FDA approval: 160% Upside (at $26.65)
This idea was shared by Marko.
uniQure is developing a treatment for Huntington’s disease. After exceptionally positive Phase 1/2 results, the company pursued accelerated drug approval from FDA. Regulators had previously agreed with the trial design and indicated it will be sufficient for the BLA application. In November 2025, FDA walked back that guidance causing QURE to plunge by 60%. The agency appears to be concerned that QURE did not use a placebo group and instead relied on historical external control data. Both parties are now in discussions, and if a timely solution to the design concerns can be found, the stock will be worth much more than it is today.
At a first glance, this might look like a standard gamble on FDA drug approval. However, it’s actually quite different:
- We already know that the drug works. Efficacy and safety have been proven, and the results turned out even better than expected. Experts are calling it “groundbreaking”. FDA does not seem be concerned with the efficacy or safety of the drug.
- The price target is clear. The stock traded at $70 (160% upside) when the market thought BLA submission was imminent.
- The key question is whether the company and FDA find common ground on trial design? This is fundamentally different from a bet on whether a drug is effective or safe.
- The agency had already blessed this exact trial design before the recent U-turn.
- There’s strong pressure from patient advocates and physicians pushing the FDA to bring the medicine to the market, which increases the odds of bringing the agency back on board.
- A couple recent precedents suggest the issue is solvable.
The market is pricing in 75% chance that QURE will be forced to conduct a long and expensive Phase 3 trial. That feels overly pessimistic, and creates an asymmetric opportunity: 160% upside versus 55% downside. The situation should play out in a month or so. Even a small position can generate a meaningful portfolio impact if the case works out favorably.
I view common stock as the simplest way to get exposure. Call options are available, but the bid-ask spreads are uncomfortably wide and implied volatility is running above 100%. That makes them unattractive, at least to me. From experience, these cases often take longer than anticipated, creating a risk of options expiring worthless and investors not getting paid anything despite being right on the case.
The situation
QURE is a biopharma company with a commercialized hemophilia B treatment and a portfolio of drugs in development. The flagship asset in development is AMT-130, a gene therapy for Huntington’s disease (HD). HD is a devastating genetic neurodegenerative disorder that causes brain neurons to gradually break down and die, typically proving fatal within 15-20 years of onset. No treatment currently exists, and roughly 40,000 people in the U.S. live with the disease. AMT-130 has legitimate blockbuster potential, with some analysts projecting $3-5 billion in peak sales.
In September 2025, QURE reported exceptionally positive Phase 1/2 results for AMT-130, showing a 75% slowdown in disease progression. The NfL biomarker (a protein that measures neuronal damage) dropped 8.2% from baseline in treated patients versus a typical 10%-15% annual increase in untreated patients, further confirming efficacy. Multiple experts called the results “groundbreaking.”
This breakthrough gene therapy for Huntington’s disease represents a historic advance in neurodegenerative medicine. The data revealing a 75% slowing of clinical progression over three years is unprecedented and genuinely transformative, as it targets the disease’s root cause. Current therapies mainly manage symptoms like movement difficulties and mood changes but do not alter disease progression.
QURE’s share price skyrocketed from $14 to $50, and the company capitalized on the momentum with an oversubscribed equity raise at $46/share. By late October, the stock price hit $70/share ($4.4 billion market cap).
QURE was pursuing accelerated approval pathway, planning to file a Biologics License Application (BLA) for AMT-130 in early 2026. The application was supposed to rely solely on Phase 1/2 data, avoiding a large, time consuming, and expensive Phase 3 study. The FDA sometimes permits this for drugs targeting life-threatening diseases that have no or only very limited treatment options. AMT-130 had already secured orphan drug, regenerative medicine advanced therapy, and fast track designations that facilitated this pathway. The agency had further confirmed to QURE a number of times that using external control data (historical patient records and disease progression from databases) instead of a placebo group would be enough for the accelerated approval. From December 2024 update:
U.S. Food and Drug Administration (FDA) agrees that data from ongoing Phase I/II studies compared to a natural history external control may serve as the primary basis for a Biologics License Application (BLA) for Accelerated Approval.
On November 3, QURE shocked the market by announcing that in a pre-BLA meeting, regulators had suddenly reversed course. The FDA apparently no longer thought that trial data comparison to external control group alone was enough to provide evidence in support of a BLA submission.
The reversal in FDA’s oppinion came just months after Vinay Prasad took over as head of the Center for Biologics Evaluation & Research (CBER), which oversees BLA approvals. Prasad, appointed in May, has been a vocal critic of accelerated approvals.
QURE has now scheduled a Type A meeting with the FDA to clarify the agency’s position. Given that the treatment’s efficacy appears solid already, management’s objective is to identify a path forward that avoids a lengthy and expensive Phase 3 trial. That could mean conducting additional analyses of the existing dataset, potentially supplemented with more external data, etc.
Management has committed to providing an update once the official meeting minutes are received. The Type A meeting was announced on January 9. These meetings are typically held within 30 days, with minutes issued within further 30 days. By early March at the latest, investors should have clearer visibility into the regulators’ thinking.
Arguments in favor of finding the common ground
One of the more obvious arguments in QURE’s favor, and likely one reason the FDA was previously open to the use of external control data, is the practical and ethical challenge of running a traditional placebo arm for AMT-130.
AMT-130 is not a simple pill or intravenous injection. The treatment requires brain neurosurgery, including drilling into the skull and delivering the therapy directly into specific regions of the brain. Asking a large group of patients to undergo that procedure only to receive a sham treatment with no therapeutic benefit raises serious ethical concerns. This makes the use of external controls quite defensible.
Another important argument is that AMT-130 showed NfL dropping by 8% from baseline over three years in high-dose patients. NfL is a structural protein inside neurons. When neurons are injured or dying, NfL leaks into spinal fluid and blood. In early HD patients, NfL typically increases 10% to 15% annually. In this case, each patient serves as their own control – it’s not so important against which group you compare the results, placebo or external. The fact that AMT-130 showed NfL reduction suggests neuronal damage was limited, so the drug is working.
On November 12, just a week after u-turn on QURE’s AMT-130, Vinay Prasad, and the FDA Commissioner Martin Makary, unveiled a new regulatory approval alternative called “plausible mechanism pathway”. The goal of this pathway is to accelerate development of cell and gene therapies for rare diseases, particularly where traditional randomized, placebo-controlled trials are impractical.
Under this framework, regulators will be open to consider alternative evidentiary approaches, including patients histories serving as their own controls as well as the use of data from disease registries or other external sources. In other words, the agency is publicly acknowledging that for certain rare genetic conditions, the conventional Phase 3 trial with a control arm may not always be the right tool.
The new approval pathway for bespoke treatments is expected to become available later this year. And while this does not apply to AMT-130 directly, the broader point is that FDA is actively constructing more flexible approval routes for rare gene therapies and explicitly endorsing methods that rely on intra-patient comparisons and external datasets. Yet it has just reversed course on AMT-130, which relied on a similar evidentiary logic, at least in part because having a placebo group would be hardly justifiable.
At a minimum, the contradiction suggests the FDA likely isn’t locked into a hardline position on QURE’s trial design. A workable solution might be closer than it looks. From FierceBiotech:
Health officials including FDA Commissioner Makary and Center for Biologics Evaluation and Research Director Prasad have openly voiced support for the development of novel cell and gene therapies. However, several recent negative FDA decisions have put a damper on optimism in the field. The new pathway represents a major move that may boost enthusiasm in developing these novel therapies.
Finally, there’s strong public support from patient groups and doctors that have sent letters to the FDA leadership supporting the urgent approval of AMT-130. Last month, five advocacy groups delivered a petition with 50k signatures to the agency. Huntington’s patients have also lobbied congressional representatives, who have sent letters to the FDA.
This kind of public pressure can move the needle, and there’s a recent precedent of that. Last July, the FDA halted all shipments of Sarepta Therapeutics’ commercialized DMD drug after three reported patient deaths. The decision triggered substantial public and political outcry. Critics argued the FDA had overreacted and that patients still needed access to the drug. Vinay Prasad even resigned over the controversy. He was reinstated a few weeks later, and the FDA eventually allowed Sarepta to resume shipments for ambulatory patients, the more severely affected group.
There’s another, even a more relevant precedent with Replimune Group. In July 2024, the FDA issued a Complete Response Letter rejecting REPL’s melanoma therapy. The issue wasn’t efficacy, as the drug showed a 33% objective response rate, which is an outstanding result in oncology trials. The problem was the trial design – REPL had no control group and sought approval on Phase 1/2 trial data. Similarly as with QURE, REPL noted that the FDA’s comments regarding trial design represented a reversal from previous discussions, in which the FDA had not flagged any such issues. The stock tanked 80% upon rejection. Public outcry followed, including a series of very critical WSJ opinion pieces aimed at the new FDA leadership. What happened next was interesting:
- September 2024: REPL held a Type A meeting with the FDA, after which the company commented: “At this time, a path forward under the accelerated approval pathway has not been determined.”
- October 20, 2024: The FDA accepted REPL’s BLA for review. PDUFA date was set for April 10, 2026. REPL’s share price jumped by 100%, returning almost to the pre-CRL levels.
The market clearly took the BLA acceptance as a signal that FDA had yielded on the trial design issue and would now approve the drug. If that’s really the case, REPL is the second fresh precedent where public outcry helped to reverse the agency’s stance.
For what it’s worth, some biopharma investors (e.g. Adam May) argue that QURE’s situation carries more weight and public visibility than the Sarepta or Replimune cases, which could mean public pressure has an even stronger chance of prompting FDA reassessment.
It is safe and effective and can work from here with foreign sales. The FDA was wrong. Maybe truth outs. Maybe not, but their wrongness is unlikely to carryover to other jurisdictions. Long.
Thank you for sharing the idea, Marko.
I agree the situation is interesting, unusual, and quirky. The upside is undeniably intriguing. I really wanted to like it. But after digging deeper, I’ve decided to hit pause as there are a few concerns that in combination are hard to ignore (at least to my untrained eye). I’m very curious to hear more opinions from other SSI members.
It’s not entirely clear to me that the FDA’s feedback on AMT-130 was purely due to trial design and external control data concerns. Multiple experts (the same ones who generally agree the trial results look promising) have also identified other concerns, including around the efficacy data quality. Many of those who are excited about the trial results, still apparently think a better trial is needed for confirmation.
Furthermore, those trial design concerns also don’t appear to be merely philosophical (i.e. FDA is just posturing). Some of them sound quite serious and I’m not sure how addressable they are without running an additional trial.
Those issues are:
– Tiny sample size. The trial included just 29 patients, with only 12 in the high-dose cohort. This raises concerns about patient selection, perhaps enrolling individuals with naturally slower disease progression. With such small numbers, even two outliers could significantly skew results. https://www.biospace.com/drug-development/uniqures-huntingtons-breakthrough-brings-hope-to-patients-but-experts-urge-caution
– Limited data disclosure. There’s no data on the low-dose cohort. More importantly, there’s no information on the mechanism of action, which, as I understand it, is the most important metric – does AMT-130 actually reduce the mutant huntingtin protein in the brain?
– The 75% disease progression slowdown was inferred by measuring the Unified Huntington’s Disease Rating Scale (cUHDRS) results of the treated group against external data. The 75% looks impressive partly because the external data showed rapid decline. One expert noted that if you instead measure QURE’s patient results against their own baseline, the improvement is not clinically meaningful. https://www.youtube.com/watch?v=rU0deu8bmq8&t=10s
– As for the NfL data, the results chart provided by QURE showed wide error bars, suggesting high variability among patients. Given the small sample size, a few outliers might have also significantly skewed the results. https://factor-h.org/amt-130-marks-a-historic-moment-for-huntingtons-now-comes-careful-communication
– Experts are generally cautious about viewing NfL as a strong metric for HD treatment efficacy. It can fluctuate for many reasons, and, if I understand correctly, research has shown it’s more of an indicator for disease onset than a biomarker for treatment effectiveness. https://www.sciencedirect.com/science/article/pii/S1353802021001504
– No peer review. AMT-130 results were announced only through the company’s press releases, not published in any peer-reviewed journals. Several experts have flagged this.
– The absence of a control group can generate strong placebo effects on the treated group. Everyone undergoing the procedure knows they’re receiving the real treatment. Invasive procedures amplify this effect. One expert has noted it’s common for such trials to appear promising in small studies but fail in larger ones.
– There is a precedent – Roche’s tominersen (also an HD treatment). It also showed encouraging results in a Phase 1/2 trial with 46 patients. It was also conducted without a placebo group. Roche then launched a Phase 3 trial (with 800 intended patients), which eventually ended up terminated because of unfavorable benefit/risk profile.
– I got the impression that one reason behind those recent FDA U-turns is cost savings. New drugs are expensive, and regulators want to limit spending, especially when evidence isn’t abundant. This aligns with the current administration’s overall policy direction, and it’s unclear how easily such a thing might be.
Good overview. I wrote about this one a while ago. A few points to add:
1) They have an epilepsy treatment that may cure drug resistant versions of it. Their first patient had a 90 percent reduction in seizures so they have a second shot on goal.
2) Even if the FDA screws the pooch again, this will get approved in Europe
3) IMO you are much better off buying call spreads or buying covered calls. 90% of my position is covered calls as they sell with a 40 percent premium.
This is a fantastic idea. Are you selling March 2026 $20 calls here and just collecting the premiums?
Aprils
Agree with BKgal – call spreads are extremely cheap. Further – March 20-30-40 call fly is trading under $1 with the stock above $25. So the options market is pricing in a decision by then, resoundingly.
Like DT said though, these things take longer than anticipated so if that’s the case these call flies could be a gift and a half. Not worth delving into it if you aren’t very familiar with the structure though.
I would be very interested in hearing more. Never played these pharma/biotech names with imminent regulatory catalysts before. This seems like the type of trade you can take in size with capped upside but limited downside. I did not realize how expensive these calls had gotten. Big thanks to this thread for calling it out
What would be a fair stock price, or expected stock price, if the FDA keeps its stance and a Phase 3 trial is needed? And why?
For Marko, I see you have written “55% downside” from $26.65, so that would be ~$12/share. Is that your best guess, or was it just to be conservative to keep the focus on your point that the market is calculating a 75% odds on rejection, and that those 75% is too low?
The company now has plenty of cash to run the Phase 3 trial, right. If it is needed to wait 2-4 years for a Phase 3 trial, and the base case is $70/share after the 2-4 years waiting (by assuming the same market is still there, and no new competition has shown up in the meantime, and the trial runs successfully). Then for instance a $14/share after the FDA decision would correspond to a 5-bagger in 2-4 years. (70/14 = 5). That seems a bit too low to me.
The $14/share seems a bit too low to me
Appreciate the question, I used $12 because it is the share price level before the news of a potential accelerated approval broke, i.e. the “undisturbed price”. As with unprofitable, heavily cash-consuming companies it is difficult to settle at a fundamental valuation (no profit or cash flow to anchor).
At current cash burn they will survive 3 years. They could need another capital increase. If the market then decides the pipeline is only worth $5 and we only underwrite at $5, there is not much you can do.
I think the discussion if $12 or $14 misses the point. There is substantial upside if things go right but also substantial downside when buying today at $25. $12 or $14 should not determine if you participate or not.
QURE is up >10% today. I do not see any company-specific news.
However, there is another FDA reversal this time with regards to Moderna’s biologics license application for seasonal influenza vaccine candidate.
You can read more here:
https://www.cnbc.com/2026/02/18/fda-agrees-to-review-modernas-flu-shot-application-after-refusal.html
Obviously, this carries over to QURE potentially benefiting from an FDA reversal as well.
Quite a bit of reversals, as you mentioned we had MRNA where VP got overruled. Positive type B meeting on Spruce, now also this paper: https://www.nejm.org/doi/full/10.1056/NEJMsb2517623
I think this one will be a winner.
Hey Marko, have been following this stock from the sidelines, but this looks like pretty good news.
I’m not sure if I understand this correctly, but wasn’t the whole reason QURE’s stock crashed was because the market thought the FDA would force them to run a second, massive Phase 3 trial. Now, the FDA leadership is announcing a “new FDA policy that the default requirement for FDA approvals will be one robust pivotal trial plus confirmatory evidence, rather than two trials”.
https://www.nejm.org/doi/full/10.1056/NEJMsb2517623
Moderna received a “Refusal to File” letter from the FDA. But after they sat down for a “constructive” meeting with the FDA, the agency changed its mind and accepted a “revised regulatory approach”. Seems like the FDA is loosening up its policies at least for now.
Apparently this all went to hell based on some comments by the FDA Commish, though I’m seeing conflicting reports as to whether he was referring to QURE or another company’s drug?
yeah anyone with reasonable opinion?
Here is the full 13min interview: https://www.cnbc.com/video/2026/02/26/fda-commissioner-dr-makary-on-rare-disease-therapy-approvals-internal-politics-at-the-agency.html
It is still questionable if he refers to QURE, because he said the FDA was pressured to approve a drug but in QURE’s case it was about disagreeing on trial design and not approval.
However, it is still a negative because the FDA made clear that they will take a very tough stance when it comes to approving any gene therapy in general.
“uniQure (QURE) shares fell ~28% on Thursday after FDA Commissioner Marty Makary, in a potential reference to Danish biotech’s gene therapy AMT-130, suggested his agency will not approve drugs that are associated with patient morbidity.
However, Leerink Partners reaffirmed its Outperform rating on uniQure (QURE), arguing that the drug Makary referred to could be Regenxbio’s (RGNX) RGX-121 and not AMT-130.”
https://seekingalpha.com/news/4557908-uniqure-falls-fda-commissioners-comments
Does anyone know how to attribute the CNBC interview comments to either RGNX, QURE, or both?
Not a good outcome for the longs. As a physician, I’m stunned that the FDA recommended a double-blind trial. That makes absolutely sense to me.
Seems pretty crazy to require a company drill holes into people with an awful disease and then give them false hope in a placebo.
Is this type of decision appealable?
Unfortunately, the worst case happened, and the FDA rejected accelerated approval form AMT-130 and instead recommended a Phase III randomized double-blind sham surgery-controlled study. Here is the edited Q4 call transcript: https://seekingalpha.com/news/4559813-uniqure-outlines-next-steps-for-huntington-s-program-as-fda-recommends-phase-iii-sham
Management is still very confident (of course they are) in AMT-130 and the data set. It is just that the FDA sees it differently.
What are the next steps? First, they will ask for another meeting with the FDA “We plan to request a Type B meeting in the second quarter of 2026 to further discuss potential Phase III study design approaches that address the agency’s feedback while also considering feasibility and patient risk.”
The question is what QURE can offer that is different from now and to what extent the FDA will soften its stance. Given the current trajectory my expectations are low.
Secondly, they will engage with regulatory bodies in UK and Europe regarding approval there. It is unknown how long it will take and how big the opportunity is. It is definitely smaller than the US.
At current share price ($9.0) the market cap is $560m vs. $620m net cash. Of course, they will burn through that cash over time and management mentioned they can continue until H2 2029 before running out of current cash.
Realistically, it is time to acknowledge defeat, take the losses and move on. On the other hand, H2 2029 is still a long time for something good to happen. The immediate downside is gone other than a slow bleeding to death. That is why I keep my small position that is left.
This situation has further developed over last few days with FDA official ‘anonymously” briefing media on FDA’s decision on not allowing QURE to file for approval. This ha now become a similar situation to Moderna where FDA initially refused to accept filing for a vaccine but reversed course amid pressure from public and following a meeting of FDA comish with Trump.
There is a tremendous public presure on QURE decision just the same with articles in WSJ, WP, NYT and all over twitter. Stock is back to where it was most recently before decision was officially announced. I entered late around $15 and decided to hold on after 36% drop based on cash position of the company and possible better exit. I am debating if i shoudl stay in or leave the bet on and leaning towards staying in as this is not done yet and there will be a few more ups and downs along the way.
anyone have any idea what’s going on here? it’s up 40% today alone and back up near $15 from bottoming around $8.
@TheTexan
Huntington community is on the offence. Some tweets from congressmen. A retired FDA official who approved SEREPTA’s gene therapy drug criticizing the decision.. FDA ‘explaining’ itself which it never does. The person behind the FDA denial, Dr. Vinay Parsad, being asked how long he’ll be with FDA and giving the stanadrd answer that I serve at the pleasure of FDA comish, HH Secertary and president and saying that he misses his podcast and being able to speak freely. He had ruffled feathers with Moderna before and had to reverse.. Looks like market is hoping it will be the same again. Tump doesnt like bad press and this is getting bad press in election year..
Further interesting development. Stock up another 60% (close to $24) after news that FDA official responsible for this situation will leave in April.
https://www.reuters.com/business/healthcare-pharmaceuticals/fda-vaccines-chief-vinay-prasad-step-down-april-2026-03-06/
Obviosly news leaked and hence there was major options volume as well as ordinary shares.
I am holding from $15.. debating if I should take some off or let it ride and see what happens.. This is mostly speculative investment for me.. I think it will go up further over new two months..
Not sure if anyone else is still in this trade..
FWIW I was a buyer Friday AH. The way I’m thinking about it is that QURE was trading ~$24 last week with the uncertainty of the Type A outcome and Prasad still running CBER. Now the regulatory risk unknown at $24 has materialized, was rejected by the political system and the person responsible has been removed. The Type B meeting will happen with new leadership and I’d think fair value should be higher than $24 in the near-term to reflect that.
I think it has to do with the FDA acting quite aggressively recently and pressure is building.
An article from yesterday:
https://www.statnews.com/2026/03/06/fda-uniqure-rare-disease-huntingtons/
Marko, post Prasad departure/thoughts on thread below?
https://x.com/LabbRadar/status/2030303717971435663
A little too promotional for my taste.
Surely, odds for a positive outcome improved after Prasad’s departure. But how can be know that the Q3 meeting with the FDA will see a 180 degree turn? Still a long way for an accelerated approval. But sure, odds are higher now. I HODL.
I hold on the basis that one way or the other a submission pathway will be carved, even if just to pacify the HD community or punt this issue further out, perhaps after 4 year data. I also think that news will move the stock and gradually towards previous highs.
Surprised this doesn’t lead to a bigger jump…..or pump
https://www.bloomberg.com/news/articles/2026-03-10/key-us-senator-investigates-fda-over-rare-disease-drug-denials?srnd=undefined
Something to be cautiously optimistic, i.e. a sliver of hope that uniQure could still seek an accelerated approval pathway for AMT-130 using natural history comparisons.
Teresa Buracchio, head of the FDA’s Office of Neuroscience, clarified that the new “plausible mechanism framework” can be applied to non-individualized therapies, potentially including uniQure’s AMT-130.
https://www.fiercebiotech.com/biotech/fda-official-plausible-mechanism-principles-not-exclusive-bespoke-gene-therapies
From Apr 15, 2026 4:00am
Another Fierce Biotech article indicating we are getting closer to having more clarity on trial designs for rare disease drugs like QURE’s AMT-130.
“The FDA is finalizing a guidance on external controls that will hopefully “give clarity to sponsors about what sort of evidence we would be looking for and willing to accept for approval of rare disease drugs”
https://www.fiercebiotech.com/biotech/small-pools-big-ideas-how-rare-disease-community-reimagining-clinical-trials
QURE is waking up from the dead. I think this is for 2 reasons:
First, QURE is going to ask for a marketing authorization for AMT-130 in 3Q26 based on the 3-yr analysis from US/EU Phase 1/2 trial.
Secondly, QURE also confirmed they will have another FDA type B meeting in 2Q26 to discuss Ph3 design.
Lastly, on their Q1 call they confirmed a cash runway until H2 2029.
Rumors of Markary getting fired. This could be what has pushed QURE higher the past week. The FDA has been a mess since he started, I’m not sure it could be more dysfunctional regardless of who takes over. I get a great newsfeed from Endpoints News. all biotech. It’s behind a paywall, so no link:
FDA Commissioner Marty Makary is expected to be fired from his role, according to multiple media reports.
The plans haven’t been finalized and could still change, said the Wall Street Journal, which was first to report the news. Representatives for the White House and Makary didn’t immediately respond to requests for comment on Friday. Other outlets issued similar reports Friday, with Bloomberg News saying that Makary’s ouster could be followed by other changes at the FDA.
Makary has experienced a brutal run of bad headlines over his handling of drug reviews, nicotine vapes and abortion medications, coinciding with a campaign of criticism incorporating everyone from biotech companies to pro-life conservatives. In recent weeks, multiple news reports documented the White House’s frustration with Makary’s performance.
On Friday in Washington, Trump was asked about whether he planed to Makary. “I’ve been reading out it, but I know nothing about it,” he told a reporter.
Makary’s goal when he took over the FDA in 2025 was a streamlined, modern-day regulatory process to get new drugs to patients more quickly and compete with China. Instead, his time at the agency has been marked by press announcements that didn’t turn into regulation, an inconsistent application of policies that frustrated industry critics and allies alike, and leadership and people turmoil that has been an ongoing distraction.
His exit would leave the FDA leaderless at a time when there are already holes atop the agency. There is no permanent leader of CBER, which regulates vaccines and biologics, or a permanent head of CDER, which oversees small-molecule drugs. The drug center job, under Makary, has in fact been through five different directors.
Chaos and change
The turmoil wasn’t limited to the top. At the start of the Trump administration, Elon Musk’s Department of Government Efficiency, or DOGE, forced about 3,500 agency staffers out of their jobs. That was followed by a parade of exits from senior leadership roles, costing the FDA large amounts of institutional knowledge.
Makary has criticized the depth of the DOGE layoffs, and claimed he was taking steps to fill the empty slots, and that the agency was in the process of hiring 3,000 new scientists — even as it has struggled to fill many roles.
As commissioner, Makary tried to expedite the drug development process through a series of new initiatives, many of them pilot programs and not full regulations. He advocated for one Phase 3 trial requirement versus two, to cut time and cost from drug development. He created the Commissioner’s National Priority Review Voucher to expedite promising drugs. And he worked in tandem with HHS Secretary Robert F. Kennedy Jr. on removing some food dyes and establishing a new food pyramid.
He also drew new focus to out-competing China, teasing early-stage trial reforms and announcing a new real-time clinical trial platform. That effort was generally embraced by the White House, which itself carved out money for the FDA to try an Australia-like clinical trial notification pilot to more quickly launch first-in-human studies.
While many of those efforts were launched through media announcements, journal articles or pilot programs, the agency made far less progress in turning them from ideas into detailed regulations that could have deep impact beyond their announcement.
Critics on all sides
Criticism of Makary came not just from Democrats, but from conservatives. Former Sen. Rick Santorum (R-PA) said in a social media post Monday that he had initially supported Makary. But his trust evaporated over a stalled review of the abortion pill mifepristone, which has angered pro-life conservatives for months and prompted politicians like former Vice President Mike Pence to call for Makary’s ouster in December.
A smattering of rejections and unclear data standards for some rare disease treatments had galvanized conservative lawmakers and media who have pushed for regulatory flexibility, and they loudly voiced their concern.
And the WSJ issued a relentless barrage of editorials against Makary, publishing at least five since mid-March.
The biotech industry piled on as well, breaching long-held convention that there is little to be gained by publicly criticizing your regulator. Companies whose experimental drugs were rejected by the agency described shifting goalposts for trials, expressing “surprise” about the agency’s actions, and Makary often alluded to what he saw as a campaign by those companies to force him out.
“There is corporate spin out there, maybe people don’t recognize it,” he said in a combative CNBC interview on May 5. “We’re not out to smear any company.” He insisted, repeatedly, that the FDA had made all its decisions by the book, following the recommendations of scientific reviewers.
At the heart of much of that criticism was one of Makary’s key deputies, Vinay Prasad, who Makary hired to run CBER and elevated into several other key positions, calling him a “genius” and defending his work even as he overruled reviewers and was disliked and distrusted by many staff at the agency. Last year, after a barrage of criticism and bad headlines, Prasad left the agency — only to be brought back after Makary lobbied extensively for his return. Prasad then exited the agency for good this year, at the end of last month.
Markary out, QURE up 5%.
Already a reversal of a prior ruling at the FDA https://www.biospace.com/fda/modernas-once-rebuffed-mrna-flu-shot-to-face-scrutiny-from-fda-adcomm?utm_campaign=33719445-2026%20%7C%20Daily%20Social&utm_content=378542457&utm_medium=social&utm_source=linkedin&hss_channel=lcp-424124
The WSJ Journal reports that Replimune has agreed with the FDA on a new trial design that allows resubmitting its novel treatment for approval.: https://www.wsj.com/health/pharma/replimune-gets-third-try-at-fda-approval-after-makary-departure-831e07ee
As the situation is similar to QURE, optimism increases that QURE has a shot at resubmitting its AMT-130 treatment for approval as well. Shares +20% pre-market
That looks like it’s behind a paywall. I’ve copied from Endpoints, and this article may discuss the science a little more in depth:
Replimune to ask FDA for re-review of melanoma drug, as agency stands by past rejections
Max Bayer
Senior Reporter
Third time’s the charm?
Replimune announced Friday that it will submit its advanced melanoma drug RP1 for FDA review after two prior rejections. It said it has had new discussions with the agency, after previously claiming that it got unfair treatment under since-fired Commissioner Marty Makary.
A new application will be submitted in the coming days, Replimune said, adding that it and the FDA “have aligned on a path forward for resubmission and reconsideration.” Replimune said that the FDA has indicated it will treat the application as an “urgent matter upon receipt and will prioritize its review.”
It is expected to bring new data as part of the application, said a government source familiar with the matter. The source, who spoke to Endpoints News on condition of anonymity, said the FDA conducted a review of the two rejections of the drug and found that those reviews were done properly. But there were mixed opinions across the agency: The first review team did conclude that RP1 should receive accelerated approval, but agency leadership had concerns. The quality of Replimune’s additional data will determine whether the third application is successful, the source said.
The biotech company’s attempts to get RP1 through the FDA became a symbol of industry-agency tension during Makary’s tenure. The company accused FDA leadership of shifting the goalposts on its review after the application was first rejected last year — a characterization Makary disputed. Replimune then resubmitted the application, which was conducted by a new review team, only to be rejected again in April.
A torrent of columns from the Wall Street Journal editorial board lambasted Makary and others at the FDA for not approving RP1, and put pressure on President Donald Trump’s administration to make changes at the regulator. Makary was fired earlier this month.
Lobbying government, targeting Makary
Friday’s news is a best-case scenario for Replimune following Makary’s exit, after it lobbied the White House about the potential of RP1.
Its stock $REPL gained about 70% in premarket trading after the news.
Endpoints previously reported that Replimune met with members of the White House’s Domestic Policy Council earlier this month, presenting a timeline of its FDA engagement and including testimonials from melanoma doctors who were supportive of the application. A source familiar with the meeting told Endpoints that White House officials were in a “listening” mode.
That a single drug company was able to appeal directly to the White House rather than standard FDA reviewers is emblematic of a regulatory process that looks little like anything in recent history. In Makary’s final weeks, jilted biotech companies began to make appeals to Congress and the White House, arguing Makary was impeding Trump’s long-held stance that there should be more regulatory flexibility in drug development, especially for rare diseases.
Other companies may now see a window where they too could receive reconsideration under new FDA leadership. UniQure, for example, was previously told that the FDA would not consider natural history data as part of an accelerated approval submission and instead wanted the company to conduct a new placebo-controlled study. Its shares $QURE gained about 16% in early trading.
uniQure Announces Plan for BLA Submission for AMT-130 in Huntington’s Disease
The key phrase:
“The FDA has agreed that our current clinical data can support a near-term BLA submission and has committed to work expeditiously with us to align on the design of the required confirmatory study. The consistency and strength of the clinical data generated to date give us great confidence in the product’s potential to make a meaningful difference for patients.”
https://www.globenewswire.com/news-release/2026/06/17/3313322/0/en/uniQure-Announces-Plan-for-BLA-Submission-for-AMT-130-in-Huntington-s-Disease.html
Price is up nearly 70% as market opens to mid 44.
FDA reversal, as was the likely outcome once Makary and Prasad resigned. The key paragraph is in the middle: “The reversal also ostensibly leaves uniQure in a stronger position than before the multiple flip-flops. FDA is now asking for three-year data from a Phase 1/2 study for the Huntington’s gene therapy, known as AMT-130, rather than the initial two-year cut. It allows the results more time to mature, and the biotech will still compare those data to the same natural history study that was part of the original path forward.”
In another reversal, FDA gives uniQure accelerated approval path for Huntington’s gene therapy
Max Gelman
Senior Editor
Regulatory flexibility appears to be back on the FDA’s menu following the departures of Marty Makary and Vinay Prasad.
At the center of the debate, once again, is the rare disease biotech uniQure and its experimental gene therapy for Huntington’s disease. The FDA has walked back its previous about-face, uniQure announced Wednesday morning, and will allow the company to seek accelerated approval in Huntington’s rather than conduct a placebo-controlled study that likely would have required a 12-hour sham brain surgery.
Wednesday’s update represents an apparent rebuke to Makary and Prasad, the agency’s former commissioner and CBER director. Spearheaded by Prasad, the two former officials often requested more stringent examinations of drugs under review — impacting rare disease treatments. In recent years, previous FDA leadership had sometimes lowered the bar for approvals where large, placebo-controlled trials were not readily doable.
But Prasad departed the FDA at the end of April, and Makary followed him out the door a few weeks later. Under Acting Commissioner Kyle Diamantas, who previously ran the agency’s food division, industry analysts view the uniQure update as officials signaling that the new approach is the same as the old.
“We believe the current FDA, largely in caretaker mode, appears to be more flexible on regulatory paths for applications where concerns were previously raised,” William Blair analyst Myles Minter wrote in a note to investors Wednesday morning.
Shares of uniQure $QURE rose more than 65% in early Wednesday trading.
The news adds to the growing trend of the FDA attempting to reverse some of Prasad and Makary’s requests that the industry viewed as burdensome. Since late May, the agency has either reversed the rejections or allowed resubmissions for a number of biotechs that ran into roadblocks, including Replimune, Capricor, Ocular Therapeutix and the tandem of Pierre Fabre and Atara. Regenxbio is also appealing an FDA rejection of its own gene therapy.
Stephen Majors, a spokesperson for the Alliance for Regenerative Medicine, told Endpoints News on Wednesday morning that the uniQure update is “clearly” a positive for rare disease drugmakers and patients.
“It’s a reconsideration of the facts and the data, and a recognition that these rare disease therapies and these rare disease populations can’t be treated like traditional, large-population clinical trials,” Majors said.
Is uniQure better off now?
The reversal also ostensibly leaves uniQure in a stronger position than before the multiple flip-flops. FDA is now asking for three-year data from a Phase 1/2 study for the Huntington’s gene therapy, known as AMT-130, rather than the initial two-year cut. It allows the results more time to mature, and the biotech will still compare those data to the same natural history study that was part of the original path forward.
The biggest remaining question is how the confirmatory trial will be designed. In the press release, uniQure said the FDA is considering letting the company use a control arm with standard-of-care therapy instead of a sham procedure, but that no final decision has been made.
That seems to suggest the trial would be open-label, rather than double-blinded like Prasad had requested. UniQure had not previously disclosed how a confirmatory study might be designed, but a standard-of-care control arm could represent a middle-of-the-road approach — not as strict as Prasad’s requests, while not as lenient as continuing to use a natural history comparison. The company had said a placebo-controlled trial using a sham brain surgery would not be feasible or ethical.
A uniQure spokesperson declined to comment beyond the company’s press release, saying the FDA has not yet sent the final meeting minutes that would put the agency’s recommendations in ink rather than pencil.
The update is the latest in what’s become a long-running and unusually public back-and-forth over uniQure’s gene therapy. In June 2023, the company reported mixed data from a Phase 1/2 study of AMT-130, disappointing investors and leading to a major restructuring. But the next year, in July 2024, two-year results illustrated a more positive picture and put accelerated approval on the table.
In December 2024, uniQure announced it would seek accelerated approval after the FDA said using a natural history study as a control arm was acceptable. But under Prasad’s influence at CBER, the FDA began to suggest it would walk back that blessing in November 2025, before confirming it this past March. Makary had also alluded to the therapy in a widely circulated CNBC interview, saying an unnamed experimental drug showed no benefit despite doctors drilling a “burr hole” in patients’ heads.
Makary’s comments and the agency’s reversal on uniQure prompted significant pushback from industry officials and patient advocates, with some — including Majors, the ARM spokesperson — accusing the FDA of hypocrisy. The uproar snowballed in early March after Endpoints reported on the blowback, and a senior FDA official called Endpoints within 45 minutes of publication to dispute that viewpoint under the condition of anonymity.
Later that week, the official held a conference call with dozens of reporters, where they continued to slam uniQure’s data as “distorted” and “manipulated.” But the call spurred an abundance of negative headlines across the mainstream media ecosystem, and left the Trump administration in the unfavorable position of defending itself from accusations that it was preventing rare disease drugs from reaching patients.
The week concluded with Prasad announcing his intent to resign by the end of April. At least one member of Congress, Rep. Jake Auchincloss (D-MA), claimed Prasad was the anonymous senior official and called his actions around the uniQure application illegal.
AUTHOR
Great for QURE investors, for sound public policy, and most of all for patients with nowhere to turn.
Marko, congratulations on the return! what’s next for the setup in your eyes? still holding?
I have a very unscientific approach to the position. QURE was trading between $60 – $70 before the FDA reversal.
If it returns to that level I will sell most of my position and maybe leave a small “lottery ticket” in case they receive regulatory approval and shares most likely will go above $100.