When someone cuts herself and starts to bleed, her platelets aggregate to stop the bleeding. Over time, the body’s enzymes will break down that clot, providing the body’s stem cells with the regenerative factors naturally contained in platelets and plasma. In this way, platelets help the body to regrow tissue, and that’s how people heal.
For years, orthobiologics and other forms of regenerative medicine have sought to mimic and enhance the body’s natural ability to heal itself. Carmell Therapeutics has a new approach to that end-goal.
The company’s proprietary process is designed to bind and cross-link regenerative factors in lyophilized platelet-enriched plasma into solid and semi-solid plasma-based materials to accelerate healing in bone, tendon and wound care.
“We’re a regenerative medicine company that has a unique technology to accelerate and enhance healing and reduce infections,” said Randy Hubbell, Chief Executive Officer. “Our technology is delivering regenerative factors, specifically growth factors, locally to an injured site and has a time-release mechanism.”
Expanding on Existing Science
The foundation of the technology is the allogenic plasma source material that has been used for decades in other medical applications. Carmell Therapeutics, however, does not separate, isolate or fractionate the material, so that all of the growth factors in the platelets are present as well as regenerative factors associated with the plasma that participate in the healing process.
“We are able to process the unfractionated platelet-enriched plasma for safety without deactivating the regenerative factors, keeping the final product bioactive,” Hubbell said. “That’s the first big breakthrough that was discovered by scientists at Carnegie Mellon University.”
The second component of what makes Carmell Therapeutics’ technology unique is the ability to take the plasma and lyophilize (or freeze-dry) it, mix the resulting powder with glycerol, and then make different solid forms.
“We call it plasticizing,” Hubbell said. “The first product is a putty, the second is a paste; we can do a sheet, a plug, we’ve even done a hard screw. So, that is unique to us and very beneficial for form and function.”
Hubbell describes the technology’s time-release mechanism as the game-changer. Genipin—a material derived from the gardenia plant—cross-links the processed plasma before it is delivered to the injured site to make active growth factors available over days, weeks or months. Genipin is what gives the technology the time-release capability.
“We have unfractionated platelet-enriched plasma that can be put in different shapes that degrade over time, and we have both preclinical and human data showing that we can accelerate healing and reduce infections,” Hubbell said. “The crosslinking of the platelet-enriched plasma with genipin slows the breakdown of the final product once implanted, allowing for growth factors to be released slowly over time. We can control the degradation rate by the amount of genipin we put in.”
Furthermore, the product is standardized for consistent quality.
“Because it’s a biologic, we control every lot for identity, purity and potency and ensure that every lot and every dose has the same growth factor levels and bioactivity,” said Stephanie Kladakis, Ph.D., Chief Scientific Officer. “That makes us stand out over products like autologous PRP [platelet-rich plasma], or other products like stem cells that haven’t gone through the BLA [Biologic License Application] approval process. There’s a lot more rigor and consistency, and we’ll have efficacy data from two Level 1 clinical studies.”
The Regulatory Approach
Carmell Therapeutics’ product is a combination biologic and device. It is regulated as a biologic, and the company has completed a human clinical study. Carmell Therapeutics’ regulatory pathway for its first product, Bone Healing Accelerant (BHA), requires two pivotal clinical studies to submit for a BLA.
Carmell Therapeutics submitted for an IND later than usual in the development process. After completing a pilot study demonstrating the capabilities of the technology outside the U.S., FDA has accepted this study as a phase II study and now Carmell is waiting for IND clearance to begin the first of two pivotal studies, which it expects by the end of 2019.
“That level of rigor, completeness and expectation from the agency is higher because what you produce from a manufacturing perspective during your pivotal studies used for demonstrating efficacy is what you’re going to commercialize with,” Hubbell said. “So FDA wants you to have your manufacturing fully completed, validated with all the tests, have multiple batches run with stability data, and release tests that are fully developed and validated that can measure the potency and identity and stability of the technology. We’re on the last question associated with the IND, and once we have that clearance, they’ll allow us to start enrolling in our first pivotal study.”
Since 2016, Carmell Therapeutics has equipped its manufacturing facilities to support its clinical trials and pilot launch. They have an ISO certified clean room and recently became an ISO 13485 certified facility.
One of the requirements of a BLA is two independent efficacy trials, so Carmell Therapeutics will conduct two randomized trials showing superiority over standard of care. That clinical efficacy data is extremely valuable from a company perspective. A BLA will likely grant Carmell Therapeutics 12 years of exclusivity, meaning that FDA will not license another application for lyophilized bioactive regenerative medicine during that time.
“We’re at a critical inflection point where we are validating manufacturing, and that allows us to go into our pivotal clinical trial program,” Hubbell said. “That now allows us to see the end where we can get BHA to patients. We fully believe BHA is going to help patients heal faster and make a difference in their lives.”
The trial completed thus far has shown accelerated healing, reduction in infection and a high safety profile.
“One of the most exciting things is the safety profile,” Dr. Kladakis said. “We’ve done a complete biocompatibility series in which we look at the results in animals, and we haven’t seen any adverse effects. Specifically, in our clinical trials, there were no implant-related adverse events.”
Carmell Therapeutics has undergone a Phase II trial and eight animal studies for bone healing, wound healing and infection reduction. They are preparing to start a pivotal study, and plan to have CE Mark approval by mid-2021, according to Hubbell.
Future applications of the technology will require an iterative process. Approximately 70% of all of their products will be the same drug substance, powder created from freeze-dried, platelet-enriched plasma. Then, the other 30% can be modified by the amount of genipin or the form, depending upon the application.
The first technology, BHA, is developed for long bone fracture to accelerate healing, which potentially could be used as a bone void filler in spine, as indicated by animal studies. A second product will be used for wound care. Future applications are likely in rotator cuff repair and diabetic foot ulcer healing.
“There is data to support reduction in wound infections, and that is a critical aspect, too,” Dr. Kladakis said. “We use platelet-enriched plasma, and within the platelets of the plasma are growth factors that are very powerful. These growth factors are the body’s native mechanism to induce angiogenesis, healing and infection reduction. Those growth factors, in the physiologic ratios that are supplied, are very impactful.”
The BHA for the long bone fracture is the tip of the sword. If it works there, that strongly suggests that it will work in many other areas. Aside from orthopedic applications, other spin-out opportunities exist in the aesthetics market for things like facial rejuvenation and hair growth. The technology could even be a scaffolding to deliver stem cells.
“The way that [Dr. Kladakis] has designed the developing and manufacturing of this technology allows for product iterations for many, many years to come, all based on the same manufacturing process,” Hubbell said.