On February 28, 2023—which happened to be Rare Disease Day—the US Food and Drug Administration (FDA) approved Reata Pharmaceuticals’ omaveloxolone (Skyclarys™)—making it the first drug ever granted authorization to treat Friedreich ataxia (FA).
This landmark approval marked a bittersweet victory for Ron Bartek, founding president of the Friedreich’s Ataxia Research Alliance, also known as FARA. Bartek and his wife Raychel began the organization in 1998, a year after their son Keith was diagnosed with FA at 11 years old.
Keith died in 2010 at the age of 24, but the Barteks—through FARA—never stopped pushing for a cure for this rare progressive neuromuscular condition, which is believed to affect about 1 in 40,000 to 50,000 people of European origin. That translates into 15,000 to 20,000 people worldwide, including 5000 Americans.
“This is the first-ever treatment for our disease, and its significance is profound,” Bartek said in a recent interview. “According to the clinical trial data, it slows progression of FA by about 55%. This will give these young patients a couple more years of a high quality of life, and more ability to perform their activities of daily living.”
Bartek spoke to Rare Disease Advisor on the sidelines of the Muscular Dystrophy Association’s 2023 Clinical & Scientific Conference, which took place March 20-23, 2023, in Dallas, Texas.
Omaveloxolone, taken daily as a pill, contains a small molecule whose function is to activate the Nrf2 pathway, which Bartek said is counterintuitively driven down by patients’ low levels of frataxin protein.
“It should be driven up, because its active mechanism is to combat the oxidative stress that comes from low levels of frataxin protein. But because it’s counterintuitively reduced to activate it, this drug gives these patients the ability to compensate, or to begin to reduce that oxidative stress,” he explained.
Disease Burden Significantly Lessened
While omaveloxolone doesn’t cure FA, said Bartek, “it’s very exciting for the patient community to finally have a therapy” that lessens its burden to some degree.
“Skyclarys sets the bar as to what’s clinically meaningful,” he said. “I think patients would rather see, in the long run, hope for greater reversal of disease. But for now, this brings hope to families and patients who had no treatment at all.”
FA, first identified in 1863 by the German physician Nicholas Friedreich, is caused by a mutation on the frataxin gene which reduces production of the frataxin protein. About 95% of patients with FA have the guanine-adenine-adenine, or GAA, mutation of the frataxin gene on both alleles. The recessive trait disorder is generally diagnosed between the ages of 7 and 15, though some later-onset patients aren’t diagnosed until their 20s or 30s.
All told, it’s usually about 11 years from symptom onset to loss of ambulation, though for late-onset FA patients aged 24 and up, that progression takes about 25 years.
“Lack of coordination is the first symptom,” Bartek said. “It then extends to loss of vision, hearing and speech, then scoliosis or curvature of the spine, requiring implantation of metal rods to get and keep the spine straight, much‑increased risk of diabetes, and loss of strength in coordination in all four extremities, which means you’re in a wheelchair usually by your mid‑teens.”
FA patients have a shortened life expectancy and generally die by early adulthood due to congestive heart failure.
MDA: Omaveloxolone Approval ‘An Incredible Milestone’
FARA, headquartered in Downingtown, Pennsylvania, employs 18 people and operates on an annual budget of $9 million. Within a year of its establishment, the organization conducted the world’s first scientific conference on FA, and in 2001, it developed the first animal model.
Two years later, with funding from the Muscular Dystrophy Association (MDA), FARA launched a 5-site study to identify endpoints that would be needed to conduct later clinical trials.
“We have since grown that 5-site network to 15 sites that now constitute the Collaborative Clinical Research Network,” said Bartek, adding that these sites are located in the US, Canada, Australia, New Zealand, Brazil, and India.
“We’re now bringing all those natural history data together in one collection so that it can be even a more powerful tool to drive clinical trial design,” he said. “That kind of natural history data was absolutely essential in driving the FDA’s approval of Skyclarys.”
The FDA based its approval of omaveloxolone on “efficacy and safety data from the MOXIe part 2 trial and a post hoc propensity-matched analysis of the open-label MOXIe extension trial,” according to the MDA.
“This is an incredible milestone for the Friedreich ataxia community,” said Sharon Hesterlee, PhD, the MDA’s chief research officer. “Any therapy with the potential to alter the course of disease progression offers hope for this disease to so many families we serve.”
FARA Founder Says ‘Time Is Not on Our Side‘
The MOXIe trial involved just over 100 patients, while the open-label extension lasted 3 years and had 137 patients.
“In the final analysis, Reata was able to use our natural history database to closely match those 137 patients on [omaveloxolone] for 3 years, with patients out of the natural history study not on anything. It showed that their progression was 55% slower than those not on the drug,” he said.
“It slows the progression and just gives us more time,” Bartek said. “Time is not on our side. These patients are losing their abilities every day. This gives them a little longer while clinical trials are completed in other therapies, so that a combined cocktail therapy can be formed.”
Bartek added: “At the end of the day, it’s not going to be one‑and‑done for any one of these therapies. But we fully expect there to be a cocktail therapy that could include omaveloxolone even in the final analysis. There’s every reason to believe that this combination of therapies is going to get us very close to the cure.”
Bartek said he expects omaveloxolone to retail for about $375,000 per year. Funding for the drug will come from payers, insurance companies, and government payment plans, though he said the manufacturer, Reata, has been “very studious” about setting up a patient assistance program.
“Their pledge is that if you’re eligible for this therapy—meaning that you’ve got a confirmed FA analysis or a diagnosis, and you’re over 16—you will have access to this drug,” he said. “If you are uninsured or underinsured, they will make sure they give you the help you need to gain access to the treatment.”
