Top News for Duchenne Muscular Dystrophy Awareness Week

In recent months, the NeurologyLive® team has been covering the news and conducting interviews with experts on the latest updates in the clinical care of individuals with neuromuscular disorders, including those with Duchenne muscular dystrophy (DMD).

For Duchenne Muscular Dystrophy Awareness Week — February 13, 2023, to February 19, 2023 —the team has culminated some of the biggest pieces of news to offer updates on new developments in literature about DMD to spread awareness on the prevention and treatment of the condition.

Click here for more coverage of the latest neuromuscular news from NeurologyLive®.

Latest Literature

Small Differences in Motor Function Outcomes of Duchenne Muscular Dystrophy Genotypes Prompt Implications for New Trials

A recent multi-institution, meta-analysis study suggested that often targeted Duchenne Muscular Dystrophy (DMD) genotype classes have small and estimated precise effects on 1 year motor function outcomes.¹ In the analysis, investigators observed DMD genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations.

Pooled effect estimates for studied skip-amenable mutation classes were all small in magnitude (less than 2 units in North Star Ambulatory Assessment total score [ΔNSAA] total score in 1 year follow up), with smaller than clinically critical differences in NSAA. Notably, skip-amenable mutation classes were estimated precisely with standard errors less than 1 unit after adjustment for non-genotypic prognostic factors across all data sources.

Lead author Francesco Muntoni, MD, pediatric neurologist, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom, and colleagues wrote, “Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study.”¹

At least 700 patients with DMD diagnosis and over 1600 patient-years of follow-up were studied from 6 data sources. The time periods of collected data were between 2011 and 2016 for Leuven, 2012 and 2016 for PRO-DMD-01, 2012 and 2018 for iMDEX, 2005 and 2015 for NSUK, 2004 and 2016 for CCHMC, and 2008 and 2013 for DMD Italian Group. In each data source, associations between genotype class and 1-year changes in ΔNSAA and in 10-meter walk/run velocity (Δ10MWR) were studied with and without baseline prognostic factors. Approximately every 6 or 12 months, clinical assessment of the data sources were conducted.

REGENXBIO's Clinical Trial for Duchenne Therapy RGX-202 Begins Patient Recruitment

News from REGENXBIO, as the company recently announced the start of patient recruitment for the phase 1/2 AFFINITY DUCHENNE clinical trial (NCT05693142) for RGX-202, an investigational adeno-associated virus (AAV) vector-based gene therapy for Duchenne muscular dystrophy.² The multicenter, open-label trial will initially seek to recruit 6 patients aged 4 to 11 years with DMD who are ambulatory.

The patients will be divided into 2 cohorts that include 3 patients each, with the lower-dose cohort receiving 1x1014 genome copies (GC)/kg body weight and the higher-dose cohort receiving 2x1014 GC/kg body weight. The study may recruit an additional 9 patients at a later time based on the results of an independent safety data review.

"DMD is a devastating disease and there are still unmet therapeutic needs," Aravindhan Veerapandiyan, MD, a principal investigator in the study and director of the Comprehensive Neuromuscular Program, PPMD Certified Duchenne Care Center, and co-director of the Muscular Dystrophy Association Care Center at Arkansas Children's Hospital, added to the statement.² "Gene therapies, like RGX-202, have the potential to impact the progressive nature of Duchenne."

RGX-202 uses REGENXBIO’s proprietary NAV AAV8 vector and is intended to deliver a novel transgene which contains the functional elements of the C-Terminal (CT) domain seen in natural dystrophin.¹ The company has noted that the CT domain's presence “has been shown in preclinical studies to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice.”²

FDA Accepts New Drug Application for Duchenne Therapy Vamorolone

According to a recent announcement, the FDA has accepted Santhera Pharmaceuticals and ReveraGen BioPharma’s new drug application (NDA) for its investigational agent vamorolone, a first-in-class dissociative steroid, for the treatment of patients with DMD.³ The FDA has scheduled a PDUFA target action date of October 26, 2023, and does not plan to hold an advisory meeting to discuss the application. If approved, the therapeutic would be launched in Q4 of later this year.

"We are delighted that the FDA has accepted Santhera’s vamorolone NDA for filing. We believe this product addresses a clear unmet medical need and for Santhera, this represents the achievement of an important milestone with key significance for our future success," Dario Eklund, chief executive officer, Santhera, said in a statement.³ "We look forward to working closely with U.S. regulators to advance vamorolone towards approval."

The submission was based on phase 2b data from the VISION-DMD study (NCT03439670), in which the agent met its primary end point of superiority of change in Time to Stand Test (TTSTAND) velocity relative to placebo. VISION-DMD was a 2-part study that assessed the efficacy, safety, and pharmacokinetics of vamorolone administered orally at daily doses of 2.0 mg/kg/day and 6.0 mg/kg/day vs prednisone 0.75 mg/kg/day and placebo over a 24-week treatment period. The study featured ambulatory boys aged 4 to 7 years old with DMD across 33 trial sites.

FDA Pauses IND Submission for Duchenne Therapy ENTR-601-44

Entrada Therapeutics has announced that the FDA has placed a clinical hold on the investigational new drug application for its investigational Duchenne muscular dystrophy (DMD) treatment, ENTR-601-44.4ENTR-601-44 aims to target the underlying genetic cause of DMD to allow muscle cells to produce functional dystrophin, and the company estimates that ENRE-601-44 will benefit roughly 7.5% of the DMD population who are considered exon 44 skipping amenable.

"The clinical hold on our ENTR-601-44 program is disappointing and we will work to address the FDA’s concerns regarding the IND,” said Dipal Doshi, president and CEO of Entrada Therapeutics, said in a statement.⁴ “There are no approved Duchenne therapies for people with exon 44 skippable mutations and we are eager to resolve this hold and continue down the treatment development pathway."

ENTR-601-44 is currently in preclinical development with no in-human trials conducted thus far; however, the company did present nonhuman primate data on the agent earlier this year at TIDES USA 2022: Oligonucleotide and Peptide Therapeutics Conference. All told, the therapeutic showed robust exon 44 skipping in nonhuman primate biceps through 12 weeks following a single intravenous infusion, demonstrating durability of response.⁵

Duchenne Agent WVE-N531 Shows Targeted Exon Skipping in Phase 1/2 Study

Wave Life Sciences announced positive findings from its phase 1/2a proof-of-concept study (NCT04906460), which showed that its investigational agent WVE-N531 led to significant concentrations of exon skipping in ambulatory boys with Duchenne muscular dystrophy (DMD) after just 3 weeks of biweekly multidosing at 10 mg/kg.⁶ WVE-N531, the first exon-skipping candidate from Wave to use its next-generation PN chemistry, resulted in a mean tissue concentration of 42 micrograms/gram, as well as resulted in mean exon skipping of 53% (range, 48% to 62%) as measured by RT-PCR.

"There remains a significant unmet need in DMD for new treatment options. It is exciting to see this level of exon skipping in a short period of time, especially since skipping would be expected to increase over a longer dosing interval," primary investigator Laurent Servais, MD, PhD, professor of pediatric neuromuscular diseases, MDUK Oxford Neuromuscular Center, said in a statement.⁶ "Based on the data, it appears Wave’s next-generation chemistry has led to significantly improved pharmacology. Expression of dystrophin after longer exposure will, of course, be key to confirm the promise of these early data. I look forward to the continued progression of clinical research for WVE-N531."

The analysis featured 3 ambulatory boys who were on escalating doses of 1,3,6, and 10 mg/kg in the multidose portion of the trial, followed by 3 doses of 10 mg/kg every other week. With the first patients dosed in October 2021, the trial is expected to include approximately 15 total individuals who have a documented mutation of the DMD gene that is amenable to exon 53 skipping intervention. Individuals are between the ages of 5 and 18 years, are male, have a score of at least 1 on item 1 or 2 of the shoulder component of the Performance of the Upper Limb, and have stable pulmonary and cardiac function.

REFERENCES
1. Muntoni F, Signorovitch J, Sajeev G, et al. DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials. Neurology. 2023;10.1212/WNL.0000000000201626. doi:10.1212/WNL.0000000000201626
2. REGENXBIO announces phase I/II trial of RGX-202, a novel gene therapy candidate for Duchenne muscular dystrophy, is active and recruiting patients. News release. REGENXBIO Inc. January 23, 2023. Accessed February 15, 2023. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-phase-iii-trial-rgx-202-novel-gene-therapy
3. Santhera and ReveraGen announce FDA acceptance of new drug application for vamorolone in Duchenne muscular dystrophy. News release. January 9, 2023. Accessed February 15, 2023. https://www.globenewswire.com/news-release/2023/01/09/2584775/0/en/Santhera-and-ReveraGen-Announce-FDA-Acceptance-of-New-Drug-Application-for-Vamorolone-in-Duchenne-Muscular-Dystrophy.html
4. Entrada Therapeutics announces clinical hold on IND application for ENTR-601-44 in Duchenne muscular dystrophy. News release. December 19, 2022. Accessed February 15, 2023. https://www.biospace.com/article/releases/entrada-therapeutics-announces-clinical-hold-on-ind-application-for-entr-601-44-in-duchenne-muscular-dystrophy/
5. Entrada Therapeutics presents new data supporting its growing pipeline of endosomal escape vehicle (EEV) therapeutics at TIDES USA 2022. News release. May 11, 2022. Accessed February 15, 2023. https://ir.entradatx.com/news-releases/news-release-details/entrada-therapeutics-presents-new-data-supporting-its-growing
6. Wave Life Sciences provides positive update on proof-of-concept study for WVE-N531 in Duchenne muscular dystrophy. News release. December 19, 2022. Accessed February 15, 2023. https://www.globenewswire.com/news-release/2022/12/19/2576214/0/en/Wave-Life-Sciences-Provides-Positive-Update-on-Proof-of-Concept-Study-for-WVE-N531-in-Duchenne-Muscular-Dystrophy.html