This week, three developments highlight the rapidly changing rare disease treatment landscape: a Phase 3 setback in Angelman syndrome, continued competition in hereditary angioedema, and an FDA decision expanding access to a targeted lung cancer therapy.
Angelman Syndrome: Phase 3 Trial Misses Its Marks
Ultragenyx announced results from its Phase 3 Aspire study of apazunersen in Angelman syndrome. The trial did not meet its primary or key secondary endpoints.
Angelman syndrome is a rare neurodevelopmental disorder caused by the loss of a working copy of the UBE3A gene. Patients generally have a normal lifespan but can experience significant cognitive and motor impairments requiring extensive lifelong care.
Apazunersen is designed to activate the healthy paternal copy of UBE3A, providing neurons with another potential source of the missing protein. The approach is based on a promising biological strategy that has been explored successfully in other genetic diseases, such as spinal muscular atrophy.
However, the ASPIRE trial results did not demonstrate a statistically significant change in either the primary or secondary outcomes. Ultragenyx said it was disappointed, particularly given encouraging earlier-stage results. The company will now evaluate the data and determine whether there is a path forward for the program.
The results underscore one of the challenges of rare disease drug development: promising early-stage findings do not always translate into success in larger, controlled Phase 3 trials.
HAE: Treatment Options Continue to Expand
The treatment landscape for hereditary angioedema (HAE) continues to grow.
HAE is a rare genetic disorder that causes recurrent attacks of swelling, which can affect the skin, gastrointestinal tract, or airway. Treatment includes on-demand therapies for acute attacks and prophylactic therapies designed to prevent them.
There are currently 11 approved HAE treatments, with additional therapies in development. Those in development include Pharvaris’ deucrictibant, which is an oral therapy under FDA review for acute HAE attacks, with a PDUFA date expected in April 2027. The company is also developing a longer-acting formulation of the drug for prophylaxis and has reported positive Phase 3 results.
The growing competition reflects how the HAE market has evolved. Companies are now competing not only on efficacy, but also on convenience, dosing frequency, mechanism of action, and route of administration.
It also illustrates a broader rare disease trend: once the underlying biology of a disease is understood and a therapeutic target is validated, additional treatments can follow—creating more options for patients.
Targeted Lung Cancer Therapy Moves to First-Line Treatment
The FDA has expanded the indications of sevabertinib (Hyrnuo) to include first-line treatment for advanced or metastatic non-small cell lung cancer with specific HER2 mutations.
While lung cancer is common, these molecularly defined patient populations can be relatively rare. HER2-mutated tumors account for a small percentage of NSCLC cases and occur more frequently in people who have never smoked.
Hyrnuo was initially approved in November 2025 as a second-line treatment. The new approval allows eligible patients to receive it earlier in their treatment.
The decision also uses the FDA’s accelerated approval pathway, which can allow therapies to reach patients based on earlier measures of potential benefit while confirmatory studies are underway.
Bayer is conducting a Phase 3 trial, SOHO-02, comparing sevabertinib with standard therapy in the first-line setting. Those results will help determine whether the drug ultimately becomes a standard treatment for this patient population.
Looking Ahead
Two additional FDA decisions are expected September 19.
Ultragenyx’s UX111 for MPS IIIA, or Sanfilippo syndrome type A, and IntraBio’s Aqneursa for ataxia-telangiectasia both have PDUFA dates that day.
The decisions will be closely watched by patients, families, physicians, and the broader rare disease community.
The CheckRare Brief will continue to follow these developments and connect the dots across the rare disease landscape.
References
Ultragenyx Announces Phase 3 Aspire Results in Angelman Syndrome
New HAE Drugs for Acute and Prophylactic Therapies
https://firstwordpharma.com/story/7961829
FDA Grants Accelerated Approval to Sevabertinib for Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer