Muscular dystrophies - Emerging treatments

Delandistrogene moxeparvovec

Delandistrogene moxeparvovec is a recombinant adeno-associated virus vector-based gene therapy designed to deliver a gene that leads to expression of a microdystrophin comprising key functional domains of the dystrophin protein. It is administered as a single intravenous dose. Delandistrogene moxeparvovec was approved by the Food and Drug Administration (FDA) in June 2023 for the treatment of ambulatory patients ages 4-5 years with DMD who have a confirmed mutation in the DMD gene and do not have a preexisting medical reason preventing treatment with the therapy. Approval was granted via the accelerated approval pathway. This was based on analysis of results submitted to the FDA from randomized trials, indicating that the microdystrophin was expressed in patients treated with the therapy. A clinically meaningful and statistically significant difference in North Star Ambulatory Assessment score was reported for patients treated with delandistrogene moxeparvovec compared with a propensity-score-weighted external control cohort after 1 year.[75] Adverse effects noted in the trials included myocarditis, elevations of troponin-I, acute liver injury, and thrombocytopenia. Studies are ongoing to demonstrate clinical benefit.[76][77][78]

Ataluren

In boys with DMD due to a nonsense mutation, a premature stop codon is introduced into dystrophin mRNA, resulting in a truncated protein. Ataluren (an oral drug) targets this mutation to treat the underlying cause of disease. Some benefit, as assessed by the the 6-minute walk test, has been observed in a subgroup of boys.[79][80] Ataluren was conditionally approved in Europe, but the European Medicines Agency (EMA) removed its marketing authorization because phase 3 studies failed to confirm efficacy. Ataluren is still approved in the UK for ambulatory patients ages 2 years and over who have DMD caused by the nonsense mutation, and the UK National Institute for Health and Care Excellence recommends it as an option.[81] Ataluren is not approved in the US. Long-term outcome data are awaited. Efficacy has not been demonstrated in nonambulatory patients.

Eteplirsen

The use of antisense oligonucleotide-mediated genetic therapy to induce specific exon skipping during mRNA splicing is designed to repair genetic mutations, to modify genomic sequences in order to compensate for gene deletions, or to modify RNA processing in order to ameliorate the effects of the underlying gene mutation.[82] The antisense oligonucleotide eteplirsen is approved by the FDA for the treatment of boys older than 5 years with DMD due to a confirmed mutation of the dystrophin gene that is amenable to exon 51 skipping. It is given as weekly intravenous infusions and there is no limit to duration at present. Slowing decline on the 6-minute walk test and in percent predicted forced vital capacity over up to 4 years has been reported.[79][83][84] Eteplirsen has not been granted approval in Europe.

Golodirsen

The antisense oligonucleotide golodirsen has been granted accelerated approval by the FDA (subject to completion of post-marketing safety studies and a placebo-controlled, post-marketing efficacy trial) for the treatment of DMD in patients with a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. Golodirsen has been reported to increase dystrophin protein expression (compared with baseline) at week 48, and to slow decline in the 6-minute walk test from baseline over 3 years, in boys ages 6-15 years.[79][85][86] Golodirsen has not been granted approval in Europe.

Viltolarsen

The antisense oligonucleotide viltolarsen has been granted accelerated approval by the FDA for the treatment of patients with DMD due to a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. In a phase 2 trial, significant increases in dystrophin production compared with baseline were seen in 16 boys with DMD (ages 4-9 years) after 20-24 weeks of treatment. Significant improvements in timed function tests from baseline were observed compared with age- and treatment-matched controls. No serious adverse events were reported.[79][87] Viltolarsen has been granted orphan drug designation in Europe.

Casimersen

Casimersen (also known as SRP-4045) is an antisense oligonucleotide that is FDA-approved for the treatment of DMD in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. Safety and tolerability were demonstrated in a phase 1/2 trial.[88] Interim analysis of muscle biopsy endpoints from a phase 3 study demonstrates a statistically significant increase in dystrophin production in patients who received casimersen (compared with baseline and placebo).[89]

SGT-001

SGT-001, an adeno-associated viral vector-mediated gene therapy candidate that contains an engineered version of the dystrophin gene (microdystrophin), has been granted orphan drug designation by the FDA for the treatment of DMD. Recruitment to a phase 1/2 trial to evaluate the safety and efficacy of SGT-001 in adolescents and children with DMD was suspended because of serious adverse events; the trial was subsequently restarted with a revised safety management plan.[79][90][91]

Rimeporide

Rimeporide can correct ionic dysregulation for patients with DMD by inhibiting sodium-proton exchanger type 1 (NHE-1) on muscle cells. It has been granted orphan drug status by the FDA and the EMA. An open-label phase 1b clinical trial reported that rimeporide was well tolerated, with no serious adverse events.[92] A phase 2 study is planned to further assess the efficacy of rimeporide in DMD patients.

Idebenone

Idebenone is a synthetic short-chain benzoquinone and a cofactor for the enzyme NAD(P)H:quinone oxidoreductase (NQO1). Trials demonstrated that idebenone was associated with slower decline in respiratory function in DMD patients not taking corticosteroids.[93][94] However, development was terminated when interim analysis of a randomized, placebo-controlled phase 3 trial showed that the primary endpoint would not be met.[79][93]

Vamorolone

Vamorolone is a first-in-class steroidal anti-inflammatory drug for the treatment of DMD. It binds to the same receptors as corticosteroids, but modifies downstream receptor activity, and so is predicted to be associated with fewer adverse effects.[79] Vamorolone is approved for the treatment of DMD in patients 2 years and older by the FDA, and in patients 4 years and older by the EMA. Vamorolone treatment for 24 weeks was shown to be effective and safe for the treatment of boys with DMD in a randomized, double-blind, placebo- and prednisone-controlled trial. Time taken to stand from a supine position was reduced and walking ability was improved with vamorolone compared with placebo. Markers of bone turnover declined with prednisone but not with vamorolone.[95]

Givinostat

Givinostat, a histone deacetylase (HDAC) inhibitor, has been granted orphan drug, fast-track, and rare pediatric disease designations by the FDA for the treatment of DMD. In an open-label phase 2 study, treatment of ambulant boys with DMD (age 7 to <11 years; on stable corticosteroid treatment) for at least 12 months with givinostat significantly increased the fraction of muscle tissue, and reduced the amount of fibrotic tissue in muscle biopsies.[96] A phase 3 study of the efficacy and safety of givinostat in ambulant patients with DMD is ongoing.[79][97]

Fordadistrogene movaparvovec

Fordadistrogene movaparvovec (also known as PF-06939926), a recombinant adeno-associated virus serotype 9 (rAAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle-specific promoter, has been granted fast-track designation by the FDA for the treatment of DMD. Preliminary results from a phase 1b study in boys ages 6-12 years indicated lasting and statistically significant improvements in several efficacy endpoints measured 12 months after infusion. Three out of nine participants experienced serious adverse events that resolved fully within 2 weeks.[98][99] One patient in the trial subsequently died. Recruitment to a phase 3 study was paused after the death, but was resumed.[79][100]

RGX-202

RGX-202 is a gene therapy that includes an optimized transgene for a novel microdystrophin. RGX-202 has been granted fast-track designation by the FDA for the treatment of DMD. A phase 1/2 trial is under way.[101]

Cardiosphere-derived cells

Cardiosphere-derived cells (CDCs) are a type of stromal or progenitor cell that have been shown to exert immunomodulatory, antifibrotic, and regenerative actions in dystrophinopathy and heart failure. CAP-1002, a clinical formulation of allogeneic CDCs, appeared to be safe and effective in reducing deterioration of upper limb function at 12 months in patients with late-stage DMD in a multicenter, randomized, double-blind, placebo-controlled phase 2 trial. Measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. The main adverse effect was infusion-related hypersensitivity reactions without long-term sequelae.[102]

ATYR1940

An intravenous protein therapeutic, derived from a naturally occurring protein released by human skeletal muscle cells. ATYR1940 has been granted orphan drug designation by the FDA and the EMA for the treatment of all types of limb-girdle muscular dystrophy. Studies are in progress.[103][104]

Apitegromab

Apitegromab (SRK-015), a selective inhibitor of myostatin activation, has been granted fast-track designation by the FDA and priority medicines (PRIME) designation by the EMA for the treatment of SMA. In a randomized double-blind phase 2 study, patients with type 2 or type 3 SMA who received apitegromab demonstrated improvements in motor function scores from baseline.[105][106] A phase 3 trial is under way.[107]

Taldefgrobep alfa

Taldefgrobep alfa, a novel anti-myostatin biologic agent, has been granted "fast track" designation by the FDA for the treatment of SMA. A phase 3 study is under way.[108]