Regenxbio’s gene therapy for Duchenne muscular dystrophy has smashed the primary endpoint of its pivotal trial, securing a win for a biotech that has struggled in recent months under the weight of a rejection and clinical hold from the FDA.
Twelve weeks after receiving RGX-202, which contains a truncated version of the dystrophin gene wrapped in a viral shell, 28 of 30 patients in Regenxbio's phase 3 trial had levels of the gene’s protein product at or above 10% of a healthy control. The average level of the protein across all patients was 71.1% after treatment, the company reported on May 14.
Regenxbio wanted to differentiate RGX-202 from competitor Sarepta Therapeutics’ approved gene therapy Elevidys in terms of protein expression, safety and functional outcomes, the biotech’s Chief Medical Officer, Steve Pakola, M.D., told Fierce Biotech.
“That's what's panned out,” he said. “We couldn’t hope for more.”
Patients with DMD lack dystrophin, a vital protein that helps keep muscle structurally intact. Primarily found in boys, the lack of dystrophin in DMD leads to progressively worsening muscle function that robs children of their movement and eventually ends in a shortened lifespan.
Because the dystrophin gene is so large, Regenxbio’s approach, similar to that of Sarepta’s Elevidys, is to deliver an abbreviated version of the gene that makes a smaller dystrophin protein. RGX-202 leads to higher levels of microdystrophin across the board compared to Elevidys, including in older boys aged eight and up.
“Elevidys, in eight and above ambulatory boys, the reported microdystrophin expression levels are 12%,” Pakola said. At 41.6%, RGX-202’s expression in this group “is easily over threefold that.”
Elevidys has also been dogged by concerns of liver toxicity after several patient deaths. Here, too, RGX-202 has an edge, Pakola said. Regenxbio saw one patient out of 31 develop severe liver injury, a rate just above 3%; Elevidys, in contrast, has reported liver injury rates of about 40%.
“We're really pleased with the safety profile and clearly differentiating from existing therapy,” Pakola said.
Regenxbio has also shown a strong correlation between microdystrophin expression and positive physical outcomes. Nine boys treated with RGX-202 posted higher scores on multiple measures of muscle function, like time to stand and time to run and walk, compared to what would be expected based on the disease’s natural history.
This correlation hasn’t been seen with Elevidys, which Pakola said likely comes down to the fact that not all microdystrophin is created equally.
“Our goal was to not just have any microdystrophin, but one that contains the key functional elements of dystrophin,” he said, especially a region of the protein called the C-terminal domain. He thinks this tight relationship between microdystrophin expression and physical improvements will be compelling to the FDA as Regenxbio pursues accelerated approval.
The exact timing of when the company plans to bring the new data to regulators is a bit in flux, Pakola said, because of all the leadership turmoil currently swirling around the agency. FDA Commissioner Marty Makary, M.D., recently resigned from his post, while top gene therapy regulator Vinay Prasad, M.D., also left the agency not too long ago.
“Obviously, it's kind of a pretty dynamic time at the FDA,” Pakola said, so Regenxbio will make plans to approach the agency about RGX-202 “as dust settles.”
Even stronger than the functional data are home videos shared with Regenxbio of patients who received RGX-202, some of which were viewed by Fierce. They show young boys jumping up off the ground, racing up the stairs and even bouncing on a trampoline.
While formal tests of muscle function can feel more abstract, Pakola said, “when you see a child actually being able to climb their home stairs, it kind of strikes home.”
The DMD win comes at a crucial time for Regenxbio, which recently faced a rejection for its Hunter syndrome gene therapy candidate, RGX-121. Part of the FDA’s issue with RGX-121 was the use of a natural history control arm, which the company is also using for its DMD trial.
But the DMD situation is very different from Hunter syndrome, Pakola explained, because DMD has much more data. This allows for an “apples to apples” comparison between patients in the RGX-202 trial and boys with DMD who no receive treatment.
Just before its rejection, RGX-121 was also hit by a clinical hold in January due to a brain tumor reported in a child treated with a different Regenxbio gene therapy, for a related disease called Hurler syndrome. On Wednesday, scientists confirmed that the boy’s tumor was caused by the viral vector integrating its DNA into a known cancer-causing gene.
The boy’s tumor was successfully removed after it was found, and he is now showing levels of cognitive function greater than what would be expected at his age, the scientists reported.
DNA integration from a viral vector has long been a known theoretical risk of gene therapy.
The paper is “very consistent with what we've reported before,” Pakola said. “Fortunately, the boy is doing well,” he added, and he “continues to be advanced for age.”
Regenxbio also announced today that the hold on RGX-121 has been lifted, while one remains in place for RGX-111. The biotech still plans to pursue an accelerated approval for RGX-121, Pakola told Fierce, using longer-term data to address the agency’s concerns.
Some options the FDA proposed to address the rejection, like running a new placebo-controlled trial, “aren’t realistic,” Pakola said. But the agency also included longer-term follow-up data as an option, which Regenxbio already has in hand since the February rejection.
Discussions about RGX-121, though, will have to wait until the FDA sorts out its leadership situation, the CMO added.