NeurologyLive® Top Stories of 2021: Neuromuscular Disorders

The neuromuscular field has progressed greatly over the past year, with new treatments in the pipeline for Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA). The NeurologyLive® team works hard to bring you the latest news, research developments, and conference coverage on these topics, making sure you are kept in the loop on clinical care and management for these patients. 

In 2021, a few stories stood out as the top-viewed from our coverage, including the efficacy of PF-06939926 in DMD, an investigational new drug (IND) application for LION-101 in the treatment of Limb-Girdle Muscular Dystrophy Type 2IR9 (LGMD2I/R9), and the FDA approval of efgartigimod for generalized myasthenia gravis (gMG). 

Take a moment to browse highlights from the top stories below and learn more about what has happened since, as well as directions for future research. For more information on ongoing developments in the neuromuscular space, check out our Neuromuscular clinical focus page.

Click the buttons below to learn more about each story.

1. PF-06939926 Continues to Show Safety and Efficacy in Duchenne Muscular Dystrophy

Updated data from Pfizer’s multicenter, open-label phase 1b study minidystrophin gene therapy trail (NCT03362502) were presented at the Muscular Dystrophy Association’s (MDA) Scientific and Clinical Conference 2021, March 15-18. The study is evaluating fordadistrogene movaparvovec, formerly known as PF-06939926, an investigational AAV9 gene therapy designed to treat DMD, with findings indicating the treatment continued to show efficacy with an acceptable safety profile in boys with the disease.¹

On December 20, Pfizer’s gene therapy team sent a letter to advocacy organization, Parent Project Muscular Dystrophy, announcing that a patient enrolled in the nonambulatory cohort had died. As a result, screening and dosing in the trial have been paused while experts review data alongside the Independent External Data Monitoring Committee. The investigational new drug application for the treatment was also placed on clinical hold by the FDA.² 

The separate, ongoing phase 3 CIFFREO trial (NCT04281485) of fordadistrogene movaparvovec in DMD underwent a protocol modification earlier in the year, in September, following 3 serious adverse events involving muscle weakness, 2 of which involved myocarditis and all of which were related to treatment. The amendment excluded patients with DMD who had any mutation affecting exons 9 through 13, inclusive, or a deletion affecting both exon 29 and 30, which are estimated to affect less than 15% of patients with DMD.³

2. FDA Accepts IND for Limb-Girdle Muscular Dystrophy Gene Therapy

In May 2021, Asklepios BioPharmaceutical announced the FDA had cleared an IND application for LION-101, a novel recombinant adeno-associated virus (rAAV) based vector for the treatment of LGMD2I/R9. Following the approval, the agent was to move into a phase 1/2 clinical study, beginning dosing in the first half of 2022.⁴ 

The agent, which is being developed as a 1-time intravenous infusion for patients with LGMD2I/R9, also received fast track designation from the FDA in June of 2021. “The FDA Fast Track Designation for LION-101 is an important step for the development of this program and is a clear recognition of the profound burden faced by LGMD2I/R9 patients,” Sheila Mikhail, cofounder and CEO, AskBio, said in a statement.⁵ “We look forward to initiating clinical trials with this novel therapy, and we hope to bring a new therapeutic option to patients and families in the LGMD2I/R9 community who live with this devastating disease.”

While there is a lack of approved therapies for LGMD, there are a number of other drug candidates in preclinical and clinical-stage development programs for the disease.⁶ Several of these gene therapies are in clinical development from Sarepta Therapeutics, including SRP-9003, SRP-9004, SRP-9005, SRP-6004, and SRP-9006. Deflazacort (Emflaza), an FDA approved treatment for patients with DMD, is currently being tested by PTC Therapeutics for LGMD2I/R9, while prednisone is also being evaluated in all forms of LGMD at Northwestern University. 

3. Efgartigimod Approved for Generalized Myasthenia Gravis

Earlier in December 2021, the FDA approved Argenx’s first-in-class investigational antibody fragment to target the neonatal Fc receptor, efgartigimod, for the treatment of gMG in adults who test positive for the anti-acetylcholine receptor antibody. Following approval, which is the first of a new class of medication, the drug will not be marketed as Vygart, according to an announcement from the company.⁷

At the time, clinical trial investigator James F. Howard, MD, Distinguished Professor of Neuromuscular Disease, University of North Carolina School of Medicine, told NeurologyLive®, "The approval of efgartigimod by the FDA is going to again transform our management of myasthenia gravis, without question. The ability of this drug to reduce levels of circulating antibody IgG will provide patients with a new option for therapy, a much safer option for therapy, and one that has been demonstrated in clinical trials to be of substantial durability in its duration of effect," 

The treatment was previously granted both fast track and orphan drug designations, with its latest approval being backed by data from the phase 3 ADAPT trial (NCT03669588). In the trial, 167 patients were randomized to an evaluation arm, 77% of whom (n = 129) were acetylcholine receptor-antibody positive (AChR-Ab+). Eighty-four participants were randomized to receive efgartigimod and 83 to receive placebo. 

Findings from the study suggested that efgartigimod was well-tolerated and efficacious in treating patients with gMG, and the drug met its primary end point by improving gMG activities of daily living scores for patients with AChR-Ab+ gMG, when compared with placebo (67.7% vs. 29.7%; P <.0001). In addition, of AChR-Ab+ gMG patients treated with efgartigimod, 44% achieved minimal or no symptoms, acompared with just 11.1% of those treated with placebo. An open-label extension trial of efgartigimod, ADAPT+ (NCT03770403) is ongoing, with plans to explore a potential subcutaneous administration of the agent in addition to the current intravenous infusion formulation.⁸ 

REFERENCES 

1. Belluscio B, Beaverson K, Garnier N, et al. Safety and efficacy of PF-06939926 gene therapy in boys with Duchenne muscular dystrophy: Update on data from the phase 1b study. Presented at MDA Clinical and Scientific Conference 2021; March 15–18. Poster 77.
2. Pfizer announces patient died in the non-ambulatory cohort of its phase 1b mini-dystrophin gene therapy trial for Duchenne muscular dystrophy. Accessed December 22, 2021. https://www.parentprojectmd.org/wp-content/uploads/2021/12/DMD-Study-1001-Update_Letter-to-the-Community.pdf
3. Pfizer announces protocol amendment for gene therapy clinical program for DMD. September 28, 2021. http://join.parentprojectmd.org/site/DocServer/A_Message_from_Pfizer_on_our_DMD_Clinical_Program_-_Sept.pdf
4. AskBio announces IND for LION-101, a novel investigational AAV gene therapy for the treatment of Limb-Girdle muscular dystrophy type 2I/R9, cleared to proceed by US FDA. News release. Asklepios BioPharmaceutical. May 25, 2021. Accessed December 22, 2021. https://www.prnewswire.com/news-releases/askbio-announces-ind-for-lion-101-a-novel-investigational-aav-gene-therapy-for-the-treatment-of-limb-girdle-muscular-dystrophy-type-2ir9-lgmd2ir9-cleared-to-proceed-by-us-fda-301298246.html
5. AskBio receives FDA Fast Track Designation for LION-101, a novel investigational AAV gene therapy for the treatment of Limb-Girdle muscular dystrophy type 2I/R9 (LGMD2I/R9). News release. Asklepios BioPharmaceutical. June 28, 2021. Accessed December 22, 2021. https://www.prnewswire.com/news-releases/askbio-receives-fda-fast-track-designation-for-lion-101-a-novel-investigational-aav-gene-therapy-for-the-treatment-of-limb-girdle-muscular-dystrophy-type-2ir9-lgmd2ir9-301320701.html
6. How MDA is supporting LGMD research and care in 2020. News release. MDA. August 10, 2020. Accessed December 22, 2021. https://strongly.mda.org/how-mda-is-supporting-lgmd-research-and-care-in-2020/
7. FDA Approves New Treatment for Myasthenia Gravis. News release. FDA. December 17, 2021. Accessed December 22, 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis
8. Howard JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021;20(7):526-536. doi:10.1016/S1474-4422(21)00159-9