Engensis, Gene Therapy for CMT1A, Shows Potential in Phase 1 Trial
The investigational gene therapy Engensis (VM202) was generally safe and showed signs of effectiveness at easing sensory neuropathy, or nerve damage, and improving muscle health in people with Charcot-Marie-Tooth disease type 1A (CMT1A), according to data from a Phase 1 clinical trial.
CMT is a group of inherited progressive disorders that affect the peripheral nervous system, which controls movement and sensation in the limbs. CMT1A is the most common subtype of CMT, accounting for up to 50% of all cases.
Caused by a duplication of the PMP22 gene, CMT1A is characterized by muscle weakness and atrophy (wasting) of the lower legs beginning in adolescence, followed by hand weakness and reduced sensation later in life.
Engensis, a non-viral gene therapy, uses small circular DNA molecules called plasmids to deliver the hepatocyte growth factor (HGF) gene directly to patients’ nerve and nerve-supporting cells.
HGF provides the instructions to produce a protein of the same name that is involved in the formation of new blood vessels, and muscle and nerve cell regeneration. Notably, Engensis contains the instructions for two HGF forms, whose combination was previously shown to result in therapeutic effects.
The therapy is injected directly into selected muscles to regenerate both damaged muscles and motor neurons, the specialized nerve cells that control voluntary movement. Given that the delivered gene is not integrated into the patient’s DNA and is eventually degraded and removed from the body, the therapy must be administered periodically.
Previous studies, including clinical trials in other health conditions, showed Engensis’ therapeutic potential in nerve regeneration, blood vessel growth, and the prevention of muscular damage. It was also shown to suppress pain-related factors in people with neuromuscular disorders.
The Phase 1 clinical trial, launched in July 2020, evaluated the safety, tolerability, and preliminary effectiveness of Engensis in 12 CMT1A patients with muscle atrophy and peripheral nerve damage; all were recruited at the Samsung Medical Center, in Seoul, South Korea.
Patients, 10 with moderate disease and two with mild disease, received Engensis injections directly in their leg muscles over 270 days (about nine months).
Besides safety and tolerability, the study’s main goals, changes in patients’ disease severity, functionality, and muscle health were also assessed as exploratory effectiveness measures.
Disease severity and functional disability were assessed with the CMT neuropathy score version 2 (CMTNSv2), the functional disability scale (FDS), and the overall neuropathy limitations scale-lower limb section (ONLS-Leg). Muscle health was measured through changes in MRI-based fat fraction, which is greater in muscles of CMT patients due to nerve damage.
Results showed that Engensis was generally safe and well-tolerated, based on lab tests and vital signs throughout the study. This was consistent with its safety profile in previous trials in other disorders.
Two adverse events, ankle swelling and injection site itching, were deemed possibly related to the therapy, but they resolved on their own and required no change in treatment dose.
A trend toward improvement was seen in FDS and ONLS-Leg, with a one-point score drop reported in seven participants for FDS and in four for ONLS-Leg. The remaining patients showed no changes in these measures after nine months, suggesting at least a preservation of functionality.
Notably, a one-point change in at least the ONLS is considered clinically meaningful.
Engensis was also associated with a significant, 2.17-point reduction in the CMTNS-v2 score, reflecting a 14% drop since study’s start (baseline). These significant improvements were detected in three items: sensory symptoms, pinprick sensibility, and vibration.
There was also evidence that Engensis may help slow muscle degeneration, as patients with more than 10% of fat in their muscles at baseline showed a slower fat accumulation (range, 0.8% reduction to 1.2% increase), compared with that previously reported for untreated CMT1A patients (a 3% increase).
These findings support the therapy’s overall safety, and its potential to improve sensory functions, lessen functional disability, and slow muscle damage.
The trial was conducted by Choi Byung-Ok, MD, a professor of neurology at Sungkyunkwan University School of Medicine, and the director of the Korean Organization for Rare Diseases.
According to Helixmith, more than 500 patients have been treated with Engensis across 10 clinical trials in six different conditions, such as amyotrophic lateral sclerosis, diabetic foot ulcers, and diabetic peripheral neuropathy.