January 13, 2021
By Sunyoung Kim, CEO, and William K. Schmidt, senior vice president, Clinical Development, Helixmith Co, Ltd
All of us have experienced various types of acute and chronic pain throughout our lives and, in many cases, we are fortunate to see the pain go away or diminish over time as the body uses its innate restorative capacity to heal wounds, resolve inflammation, and repair damaged nerves and blood vessels. But in many cases, natural healing doesn’t occur, and chronic pain may persist for a lifetime.
We have had the privilege to work together on an advanced plasmid DNA program that may change this paradigm for patients with persistent cramping, burning, lancinating pain that often starts in both feet, spreads up their legs, eventually reaching their hands in what is called a “stocking-glove” distribution of pain and destruction of sensory nerves that cause painful diabetic peripheral neuropathy, or DPN for short. DPN is the most common form of nerve damage worldwide.
Recent data from the US Center for Disease Control and Prevention (CDC) indicate that 34 million people in the United States have diabetes. DPN may occur in approximately half of these patients. It often leads to patients who become so disabled that they can’t walk and become wheelchair bound. For some, nerve damage may progress to their eyes and cause permanent blindness. DPN is not a disease that you want to get; until now, the only drugs available to patients are ones that blunt the degree of pain that they experience. Patients generally don’t recover from DPN once it occurs, even with optimal glycemic control (HbA1c levels less than 7%), as their peripheral sensory nerves become damaged beyond repair.
How would it be then if a new medication contained a blueprint for nerves and blood vessels to regrow, or regenerate in medical terminology, along with instructions for how to do this on a cell-by-cell basis? This is the promise of regenerative medicine–to restore health by turning the clock back and rebuilding damaged cells or networks of nerves with their supporting micro-blood vessels. This may be possible with the use of medications that contain small pieces of DNA with the instructions for cells to manufacture a natural growth hormone that stimulates nerve and blood vessel growth. Human hepatocyte growth factor (HGF) is such a hormone and, since it was discovered in the 1980s, researchers have found that it is one of the most potent growth hormones for the same small sensory nerves and large diameter motor nerves that are damaged in DPN and in several other neurological disorders. HGF is one of many growth hormones that we’ve all had since before birth and that continue to be present in our bodies through adulthood to help maintain the health of various types of cells.
Helixmith has now developed a non-viral plasmid DNA-based medicine that, when injected into muscles, stimulates the synthesis of twin proteins that are, in fact, identical to the natural twin HGF proteins that our bodies produce. However, by injecting Engensis (VM202) into the calf muscles of patients with DPN, individual muscle cells and nerve cells within a radius of about 1 centimeter from the injection site take up the DNA and start locally enhanced synthesis of HGF. Studies in animals show that this lasts for about two weeks. In human therapeutics, if a series of injections are planned in both legs at Day 0 and again at Day 14, enhanced intracellular synthesis of HGF may occur for about a month. The benefits may last far longer than that, particularly if there is stimulation of regrowth of damaged nerves. Our early Phase 1 and Phase 2 studies show that the benefits of only two days of treatment (Day 0 and Day 14) may produce a reduction in foot and leg pain that may last for 9 months or more.
Engensis is currently in advanced Phase 3 clinical trials which, if successful, will form the basis for applying for approval to the FDA and other regulatory authorities throughout the world. Despite some recent setbacks in the analysis of our first Phase 3 trial, we’ve learned through successive Phase 1, Phase 2, and the first Phase 3 clinical trial that the product appears to be well tolerated by DPN patients with no clinically significant differences in side effects between the active and placebo treatment groups.
A potential advantage of gene medicine is that therapeutic benefits may last for weeks, months, or longer following initial treatment with no need for daily or weekly administration of the medication. In fact, the US FDA awarded Engensis the special designation of Regenerative Medicine Advanced Therapy (RMAT) in May 2018 based on animal and early clinical studies with the medication. Animal studies with Engensis have shown photographic evidence of regrowth of damaged nerves and blood vessels. We hope, in future clinical trials, to show the same benefits in humans along with reductions in pain and increases in functional benefits that may lead to reductions in the disability that patients with DPN may experience over time.