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During the study researchers assessed adverse events of special interest (AESI), treatment-emergent adverse events (TEAEs), and serious adverse events (SAE). The AESI that researchers anticipated were injection site reactions, ophthalmologic events, acute cardiac events, foot ulcers, adn symptoms of CNS depression observed in gabapentinoid ulcers. The most common AESI subjects encountered were diabetic retinopathy, peripheral edema, and skin ulcers. Diabetic retinopathy was commonly found in the placebo group versus VM202.

in DPN 3-1 241 of 332 VM202 treated and 111 of 161 placebo receieving subjects had one TEAE
57 of 332 VM202 treated and 27 of 161 placebo recieving patients had AESI

Throughout the course of the study there werent any singnifcant differnces between the two groups.

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this figure shows there 1191 patients that were screened for enrollment into the study. There were 684 subjects that failed screening while 507 were added to the study for part 1.

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This picture represents the different treatments days of the subjects, days 0-14 and days 90-140. During these treatments patients received 16 injections each. 

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Gene Therapy for diabetic peripheral neuropathy was a double-blinded, randomized phase III clinical trial. Due to the nature of this study, participants or researchers were unaware of which treatment participants would receieve. This phase was divided into two parts, the first comprising 500 subjects and the later enrolling 100 patients from the first half into a 3-month safety extension. Patients were randomized using the EDC master randomization file. Some patients would receive the VM202 or placebo, both administered via intramuscular injections three months apart. Patients were monitored from first dosage to day 270 when the study was completed.

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Future research is necessary to unravel the mechanisms responsible for the differences in VM202 efficacy between the DPN 3-1 and DPN 3-1b groups. It is important to focus attention on identifying highly specific and sensitive biomarkers used to predict treatment response in patients with diabetic neuropathy.

Additional research is needed to better understand the role of glycosylation in HGF function. Specifically, the differences in N-linked glycosylation patterns on HGF isoforms (HGF728 and HGF723) may modulate its conformational stability, solubility, and proteolytic processing (Hu, 2020). Importantly, these highly conserved differences in N-linked glycosylation can affect HGF binding to its receptor c-Met and alter downstream signaling pathways (Hu, 2020).

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Diabetic peripheral neuropathy (DPN) is the most common complication associated with diabetes mellitus (DM) and it is responsible for significant negative impacts on quality of life (Anandhanarayanan, 2022). DPN is estimated to affect nearly half of all patients with DM and accounts for more hospitalizations than any other DM-related complication (Anandhanarayanan, 2022).

Current therapies for DPN are palliative and do not target the underlying mechanisms. Furthermore, there is sparse evidence to support combination pharmacotherapy (Feldman, 2023). Thus, symptomatic management focuses on slowing the progression of DPN and preventing complications (Feldman, 2023).

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VM202 (Engensis) is a non-viral plasmid DNA that encodes two isoforms of hepatocyte growth factor (HGF) and has been shown to reduce pain in a previous phase II study for 3 to 9 months following treatment. HGF exhibits neurotrophic and angiogenic properties and contributes to neuronal survival and axonal outgrowth from sensory and motor neurons.

The aim of this phase III randomized, double-blind placebo-controlled study was to evaluate the safety and efficacy of VM202 in patients with DPN. The trial was conducted in two parts: the first part (DPN 3-1) involved 500 subjects and assessed changes in the average daily DPN pain scores; the second part (DPN 3-1b) involved 101 subjects and evaluated the safety and efficacy of VM202 in a non-interventional extension study.

VM202 was well-tolerated in both studies and showed significant and clinically meaningful pain reduction versus placebo in DPN 3-1b. Symptomatic relief was maintained for eight months after the last injection. Surprisingly, efficacy endpoints in the full DPN 3‐1 population were not met. Despite this discrepancy, the safety and long-lasting pain-relieving effects of VM202 observed in DPN 3-1b warrant another rigorous phase III study. In summary, this study provides proof of concept of a novel therapeutic approach for the treatment of DPN.

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Mean Pain Scores on daily pain diary. Not included was data for sleep interference as there was no significant difference between placebo and VM202

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Failed to meet primary endpoints.
No meaningful difference between placebo and participants receiving VM202 in daily pain reduction (Figure XA) and sleep interference (Figure XB)

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TEAE= Treatment Emergent Adverse Events
SAE= Serious Adverse Event
AESI= Adverse Events of Special Interest

No difference between placebo and drug related adverse events.
Endpoint for Safety profile met

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Subset of patients recruited by 2nd CRO to fill DPN 3-1

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 Reduction in Pain of subjects enrolled by 2nd CRO: 6 Months

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 Reduction in Pain of subjects enrolled by 2nd CRO: 6 Months

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Mean Pain Scores for Daily Pain Diary (NRS-Pain) and Brief Pain Inventory (BPI-DPN)
n= 46 Placebo and n= 96 VM202

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Timeline of dosing with either VM202 or placebo. Two groups were studied: DPN 3-1 until day 270 and DPN 3-1b until Day 365.