uniQure Files Huntington's Gene Therapy — FDA Reversed Twice Already

The FDA spent most of last year telling uniQure its Huntington's data wasn't fileable. This morning uniQure filed it anyway — with the agency's blessing, and an action date in spring of 2027.

The same day, the other rare-disease readout went the other way. Ultragenyx's Phase 3 in Angelman syndrome missed, and the cost cuts were in the same press release. Akeso says its bispecific beat pembrolizumab on overall survival in first-line lung cancer, without publishing a single number. And newly released memos show a CBER official overruled her own review team to approve Replimune's melanoma drug. Busy Wednesday. Let's get into it.

I'm Alex Mercer.

And I'm Maya Patel.

So, uniQure. The BLA went in this morning for AMT-130, its Huntington's gene therapy, with a parallel application to the MHRA in the UK. Priority review requested — sixty days of filing review, then a six-month clock, which lands an action date for potential accelerated approval in late April or early May of 2027. The company says approval would make this the first genetic treatment for Huntington's disease.

And the remarkable part isn't the molecule. It's the agency. In February, then-Commissioner Makary went on CNBC and described researchers drilling a burr hole in patients' skulls and finding no benefit. He didn't name the product. Nobody had to guess.

And four months later he was gone. Prasad too.

And the agency reversed itself again — same dataset, opposite answer.

The evidence never moved. The chairs did.

Which is why I'd read the filing as sturdier than the last twelve months suggest, but only on the science. That external control is the entire argument, and William Blair pointed out this morning that the design lines up with the FDA's own plausible-mechanism pathway paper and its draft guidance on gene therapies for small populations — which explicitly allows external controls in certain contexts.

So I'd call this substantially de-risked. Same data, an agency that's now endorsed the approach twice, and a design that matches the FDA's own published thinking. That's about as clean a setup as a controversial filing gets.

That's the framing I'd push on. Nothing about the science got safer between February and today, and William Blair didn't say it did — their note this morning explicitly kept regulatory risk on the table, because leadership at the agency keeps turning over. You can model a survival curve. You cannot model a personnel file.

All right, I'll take that — it changes the category of risk, not the amount.

It reclassifies it entirely, and that matters for every sponsor watching this. Clinical risk you retire with data. Governance risk you can only wait out. The external-control precedent here is real and usable today — and its shelf life is exactly as long as the tenure of the people who granted it.

The competitive read: if you're running strategy anywhere in gene therapy, the analyst language is the tell. William Blair is forecasting a measured launch because AMT-130 requires surgically guided administration, and even with that constraint they model peak global sales around three point two billion dollars in 2035, calling it a potential first- and best-in-class treatment. That's a capacity-limited asset, not a volume story — you win it by building surgical centers, not sales forces. And the open question sitting underneath all of it is whether an agency that has changed its mind twice on this exact dataset can hold one position through April.

Akeso reported at five o'clock this afternoon, out of Hong Kong, and it's the pipeline story of the day. Its PD-1 by VEGF bispecific, ivonescimab, met overall survival against pembrolizumab in HARMONi-2. That's first-line, PD-L1-positive non-small cell lung cancer — randomized, double-blind, head to head. Statistically significant and clinically meaningful at the interim analysis, in the company's words. The field has been waiting on that survival endpoint since the progression-free result more than two years ago.

There's no hazard ratio in that release.

The progression-free numbers from May of 2024 were eleven point one four months against five point eight two months. If survival tracks anywhere near that, this is a head-to-head survival win over Keytruda in its biggest indication.

It's also a trial run in China, against pembrolizumab alone, in PD-L1-positive patients. Every one of those qualifiers is doing work. The company's phrase, statistically significant and clinically meaningful, is a sentence, not a result — no medians, no patient count, and the data go to a conference and a journal later. The US question runs through Summit Therapeutics, Akeso's partner for the US and Europe, and through HARMONi-3, the all-comers study against pembrolizumab plus chemotherapy. That's the trial that decides whether this is a Keytruda story or a China story.

Merck's answer to the Keytruda cliff has been to build on top of Keytruda — combinations, a subcutaneous version. Ivonescimab argues for replacing it instead, and every PD-1 franchise plan in the industry now has to model around a survival win nobody can see. Tonight's release is Pharma Theatre. The superlatives arrived. The numbers didn't.

Until the medians and the curve are public, Akeso has an endpoint, not a magnitude. Magnitude is the thing every one of those franchise plans actually needs.

Staying in the pipeline — Teva's anti-IL-15 antibody, TEV four-oh-eight, hit its primary endpoint in a fifty-patient Phase 2a in celiac disease. One subcutaneous dose, then six weeks of daily gluten, and the treated arm showed significantly less intestinal damage on biopsy than placebo. Teva calls it pipeline-in-a-product — a Phase 2b in vitiligo is already moving, with up to five hundred million dollars of Royalty Pharma funding behind the program.

Fifty patients and one dose. The treatment difference on the biopsy endpoint is zero point four five, with a confidence interval that starts at zero point zero six. Real signal, no answer yet on dosing or durability — and the release says additional analyses are underway. Pipeline-in-a-product is a platform claim, and that's where the Second-Asset Test applies. Celiac is the one asset. Vitiligo is where we find out whether there's an engine underneath it.

Shifting to the deal side — Alteogen and Novartis. Novartis takes multiple options to obtain exclusive rights to develop and commercialize subcutaneous formulations across multiple products using ALT-B4, berahyaluronidase alfa, from Alteogen's Hybrozyme platform. Exercise everything, hit everything, and Alteogen is eligible for up to three point two two three billion dollars, plus royalties.

Fourth licensing deal Alteogen has signed this year.

Which reads as validation to me.

It reads as validation and as hedging, and the second half is the one nobody says out loud. Every dollar in that headline is contingent — option fees, development milestones, commercial milestones. Novartis bought the right to decide later, product by product, which tells you they haven't settled on which IV franchises actually need converting.

Fair. And what would change your read?

Which products get named. Because when the same enabling enzyme shows up in four portfolios inside a single year, subcutaneous conversion stops being a differentiator any one company can defend and starts being shared infrastructure everybody rents.

And that flips the lifecycle math. If you're modeling the back half of an IV biologic, the subcutaneous version isn't a moat you build anymore — it's a toll you pay, and your competitor is paying it to the same vendor on the same terms.

On the regulatory side, the counterweight to this morning's filing arrived from Novato later the same day. Ultragenyx's Phase 3 Aspire study of apazunersen in Angelman syndrome missed its primary endpoint, change from baseline in the Bayley-4 cognitive score. It missed the key secondary as well, net response on the Multidomain Responder Index. Safety was consistent with the earlier Phase 1/2 studies. The efficacy wasn't there.

Clean safety, no efficacy — nothing to salvage.

Which is why I wouldn't read today as proof that the pathway works, or proof that it doesn't. Apazunersen had open-label early data that looked meaningful. So does AMT-130. One of them ran into a controlled study today, and it didn't hold up. The read-through for anyone modeling accelerated approval on a single-arm dataset isn't that external controls are dangerous. It's that the confirmatory study is where the program actually gets decided.

uniQure filed on an external control because a randomized trial in Huntington's is close to impossible. Ultragenyx ran the randomized, controlled Phase 3 the field keeps asking for, and the answer was no. And the pivot is already explicit. A program review and significant expense reductions in the same press release. Commercial business first, profitability targeted in 2027, and a pipeline that just lost its largest neurology bet.

One policy item before we close the segment. The White House added nine more manufacturers to its most-favored-nation pricing agreements on Monday — Alcon, Astellas, BeOne, BridgeBio, CSL, Kyowa Kirin, Sun Pharma, Teva and UCB. That takes the program to twenty-six companies and, by the administration's count, eighty-nine percent of the branded market. What the nine committed to is Medicaid access at MFN prices, and MFN pricing on new launches. Plus a collective pledge of at least nineteen point six billion dollars in US manufacturing.

Nine more names. Two of them mid-caps.

Medicaid access is the headline concession, and Medicaid was already the floor of the US price ladder. Which is why the read on this round is a shrug.

And what's not in the fact sheet matters more than what is. STAT's read is that the deal terms are undisclosed. The open question for every one of those nine is whether signing buys them out of tariffs or the mandatory Medicare pilots. BridgeBio and BeOne are the tell. This is the clearest sign yet that the program has reached below big pharma. The price of admission looks like a Medicaid concession most of them could afford.

The real question isn't twenty-six companies. It's whether the next round names Medicare.

Quick note before our second story — if The Pharma Closeout is how you close out your pharma day, follow the show on Spotify or Apple Podcasts. Endpoints reported this morning on newly released memos showing Asha Das, director of the FDA biologics center's office of clinical evaluation, overruled the agency's own review team to grant accelerated approval to Replimune's melanoma drug, Tudriqev. The reviewers said no. The office director said yes. The drug is approved.

And it's the second consecutive high-profile override at that center. One override is a judgment call in a system built to allow judgment calls. Two in a row, both here, both now sitting in memos anyone can read — that's a posture.

And the memos being public is the new part.

It changes who's planning around it. Sponsors now have to guess which standard their application gets measured against, and the review divisions have to work knowing their recommendation is a step in the process rather than the end of it. And this is landing the same week uniQure's application walks into that same center. For AMT-130 the question stops being whether the data clears the bar. It's which bar — and whose signature is under it in April.

Looking ahead — the first real checkpoint on uniQure is that sixty-day filing review. Acceptance, and whether priority review gets granted, is the gate that sets the late-April-to-early-May action date. Everything else on this program is noise until that letter arrives.

Three slower threads. Akeso's full HARMONi-2 survival data at that conference, where the hazard ratio is the whole story. Ultragenyx's disposition decision on apazunersen, and how deep the expense reductions go. And whether additional CBER memos surface, because two documented overrides is a pattern, and a third would make it a policy.

The next sixty days aren't really about Huntington's. They're about whether this agency's accelerated-approval posture is a policy or a personality — and every small-population program in the industry finds out at the same moment uniQure does. Ultragenyx just found out what the other answer costs.

The document I'll be watching for is the acceptance letter. It's the quietest thing in this story and it sets the entire 2027 calendar. Have a good evening.

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