VM202, a plasmid DNA that expresses 2 isoforms of hepatocyte growth factor, is both safe and effective in providing long-lasting pain relief in painful diabetic peripheral neuropathy (DPN), according to results of a phase 3-1b study published in Clinical and Translational Science.
Following positive efficacy and safety data results from phase 1 and 2 studies, researchers conducted a large scale, double-blind, placebo-controlled phase 2 study of VM202 for painful DPN. The study was conducted in 2 parts: the main study took place over 9 months (DPN 3-1; ClinicalTrials.gov identifier NCT02427464; N=500 participants), followed by a noninterventional 3-month safety and efficacy extension that included a subset of later-enrolling main study participants (DPN 3-1b; ClinicalTrials.gov identifier NCT04055090; n=101).
Researchers hypothesized that VM202 administration would reduce the average daily diabetic peripheral neuropathy pain scores more than placebo. The primary efficacy endpoint was the mean 24-hour numerical rating scale pain score, recorded in a daily pain and sleep diary at 3 months.
In both studies, most participants were White (74.4% and 80.2%) with an overall mean age of 61.5 years. Many participants had comorbid conditions, including hypertension, dyslipidemia, and obesity.
Between-group demographic and baseline characteristics were similar. At the time of randomization, roughly half of the participants were not receiving either pregabalin or gabapentin to manage DPN.
Researchers assessed safety based on incidence of treatment-emergent adverse events, serious adverse events, and adverse events of special interest (injection site reactions, ophthalmologic or acute cardiac events, foot ulcers, and symptoms of central nervous system depression).
In DPN 3-1, 72.6% of those treated with VM202 and 68.9% of those treated with placebo reported at least 1 treatment-emergent adverse event. The most common adverse events were infections and infestations, which were similar between groups.
Adverse events of special interest occurred in 17.2% and 16.8% of VM202 and placebo patients, respectively. The most common adverse events were diabetic retinopathy, peripheral edema, and skin ulcers. The incidence of these events that were deemed related to the study drug was low, with no difference between groups.
Serious adverse events were reported in 9.6% of the VM202 group and 9.9% of the placebo group. In the VM202 group, adenocarcinoma and vitreous hemorrhage were “deemed possibly related to the study drug.” Three myocardial infarctions were deemed not related to the study drug due to patients’ medical history.
In DPN 3-1b, 15.4% and 22.2% of VM202- and placebo-treated patients, respectively, experienced treatment-emergent adverse events. Adverse events of special interest were experienced by 3.1% and 2.8% of VM202- and placebo-treated patients, and included peripheral edema, chest pain, and angina pectoris. One participant in the VM202 group and 2 in the placebo group reported serious adverse events, but all 3 of these participants had relevant medical histories.
DPN 3-1 failed to meet the primary endpoints, with between-group differences that were not statistically significant for any endpoint measure. When the participants who were not receiving concurrent gabapentinoids were analyzed separately (n=251), endpoints remained statistically nonsignificant compared with placebo.
In DPN 3-1b, efficacy data differed “strikingly,” despite similar participant demographic and baseline characteristics. Although there was no significant pain severity difference at baseline, there were significant reductions in the primary efficacy endpoints at 12 months in the VM202 group compared with placebo. Significant pain reductions were also noted at 6 and 9 months, and greater pain reductions were identified in patients who were not taking gabapentin or pregabalin during the 12-month study, which was consistent with Phase 2 study results.
The researchers stated, “To our knowledge, this is the first Phase 3 gene therapy study for pain that has ever been done. VM202 did not meet efficacy endpoints in the full…population, but VM202 demonstrated long-term, clinically significant reductions in pain in [DPN 3-1b], particularly in [participants] not on gabapentinoids”
They concluded, “Given the excellent safety profile of VM202, the potential for disease modifying effects, and the high unmet medical needs of the DPN patient population not on gabapentinoids, further study is warranted.”
Disclosure: This clinical trial was supported by Helixmith Inc. Please see the original reference for a full list of authors’ disclosures.
Kessler JA, Shaibani A, Sang CN, et al; for the VM202 Study Group. Gene therapy for diabetic peripheral neuropathy: a randomized, placebo-controlled phase 3 study of VM202, a plasmid DNA encoding human hepatocyte growth factor. Published online January 19, 2021. Clin Transl Sci. doi:10.1111/cts.12977