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 / urn:li:activity:7501404380412145https://www.linkedin.com/feed/update/urn:li:activity:7501404380412145665/665
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
CURE SYNGAP1 CONFERENCE — 86 DAYS
December 3–4 — Denver, Colorado https://www.cureSYNGAP1.org/Denver
Below is a transcript from the video:
[00:00:00] Hello SYNGAP land, my name is Mike Graglia of this episode 217 of the CURE SYNGAP1 podcast, and I’m only going to talk about ASOs today. Believe it or not, this is my fifth attempt at recording this episode because I have way too much content to get through. So I am going to really move quickly and point you to show notes because all of these thoughts go together, but cramming them into 10 minutes is just going to be tricky. Thought one, last week, Alexander disease, which is a terrible disease. It has a fatality rate, got FDA approval from a company named Ionis. Links in the show notes. Really exciting to see an antisense oligonucleotide, which is an ASO, which is a kind of medicine.
[00:00:36] Be approved for a rare disease, especially a rare disease like Alexander disease that has no treatment. Should we take this to mean that the CAMP4 ASO is gonna work because the Alexander disease ASO worked? Absolutely not, that would be crazy. Every ASO is different. Remember, an ASO is not a medicine, it is a category of medicines. It’s kind of like saying pills, tablets, gene therapies, ASOs. They’re just types of medicines. So that was on September 3rd that the Alexander community got that great news. Huge congratulations to them. Well done. The Angelman community the day before got the exact opposite news.
[00:01:09] And we should no more assume that we’re going to win because of the Alexander disease than assume we’re going to lose because of the Angelman disease. That’s the point I’m trying to make here. But I do want to really talk about the Angelman study, because there’s a lot to learn from this. And Angelman and SYNGAP are incredibly similar. I’d say aside from the aggression that our patients demonstrate, these diseases have a lot in common. So the company involved was Ultragenyx, and they announced, press release in the show notes, that they failed to meet both their primary endpoint, which was the Bayley-4 cognitive raw score, and their secondary endpoint, which is the Multidomain Responder Index, or MDRI, which measures five things.
[00:01:45] Why do you care about that? Because this was a phase three trial. Phase three trials are very big, very rigorous. They measure a lot of things. They have clinicians come in, measure the heck out of these patients. They collect all this data and no company launches a phase three trial if they don’t think it’s gonna work, right? So before they did phase three, just like CAMP4, they did a phase one, two, they gave drug to kids. They thought they saw improvements. The families thought they saw improvements. The clinicians thought they saw improvements. And they decided to spend millions of dollars doing this phase three trial in the hopes of getting this drug approved.
[00:02:11] And to quote a financial analyst, these are all publicly traded companies. They have smart financial analysts who do this work. Quote, a complete double miss with no data to argue about. In other words, absolutely didn’t work. We learned this from the placebo-controlled trial. Now, placebo-controlled trial. Let me interrupt myself to say, thank God we did a placebo-controlled trial, right? This is why the FDA insists on placebo.
[00:02:33] You have to give drug and not drug to a bunch of kids who otherwise have no idea that they’re getting drug and have clinicians analyze those kids and the clinicians have no idea who’s got drug so that we can get data and know for sure this is a drug worth giving to kids for a long time or this drug should not be approved and paid for, right? That’s what we learned from this trial. Other point I want to make is that if you’re an Angelman, right, if you’re in the Angelman community right now, you are incredibly sad to hear about this news because we’re human.
[00:02:59] But you’re incredibly grateful that there’s at least three companies working on trials for Angelman right now with ASO. Ultragenyx, who I’ve just talked about. Ionis, the same company from Alexander disease, is currently in their phase three. And Oak Hill Bio is starting or has started, I’m not quite sure, their phase three trial. So you’re really grateful that now that Ultragenyx is out of the race, at least for now, these other two companies are actively working on a different molecule with different biology to cure your disease. Really, really exciting. To go back to the financial analysis on the Angelman drug, same investment report, quote, we think the mechanism still works and the constraint was dose.
[00:03:38] I don’t really have time to jump into this, but I’m going to point you to a deck from Oak Hill Bio, a publicly traded company. Their investor decks are with the SEC. The link’s in the show notes, sec.gov, blah, blah, blah. Look at slide 10 and 11. In slide 10, they show you head-to-head that their drug did a better job than the Angelman drug. Sorry, it’s not head-to-head. In fact, they explicitly say this is not head-to-head. They took some Angelman data from, they took some Ultragenyx data about their drug and they did similar experiments and they said, look, we got better upregulation of UBE3A, which is the gene for Angelman.
[00:04:10] Angelman, they found the patients before the gene, so it’s called Angelman, but if it was comparable to us, it would be called UBE3A disease, whatever. Slide 11, they show that their drug was 20 to 100 times more potent. Why does potency matter? The ASO is delivered to the spine in a spinal tap. Spinal tap, very safe procedure. We’ve been doing it forever. Because we want the medicine in the brain and we don’t want to drill a hole in the skull, the only other place we can go is in the spine. So we do a spinal tap. We inject the medicine. Medicine goes to the brain. That’s how you treat these patients. Worked for SMA. Worked for Dravet. Worked for Alexander.
[00:04:39] We got the drug to the patients for Ultragenyx. We just didn’t get them enough. That’s what we’re saying here. Why didn’t we get them enough? Because if your drug isn’t potent enough, and this is why Oak Hill talked about potency, you’ve got to inject a lot into the spine. The spine is not meant to get huge injections. It can take small injections. And in fact, when they inject the medicine in, you know what they do? They stick the needle in, they take a little spinal fluid out, and they replace it with medicine just to keep the pressure. Very, very, very cool stuff. But for the Angelman drug, because they have potency, this is all hypothesis.
[00:05:05] There’s going to be a lot of unpacking this. They had to put in so much drug that at the beginning, it created issues in the spine and that created lower limb problems. The lower limb problems passed. It was all transitory. Don’t worry about it. But as a result of that, they were limited on dose. And because they didn’t give the kids enough medicine, that’s the hypothesis here, we think maybe that’s why the trial didn’t work. Don’t trust me. Trust Oak Hill. Look at the SEC document. Links in the show notes. So, super interesting, right? What we’re starting to appreciate here is the complexity around ASOs, right? You gotta think about so many moving parts. You gotta think about the biology you’re going after.
[00:05:43] You gotta think about the dosing. You gotta think about the clinical trial design. I’m gonna interrupt myself here. We need the best possible clinical trial design so that we, when our drugs go into patients with CAMP4 and with others, we are… understand the disease well enough that we know what to measure. That is why every single SYNGAP patient, responsible SYNGAP patient in the United States has signed up for Citizen and is sharing their data for Citizen and is trying to get into the PrOMMiS Natural History Study so we can measure as many kids as possible and design the best possible clinical trial. But really the big point here is this is why phase three matters, right? This is why we do placebo-controlled.
[00:06:20] You have to, at the end of the day, do a very large trial, dose a bunch of patients with drug, dose a bunch of patients with placebo, measure them both in the best way you know how, and figure out if you got the results you thought you were getting in phase one, two, right? So when you get recruited to a trial, don’t say, I don’t want to do it because I might get placebo. That’s just life. The only way we as a community are gonna get drug at the end of that trial is if people sign up and if they get placebo, they get placebo and if they get drug, they get drug.
[00:06:49] At the end of that trial, you will go on open-label extension and you will get drug until approval comes through. But my point is, placebo is essential so that we have a phase three trial that we can trust and that we know this drug works. Let’s give it to our kids, which is what the people in the Alexander community are saying today, versus this drug doesn’t work. Let’s not spend hundreds of thousands of dollars on it, which is what they’re saying in the Ultragenyx community, I mean, the Angelman community today.
[00:07:14] But they are still hoping and looking forward to hearing results from Oak Hill Bio and Ionis for their ASOs, which is why we in the SYNGAP community have worked so hard, by the way, to involve multiple companies. So we know that CAMP4 is starting. Stoke has had us on their pipeline for a long time. Praxis has had us on their pipeline for a long time. Hurry up, Praxis. I don’t know what’s taking you guys so long. And, you know. Who’s the other company who’s been public about it? GondolaBio, part of BridgeBio, has had us on their pipeline for a long time. There’s a lot we can learn about ASOs here. I need you guys to pay attention.
[00:07:43] One of the other questions I’ve gotten beyond placebo is Australia. Hey, why is CAMP4 going to Australia? Should I move to Australia? Answer, do not move to Australia. How come Australia was first? Why does CAMP4 like Australia better? It’s not CAMP4. It’s the entire pharmaceutical industry. And why does the entire pharmaceutical industry go to countries other than America? Because the American process for rare disease is utterly and completely broken. Don’t trust me. Read the New York Times article. The New York Times article uses cancer as an example. This makes sense. Cancer is much bigger than rare disease. They have a lot more money. There’s a lot more data points.
[00:08:15] But if you want to know where rare disease is going tomorrow, look at cancer today, right? That is what the takeaway is. You can read this entire New York Times article that feels like it’s about cancer, and it’s not. It’s about the FDA. It’s about trial design. Ignore the word cancer. Replace it with rare disease, you’re going to get the same answer. Everything in there is true. And what they basically say is because the FDA treats very large diseases, think obesity, think diabetes, think heart risk, whatever, heart disease, and very small diseases, think SYNGAP, think Angelman, think Alexander disease, the same, the same rigor, the same humps that you… hoops to jump through, all the things.
[00:08:50] They just make it too damn hard in a disease when we’re talking about hundreds and thousands of patients and really precise biological understanding, right? And so some countries have figured out that that doesn’t make sense and they have different rules for rare disease. Example, Australia. And that’s why companies go to Australia. So I have gotten this question countless times. Why is Australia in here? Why aren’t they coming here? Go read the New York Times article. It is excellent. I wish I had more time to talk about it, but I don’t. 10 minutes. I want to wrap this up by, again, acknowledging the Angelman community. We have learned a lot from them.
[00:09:21] We have cribbed their notes many, many times, and there is no shortage of incredible leaders there. Two of the leaders are Allyson Berent, who shared her thoughts on LinkedIn, and I put that link in the show notes, and Dr. Terry Jo Bichell, who is a legend and the head of COMBINEDBrain and somebody I’ve learned a lot from. I put her link in the show notes. Read those notes. It is an example of the grace and wisdom that you need to plow through trials and work with industry. We have events coming up, links in the show notes. Check them out. Thanks for listening. ASOs are important. They’re a big part of our story.
[00:09:53] Please read these articles in the show notes and let me know if you have questions.