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BOSTON – Becker (BMD) and Duchenne muscle dystrophy (DMD) progress largely from irreversible contraction-induced injury of skeletal muscles, making the very positive interim results of an early-phase trial with a drug that prevents these injuries worth attention.

The phase 1b data in BMD, presented at the 2023 annual meeting of the American Academy of Neurology, were sufficiently promising that controlled phase 2 trials in both BMD and DMD are already enrolling, reported Joanne Donovan, legea somajului 76 2002 actualizata 2014 MD, PhD, an adjunct professor at Boston University and chief medical officer of Edgewise Therapeutics, the company developing the drug.

Phase 1 study

Early phase studies are largely focused on safety, but the 6-month interim data of a 12-month study showed rapid reductions in multiple biomarkers of muscle injury, reductions in anti-inflammatory markers, proteomic changes consistent with sustained effects, and a trend for functional improvement in muscle dystrophies.

Moreover, the evidence of a clinical effect was achieved in adult patients with a North Star Ambulatory Assessment (NSAA) score of 15, signifying advanced disease. Only 12 patients were enrolled and there were no controls, but objective evidence of a favorable effect was generated by highly significant reductions in creatine kinase (CK) and fast skeletal muscle (TNNI2) troponin, which are both biomarkers commonly used to track muscular dystrophy progression.

In patients with BMD or DMD, a lack of dystrophin is a key pathogenic feature, according to Dr. Donovan. She explained that dystrophin in muscles connects contractile proteins to membranes and surrounding matrix. In the presence of dystrophin, muscle fibers support each other, but when this protein is absent, contraction causes injury.

The drug in development, currently identified as EDG-5506, is a selective fast myosin inhibitor. This agent was shown to prevent the muscle injury caused by lack of dystrophin in animal models of muscular dystrophy and is now showing the same effect in humans. Preservation of muscle is critical to preventing BMD and DMD progression according to several sets of data, according to Dr. Donovan.

For one, it has been shown that BMD or DMD patients with relatively preserved function as defined by a NSAA score above 32 have minimal muscle damage. As NSAA scores fall below 32 points, muscle mass diminishes and fat accumulates. In natural history studies of BMD, there is a 1.2-point decline in NSAA score over 5 years, and this tracks with muscle loss and not with other variables, such as patient age.

“Progression depends on the degree of muscle loss,” Dr. Donovan stated, providing the rationale for moving forward with EDG-5506.

Proof of concept

In experimental studies, modulation of fast myelin provided complete protection against muscle injury while preserving its contractile function, and this translated into protection against loss of function. Phase 1 studies in BMD patients and healthy controls have already provided evidence that EDG-5506 is well tolerated and safe, but the new phase 1b provides a proof of concept for its ability to inhibit muscle injury in BMD patients.

In this study, called ARCH, 12 adults 18 years of age or older with a dystrophin mutation and a BMD phenotype who could complete a 100-meter timed test were enrolled. The median age at entry was 32 years. Several patients had participated in a previous phase 1 safety study. The daily starting dose of 10 mg was increased from 10 mg to 15 mg at 2 months. The dose was increased again to 20 mg at 6 months, but the data presented by Dr. Donovan were restricted to the first 6 months.

At the interim 6-month analysis, creatine kinase was reduced by 40% and TINN2 was reduced by 84% (both P < 0.001). The significant reductions in these biomarkers and others, such as myoglobin, were mostly achieved within the first month, although further reductions were observed for some biomarkers subsequently.

The NSAA score at 6 months improved on average by about 1 point on treatment. Natural history studies of BMD predict a 1-point reduction in NSAA score over this period of time. The modest improvements from baseline in pain scores at 1 month were sustained at 6 months.

On the basis of a proteomic analysis, 125 proteins mostly associated with metabolic pathways consistent with muscle injury were found to be altered in BMD patients relative to healthy controls. The majority of these proteins, whether assessed collectively or individually, normalized after 1 to 2 months of treatment with EDG-5506 and have remained stable during follow-up to date, according to Dr. Donovan.

As in previous studies, the drug was well tolerated. The three most common treatment-emergent events were dizziness, somnolence, and headache. Each was reported by about 25% of patients, but no patient discontinued therapy as a result of adverse events.

Findings deemed ‘a big deal’

These data, despite the small number of patients in the study and the limited follow-up, “are a big deal,” according to Nicholas E. Johnson, MD, division chief, neuromuscular disorders, Virginia Commonwealth University, Richmond. He pointed out that there are no effective treatments currently for BMD, and the mechanism of action is plausible.

“I am excited about the potential of this treatment, although we clearly need longer follow-up and more patients evaluated on this treatment,” Dr. Johnson said. He said that clinicians with BMD patients should be aware of the phase 2 trial that is now recruiting adult subjects.

“Becker muscular dystrophy is highly disabling. As disease advances, most patients have very limited function,” said Dr. Johnson, emphasizing the urgent unmet need for an effective therapy.

Dr. Donovan is a full time employee of Edgewise Therapeutics, which funded this study. Dr. Johnson has financial relationships with Acceleron, Arthex, AveXis, Avidity, Biogen, Dyne Therapeutics, Entrada, Juvena, ML Bio, Sarepta Therapeutics, Triplet Therapeutics, and Vertex Pharma.

This article originally appeared on MDedge.com , part of the Medscape Professional Network.

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