Obudanersen

iStock, Rocco-Herrmann Zanvastro, an antisense oligonucleotide therapy, represents the first independent neurology launch for Ionis Pharmaceuticals, which intends to leverage the foothold for more approvals in rare neurodegenerative diseases, including Angelman syndrome. Ionis Pharmaceuticals is set to launch its first independent neurology drug after the FDA signed off on Zanvastro, formerly zilganersen, as the first disease-modifying treatment for an ultrarare genetic condition called Alexander disease. The approval, which came more than two weeks before its Sept. 22 PDUFA date, is the first therapy to directly target the protein buildup that drives Alexander disease, or AxD. “For patients with Alexander disease and their families, there have been no approved treatment options—only supportive care while the disease progresses,” Emily Freilich, director of the Division of Neurology I in the FDA’s Center for Drug Evaluation and Research (CDER) said in a statement alongside the FDA’s announcement, adding that the approval is a “landmark moment” for the AxD community. Alexander disease is an extremely rare leukodystrophy, affecting as few as one in 3 million people worldwide. It is caused by changes in the GFAP gene that lead to its overproduction and toxic accumulation in glial cells in the central nervous system. Over time, this dysfunction can damage neurons and myelin, leading to symptoms including motor and cognitive dysfunction, a loss of independence and the inability to control muscles for swallowing, airway protection and purposeful movements. AxD can begin in childhood or later in life. In early onset cases, “You’ll have kiddos that are developing normally, then they begin to show symptoms, and then they’ll have a decline and a degeneration that happens, and it’s almost always fatal,” Holly Kordasiewicz, head of Development at Ionis, told BioSpace last month prior to the approval. “It’s a really tough disease.” An antisense oligonucleotide (ASO), Zanvastro works by binding to the RNA to decrease the body’s production of the GFAP protein, explained Amy Waldman, medical director of the Leukodystrophy Center and a pediatric neurologist at Children’s Hospital of Philadelphia. Zanvastro met the primary endpoint in Ionis’ pivotal Phase 3 trial, which tested the therapy in 49 patients who were at least 5 years old, according to Ionis. Participants given a 50-mg dose of Zanvastro saw statistically significant and clinically meaningful stabilization of gait speed as assessed by the 10-meter walk test—a commonly used measure of motor function in neurologic disease—compared to those received no treatment at week 61. “A flat line in a degenerative disease and not have that progression is really remarkable,” Kordasiewicz said. A separate open label substudy tested Zanvastro in four patients less than 2 years of age. As walking speed is not a “reliable measure of progress” in children this age, the FDA said, a broader motor skills assessment including standing, walking, running, and jumping was deployed. In this group, “children treated with Zanvastro showed improvement on this measure while those in the control group declined,” according to the release. Zanvastro is approved for patients of all ages with AxD. “To see improvement, that they’re allowing some of that neurodevelopment to happen in those earlier ages because we’ve stopped this, that was really exciting,” Kordasiewicz said. Despite the positive data, Waldman, who is the lead investigator on Ionis’ pivotal Phase 3 trial, offered a more subdued perspective. With rare leukodystrophies like AxD, she said, stability is the ultimate goal. “Families really want patients to improve, and they want something to be cured, and they want the brain to heal in the different ways,” she told BioSpace . “But really, stability is what we’re trying to do and slow down disease progression. We don’t expect to reverse permanent neurologic damage.” Approvals Ionis secures market expansion for Tryngolza as FDA clears severe hypertriglyceridemia use The approval of Ionis Pharmaceuticals’ Tryngolza for severe hypertriglyceridemia could spur “substantial growth” for the product, according to William Blair. June 25, 2026 · 2 min read · Tristan Manalac Read more A new chapter for Ionis Zanvastro is Ionis’ second independent launch this year, after the biotech notched what William Blair called a “major market expansion” in June for another ASO, Tryngolza , in severe hypertriglyceridemia. Tryngolza was initially approved in 2024 as the first treatment for familial chylomicronemia syndrome, a rare, life-threatening disease. Ionis has a deep history in neurology. In 2016, the biotech, along with Biogen, won approval for Spinraza, the first FDA‑approved treatment for spinal muscular atrophy. Then, in April 2023, the longtime partners secured the FDA’s nod for Qalsody , just the fourth-ever therapy for amyotrophic lateral sclerosis (ALS) and the first to treat a genetic form of the disease. “We’ve been in this space for a long time, but we haven’t launched any of our own medicines in neurology,” Kordasiewicz said. When Brett Monia took over as CEO in 2020, Ionis started to build and launch its own commercial products and building out a commercial infrastructure, she added. While the biotech had already accomplished this feat in the cardiovascular space with Tryngolza, Ionis had not yet secured that position in neurology—until Thursday. “This [approval] gives us a footprint in neurology out there in the community,” Kordasiewicz told BioSpace last month. The launch of Zanvastro will also help to prepare Ionis for independent neurology approvals to come, she added, including in Angelman syndrome, where the company is conducting the Phase 3 REVEAL study . Also an RNA-based therapy, obudanersen is designed to inhibit the expression of the UBE3A antisense transcript and increase production of UBE3A protein, whose function is lost in Angelman. Angelman syndrome is another rare, neurodegenerative disease—and a difficult one to target. Ultragenyx crashed on Thursday after reporting the previous day that its own ASO for the disease, apazunersen, failed to improve cognition in a Phase 3 trial. While Ionis shares were also down 3% in post-market trading on Wednesday following Ultragenyx’s announcement, William Blair expressed confidence in obudanersen, writing in a note to investors on Wednesday that Ionis’ Phase I/II HALOS trial results “leaves us confident that obudanersen could elicit signal in Angelman where insufficient dosing from apazunersen could not.” REVEAL is expected to read out in August 2027, per ClinicalTrials.gov. For now, Ionis—and the Alexander disease community—can celebrate a landmark win. Rare diseases Ultragenyx’s ‘high-risk’ Angelman bet fails, cratering stock and forcing strategic review The success of apazunersen in a Phase 3 trial for Angelman syndrome was a key driver of Ultragenyx’s value, according to William Blair, and the asset’s failure robs the biotech of any meaningful near-term milestones. September 3, 2026 · 2 min read · Tristan Manalac Read more

Investors' high hopes for Ultragenyx Pharmaceutical's experimental Angelman syndrome treatment came crashing down on Wednesday when the biotech disclosed that apazunersen (GTX-102) missed its primary and secondary endpoints in the Phase III Aspire trial. The late-stage study had been a make-or-break moment for Ultragenyx, and its failure sank the company's shares by about 45% during after-hours trade (see – Vital Signs: Ultragenyx preps for key ASO test).In patients with Angelman, the maternally inherited allele of the UBE3A gene is either missing or mutated; the paternal allele is naturally silenced by the antisense transcript UBE3A-AS. An intrathecally administered antisense oligonucleotide (ASO), apazunersen is designed to inhibit expression of UBE3A-AS — effectively silencing the silencer — to reactivate expression of the paternal allele and enabling production of the deficient protein.Ultragenyx is the first ASO developer to collect late-stage data in Angelman, though the findings could cast a pall on Ionis Pharmaceuticals' own UBE3A-AS–targeting ASO. It recently completed enrollment in the Phase III REVEAL trial of obudanersen (ION582), with a primary readout due next August. Ionis' shares dipped down about 3% after-hours on Wednesday. 'No difference' Ultragenyx reported that there were no differences between patients treated with apazunersen and the control groups in their change from baseline in Bayley-4 cognitive raw score, Aspire's primary endpoint. On the key secondary endpoint of net response in Multidomain Responder Index (MDRI), again there was no notable difference in results between the two groups that could support efficacy, the drugmaker said. Ultragenyx will evaluate its apazunersen programme "in light of this outcome and make a decision on its disposition," and will also pursue "significant expense reductions."The company already cut 10% of its workforce, or around 130 employees, earlier this year in an effort to reach profitability next year. Gene therapy pipelineThe disappointment in Angelman comes about two weeks after Ultragenyx scored its first FDA approval for one of its gene therapies. The US regulator last week granted accelerated approval to Genglycos (pariglasgene brecaparvovec-opnr) in adults and children eight years and older with glycogen storage disease type Ia (GSDIa) (see – Spotlight On: Ultragenyx sets $2.7 million price for newly approved GSDIa gene therapy).The biotech is also approaching a Sept. 19 PDUFA data for UX111 (rebisufligene etisparvovec) in Sanfilippo syndrome type A. The gene therapy, however, has been previously rejected by the FDA twice due to manufacturing concerns.