As more and more gene therapies are approved, the elements that determine their success depend, increasingly, on the business decisions made early on.
As more and more gene therapies are approved, the elements that determine their success depend, increasingly, on the business decisions made early on.
“There is nuance to every program but, (across-the-board) the cost of production is a big challenge,” Mike Clayman, M.D., CEO and co-founder of Flexion, told BioSpace.
Flexion’s lead candidate, FX201 (humantakinogene hadenovec), is a case in point. This is an intra-articular gene therapy product for osteoarthritis (OA). It uses a helper-dependent adenovirus (HDAd) vector whose genetic construct – the payload – is a gene that expresses the interleukin-1 receptor antagonist (IL-1Ra) in the joint to control inflammation.
Inflammation is a known cause of pain, and chronic inflammation is believed to play a key role in the progression of OA, he explained.
“FX201 is taken up rapidly by cells lining the joint, converting them into factories to make IL-1Ra. It quells the inflammation and then turns off the gene construct,” Clayman said. It has the potential to provide long-term pain relief, functional improvement, and to actually delay the progression of the disease.
By injecting the product directly into the approximately 5 ml volume of the knee joint, he continued, “The absolute amount of protein you need to create an effective intra-articular concentration is far less than that which would be needed to achieve systemic therapeutic levels. That translates into what we expect will be much lower doses of FX201, which would reduce manufacturing cost and give us flexibility to charge a price that would still be proportional to value delivered.”
The product entered Phase I, a single ascending dose study, this year. Preclinical work suggests that once injected, there is no significant distribution outside the joint.
“It is a non-integrating, non-replicating vector,” Clayman said. “There is preclinical evidence that it delivers meaningful improvement for at least one year, with the slowing of disease progression.”
Company scientists believe a single injection FX201 has the potential to provide at least 6 to 12 months of pain relief and functional improvement in addition to possibly slowing disease progression, Clayman said. “We believe this product profile, if realized, would represent a transformative new treatment for knee OA.”
Currently, “Flexion is actively pursuing the possibility of identifying sub-populations of OA patients who may differentially benefit,” Clayman said.
The initial study is open broadly to OA patients to evaluate safety and tolerability. Once those data are analyzed, he said subsequent studies will consider and, if possible, incorporate biomarker, phenotypic or genotypic criteria to focus on a more restricted population.
“There may be a marker – perhaps a serum marker – to identify a patient subset that may most benefit from the therapy,” Clayman said. “With 15 million patients in the U.S. with knee symptoms of OA, and 8 million annual injections to relieve knee pain, it behooves companies to identify a focal population that can most benefit.”
But, he acknowledged, “The genetics of OA are very complex. It’s clearly a multigene disease with additional contributions from environmental and other external factors. It’s not as though there are clearly defined genetic subtypes of the disease.”
FX201 isn’t the first OA product Flexion has developed. Zilretta® (triamcinolone acetonide extended-release injectable suspension), an extended-release, intra-articular corticosteroid, was approved by the FDA in 2017 to relieve OA-related knee pain. In Phase III trials, it significantly reduced knee pain for 12 weeks and, for some patients, 16 weeks or more. Since approval, it has completed a Phase IIIb trial for synovitis.
Flexion also is developing FX301 (funapide, a selective sodium channel blocker, formulated in a thermosensitive gel) for acute post-operative pain.
“This isn’t a gene therapy,” Clayman said. This is a peripheral nerve block that is expected to enter the clinic in 2021. The preclinical data so far suggest it may durably prevent post-op pain while preserving motor function.
The FDA and EMA are up-to-speed on gene therapy now. At Clayman’s meetings with the FDA, “We had very robust scientific exchanges. I left impressed with the sophistication that was applied to the discussion.” The EMA was similarly sophisticated, he said.
Coincidentally, the criteria for RMAT designation – comparable to breakthrough designation for other products – illustrating the points for clinical conditions, used OA as the example.
“This indicates the FDA is thinking about creative approaches to complex diseases,” Clayman said. “If we have compelling data, we would not hesitate to pursue RMAT designation.”
Flexion already has begun its health economics and outcomes research, modeling this therapeutic in terms of its ability to delay the need for knee replacement (which costs $25,000 to $50,000), and quality of life.
Whether payers will reimburse for gene therapies often depends as much on the price as on delivered value.
“Our dose likely will give us manufacturing costs that will allow us to price FX201 much lower than a systemic therapy, which puts us in a better position,” Clayman said. Of course, “We still must generate compelling data.”
