FDA Action Update, January 2023: Approvals, Refusals, Clinical Hold Lifts, and Submissions

The FDA was busy in January 2023, making a number of decisions on potential new therapeutic agents, clearing a couple clinical trial holds, issuing some guidance on stroke risk, and clearing new devices, among other actions.

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 Clears First Stroke-Specific Radial Access Platform for Mechanical Thrombectomy

Early in the new year, on January 4, the FDA granted 510(k) clearance to Imperative Care for its Zoom RDL Access System, making the system the first radial access platform developed specifically for treating patients with ischemic stroke. The company also announced the successful completion of the first-in-human case using Zoom RDL. The newest addition to Imperative’s Zoom Stroke Solution, the system features an extended hydrophilic coating and the longest optimized vessel dilator on the market, allowing for a smooth introduction into the radial artery.

The system also includes a large .088-inch lumen for compatibility with large-bore aspiration catheters. Designed to reach the intracranial vasculature, this new approach may allow clinicians to get higher into the brain and closer to the stroke-causing clot, thus improving control throughout the procedure.

"As we continue to advance how we care for our stroke patients and see the overwhelming benefit of performing radial interventions, it’s remarkable to have a company like Imperative Care respond with much-needed tools for a radial approach,” Justin Singer, MD, neurosurgeon, Spectrum Health, who performed the first in-human operation using Zoom RDL on a patient with a complex anatomy that would have made femoral access challenging, said in a statement.¹ "I am impressed with the performance of the Zoom RDL in my initial experience and look forward to continuing a patient-first approach in my stroke practice. The addition of this new technology will allow me the first capability to choose the best access approach for each patient without limitations."

FDA Designates Myasthenia Gravis Agent Rozanolixizumab Application for Priority Review

A few days later, on January 6, UCB Pharma announced that the FDA had granted priority review for the biologic license application (BLA) for its agent rozanolixizumab, a potential treatment for adults with generalized myasthenia gravis (gMG) who are antiacetylcholine receptor or antimuscle-specific tyrosine kinase antibody positive. If the FDA approves the review, it could deliver significant improvements for the safety and effectiveness of the treatment, diagnosis, or preventative care for this patient population.²

Charl van Zyl, executive vice president, Neurology Solutions, and head of EU/International Markets, UCB said in a statement, “People living with MG suffer from unpredictable, fluctuating, and debilitating symptoms that have a huge impact on their lives, and there is a clear need for additional targeted treatments. We are firmly committed to supporting the gMG community by providing solutions to help improve outcomes for patients and reduce the day-to-day burden of the disease. The FDA’s decision to assess rozanolixizumab via their priority review process, as well as the recent filing of the MAA in Europe, brings us important steps further on our journey towards approvals for rozanolixizumab. We look forward to working with the FDA and EMA to help bring this new treatment option to patients.”

FDA Approves Eisai’s Lecanemab for the Treatment for Alzheimer Disease

That same day, on January 6, the FDA approved lecanemab (Leqembi; Eisai), a humanized IgG1 monoclonal antibody that binds with high affinity to amyloid-ß (Aß) soluble protofibrils, for the treatment of patients with early-stage Alzheimer disease (AD). It became the second antiamyloid therapy in its class, joining aducanumab (Aduhelm; Biogen), which earned approval in June 2021 and was developed by Biogen, which also partnered with Eisai on lecanemab's development.³

"Ultimately, it adds to the treatment options beyond symptomatic therapy," Marwan Sabbagh, MD, a behavioral neurologist Barrow Neurological Institute, and clinical investigator in the agent's development program, told NeurologyLive^®. "Patients are highly motivated to change their future. This is an important first step in transforming AD from a terminal disease to a chronic disease."

Similar to its predecessor, lecanemab was greenlit via the accelerated approval pathway, with the application supported by data from the phase 2b proof-of-concept clinical trial, known as Study 201 (NCT01767311). The pivotal phase 3 Clarity AD trial (NCT03887455), which is anticipated to serve as supplementary data and is still pending review by the FDA—Eisai submitted the supplemental BLA the same day.⁴

FDA Accepts sBLA for Revance’s Cervical Dystonia Treatment DaxibotulinumtoxinA

Again on January 6, the FDA has accepted Revance Therapeutic’s supplemental BLA for daxibotulinumtoxinA injection (Daxxify), as a new treatment for adults with cervical dystonia. The agency scheduled August 19, 2023, as the PDUFA date for the therapy.⁵

"Painful symptom reemergence is very common for patients with cervical dystonia and up until now physicians have not been able to fully address this issue with existing treatment options," Peter McAllister, MD, medical director, New England Institute for Neurology and Headache, said in a statement. "As an ASPEN investigator, I am excited about the results of the Daxxify phase 3 trials, which demonstrate that a long-acting botulinum toxin can help address this significant unmet need in the treatment of cervical dystonia."

DaxibotulinumtoxinA is an acetylcholine release inhibitor and neuromuscular blocking agent indicated for the temporary improvement of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adults. To date, the therapy has shown promising results in 2 phase 3 studies of cervical dystonia, ASPEN-1 (NCT03608397) and ASPEN-OLS (NCT03617367).

Neurelis Files IND for Potentially First Therapy to Treat Cerebral Cavernous Malformations

On January 9, Neurelis successfully filed an investigational new drug application (IND) for its rho kinase (ROCK) inhibitor NRL-1049 as a potential treatment for individuals with cerebral cavernous malformations (CCM). The company plans to initiate a study in early 2023 to assess the agent.⁶

CCM, a disease characterized by abnormally enlarged capillary cavities, most commonly found in the cerebral cortex, brainstem, and spinal cord, currently has no FDA-approved therapeutics to treat the condition. Patients with the condition have typically turned to antiepileptic drugs and surgical interventions to remove lesions; although, most cavernous malformations have been conservatively managed by observing for changes in appearance, recent hemorrhages, or other clinical symptoms.

Adrian L. Rabinowicz, MD, senior vice president, Clinical Development and Medical Affairs, Neurelis, said in a statement, that "this is a significant milestone for Neurelis and represents an opportunity to further explore the clinical utility of NRL-1049 for the treatment of cerebral cavernous malformations," adding that, "following favorable preclinical study results, we are excited to advance our mission to introduce new treatment options for patients with critical unmet medical needs."

CDC and FDA Announce Stroke Safety Concern Related to Pfizer-BioNTech Bivalent COVID-19 Vaccine

On January 16, the FDA and Centers for Disease Control and Prevention (CDC) issued a joint statement claiming that the agencies were assessing data regarding Pfizer-BioNTech's COVID-19 vaccine bivalent increases the risk of ischemic stroke in elders.

"CDC’s Vaccine Safety Datalink (VSD), a near real-time surveillance system, met the statistical criteria to prompt additional investigation into whether there was a safety concern for ischemic stroke in people ages 65 and older who received the Pfizer-BioNTech COVID-19 Vaccine, Bivalent," the CDC/FDA statement read. "Rapid-response investigation of the signal in the VSD raised a question of whether people 65 and older who have received the Pfizer-BioNTech COVID-19 Vaccine, Bivalent were more likely to have an ischemic stroke in the 21 days following vaccination compared with days 22-42 following vaccination."

FDA Hands Eli Lilly Complete Response Letter for Donanemab After Lack of Long-Term Data

Then, on January 19, the FDA issued a complete response letter to Eli Lilly for its investigational antiamyloid therapy donanemab, a humanized IgG1 monoclonal antibody, for the treatment of symptomatic AD. A lack of participants who received continuous treatment with donanemab for at least 12 months was the reason for the decision, with no other noted concerns.⁷

In its response letter, the FDA requested the company provide data from at least 100 patients who have received a minimum of 12 months of continuous treatment with donanemab. The phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the biologics license application of donanemab, included more than 100 patients; however, it was designed so that patients would complete the treatment course once they reached a predefined level of amyloid plaque clearance.

"We look forward to our upcoming confirmatory TRAILBLAZER-ALZ 2 phase 3 results and subsequent FDA submission, which we've always seen as the most impactful next steps for patients," Anne White, executive vice president and president of Lilly Neuroscience, Eli Lilly, said in a statement. "We anticipate this study will confirm the benefit and safety profile we observed in the TRAILBLAZER-ALZ phase 2 study and believe that patients and physicians will be well served by having the full phase 3 data available alongside our phase 2 data when they need to make treatment decisions."

FDA Clears Trial Hold on Late-Onset Pompe Disease Gene Therapy AT845

Later in the month, on January 20, the FDA lifted a clinical hold on Astellas Pharma's phase 1/2 FORTIS clinical trial (NCT04174105) assessing its investigational agent AT845 for the treatment of adults with late-onset Pompe disease (LOPD).⁸ FORTIS is the first-in-human trial of the gene replacement therapy, which is designed to use the adeno-associated virus vector 8 to deliver a functional copy of the GAA gene under a muscle-specific promoter.

"With that same spirit and focus on patient safety, we look forward to resuming the FORTIS clinical trial and the continued development of AT845 as an important potential new treatment for adults living with LOPD," Ha Tran, executive medical director, Astellas, said in a statement. "As always, we are grateful to the patients participating in the FORTIS clinical trial and we remain committed to developing novel therapies for those with a high unmet medical need."

FORTIS formerly was placed on hold because of a case of a serious adverse event (AE) of peripheral sensory neuropathy. The AE was classified as grade 1 and mild although it was serious because of medical significance. Therefore, the FDA told Astellas that there was not enough information for assessing the risks of the participants and that more information is needed about the incidence of neuropathy.

FDA Lifts Hold on Phase 2 Trial of Parkinson Agent IKT-148009

Then, on January 25, the FDA lifted a full clinical hold on Inhibikase Therapeutics’ phase 2 trial 201 (NCT05424276) assessing its lead product candidate IKT-148009, an Abelson Tyrosine Kinase (Abl) inhibitor for patients with Parkinson disease (PD). Those in the 50- and 100-mg groups will resume dosing immediately, with ongoing safety observations for the 200 mg group.⁹

"We are grateful for the expeditious review by the FDA of our response to the Clinical Hold on IkT-148009 in PD," Milton H. Werner, PhD, president and chief executive office, Inhibikase, said in a statement. "We believe that we now have clarity on the FDA's expectations as we move forward in the 201 clinical trial for IkT-148009. We are now working to reopen clinical trial sites and initiate screening and enrollment of patients for the trial following agreed upon updates to the Protocol and Informed Consent form. We anticipate completing these restart tasks by the end of the first quarter."

In early December 2022, the FDA placed the hold on the company’s PD and multiple system atrophy (MSA) programs for the agent, citing several points. The agency requested further evaluation of the existing safety and pharmacokinetic (PK) data of the 200 mg dose, a better understanding of how the trial will monitor the potential for detecting adverse events (AEs) that could affect vision in trial participants, and the need for material additions to the disclosures made to investigators and patients related to the clinical and safety measures completed to that point, including the potential vision risks.

Proclaim XR Spinal Cord Stimulation Wins Approval for Painful Diabetic Peripheral Neuropathy

Finally, on January 26, the FDA approved the Proclaim XR spinal cord stimulation (SCS) system for the treatment of painful diabetic peripheral neuropathy (DPN), according to an announcement from Abbott.¹⁰ The company noted the system offers alternative options for those patients receiving other medications.

The system was previously approved in 2019 for the treatment of chronic pain. After a minimally invasive trial and the device implantation, patients can then control their therapy via an Apple device. Abbott also noted in its announcement that individuals who receive therapy from the Proclaim XR SCS system will have access to the company’s NeuroSphere Virtual Clinic, a connected care app that allows for patient-physician communication and remote treatment adjustments via cellular or Wi-Fi connection.

Jason E. Pope, MD, DABPM, FIPP, president of Evolve Restorative Center in Santa Rosa, California, said in a statement, "Diabetic peripheral neuropathy has long plagued people affected by type 1 and type 2 diabetes, often adding another area of disease management on top of their ongoing monitoring of their glucose levels to manage this challenging disease. Abbott's Proclaim XR spinal cord stimulation system provides patients with painful diabetic peripheral neuropathy the opportunity to obtain a better quality of life while more seamlessly fitting into their current lifestyles."

REFERENCES
1. Imperative Care announces FDA clearance and initial cases of Zoom RDL, the first stroke-specific radial access platform for mechanical thrombectomy. News release. Imperative Care. January 4, 2022. Accessed February 7, 2023. https://www.businesswire.com/news/home/20230104005059/en/
2. UCB announces rozanolixizumab BLA for the treatment of generalized myasthenia gravis filed with U.S. FDA and designated for Priority Review. News Release. UCB. January 6, 2023. Accessed February 7, 2023. https://www.ucb.com/stories-media/Press-Releases/article/UCB-announces-rozanolixizumab-BLA-for-the-treatment-of-generalized-myasthenia-gravis-filed-with-US-FDA-and-designated-for-Priority-Review
3. FDA grants acclerated approval for Alzheimer's disease treatment. FDA. News release. January 6, 2023. Accessed February 7, 2023. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-disease-treatment
4. Eisai submits supplemental biologics licence application to FDA for traditional approval of Leqembi (lecanemab-irmb) for the treatment of Alzheimer’s disease. News release. January 6, 2023. Accessed February 7, 2023. https://www.prnewswire.com/news-releases/eisai-submits-supplemental-biologics-license-application-to-fda-for-traditional-approval-of-leqembi-lecanemab-irmb-for-the-treatment-of-alzheimers-disease-301715905.html
5. 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 February 7, 2023. https://investors.revance.com/news-releases/news-release-details/revance-announces-us-fda-acceptance-supplemental-biologics
6. Neurelis announces filing of its investigational new drug application for NRL-1049, a rho kinase (ROCK) inhibitor with potential to treat cerebral cavernous malformations. News release. Neurelis. January 9, 2023. Accessed February 7, 2023. https://www.prnewswire.com/news-releases/neurelis-announces-filing-of-its-investigational-new-drug-application-for-nrl-1049-a-rho-kinase-rock-inhibitor-with-potential-to-treat-cerebral-cavernous-malformations-301716126.html
7. US Food and Drug Administration Issues Complete Response Letter for Accelerated Approval of Donanemab. News release. Eli Lilly. January 19, 2022. Accessed Accessed February 7, 2023. prnewswire.com/news-releases/us-food-and-drug-administration-issues-complete-response-letter-for-accelerated-approval-of-donanemab-301726325.html
8. Astellas Announces Hold Lifted by FDA on FORTIS Clinical Trial of AT845 Investigational Treatment for Adult Patients with Late-Onset Pompe Disease. Astellas Pharma. January 20, 2023. Accessed February 7, 2023. https://finance.yahoo.com/news/astellas-announces-hold-lifted-fda-060000239.html
9. Inhibikase Therapeutics announces FDA has lifted the full clinical hold on IKT-148009 in Parkinson’s disease. Inhibikase Therapeutics. January 25, 2023. Accessed February 7, 2023. https://www.prnewswire.com/news-releases/inhibikase-therapeutics-announces-fda-has-lifted-the-full-clinical-hold-on-ikt-148009-in-parkinsons-disease-301729466.html2
10. FDA Approves Abbott's Spinal Cord Stimulation for People Living with Painful Diabetic Peripheral Neuropathy. News release. Abbott. January 26, 2023. Accessed February 7, 2023. https://prnmedia.prnewswire.com/news-releases/fda-approves-abbotts-spinal-cord-stimulation-for-people-living-with-painful-diabetic-peripheral-neuropathy-301731127.html