Gene therapies have set a high bar for outcomes in pharma by delivering curative treatments for difficult diseases in a one-and-done punch. But for Duchenne muscular dystrophy, the results of genetic innovation have been much murkier.
The market’s first breakthrough came in 2023 when Sarepta Therapeutics scored an FDA nod for Elevidys to treat non-ambulatory patients with DMD. A year later, the FDA broadened the therapy’s approval to include ambulatory patients with the muscle-wasting disease that primarily affects young boys and can be fatal. The expanded approval helped lift Elevidys sales above analyst expectations late last year.
Despite an upward sales trajectory, controversy also followed Elevidys. During its original approval process, six out of 14 members of an FDA advisory committee voted against Elevidys amid efficacy concerns. Months later, Sarepta reported that in a confirmatory phase 3 trial, Elevidys showed “meaningful” clinical outcomes on secondary endpoints but failed to hit its primary goal of beating a placebo on a common DMD motor function scale.
A failed phase 3 trial for a Pfizer treatment announced several months later cast more gloom over the gene therapy approach in DMD.
At the heart of DMD is the breakdown of the protein dystrophin, which protects muscle cells and is tied to a specific gene. Gene therapies deliver a variant of the gene dystrophin to help trigger the production of the natural protein. But because the DMD gene is so large, drug developers created a tiny version called microdystrophin that can fit into an adeno-viral vector. In theory, this gene replacement would impact the disease.
Yet, the results from Pfizer’s doomed phase 3 trial baffled scientists when it produced higher levels of microdystrophin but no clinical benefit compared to placebo.
Pfizer ultimately dropped the candidate last year, as concerns mounted that microdystrophin may not be a straight-forward solution to treating DMD or even the best biomarker to test efficacy. But other gene therapy developers targeting microdystrophin are pushing ahead with the belief that making a bigger impact for patients will come down to how the therapy is delivered.
Regenxbio’s potential breakthrough
With Pfizer no longer in the hunt, Regenxbio now has a clearer path to becoming Sarepta’s first competitor in the DMD gene therapy market. In November, the company announced that a phase 1/2 study for RGX-202 has been expanded into a pivotal trial as part of an accelerated approval plan with the FDA.
The therapy’s secret sauce is that it’s packaged in the company’s proprietary modified AAV vector — called a NAV vector — and includes a version of dystrophin that more closely approaches the real thing.
“Unlike every other gene therapy, we designed RGX-202 to include functional elements of the C-terminal domain because that is a key part of the protein function,” Dr. Steve Pakola, Regenxbio’s chief medical officer, explained. “So, our construct is closest to full-length dystrophin.”
Despite lingering questions regarding the use of dystrophin as an efficacy biomarker for DMD, Regenxbio will be able to leverage microdsytrophin levels as a primary endpoint to support accelerated approval, while scale-measured clinical outcomes will be secondary or exploratory goals.
Yet, Pakola said the company has shown consistent clinical benefits from the treatment and that it’s created a “wow effect” in the DMD world.
“This is a boy who went from not being able to ride a bike to being able to ride a bike for miles in New York City,” Pakola said of one patient. “This has created a lot of conviction in the DMD community that [RGX-202] is a next-generation gene therapy worth pursuing.”
Regenxbio expects results from the pivotal trial in 2026 — one of several upcoming tests of the microdystrophin approach.
Up next in DMD
Despite recent DMD breakthroughs, the uneven clinical outcomes have put patients and their families in a challenging spot.
In an op-ed published in Stat News, Michelle Werner, a CEO-partner at Flagship Pioneering and CEO of tRNA specialist Alltrna — who is also the mother of a son with DMD — discussed the difficulty patients face when deciding if they want to try a gene therapy formulated with adeno-associated virus vectors, a move that could make them ineligible for other AAV-based treatments down the road.
For those holding out, other candidates beyond Regenxbio’s therapy are on the horizon.
In its third-quarter earnings report, Solid Bio shared that it’s seen “encouraging early results” from an ongoing study for the microdystrophin gene therapy SGT-003. The company expanded enrollment criteria for the treatment and will continue dosing patients into this year before seeking an accelerated approval.
Insmed also gained clearance to begin dosing patients in a phase 1 trial of its DMD gene therapy. Like potential competitors, Insmed’s INS1201 delivers microdystrophin using an AAV vector, but for the first time, Insmed will test the therapy using intrathecal delivery directly into spinal fluid.
“That’s where we think the magic is,” Insmed CEO Will Lewis said.
Insmed plans to start a few patients in a dosing study with the ultimate goal of delivering the gene therapy in a way that's more effective and less toxic than others.
“A lot of gene therapies are delivered intravenously, and that goes through the liver, which cleans out a lot of the therapy … and then you’re not getting as much drug to the patient while also putting stress on the liver,” Lewis said.
While it’s much too early to determine if this delivery route will make microdystrophin-based therapies more transformative for patients, Lewis said the company is hoping their therapy will be in the realm of curative. With potential gene therapy game changers from Insmed and Regenxbio, Pakola sees a growing sense of optimism among researchers and patients in DMD.
“We are seeing light at the end of the tunnel, and they are, too,” he said.
