Engensis: Growth-Factor Inducing DNA Evaluated for Severe Diabetic Nerve Pain

MedicalResearch.com Interview with:

William K. Schmidt, Ph.D. Senior VP Clinical Development

Dr. Schmidt

William K. Schmidt, Ph.D.
Senior VP Clinical Development
Helixmith Co. Ltd.

 MedicalResearch.com: What is the background for this study? How common is diabetic peripheral neuropathy and how does it affect patients?

Response: According to the Centers for Disease Control and Prevention (CDC), over 34 million people in the United States have diabetes (about 10% of the U.S. population) and about one in four patients do not know that they have it (https://www.cdc.gov/chronicdisease/resources/publications/factsheets/diabetes-prediabetes.htm).  Diabetes can cause significant damage to nerves in the feet, hands, eyes, and other parts of the body.

Diabetic peripheral neuropathy (DPN) is the most common form of nerve damage worldwide; it affects approximately half of the patients with diabetes (Iqbal et al., 2018).  In many individuals, severe burning, tingling, “pins and needles,” or cramping pain can occur simultaneously in both feet without external evidence of foot damage. Despite the pain, symptoms may be accompanied by numbness or loss of sensation in the feet. This is called painful diabetic peripheral neuropathy (painful DPN or P-DPN) and may affect up to one-third of the general diabetic population (Yoo et al., 2013). P-DPN may cause increased anxiety and depression, sleep impairment, and difficulties with walking.  Up to one-third of P-DPN patients may require the use of a cane, walker, or even a wheelchair due to extreme foot pain.  Once P-DPN occurs, it may result in a lifetime of pain and disability.

FDA-approved daily oral medications often used to treat P-DPN include Neurontin (gabapentin), Lyrica (pregabalin), Cymbalta (duloxetine), and Nucynta ER (tapentadol).  While these “neuropathic pain” medications may dull the pain for some subjects, they produce significant side effects that may be troubling for many patients. Indeed, many patients stop using these pain killers due to lack of effectiveness at doses that they can tolerate (van Nooten et al., 2017) There is also a topical 8% capsaicin patch, but again with limited efficacy. It is well known that the most severely affected patients may require opioid analgesics to control P-DPN (Pesa et al., 2013).

None of the currently used medications have disease-modifying effects. However, our new injectable medication is now in advanced clinical development that has the potential disease-modifying effects lasting months after each treatment, with limited or no side effects for most patients aside from brief injection site discomfort.

MedicalResearch.com: What are the main findings of the first Phase 3 clinical trial in 2019?

Overall Phase 3 design:

The Phase 3 study was conducted in two parts, one for 9 months (DPN 3-1; 500 subjects) and one for 9 months with an extension to 12 months (DPN 3-1b; 101 subjects). The average daily pain score at study entry was 7.0 (moderate-to-severe pain) on a 0-10 numerical rating scale where 10 is the worst pain imaginable.  This level of pain is very high, but not unusual for this kind of study.  Two-thirds of the patients received Engensis; the remaining one-third received indistinguishable placebo medication.  Engensis or placebo was administered via intramuscular injection to the calf muscles of both legs on Days 0 and 14, and again on Day 90 and 104. The primary endpoint in DPN 3-1 was change from baseline in the average 24-hour pain score at 3 months. In DPN 3-1b, the primary endpoint was safety, while the secondary efficacy endpoint was change in mean pain score from baseline to 12 months

Excellent safety:

Safety was assessed based on the incidence of treatment-emergent adverse events (TEAE) and serious adverse events (SAEs), and their relationship to the study drug.

Engensis has been shown to be highly safe. The incidence of adverse events was similar for VM202 and placebo in DPN 3-1 and even lower for VM202 than placebo in DPN 3-1b.

Efficacy in phase 3-1:

Data from DPN 3-1 was compromised due to technical and operational problems, resulting in the primary endpoint not being met. It has to be noted that there was an unexpected procedural change during the Phase 3 study when the first Clinical Research Organization (CRO) that we hired to manage the study voluntarily resigned mid-way through the study and had to be replaced by a second, larger and more experienced CRO.  However, phase 3-1b, which was a double-blind placebo-controlled extension study, was managed by the new CRO and yielded highly interesting results, showing high level, durable analgesic response relative to the placebo group that was maintained for 8 months after the last injection.

High and durable analgesic effect in Phase 3-1b:

Of 101 subjects belonging to the intent-to-treat population who enrolled in DPN 3-1b, at 12 months, there were clinically meaningful reductions in the primary efficacy measure, mean pain score changes from baseline, for patients who received VM202 compared with the placebo group.  Analysis of earlier time points revealed that there were also clinically meaningful reductions in the VM202 group in the 24-hour average pain scores at 6 months and 9 months.

Even higher pain-relieving effect in subjects not on pregabalin and/or gabapentin:

Importantly, greater reductions in pain were found in subjects who were not on gabapentin or pregabalin, two widely prescribed medicines for P-DPN, during the 12-month study. These results are consistent with data from previous phase 1 and phase 2. This has very important clinical and commercial implications as almost half of P-DPN populations do not or cannot use the currently available medicines described above.

Disease-modifying potential:

Another very exciting observation made in this study is the possibility of VM202 being a disease-modifying drug. In DPN 3-1b, durable analgesic response after treatment with VM202 was maintained for 8 months after the last injection, suggesting that VM202 treatment may ameliorate disease progression. Given the fact that virtually all Engesis and HGF expression become non-existent by 2 weeks after injections, this strongly suggests that Engesis injections has the potential to fundamentally changes the pain circuit system in patients.

MedicalResearch.com: What is the mechanism of action of Engensis? How is it administered? 

Response: Engensis is different from all other pain medications. It is based on unique concepts and technology. Engensis is a plasmid DNA-based product that encodes the natural protein present in humans, namely human hepatocyte growth factor (HGF).  When administered by intramuscular injection, the DNA is taken up by muscle cells.  Once in the muscle, it produces the HGF proteins for about two weeks after injections.  Studies involving animal models showed that the enhanced levels of HGF stimulate nerve regeneration and the formation of new blood vessels around injected areas.  Therefore, it is by definition a regenerative medicine. We believe that Engensis has the potential to become the first analgesic drug to ameliorate and maybe even reverse disease progression in P-DPN.

In May 2018, the FDA awarded Engensis the special breakthrough designation of RMAT (Regenerative Medicine Advanced Therapy) which was the first time for a pain medication and the first time for any type of medication used to treat a disease that affects a large part of the U.S. population.

MedicalResearch.com: How many patients will be enrolled in the ongoing phase 3 study? How long until results may be known?

Response: The REGAiN-1A is our second Phase 3 trial. It will enroll a minimum of 152 subjects who will be followed for a total of 6 months after entering the trial. The final sample size (possibly up to 250 subjects) will be determined by the independent Data Monitoring Committee when half of the subjects have reached their 6-month endpoint.  Engensis or placebo will be administered at Days 0 and 14, and again on Days 90 and 104.  An observation-only extension of this study will follow participants for safety and efficacy for up to 12 months or nearly 9 months following their last injections of Engensis or placebo.  We expect that results from the main REGAiN-1A trial may be available as early as December 2021 if enrollment continues as planned. We will also start another phase 3 with a similar design to the ongoing phase 3.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: Dr. William Schmidt is the Senior VP of Clinical Development for Helixmith Inc. (San Diego, California, and Seoul, South Korea). He has worked in the area of pain medicine throughout his entire professional career and has led the preclinical or clinical development of more than 6 medications that have been approved by the U.S. FDA or by international regulatory authorities.  He has published more than 50 journal articles and presented more than 190 papers on novel drug development at national and international professional meetings.


Iqbal Z, et al. Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clin Ther. 2018 Jun;40(6):828-849.  Available at: https://pubmed.ncbi.nlm.nih.gov/29709457.

Pesa J et al., Opioid utilization patterns among Medicare patients with diabetic peripheral neuropathy. Am Health Drug Benefits. 2013 May;6(4):188-96.  Available at: https://pubmed.ncbi.nlm.nih.gov/24991356.

van Nooten F, et al. Capsaicin 8% Patch Versus Oral Neuropathic Pain Medications for the Treatment of Painful Diabetic Peripheral Neuropathy: A Systematic Literature Review and Network Meta-analysis. Clin Ther. 2017 Apr;39(4):787-803.e18.  Available at: https://pubmed.ncbi.nlm.nih.gov/28365034.

Yoo M, et al. Painful Diabetic Peripheral Neuropathy: Presentations, Mechanisms, and Exercise Therapy. J Diabetes Metab. 2013 Jun 30;Suppl 10:005.  Available at: https://pubmed.ncbi.nlm.nih.gov/25360348.

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