After Jenny Pearson’s daughter Elise first had a seizure at 16 months old, an MRI came back clean—her brain “looked beautiful,” Pearson recalled to Fierce. But a follow-up scan a year later, just days before Thanksgiving, showed her frontal lobe was now awash with white splotches. A genetic test the week before Christmas gave a troubling diagnosis: Alexander disease.
This was in 2014, and there was so little known about Alexander disease at the time that Pearson remembers being given an info sheet with just three sentences on it. She was told to expect Elise to live just three years.
“She wasn't even expected to make it through kindergarten, first grade,” Pearson said, as misshapen clumps of proteins were set to steadily build up in her brain and cause irreversible damage. “That diagnosis, it's like the ugliest snow globe you'll ever see because it's essentially like every bit of your DNA in your body gets shaken up, and where it settles is so much different than the person you were before.”
Pearson launched a nonprofit, Elise’s Corner, to raise funds for research into the ultrarare disease. And Elise hung on, trying between nine and 12 different therapies, until she could enter a clinical trial for a new drug from Ionis Pharmaceuticals called zilganersen, which just this week got commercial go-ahead in the U.S.
Zilganersen, an antisense oligonucleotide (ASO) that binds to the mutated GFAP gene that causes Alexander diseases’ deadly protein buildup, stopped Elise’s disease in its tracks, Pearson said. “The fog’s being lifted on her brain, and her personality gets a chance to come out more and more.”
While not a cure, many more children will now be able to access zilganersen. Yesterday, the FDA approved the drug as Zanvastro, the first ever medicine for Alexander disease.
“Today’s approval is a landmark moment for this community, offering the first therapy that addresses the underlying cause of this rare and serious disease,” Emily Freilich, M.D., director of the division of neurology in the FDA’s Center for Drug Evaluation and Research, said in the agency’s release.
Speaking to Fierce in advance of the FDA’s decision, Myles Minter, Ph.D., a biotech industry analyst with William Blair, said zilganersen’s approval was overwhelmingly likely.
“It's a breakthrough,” Minter said. “It's an ultra-orphan indication, but for the patients and the caregivers and the families that are unlucky enough to deal with this devastating disease, it's an option where there is nothing.”
For Ionis, this approval is meaningful not just for patients with Alexander disease: It also represents the company’s “first independent launch from our industry-leading neurology pipeline,” CEO Brett Monia, Ph.D., said in a release.
First of many
Ionis became involved in Alexander disease after connecting with Albee Messing, Ph.D., a neuroscientist at the University of Wisconsin in Madison, who was also in touch with Pearson.
“We were looking for additional targets and additional areas to go into,” Holly Kordasiewicz, Ph.D., Ionis’ chief development officer, told Fierce, following the success of other Biogen-partnered neuro ASOs like Spinraza for spinal muscular atrophy and Qalsody for amyotrophic lateral sclerosis.
Alexander disease was a perfect fit because there’s a clear genetic cause. The GFAP gene is overexpressed in astrocytes, support cells in the brain, which leads to an overproduction of protein that clumps together into toxic Rosenthal fibers. Targeting the mRNA blueprint made by the GFAP gene, then, should stop the disease from progressing.
“The preclinical data was just phenomenal,” Kordasiewicz said. “The animals got better. There was reversal of underlying pathology. You could see it as a pharmacodynamic biomarker. It had everything you could want from a drug development perspective.”
In 2021, Ionis launched a wide-ranging phase 1-3 trial of zilganersen in close collaboration with the FDA, using the disease’s first natural history study—which Pearson had earlier helped get off the ground—as a control arm. That trial hit its primary endpoint of improved mobility last fall, setting Ionis up for an approval push.
With Zanvastro now set to hit the market, Kordasiewicz said this is just the tip of the iceberg of Ionis’ plans for rare pediatric diseases. The company has a phase 3 program ongoing for Angelman syndrome, an indication where Ultragenyx just hit a major roadblock, along with other assets in development for Pelizaeus-Merzbacher disease, MECP2 duplication syndrome and Dravet syndrome.
Zanvastro’s approval “gives hope for all those other programs coming behind it and lets us start building the infrastructure to move those quickly and get those to patients too,” she said.
Building that infrastructure will also be helpful as Ionis eyes bigger and bigger indications, a model that the company is already pursuing in cardiology. Ionis launched its first solo drug, Tryngolza, back in 2024, and is now looking to get a slice of the juicy Lp(a) market in collaboration with Novarits.
If that team-up with the Swiss giant goes well, Ionis will be well-positioned to take next-gen Lp(a)-lowering drugs forward on its own, William Blair’s Minter said. A similar story could play out in Alzheimer’s disease, where Ionis is working with Biogen on a tau-targeting prospect that could ultimately become a gateway for a solo expedition into the massive indication.
Long-term, Minter sees the potential for Ionis to build into a bigger biotech player beyond its reputation as a “fantastic R&D powerhouse,” he told Fierce.
“Now that there's consistent royalty streams coming into the business, multiple deals creating collaborative revenue lines, they're over half a billion dollars on any given year coming in top line,” he said. “It's a bit of a different company.”
Ionis is now at the point, he added, where some investors may rue the wise-at-the-time decision to partner with Biogen on Spinraza and other bigger neuro drugs.
“Wouldn't it be great if you could get two billion plus in revenue from Spinraza every year instead of taking your mid-teens percentage royalties?” Minter posed. Still, the deal made sense at the time, and prevented Ionis from getting too big for its britches.
“For biotechs that are really trying to penetrate into massive markets here, it seems to be this stepwise progression,” he said.
As Ionis continues to grow and hit milestones, so too does Elise. Just a few days before Zanvastro’s approval, on Sept. 1, Elise celebrated her 15th birthday, though a prior fall prevented her from taking a beach vacation with the Ionis team as previously planned.
“Every day is a blessing that we have. She's not like normal 15-year-olds. She struggles in a lot of ways,” Pearson said. “She talks. She does her thing. She has a hilarious sense of humor. But for me, the fact that she's still with us and she's still doing as well as she is is the biggest blessing that I could ever receive in this world.”