PolarityTE: Beyond Cells, To Whole Tissue

By Wayne Koberstein, Executive Editor, Life Science Leader
Follow Me On Twitter @WayneKoberstein

This article originally appeared in Life Science Leader magazine.

The Enterprisers: Life Science Leadership In Action

If you want to be a real enterpriser, try bringing a new solution into a troubled space. PolarityTE gave itself the challenge of entering the race to regenerate skin and other tissues, a field littered with failures piled up for decades. The problem? “You can put stem cells in a petri dish and surround them with growth factors, but all you get is a mass of useless cells,” says Denver Lough, chairman, president, CEO, and CSO of the company. “Or, if you put the cultured cells into a wound, you only end up with scar tissue.”

Lough and his cofounders began their journey to enterprise in the trenches of actual patient treatment — cleaning up, dressing, and “smelling” the wounds caused by fire, chronic bedsores, and a myriad of other insults. As a group of plastic surgeons at Johns Hopkins University, they saw the destruction firsthand, as well as what they considered the pitiful failures of “artificial skin” products of the time. Besides simple compassion, their work required an intimate understanding of the composition, structure, and regenerative potential of living tissues such as skin or bone. The experience drove them on, in both motivation and informed design, to build a better way of restoring fully functional tissue.

“We left Johns Hopkins because we were tired of people telling us, ‘Here’s this incredibly novel product that’s only $40,000 a square centimeter. You can put it on your patients, and you will regenerate something.’ But all you get is scar tissue — the same thing, over and over and over again,” Lough recalls.

“Regenerative medicine cannot take form or operate in isolation,” Lough says. “Most regenerative-medicine companies are focused on making a single silver bullet to regenerate living tissue — a single stem-cell type, growth factor, drug, or polymeric scaffold. If that were possible, why have so many companies failed to do it? Polarity embodies the fact that there is no single agent or combination of agents that can make regenerative medicine work. Tissues have polarity — up, down, backward, forward, left, and right. They operate together and touch each other, connect to an extracellular matrix and blood vessels, and rely on gradients of growth factors. All of those elements together guide the development of stem cells to replace lost tissue.”

Skin is the lead product for PolarityTE, with a planned launch tethered to further clinical research in selected institutions, but it is also developing others and aims to apply its platform widely over time. Current programs include replacement products for bone, vascular, muscle, cartilage, nerve, and fat, with more areas considered for the future.

JUMP START
Creation of the basic technology for producing the tissue replacements began several years ago, but the company did not begin to form until late 2016. All of the principals had conducted discovery research in tissue regeneration and wanted to see their techniques and inventions go beyond academic science — to overturn the status quo in patient treatment. Only a business enterprise could hope to achieve that goal. Funding was especially tough from the get-go because the founders wanted to be the ones steering the company, not the funders. They already had rejected several offers from half a dozen VCs who sought control of the company in exchange. The company’s academic origins may have raised a red flag with investors, but it was actually the founders’ rejection of academic restraints that put them on a business path.

“My wish had always been to continue working at Johns Hopkins as a burn director,” Lough recalls. “I wanted to grow skin for burn patients and contribute all types of tissue substrate to other fields at Hopkins, such as orthopedics and neurosurgery. But we realized there was no way for that to become reality because of the bureaucracy associated with academia. Academia wants to get its hands involved with everything because it wants to make a name for the university.”

Venture capital presented a similar problem, in Lough’s view: “If you take away management from us, you take away the passion, you take away the innovators, you take away the leaders, you take away the people in the trenches, and it suddenly becomes all about product, margin, and profit. That leads to failure.”

Enter the angel.

Dr. Philip Frost, the well-known multibillionaire investor in Miami, approached the company, offering to take it public and give it cash up front — as long as the founders retained the management responsibility. (Editor’s note: Frost had been investigating the regenerative medicine field, and in doing so, he had read the founders’ published papers on the subject.) Lough relates Frost’s message: “If you believe in your technology, your cause, your network, and your ability to get this to market, be public. Put it on the table. Prove it to me.” As chronicled elsewhere, the plan was ingenious if a bit anachronistic. The company would merge with a struggling computer- gaming business, Majesco Entertainment, to acquire its assets and Nasdaq listing (COOL), and at the same time assume the name PolarityTE.

What’s the TE stand for? “That’s a great question; everyone always wants to know that,” says Lough. “Most assume it means tissue engineering. It is not tissue engineering, but it is in the mission statement that drives the company every day. If you want to know what it is, you have to come work for us! A clue: we don’t care about what people know, but we do care about how they learn and how they drive themselves forward.”

Before Frost came into the picture, Lough’s encounters with life science investors sparked some thoughts about key differences between “dry” high tech such as IT and the “wet” high tech of life sciences. “Biopharma takes so much money to get off the ground, and in addition, you run into all these barriers based on the current central dogma. You must make sure you fit the algorithm the oncologists want or the way regenerative medicine has been taught. But if you look at the people who founded and drove the largest high tech companies today, they are all people who defied the accepted ways.”

Lough believes the next few years will bring a tremendous shift in biopharma development, especially in regenerative medicine — from venture capitalists running virtual companies, to more “garage-based,” do-it-yourself enterprises. He trusts the result will be more innovation at lower cost. “It’s time for companies that bring real technology forward as inexpensively as they possibly can and get it to patients as quickly as they can. That will become a paradigm shift in the way biopharma and regenerative medicine truly develops.”

SUPPORT STRUCTURE
Once launched, PolarityTE composed itself and its technology with a surgeon’s perspective — focusing beyond the single-agent regenerative model to one of multicomponent support. Lough likens the company’s approach to keeping a patient in a familiar home environment with all the elements needed for treatment provided there — “offering all of the supportive components, from interfaces, to growth factors and the extracellular matrix, all integrated into the system, and processed slightly to allow it to propagate and regenerate full thickness of skin, hair, or other tissue, with all of the necessary layers.” The platform can thus cross over into regenerating viable tissue in a variety of organ systems.

The platform creates an infusible product consisting of a minimally polarized functional unit (MPFU). In the MPFU, stem cells taken from the patient are surrounded by extracellular structures in a matrix containing growth factors, mimicking natural conditions of healing in the body. That includes the aforementioned polarity of tissues arranged in ordered layers and forms that serve as substrates for other layers and forms. SkinTE reflects the polarity of natural skin, with all of those components arranged in the same order.

The resulting product is “autologous,” meaning it consists of the patient’s own cells, and “homologous,” specific to the tissue to be regenerated. It comes in a form with an almost paste or oatmeal-like consistency inside a needleless syringe for deployment and application diffusely across the open wound. With polarity intact in the implanted product, the cells and tissue are capable of self-orientation through migration into the proper layers. Over a short period of time, the regenerating skin fully aligns into its natural layers through cell migration to the appropriate location.

Lough says the company designed the product to be administered almost anywhere, even in remote, undeveloped areas of the world. From each patient, using simple tools and instructions supplied by PolarityTE in a “Harvest Box,” physicians harvest a piece of full-thickness skin, then send the sample back to the company in a FedEx UN 3373 shipment for processing into the MPFU, using the supplied carton containing a NanoCool chemical cooling agent. A smartphone app gives all caregivers involved instant, 24-hour access to a real human being at the company providing expert assistance. After the patient sample arrives, the company processes it and returns the product within 24 to 48 hours to the practitioner.

“People say it sounds too good to be true,” says Lough, “But the only assumption we ever ask them to make is your own skin can regenerate your skin.” He says SkinTE can generate full thickness skin, with hair follicles, epidermis, dermis, hypodermis, blood vessels, and appendages such as sweat glands and sebaceous glands. Touting single-agent solutions for regenerating skin, he maintains, is tantamount to claiming the ability to circumvent biology, evolution, and the immune system. Aiming to cover all the bases of tissue complexity, PolarityTE even went beyond the founders’ own deep knowledge of wounds and healing, bringing in 40 clinical advisors from numerous medical institutions to guide its technology design.

“We want to have the best product for regenerative medicine, hands down. Absolute best,” he says. “But at the same time, we want to provide it to everyone we possibly can for the most cost-effective price out there, so we can pass on the savings to the healthcare industry, and to payers, providers, and patients. We want it to be used not only by specialists, but also by nurse practitioners and physician assistants.”

Assuming the always big “if” of whether the technology works as planned, it could limit ER visits, hospital stays, and use of antibiotics — and the ill effects of the same. “You dress it as you would a typical skin graft, and you let it heal,” Lough says. “We’re not reinventing the way that dressings or skin grafts are done.” He draws a sharp contrast between the simple procedure just described and a logistically complex cellular therapy such as CAR-T. Thus, although his company’s product is a more comprehensive assembly of cell types than single-agent therapies, it is uncomplicated in administration.

Unlike drugs, human tissue products such as SkinTE do not go through three-phase clinical trials but have a much shorter potential path to market. Companies must register such products with FDA’s CBER (Center for Biologics Evaluation and Research), which mainly focuses on purity, safety, and one other subject that PolarityTE largely avoids: preventing the spread of communicable disease. The company achieved FDA registration of SkinTE in August 2017 and is doing a limited release of the product in a selection of large clinics as it scales up manufacturing and distribution capacity. Human clinical data will emerge from the early adopters.

Perhaps the preceding description seems all too simple, and of course it is. Offering a new product is one thing; winning adoption by all of the interested parties — the usual “p” chorus of patients, physicians, and payers — is quite another. In meeting that challenge, PolarityTE’s team of founders and advisors may have the advantage of coming full circle, from actual practice in the market, to product development, and back into the market with a technology they have designed for that setting. Maybe that is why the company chose an especially challenging objective in a pilot study for SkinTE — burns.

That was no accident. Lough’s team knew the stark reality and high stakes of treating burn patients, and not just from general experience. A specific, dramatic situation educated them indelibly.

EXPERIENCE FORMS
In 2014, at a dance party in an empty swimming pool in Taiwan, 512 people were burned when a festive starch-based flour lit on fire and exploded. President Ma of Taiwan called Dr. Stephen Milner, now the company’s chief clinical officer and then director of the burn center at Johns Hopkins, asking him to bring his team to Taiwan to help triage and treat the burn patients. Having read their published papers on healing burns, Ma also asked whether the team could regenerate patients’ skin.

“At that time, the company wasn’t real, it was just a concept, but right then and there I realized, as a physician at Hopkins, I had reached a terminal velocity,” says Lough. “I could only treat one patient at a time, I could only put one stitch in every 10 seconds, I could only see so many patients in a clinic. I could only give this much fluid, I could only take this much skin, and so on. If I leave Hopkins, I bring a brilliant team with me that are all dedicated physicians, saying ‘to heck with it, we need to change regenerative medicine.’”

Lough looks beyond skin regeneration in applying the technology to lost bone, muscle, fat, and cartilage. Pressure sores present an example of wounds that involve all of those components and more. “To anyone with a deep wound, we could give skin, fat, muscle, bone — we could even restore peripheral nerve elements to innervate components of those muscles so they do not atrophy. We could prevent the sort of protein degradation that will continue breakdown of surrounding tissues.”

Press coverage of PolarityTE has mainly concentrated on the issue of academic scientist turned CEO, even though Lough and his cofounders were hardly naïve to business. But the more interesting story might be how the company marries science to actual practice, out of which its business model emerges. If its technology somehow failed, at least it would have championed practice-centered discovery and development versus the arguably oversimplified early efforts in the infant field of regenerative medicine.

Lough makes the stakes emphatically clear: “People have glorified the technology of regeneration without really recognizing how the applications must be useful to people who have been in the trenches and know the full spectrum of complications that exist in wounded tissue. Deep tissue needs to heal in a certain way. The answer isn’t always just changing the dressing in a vac [i.e., vacuum therapy with vacuum-assisted closure devices]. Creating one-dimensional products like a single hairpin loop RNA for treating a pressure wound — it’s unbelievably expensive, and it’s never going to work in a human being.”

Having lost a friend, and possibly my mother, to unhealed wounds taxing the entire body, I am allowed to hope for the success of PolarityTE in the way it projects. The company appears clear-headed enough to understand how biology can perversely defeat the most convincing logic, but one could hardly argue with its complex view of tissue regeneration. Oh, and don’t worry about the academic origins of its leaders. They seem quite in touch with the real world, a primary requirement for doing business well.

REGENERATIVE REVOLUTIONARY

PolarityTE takes a strong stand on regenerative medicine — it must mirror the complexity of actual living tissue. The company’s CEO, Denver Lough, puts its technology for regrowing the patient’s own skin, bone, or other tissue into the perspective of rapidly advancing science. He also issues a challenge to the field’s status quo.

LOUGH: If you take the tissue and introduce a variable such as a new gene or new type of growth factor, you only measure the outcome you’re looking for. But what about all the things you’re unaware of? We didn’t know really what the field of metabolomics was 10 or 15 years ago. We didn’t know what micro RNA, single hairpin loop RNA, or dicer was. Then the field began to realize, we’re affecting things we don’t even understand. But the greatest discoveries of humankind all come from the realization of reality. Someone just realized this is the way the natural system works, this is the way it works. The greatest discovery in the world was probably gravity, but it just took time for people to actually understand what it really was. Our company’s technology embodies the same idea, saying, “Look, there are natural biologically sound mechanisms for the way hair follicles regenerate.” If we apply those same mechanisms, play around with the tissue just slightly to make it easy for people to deploy, then we can actually give it to people to regenerate full-thickness, organized skin, as well as organized bone, cartilage, muscle, liver. We don’t believe a single drug can do that. Of course, people love off-the-shelf products; you can have a huge margin on them, you can profit well. The problem is, in regenerative medicine, they didn’t really contribute anything, so they play these little marginal games with each other, saying, “My product is slightly better.” We’re saying, the heck with that. We need to change the paradigm — the way regenerative medicine has been propagated throughout society.