Apazunersen

Ultragenyx had been flying high after its recent FDA approval for Genglycos—but the company has been brought back down to earth with a damaging phase 3 flop. The late-stage Aspire trial was assessing its investigational asset apazunersen in Angelman syndrome, a rare genetic condition that affects the nervous system and causes severe physical and learning disabilities. The trial was a bust. The drug missed its primary endpoint of change from baseline in Bayley-4 cognitive raw score, while also falling short in its secondary endpoint, which was net response on the Multidomain Responder Index, a measure of clinical function. The company did not give specific figures or a breakdown of the trial. The Ultragenyx executive team's statement on the failure was refreshingly honest, with no attempt to shine a positive light on the poor results. “Based on everything we observed in the robust Phase 1/2 clinical development program and long-term extension study, we are disappointed by the Aspire result,” said Emil Kakkis, M.D., Ph.D., chief executive officer and president of Ultragenyx, in a release. “Even more, we are disappointed for the global patient community who has invested so much in early-stage research, working to bring a first-ever treatment to their children.” The flop sent Ultragenyx shares down 43% after hours Wednesday evening on the news. The future of the drug remains in the balance with Ultragenyx saying that it's now looking over the apazunersen program “in light of this outcome and [will] make a decision on its disposition.” This has also prompted the biopharma to “assess its planned operations to define and implement significant expense reductions.” No further details on what these reductions will look like were shared. At time of publication, Ultragenyx had not responded to Fierce’s request for more information. Ultragenyx has before warned of “expense reductions”, which eventually led to 10% of its workforce being cut back in February. This came after a pair of failed late-stage brittle bone disease trials. The new phase 3 setback comes just two weeks after the FDA gave an accelerated go-ahead to pariglasgene brecaparvovec-opnr, Ultragenyx’s AAV gene therapy for the rare genetic disorder glycogen storage disease type Ia (GSDIa), under the name Genglycos. The company is also poised for the potential approval of another gene therapy, UX111, in Sanfilipo syndrome, with a PDUFA date just weeks away on September 19. Analysts at William Blair were “disappointed” by the apazunersen data but said they had always viewed the trial as “high risk, high reward.” The shop said it sees this failure as a negative read through for the separate Aurora study, which is assessing apazunersen in patients with Angelman syndrome across genotypes and age groups. “We believe that even if the Aurora study meets its primary endpoint, commercialization will be challenging given the limited size of the addressable population,” they added. There are currently no cures or approved disease-modifying treatments for Angelman. There are other companies working on the condition however, with Ionis one of the furthest along, having this summer completed enrolment in its phase 3 Reveal trial for RNA-targeted antisense asset obudanersen.

Dive Brief:Ultragenyx lost almost half its value Thursday after reporting the failure of a key experimental treatment for the rare condition known as Angelman syndrome.Known as GTX-102 or apazunersen, the therapy missed on both the primary and secondary endpoints in the study, Ultragenyx said Wednesday after the market closed. There were no differences between the treated and control groups that could support efficacy, it said.Ultragenyx now plans to evaluate the GTX-102 program and make a decision on its disposition. In the meantime, the company is looking for significant expense reductions as it focuses more on approved products and strives toward profitability in 2027.Dive Insight:Investors had eagerly anticipated the Phase 3 study in Angelman syndrome after the treatment showed promise in early research. While study failure announcements can include a glimmer of hope about a certain subgroup or future analysis, the language from Ultragenyx leaves very little room for an optimistic interpretation, Leerink Partners analyst Joseph Schwartz wrote in a note to clients.The setback may also have a ripple effect. Two companies Ionis Pharmaceuticals and Oak Hill Bio are developing Angelman therapies that work in a similar way. Ionis shares fell 4% in early trading Wednesday; Oak Hill cut a deal in July to go public by the end of the year. Still, multiple analysts believe those companies may see better results by offering higher doses or superior potency.Angelman is a rare neurogenetic disorder that causes issues in both the brain and body. Some patients cant walk, and most cant speak; they need care their whole lives. The condition has no approved treatment and a history of unsuccessful attempts by drugmakers hoping to bring the first therapy to market.For Ultragenyx, the study outcome fundamentally shifts the view of the company for investors, Schwartz wrote. Although Ultragenyx has five approved products including its first gene therapy as of August it has yet to achieve profitability. None of its marketed medications are poised for blockbuster status. And the companys latest plan to seek cost cuts comes after layoffs and a restructuring announced in February.While Ultragenyx has another therapy for a rare condition called Sanfilippo syndrome that may be approved in coming weeks, the potential doesnt match whats now lost with the Angelman treatment, analysts wrote. Some expect peak sales for that medication, UX111, to reach $120 million to around $240 million, compared with previous estimates of $1.8 billion or more for GTX-102.The investment case has changed shape, Schwartz wrote to clients. Ultragenyx is clearly now a commercial and expense story rather than a pipeline execution story. '