzheimer’s Disease Rating Scale scores compared to placebo from baseline to 76 weeks. Furthermore, investigators found that donanemab, by targeting N3pG ß-amyloid, reduced amyloid plaque by an average of 78%, or an 84-centiloid reduction at 76 weeks compared to a baseline of 108 centiloids.8

At the time of the original data announcement in June 2021, Daniel Skovronsky, MD, PhD, chief scientific officer, and president, Lilly Research Laboratories, Eli Lilly, expressed his confidence in the results in a statement from the company.9 "This is the first late-stage study in Alzheimer's disease to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for Alzheimer's disease. We were pleased to see not only slowing of cognitive and functional decline, but also very substantial clearance of amyloid plaques and slowing of spread of tau pathology," he said.

REFERENCES
1. TG Therapeutics submits biologics license application to the US Food and Drug Administration for ublituximab as a treatment for patients with relapsing forms of multiple sclerosis. News release. TG Therapeutics, Inc. September 30, 2021. Accessed November 3, 2021. https://www.globenewswire.com/news-release/2021/09/30/2306091/8790/en/TG-Therapeutics-Submits-Biologics-License-Application-to-the-U-S-Food-and-Drug-Administration-for-Ublituximab-as-a-Treatment-for-Patients-with-Relapsing-Forms-of-Multiple-Sclerosis.html
2. TG Therapeutics announces presentation of data from the ULTIMATE 1 & 2 phase 3 trials of ublituximab in multiple sclerosis at 7th Congress of the European Academy of Neurology. News release. TG Therapeutics. June 18, 2021. Accessed November 3, 2021. https://www.biospace.com/article/releases/tg-therapeutics-announces-presentation-of-data-from-the-ultimate-i-and-ii-phase-3-trials-of-ublituximab-in-multiple-sclerosis-at-7th-congress-of-the-european-academy-of-neurology/
3. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ULTIMATE 1 and 2 trials. Presented at the 7th Congress of the European Academy of Neurology; June 19-22. Abstract A-21-00763
4. Ad hoc announcement pursuant to Art. 53 LR: Genentech’s anti-amyloid beta antibody gantenerumab granted FDA breakthrough therapy designation in Alzheimer disease. News release. Genentech. October 8, 2021. Accessed October 8, 2021. https://www.businesswire.com/news/home/20211008005371/en/Ad-hoc-announcement-pursuant-to-Art.-53-LR-Genentech%E2%80%99s-Anti-Amyloid-Beta-Antibody-Gantenerumab-Granted-FDA-Breakthrough-Therapy-Designation-in-Alzheimer%E2%80%99s-Disease
5. Avadel Pharmaceuticals announces ongoing FDA review of NDA for FT218 for patients with narcolepsy. News release. Avadel Pharmaceuticals. October 15, 2021. Accessed November 3, 2021. https://www.globenewswire.com/news-release/2021/10/15/2315210/0/en/Avadel-Pharmaceuticals-Announces-Ongoing-FDA-Review-of-NDA-for-FT218-for-Patients-with-Narcolepsy.html
6. Kushida CA, Shapiro CM, Roth T, et al. Once-nightly sodium oxybate (FT218) demonstrated improvements of symptoms in a phase 3 randomized clinical trial in patients with narcolepsy. SLEEP. 2021;zsab200. doi:10.1093/sleep/zsab200.
7. Lilly reports robust third-quarter 2021 financial results as pipeline success strengthens future growth potential. News release. October 26, 2021. Accessed November 3, 2021. https://investor.lilly.com/news-releases/news-release-details/lilly-reports-robust-third-quarter-2021-financial-results
8. Lilly’s donanemab receives US FDA’s breakthrough therapy designation for treatment of Alzheimer disease. News release. Eli Lilly. June 24, 2021. Accessed November 3, 2021. https://www.prnewswire.com/news-releases/lillys-donanemab-receives-us-fdas-breakthrough-therapy-designation-for-treatment-of-alzheimers-disease-301318931.html
9. Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD™ 2021 and published in NEJM. News release. March 13, 2021. Accessed November 3, 2021. https://www.prnewswire.com/news-releases/lillys-donanemab-slowed-alzheimers-disease-progression-in-phase-2-trial-full-data-presented-at-adpd-2021-and-published-in-nejm-301246745.html