NEW YORK – A gene therapy with roots at a Baylor College of Medicine lab is advancing to a Phase II trial as a treatment for a form of osteoarthritis.
Pacira BioSciences, in a Phase I trial it sponsored, has tested the gene therapy PCRX-201 (enekinragene inzadenovec) in 72 patients with moderate-to-severe osteoarthritis of the knee. The Tampa, Florida-based company also recently opened enrollment in a Phase II trial of the gene therapy after seeing the two-year Phase I data.
Pacira develops non-opioid pain management therapeutics, and it already has three products on the market, though PCRX-201 would be its first gene therapy. The potential for gene therapy to have long-term benefits and help patients for years, rather than mitigating symptoms for weeks or months, is particularly attractive to Derek Jackson, VP of cell and gene therapy product development at Pacira. "You're able to, with a single injection, have high levels of therapeutic protein for sustained periods of time," he said.
Pacira is initially studying PCRX-201 as a treatment for osteoarthritis of the knee, but it could have efficacy in treating osteoarthritis in other joints, too. There are millions of patients in the US with osteoarthritis, and its prevalence is expected to grow, in part driven by an aging population and rising levels of obesity that stresses joints.
There isn't a cure, but treating osteoarthritis can involve lifestyle changes, pain medication, or when these options fail, a joint replacement, which comes with risks as a surgical procedure.
"The [osteoarthritis] epidemic is something that's ahead of us," Jackson said, adding that patients have been getting the degenerative joint disease at younger ages.
PCRX-201, administered by injection to the knee, has led to sustained improvements in patients' knee pain, stiffness, and function for up to two years post-treatment, according to data Pacira presented late last year from its open-label Phase I trial, in which patients received one of three doses of the gene therapy. That result was consistent even in patients with more severe disease.
"All three of our doses achieved roughly equal efficacy with respect to pain and function," Jackson said. The gene therapy also has been well tolerated and did not result in any serious treatment-emergent adverse events, according to the company.
PCRX-201 codes for interleukin-1 receptor antagonist (IL-1Ra), a protein that blocks inflammation associated with pain and disease progression in osteoarthritis. While it is being advanced by Pacira, it was developed in the lab of Brendan Lee, a professor and chair of the molecular and human genetics department at Baylor College of Medicine in Houston.
Since out-licensing the gene therapy, Lee and his lab are no longer involved in developing the candidate therapy nor in its clinical testing, to avoid any conflicts of interest, Lee said.
At Lee's lab, researchers study genetic diseases of the skeleton in the hopes of improving their understanding of disease biology and informing the development of better treatments, as well as developing gene therapies for other conditions. Decades earlier, researchers at the lab contributed to the development of a high-capacity adenoviral vector that was less toxic than earlier iterations of adenovirus and reduced immunogenicity.
Researchers in Lee's lab in the late 2000s decided to investigate diseases of the joint, such as osteoarthritis, "combining our interest in the skeleton and the joint, plus my history in this vector system and gene therapy," Lee said. They built on previous research exploring IL-1RA as a target for osteoarthritis treatment and developed the gene therapy that became PCRX-201.
Part of their vision for the IL-1RA gene therapy was that, by locally administering it to joint tissue in the knee, the therapy wouldn't integrate into the genome and would be somewhat protected from the immune system. This premise seemingly was borne out, as researchers observed limited toxicity in preclinical animal studies, including small rodent and large equine models, Lee said.
Meanwhile, instead of using the gene therapy to overexpress IL-1RA and block inflammation generally, the lab developed an approach that uses an inducible promoter so that IL-1RA expression is only turned on when it senses inflammation in the joint. This approach was led by Kilian Guse, who was a postdoctoral associate in Lee's lab, but went on to cofound a startup in Germany called GQ Bio Therapeutics in 2012.
GQ Bio licensed and continued to advance the gene therapy through the 2010s, until it sold the product in 2017 to Flexion Therapeutics, which advanced it into a Phase I trial. In 2021, Flexion was acquired by Pacira, which dubbed the gene therapy PCRX-201 and continues to study it in the Phase I trial and soon in a Phase II trial.
"I saw great potential for this as a therapeutic," recalled Guse, CEO of GQ Bio, noting that "there's great unmet need in osteoarthritis."
In addition to its work on that IL-1RA gene therapy, GQ Bio has developed a high-capacity gene therapy vector platform, known as HCAd, and has a pipeline of gene therapies under preclinical evaluation in osteoarthritis and intervertebral disc degeneration, including another gene therapy licensed from Lee's lab targeting proteoglycan 4 (PRG4).
Lee's lab is currently collaborating with GQ Bio on preclinical testing of that PRG4 gene therapy in equine models under an investigator-initiated US Department of Defense grant. They're also testing one vector comprising both IL-1RA and PRG4 in rodent and equine models with osteoarthritis. There won't be a "magic bullet" for treating common diseases, which likely will require combination approaches, in Lee's view.
Lee said he's also interested in studying whether these gene therapies could treat rare skeletal dysplasias characterized by osteoarthritis, agnostic to their specific genetic mutations.
As GQ Bio and Pacira have continued to collaborate on PCRX-201, with GQ Bio developing a commercial-scale manufacturing process for the gene therapy, Pacira recently made moves to bring GQ Bio under its aegis. Last week, Pacira, which already had an equity stake in GQ Bio, acquired the remaining 81 percent equity stake in the company for $32 million.
The gene therapy space is a key part of Pacira's five-year plan, dubbed 5x30, which the firm announced earlier this year and that aims to transition the company into an "innovative biopharmaceutical organization." The plan includes priorities like becoming a leader in musculoskeletal pain management, growing product revenues by a double-digit compounded annual growth rate, and selling products to more than 3 million patients annually. Pacira anticipates the deal to acquire GQ Bio will provide near- and long-term financial benefits, in part because it will no longer have to pay milestone payments to GQ Bio, which could have totaled up to $64 million.
Guse said he will continue to lead GQ Bio after the acquisition, though the subsidiary's name may change, and he will lead preclinical gene therapy research at Pacira. "Because we had known Pacira already quite well, we believe that this acquisition is a great opportunity for GQ and the HCAd technology," Guse said in an email after the acquisition was announced. "We believe that together with Pacira we can bring the HCAd technology forward and get HCAd-based candidates faster into clinical trials."
Pacira did not respond to a request for comment on how GQ Bio and its employees will be integrated into the company, but in a public statement last week, said it intends to maintain GQ Bio's operations and highlighted that the acquisition would provide it with a gene therapy platform, preclinical portfolio, and R&D talent.
Also last week, Pacira said it recently opened patient enrollment within the randomized, controlled Phase II trial of PCRX-201, in which investigators will continue to study the low and middle doses included in the Phase I trial. Patients on these two doses had similar safety and efficacy signals. The company is expecting top-line data to read out from the first part of the Phase II trial late next year.
Not pursuing the high-dose therapy helps with cost-effectiveness, Jackson noted. High-capacity adenoviral vectors can also be manufactured at a relatively low cost per dose. "We need to make sure that we can price this therapy in a space where it makes sense for the osteoarthritis market," he said. While gene therapies for osteoarthritis could alleviate symptoms, the market dynamics for such treatments may not support the multi-million-dollar price tags for potentially curative gene therapies that patients with other serious, often rare diseases, have accepted.
In addition to monitoring pain management, Pacira is evaluating whether PCRX-201's mechanism makes it a disease-modifying therapy that could slow disease progression. "This will take much longer to see," Jackson said. "We're continuing to probe that."