Results from phase 3 gene therapy trial for diabetic peripheral neuropathy published online by Clinical and Translational Science

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VM202 (donaperminogene seltoplasmid) is a first-in-class, proprietary, non-viral, potentially regenerative plasmid DNA gene therapy. The Phase 3 study for painful DPN, led by Professor John (Jack) Kessler at Northwestern University, was conducted in two parts, one for 9 months (VMDN-003; 500 subjects) and one with a 3-month extension to 12 months (VMDN-003b; 101 subjects). This is the first gene therapy phase 3 trial that has ever been done for pain. Phase 3 data, published in Clinical and Translational Science, present latest clinical outcomes for VM202 (Engensis) in painful diabetic peripheral neuropathy (DPN), suggesting excellent safety and promising efficacy. VMDN-003 study achieved safety endpoints, while VMDN-003b showed clinically meaningful pain reduction vs. placebo. Safety and tolerability of Engensis continues to appear highly favorable, consistent with previous studies. In VMDN-003b, a durable analgesic response after treatment with Engensis was maintained for 8 months after the last injection, in the absence of drug product and gene expression, suggesting that Engensis treatment may ameliorate disease progression. These results have important clinical and commercial implications as more than 4.2 million people in the US are known to suffer from painful DPN and nearly 1.3 million patients to be refractory in that currently available medicines do not work for them.

“Patients with DPN have complex medical conditions with very few proven treatment options,” said Professor John (Jack) Kessler, Northwestern University. “We have seen signals of potential disease-modifying effects, especially among patients not on gabapentinoids.”

Findings from a Phase 3 study of VM202 (the active ingredient in Engensis) for the treatment of patients with painful diabetic peripheral neuropathy (DPN) have just been published in Clinical and Translational Science: The study, the first phase 3 gene therapy trial for pain, was led by Professor John (Jack) Kessler, professor of neurology at Northwestern University, and appears to show excellent safety and promising efficacy of Engensis in patients with DPN.

The Phase 3 study was conducted in two parts, one for 9 months (VMDN-003; 500 subjects) and one with a 3-month extension to 12 months (VMDN-003b; 101 subjects). Engensis or placebo was administered via intramuscular injection to the calf muscles of both legs in Days 0 and 14, and again on Day 90 and 104. The primary endpoint in VMDN-003 measured the change from baseline in the average 24-hour pain score at 3 months. In VMDN-003b, the primary endpoint was safety, while the secondary efficacy endpoint was change in mean pain score from baseline to 12 months.

VMDN-003 did not meet the primary endpoint. However, results from VMDN-003b, a double-blind, placebo-controlled extension study, showed durable analgesic response relative to the placebo group that was maintained for 8 months after the last injection.

Of the 101 subjects belonging to the intent-to-treat population who enrolled in VMDN-003b, significant reductions at 12 months in the primary efficacy measure, mean pain score changes from baseline, were observed for those who received VM202 compared with the placebo group.

In VMDN-003b, analysis of earlier time points revealed significant reductions in the 24-hour average pain scores at 6 months and 9 months in the VM202 group as well. Importantly, greater reductions in pain were found in subjects who were not on gabapentin or pregabalin during the 12-month study, consistent with the Phase 2 study results.

Of 101 VMDN-003b patients, 53 (52%) did not take gabapentinoids by prespecified design during the study period. At 6, 9, and 12 months, the treatment group not taking gabapentinoids experienced -1.34, -1.24, and -1.48 point reductions in the means of average 24-hour pain scores following treatment with Engensis compared with patients receiving placebo (p = 0.0308, p = 0.0504, and p = 0.0155, respectively). Patients who were taking gabapentinoids also showed a trend towards pain reduction, though the difference did not reach statistical significance. In VMDN-003b, a durable analgesic response after treatment with VM202 was maintained for 8 months after the last injection, suggesting that VM202 treatment may ameliorate disease progression.

“The thorough analysis of the Phase 3 study affirms the promise for Engensis to become a much-needed treatment option for painful DPN – one that again suggests a strong safety profile and durable efficacy, with potential effects on disease progression. The stronger efficacy shown among patients not on gabapentinoids is important because patients only have opioids as a treatment option today,” said Dr. William (Bill) Schmidt, Senior Vice President of Clinical Development at Helixmith. “The experiences gained in this study has guided the design of an additional Phase 3 study that recently began enrollment.”

The incidence of adverse events was similar for Engensis and placebo in VMDN-003 and lower than placebo for Engensis in VMDN-003b. Safety was assessed based on the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), and their relationship to the study drug. Because of the theoretical angiogenic potential of VM202 and the macro- and microvascular complications of diabetes, adverse events of special interest (AESIs) were also assessed. AESIs included 4 categories of TEAEs: ophthalmologic events, acute cardiac events, foot ulcers, and symptoms of CNS depression commonly observed in gabapentinoid users.

Helixmith recently enrolled its first patient in a second phase 3 trial, REGAiN-1A (VMDN-003-2), in DPN and will be launching another phase 3 in early 2021.

About Diabetic Peripheral Neuropathy

Painful DPN is a common and debilitating complication of diabetes mellitus that has a profound negative impact on quality of life, sleep, and mood. Current therapies are palliative and do not target the mechanisms underlying painful DPN. Moreover, symptomatic relief is often limited, and many patients with painful DPN still use opioids.

About Engensis

Helixmith's Engensis (VM202) is a gene therapy based on plasmid DNA. To date, more than 500 patients have been treated with Engensis across ten clinical trials in six different diseases and conditions. Data from previous clinical studies suggest that Engensis is well tolerated and has the potential to provide durable analgesic and/or symptomatic relief in a variety of disease settings. Beyond potentially alleviating pain, Engensis is designed to target the underlying causes of neuropathy through its predicted angiogenic and neuroregenerative properties. The US FDA recognized the potential for Engensis to meet the unmet need for this condition in 2018 by designating it as a Regenerative Medicine Advanced Therapy (RMAT), making it the first RMAT-designated gene therapy for a prevalent disease with over one million patients. This designation grants all the benefits afforded by the fast track and breakthrough designations, including priority review, to Engensis.

About Helixmith Co., Ltd.

Helixmith is a gene therapy company based in Seoul and San Diego, developing new and innovative biopharmaceuticals to tackle previously untreated diseases. The company has an extensive gene therapy pipeline, including a CAR-T program targeting several different types of solid tumors and an AAV vector program targeting neuromuscular diseases. Engensis (VM202), the most advanced pipeline candidate, is a plasmid DNA therapy being studied for DPN, diabetic foot ulcers, claudication, amyotrophic lateral sclerosis (Phase 2 beginning in early 2021), coronary artery disease, and Charcot-Marie-Tooth disease. The company is listed on KOSDAQ.

Helixmith clinical development and manufacturing activities are based in San Diego, California, where the company co-owns a cGMP-ready DNA production facility, Genopis, Inc., an affiliated CDMO also in San Diego. Genopis serves both Helixmith and external customers in need of plasmid DNA for medical purposes.

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