Episode 218

#Angelman ASO Fails, #AlexanderDisease ASO Wins: #SYNGAP1 CAMP4 ASO? NYT on Clinical Trials #S10E217

Sep 6, 2026

9:57

Pharma & Biotech Angelman Syndrome Clinical Trials & Research Genetics & Genomics Rare Disease Regulatory Affairs

Episode Description

Sunday, September 6, 2026 — Week 36

🛑 If you're reading this on social media, these show notes are going to get cut off. Please go to the podcast homepage and click on episode 217 to get the full show notes. https://curesyngap1.org/podcasts/syngap10

ALEXANDER DISEASE

On September 3, the FDA approved ZANVASTRO — zilganersen — from Ionis (IONS) for Alexander disease.

It is the first FDA-approved treatment for Alexander disease and the first therapy to directly target the underlying protein buildup driving the disease. Alexander disease is caused by mutations in GFAP. Zilganersen reduces production of abnormal GFAP protein.

https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-alexander-disease

ANGELMAN — ULTRAGENYX ASPIRE FAILS

On September 2, Ultragenyx (RARE) announced results from its Phase 3 Aspire trial of apazunersen, formerly GTX-102, for Angelman syndrome.

The trial failed its primary endpoint — change from baseline in Bayley-4 cognitive raw score. It also failed its key secondary endpoint — the Multidomain Responder Index, or MDRI. And there were no differences between the treated and control groups supporting efficacy in Bayley cognition, the MDRI, or any of the five individual domains that make up the MDRI.

https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-phase-3-aspire-results-angelman-syndrome

WHAT HAPPENED?

Financial analyst take on the failure was brutal: “A complete double miss, with no data to argue about.”

But this does not conclude that the underlying Angelman ASO strategy has been disproven. Broader read-through: “We think the mechanism still works, and the constraint was dose.” GTX-102 had a history of transient lower-extremity weakness.

OAK HILL BIO (RACC) BASICALLY CALLED IT

(Good to have multiple shots on goal.)

Look at slides 10 and 11 of Oak Hill Bio's July investor presentation filed with the SEC.

Oak Hill had already been making the case that the Angelman ASOs are not interchangeable.

On slide 10, Oak Hill presents primate data showing nearly full restoration of paternal UBE3A production after a single dose of rugonersen, versus a much more modest reported effect from GTX-102. Importantly, Oak Hill itself notes that this was not a head-to-head study.

Then look at slide 11. Oak Hill presents data claiming rugonersen is 20–100 times more potent at inducing UBE3A protein than the other Phase 3 Angelman ASOs. And its description of the Ultragenyx molecule is remarkably direct: “GTX-102 was dose limited.”

These are Oak Hill's claims and company-presented preclinical data — but they made this argument before Aspire failed.

https://www.sec.gov/Archives/edgar/data/2118032/000119312526316954/d101725dex992.htm

THIS IS WHY PHASE 3 MATTERS

Ultragenyx had encouraging earlier-stage data. Families appeared to be seeing improvements. Investigators saw improvements. The company saw improvements. Then came a randomized, sham-controlled Phase 3 trial. And it did not confirm efficacy.

That is an important lesson for all of us in rare disease drug development:
Phase 1/2 data are not Phase 3 data.

THE NEW YORK TIMES — GETTING TO A CLINICAL TRIAL IS HARD

There was also a New York Times piece this week that I think everyone following drug development should read.

How extraordinarily difficult it has become to actually run clinical trials and get experimental medicines into patients.

That means companies are looking outside the United States for places where trials can move more efficiently.

CAMP4 has regulatory clearance to begin its first-in-human SYNGAP1 trial in Australia and Argentina.

That's not an accident. The geography of clinical drug development is changing.

The New York Times article is largely looking at this through the lens of cancer drug development today — but rare genetic disease is confronting the same challenges.

Cancer today → rare genetic disease tomorrow. — read this article.

NEW YORK TIMES — GIFT LINK:

https://www.nytimes.com/2026/09/04/opinion/clinical-trials-drugs-science.html?unlocked_article_code=1.-lA.gxCw.n2L6DEBVdtFd&smid=nytcore-ios-share

ANGELMAN COMMUNITY IS A MODEL

One more thing. A failed Phase 3 trial is devastating for a patient community.
AB https://www.linkedin.com/feed/update/urn:li:share:7501449189785022464/
TJB https://www.linkedin.com/feed/update/urn:li:activity:7501404380412145665/

UPCOMING EVENTS — COUNTDOWN

SCRAMBLE FOR SYNGAP — 27 DAYS

October 3 — Greer, South Carolina
5th Annual Scramble for Syngap https://cureSYNGAP1.org/Scramble

SHOOT FOR SYNGAP1 — 69 DAYS

November 14 — Hurricane, Utah
Aiming for a Cure — Shooting for Hope https://cureSYNGAP1.org/Shoot

FIGHT FOR FELIPE — 83 DAYS

November 28 — Boston, Massachusetts https://cureSYNGAP1.org/Fight