PolarityTE CSO on harnessing Mother Nature’s regenerative power and Phase 3 trial in diabetic foot ulcers.
Regenerative tissue developer PolarityTE was recently granted a Regenerative Medicine Advanced Therapy (RMAT) designation from the US Food and Drug Administration for its SkinTE product. SkinTE is derived from a patient’s own skin to regenerate full-thickness, functionally polarised skin with all its layers, and including hair follicles and glands.
The publicly-traded biotech company is currently enrolling patients in a Phase 3 trial for the treatment of diabetic foot ulcers, which occur in around 15 percent of patients with diabetes, and can lead to infections, hospitalisation and lower extremity amputations.
Longevity.Technology: The FDA says that a regenerative medicine therapy is eligible for RMAT if it is intended to “treat, modify, reverse, or cure” a serious or life-threatening condition, and preliminary clinical evidence indicates that the therapy has the potential to address unmet medical needs for that condition. The new designation gives PolarityTE an opportunity to accelerate the progress of its regenerative technology to the market. To find out more, we spoke with Dr Nikolai Sopko, PolarityTE’s Chief Scientific Officer and VP of R&D.
PolarityTE was formed in 2016 based on the research of two surgery residents at Johns Hopkins Hospital. While early approaches to skin regeneration were focused on one cell type or one scaffold, Sopko says that these approaches were limited.
“It’s infrequent that you find diseases, especially non-genetic diseases, where there’s just one protein driving the disease,” he says. “Generally, they’re considerably more complex than we thought. And healing is the same.”
“In classic biotech research, the approach is to try and figure out what Mother Nature is doing, disassemble it, and then try and reassemble it for your own purposes,” adds Sopko. “Everyone was focused on finding the holy grail – a specific cell type or a special protein that can drive a cure. But we now know that Mother Nature doesn’t work in that way – she’s very redundant and she uses a lot of parallel pathways.”
Harnessing Nature’s capacity for regeneration
As it turns out, Mother Nature is already very good at doing the kind of regeneration that researchers have spent years struggling to recreate.
“On average, we get cut over a 1,000 times in our lifetimes, and 99% of the time we heal perfectly well,” says Sopko. “But there are situations in life that our biology hasn’t evolved to deal with – car accidents, house fires, and the chronic wounds that occur when we age.”
PolarityTE was formed to harness systems already put in place by Nature and optimise them for diseases and conditions that we haven’t yet evolved defences for.
“Evolutionary pressure on humans generally fades away after three to four decades, when we’ve raised our children,” says Sopko. “And that’s when we see a lot of these diseases of aging occur, because we haven’t really had to evolve to deal with living that long.”
The company’s approach is to harness our body’s natural regeneration capabilities, inducing cells to create functional tissue. Its first product, SkinTE, which is being evaluated in randomised controlled trials, is intended to regenerate skin. SkinTE is an “autologous heterogeneous skin construct” created from a small piece of the patient’s healthy skin at PolarityTE’s facility in Salt Lake City, Utah. It looks like a thick paste that is spread across the patient’s wound and it contains multicellular segments that include cells and extracellular matrix to promote natural wound healing.
“We’re currently going after chronic wounds – diabetic foot ulcers, pressure injuries and venous leg ulcers,” says Sopko. “These tend to impact older individuals with chronic diseases, where the native healing response of our skin is already overwhelmed.”
“When we have a wound, our body tries to close it from the outside in, but there’s a limit to how fast cells can grow and migrate inwards. And in chronic wounds, even though they can be relatively small, the tissue is essentially biologically bankrupt, it’s just exhausted.”
When SkinTE is pasted into a wound, you’re basically receiving a supply of “fresh troops” for your body’s natural defences to put into action.
“The new skin cells are healthy, activated and can contribute to cellular material,” says Sopko. “They can engraft, proliferate and migrate within the wound bed, in addition to signalling to the other cells in your body to really enact that wound healing process.”
The unique manufacturing process developed by PolarityTE also aims to ensure that all the new skin cells being added into a wound are “activated.”
“When you get cut, only the cells within about 80 cells distance from the injury are actually activated,” says Sopko. “One reason why we can use such a small piece of a patient’s skin is that we’re able to activate a large majority of the cells in that harvest, so that they’re all primed and ready to go into this wound healing mode. And because we’re doing a full thickness harvest and not just taking the top layer of skin, we can also treat a much larger wound area.”
Working with the FDA
PolarityTE initially decided to commercially launch through a lesser-known pathway at the FDA for regenerative tissue products.
“We actually treated 1,200 patients and ran a couple of postmarketing trials to support safety and efficacy,” says Sopko. “But that pathway is typically for simpler products than ours, so we decided to take SkinTE off the market and go through the more formal Biologics License Applications pathway that we are going through now.”
Progress with the FDA was initially slow, mostly due to the very new technology that PolarityTE has developed.
“We are the first multicellular autologous biologic drug out there,” says Sopko. “The FDA has never seen a product like ours before, and that comes with new challenges, understandably. We need to help them understand what they’re dealing with.”
One of the major challenges is around manufacturing. Good manufacturing practice demonstrates that a biotech company is developing a product that is consistently pure and of good quality.
“When you’re dealing with a biologic like ours, this is actually a really hard aspect because our raw material comes from the patient,” says Sopko. “You’re not just buying bulk ingredients from a pharmaceutical company that you then package. And so that process was pretty challenging and pretty fun. We had to develop a lot of new assays, which the FDA likely hadn’t seen before in this context, to show that we’re activating the tissue, we have the right cell types, and that the cells are viable.”
Phase 3 trial under way
Happily, PolarityTE was still able to leverage the clinical data from its earlier trials, which means the company was able to go straight into Phase 3 pivotal trials, starting in diabetic foot ulcers.
“We specifically chose the tough ones – more complex ulcers that have things like exposed tendon, muscle and bone,” says Sopko. “In these cases, the skin really has a hard time trying to grow back over, and patients are in significant risk for infection, amputation and loss of that limb.”
All in all, this process took about a year, but PolarityTE was given the go-ahead in January this year and the trial enrolled its first patient in April.
“We anticipate the trial will include a 100 patients total, who are randomized one-to-one to standard of care versus SkinTE plus standard of care,” says Sopko. “We’re basically comparing other advanced wound treatments that are currently available in the market to our product. It’s a challenging area – there haven’t been a lot of trials involving these more severe DFUs – we’re one of maybe two FDA-registered trials in this wound type, ever.”
Over the course of the next year or so, PolarityTE hopes to complete both the current Phase 3 pivotal trial in diabetic foot ulcers, and a subsequent Phase 3 trial in more severe cases.
“We really want to see this product working well, in difficult situations,” says Sopko. “There are a lot of good products for more simple wounds out there, but there are many patients in difficult situations who really don’t have many options. And we really see this product differentiating itself in these tough situations.”
