Gene therapies in the knee? With the help of a small herd of horses, a new startup hopes to crack osteoarthritis
Running preclinical animal studies in mice, rats and rabbits is par for the course in biotech, but horses? Usually too big and too expensive. But it turns out horses have one major advantage for musculoskeletal researchers: As large mammals, their knee joints are big enough to provide a meaningful comparison to human patients.
That’s why a new gene therapy startup out of Palo Alto, CA, dubbed Genascence, used more than 50 of the animals in an early test for its osteoarthritis candidate. Running tests on horses provided the earliest clues on structural improvement and pain reduction — horses don’t limp unless they’re feeling pain, CEO Thomas Chalberg tells me — that Genascence is now hoping to replicate for the first time in humans.
On Wednesday, Genascence uncloaked with early interim safety and tolerability data from that Phase I test of candidate GNSC-001, an AAV-delivered gene therapy containing the coding sequence for the IL-1 receptor antagonist. Developed on the back of science from co-founders Chris Evans, Steven Ghivizzani and Paul Robbins, the therapy looks to tamp down IL-1 signaling, a key driver of inflammation and cartilage destruction in patients with osteoarthritis, the company said.
In the nine-patient, three-cohort dose escalation study, just one patient posted a mild/moderate side effect on the therapy with no signs of neutropenia associated with systemic IL-1 antagonist therapy, the company said. Those results are good enough for Genascence to push its lead drug into a Phase II study, for which it has already filed its IND with the FDA’s backing.
The story of how Genascence came to be started back in 2004, with a pivotal paper from Evans describing the applicability of gene therapy for osteoarthritis in joints. It wasn’t a no-brainer pursuit, Chalberg said, as researchers at the time saw joints as “biology-free” targets
But the idea of a gene therapy for osteoarthritis wasn’t new. In fact, in July 2007, the field nearly came to a screeching halt. After a patient’s death following two doses of a therapy that encapsulated a molecule identical to Enbrel inside an AAV2 capsid, the FDA slammed a clinical hold on the study from a company named Targeted Genetics, according to a review Evans, Ghivizzani and Robbins later penned in Arthritis Research & Therapy.
Even before the death, eight patients in that Phase I study showed severe side effects, casting doubt both on whether the drug was adequately injected in the intra-articular space of the knee and whether a second dose of the therapy spurred a severe immune response. The post hoc results were inconclusive, but importantly the FDA later allowed the trial to resume, adding a big red flag but not killing the field’s chances altogether.
During his time at Pitt, Evans, now the director of the musculoskeletal gene therapy research laboratory at the Mayo Clinic, worked with both Ghivizzani and Robbins and were certainly aware of the setback. All three eventually moved on to other universities but stayed in contact with the idea.
With the goal of succeeding where others had failed, the three first tried their therapy in horses housed at the University of Florida, where Ghivizzani currently works. Chalberg, a Genentech vet and former CEO at Avalanche Biotechnologies before it merged with Annapurna to become Adverum, first heard of the concept in 2016 and was interested in the implications of taking gene therapies out of the field of monogenic rare disease and into broad disease areas, like immunology, where there are still big unmet needs.
“We sort of initiated a conversation at that point before the Phase I trial had started about setting up a company and bringing this project forward,” he said.
Osteoarthritis of the knee is a case in point. The most common therapies for the condition are acetaminophen, NSAIDs and steroids, Chalberg said, and don’t work very well for patients. Many patients progress to needing a knee replacement, which offers more complications later in life. Meanwhile, biologics haven’t provided much help as they rapidly clear out of the knee, and systemic therapy can be tied to serious side effects.
Using a localized gene therapy enclosed in the knee joint, meanwhile, offers the opportunity to use minuscule amounts of the AAV vector used to transport the therapy and prevent any “systemic leakage” into other tissues, Chalberg said. The Phase I data that Genascence will highlight at next week’s American Society of Gene & Cell Therapy meeting shows a manageable safety profile without systemic side effects. The study wasn’t powered to determine efficacy, Chalberg noted, but the Phase II test is expected to be controlled to draw some conclusions there.
Genascence is focusing its efforts primarily on GNSC-001 as it enters Phase II, but Chalberg said the biotech is thinking of ways to expand its pipeline into other osteoarthritis indications and beyond. The immediate next steps seem obvious — going after OA in the hips, hands and spine — but the possibility for other localized immunology therapeutic uses isn’t out of the question for a later focus.
“What we’re really interested in here is addressing the major unmet need,” Chalberg said. “We’ve so learned so much about these (AAV) vectors … over the last 20 years in the gene therapy field, but taking this into an area that’s not monogenic but still a major unmet need, we think there really may be something exciting to pursue.”
Editor’s Note: This story has been updated.