Gene therapy Engensis shows early signs of benefit in CMT1A patients
Experimental treatment reduced disease severity, lessened functional disability
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The experimental gene therapy Engensis (VM202) was found to be safe and showed early signs of benefit for people with Charcot-Marie-Tooth disease type 1A (CMT1A), according to results from a small Phase 1/2a clinical trial.
Treatment reduced disease severity, mainly by easing sensory neuropathy, or nerve damage affecting sensation, and lessened functional disability linked to the disease over about nine months of follow-up. Although trends toward improvement were also observed in walking ability and lower-limb function, these changes did not reach statistical significance.
“This is the first phase 1/2a gene therapy trial performed for patients with CMT1A,” researchers wrote. They added that the improvements observed with Engensis over the study period, combined with the “high unmet medical need in CMT1A patients,” support further testing of the therapy in larger, controlled clinical trials.
The study, “An open-label single-arm phase 1/2a study to evaluate the safety and exploratory efficacy of a VM202 in patients with Charcot-Marie-Tooth disease 1A,” was published in the Orphanet Journal of Rare Diseases. Helixmith, the company developing Engensis, sponsored the study.
Engensis promotes expression of key protein
CMT1A is the most common subtype of CMT, a group of inherited disorders marked by damage to peripheral nerves — the nerves outside the brain and spinal cord that control movement and sensation in the limbs.
Usually caused by a duplication of the PMP22 gene, CMT1A typically begins in adolescence with muscle weakness and atrophy (wasting) in the lower legs. Over time, people with the condition may also experience hand weakness and sensory loss.
Engensis uses a small circular DNA molecule, called a plasmid, to deliver instructions for producing hepatocyte growth factor (HGF) in patients’ cells. HGF is a protein that supports the growth of new blood vessels and promotes the growth and survival of muscle and nerve cells.
The therapy carries instructions for two forms of HGF, which together are believed to stimulate blood vessel growth and nerve regeneration more effectively.
Injected directly into selected muscles, Engensis aims to help regenerate both damaged motor neurons — the nerve cells that control movement — and muscle tissue. Because the delivered gene does not integrate into a patient’s DNA and is gradually broken down and cleared from the body, the treatment must be administered periodically.
Previous studies in other health conditions, such as amyotrophic lateral sclerosis, have suggested Engensis may help promote nerve regeneration, blood vessel growth, and protection against muscle damage.
Gene therapy safe, well-tolerated
To assess the therapy’s safety, tolerability, and preliminary effectiveness in people with CMT1A, a team of researchers in South Korea conducted a Phase 1/2a study (NCT05361031) launched in 2020. The study included 12 patients who were enrolled between September and November 2020 at Samsung Medical Center in Seoul.
Participants’ mean age was 40.2, and 58.3% were men. All received four intramuscular injections of Engensis into the muscles of both lower legs at the study’s start and on days 14, 90, and 104. Participants were then followed for 270 days, or about nine months.
Besides safety and tolerability — the study’s main goals — researchers also assessed changes in disease severity and physical function as exploratory measures of effectiveness.
In line with previous reported results, Engensis was generally safe and well tolerated, meeting the trial’s main goal. Two mild cases of injection site itching and peripheral edema (swelling) were the only adverse events deemed possibly related to the treatment, and resolved without further therapy.
No participants developed antibodies against the HGF protein, indicating the therapy did not trigger an immune response.
Clinical scores used to assess disease severity improved significantly
Clinical scores used to assess disease severity improved significantly between the start of the study and day 270. These included the CMT Neuropathy Score version 2 (CMTNSv2), the CMT Examination Score (CMTES), and their revised versions.
On average, CMTNSv2 scores dropped by 2.17 points, while its revised version (CMTNSv2-R) decreased by 2.08 points. CMTES scores dropped by 2.5 points, and its revised version (CMTES-R) decreased by 2.33 points.
By day 270, some participants who had been classified as having moderate or severe disease according to CMTNSv2-R, CMTES, and CMTES-R scores shifted into mild or moderate disease categories.
Improvements in the CMTNSv2 score were mainly driven by changes in sensory symptoms and sensory signs, such as pinprick and vibration sensation, rather than by improvements in motor symptoms or muscle strength, the researchers noted.
Scores on the Functional Disability Scale, which measures how symptoms affect everyday activities, also improved significantly, with a mean decrease of 0.58 points.
A trend toward improvement was also seen in the Overall Neuropathy Limitations Scale leg score, which measures lower-limb function, and in the 10-meter walk test, which measures walking ability. However, these changes did not reach statistical significance.
These findings support the therapy’s overall safety and tolerability in people with CMT1A, as well as its potential to improve sensory functions and lessen functional disability, the researchers wrote.
Engensis’ effectiveness in exploratory measures warrants “confirmation in a [Phase 2b] randomized controlled trial,” the researchers concluded.
