$QURE This is a great post. I’d add that this management team has navigated an incredibly tumultuous year. They had the FDA commissioner go on national TV and publicly accuse the company of something that simply wasn’t true. The head of CBER appeared openly hostile to their regulatory approach. Meanwhile, they’re trying to deliver the first disease-modifying treatment to a patient population that has never had one. Through all of it, management never once got in the mud. They stayed quiet, kept working, and let the science do the talking. I'll give them some grace on the 4 year data release.

$qure $clpt Delighted If Q-motor is good, nfl and 4 year data is good, we got some interesting things on the table… Market thinks something bad has come up, I don’t think so, might want to invert the situation.

RISE to the Challenge: Statistical Considerations for Rare Disease Clinical Investigations is on September 29th. fda.gov/news-events/fda-meet… The FDA has attached a Request for Information and Comments to this meeting. thefederalregister.org/docum… Here is what it is asking for information on. This seems applicable to AMT-130 $QURE

$qure $clpt A lot of funny takes today, if you believe Sarah Tabrizi was talking about the 4 year data I don’t know what to tell you. If people think something is wrong and are scared Uniqure is going to miss the deadline that I at least could respect. That could be a legitimate and understanding reason for someone to want to sell. Like maybe something bad came up from a safety standpoint and they need to delay the data that can be a fair concern as an investor. Nothing Tabrizi said in that interview actually was new, do people really think a KOL can make a statement that they believe anyone that takes this drug will have 75 percent slowing past 10 years? Because that is what we are saying with her comment. That is impossible, no KOL can make that statement because they sure as heck don’t know what year 10 looks like. This whole thing is pretty laughable tbh. If you think about it, 40-50 percent super long term with lots of patients as an estimate really isn’t a bearish statement. We can agree, if she says 4 year data would likely be 40-50 percent slowing that is a bearish statement. That isn’t what she said. “Where do you think the drug will end up?” Tabrizi

She says amt-130 is telling them where they have to target to develop molecules that would be accessible to everyone. That doesn’t sound to me like she thinks amt-130 doesn’t work $qure

$qure $clpt Per @Tim_Corr She has already said this, I guess she could be cautious because of the criticism she got last year. We also have to remember she is working on her own new drug now and she is personally looking to treat the entire world. Factually, she sounded very different to me. Sung was a completely different animal, at this point I am going with cautious stance from her but I can’t line the 2 comments up. I don’t believe chudrs is 40-50 percent. That doesn’t make any logical sense compared to Sung’s comments and what would be having to happen for it to do 40-50. hdfoundation.org/hd2026-reca…

$rare $clpt $qure call today “The agency recognized our robustness of the package, we asked for AA, during the review they granted standard traditional approval. Gave a very strong label also. Lifetime costs can exceed 8 million dollars. Wholesale cost in the US 3.95 million. Net price they said 2-4 million We are expecting fairly rapid requests for treatment. We expect product to be shipped in 30-60 days and people treated. They do not seem concerned about insurance. Company sounds like the label they feel was extremely generous. Godspeed to amt 130

Looks like full approval ir.ultragenyx.com/news-relea… $QURE $RARE

Reading this approval from the FDA no mention of Accelerated Approval, or confirmatory trial etc. Looks like full approval when the company was requesting Accelerated Approval $QURE

$qure $clpt "The Trump Administration is committed to bringing safe and effective treatments to patients with the most urgent and unmet needs. The approval of Fayuvi marks a historic moment for children and families living with MPS IIIA, which is a disease that has, until now, offered no approved treatment to alter its devastating course,” said Acting FDA Commissioner Kyle Diamantas, J.D. “Gene therapy holds tremendous promise for rare diseases like Sanfilippo syndrome type A, and this milestone reflects the FDA's commitment to action.”   “For families living with Sanfilippo syndrome type A, the trajectory of this disease is heartbreaking — children who develop normally in their earliest years facing a relentless regression with no approved treatment to slow it. Parents and clinicians have been waiting far too long for an option,” said Karim Mikhail, B. Pharm., M.S., Director of the Center for Biologics Evaluation and Research. “Today’s approval of Fayuvi is a meaningful step forward — not only for these children and their families, but for the promise of gene therapy to address rare and devastating diseases where the need for safe and effective treatment is the most urgent.” fda.gov/news-events/press-an…

$QURE Interesting Paper on HD biomarkers. Researchers tested 734 proteins in CSF from HD gene carriers and healthy controls. After correcting for multiple comparisons, only NfL and sCD30 remained significantly different. Average NfL was 470 pg/mL in controls, 1,387 in premanifest HD and 3,803 in manifest HD. That is a pretty clear relationship between NfL and HD progression. The other finding may be even more interesting. sCD30 was roughly 50% lower in HD, continued declining over time and correlated with functional decline. This independently confirms earlier CHDI-funded PREDICT-HD work connecting sCD30 with striatal atrophy and neuroimmune dysfunction. I wonder if $QURE has stored CSF and has tested for it. link.springer.com/article/10…

$qure $clpt God Bless Amt 130 and good luck to the pills, nothing currently in human trials will even come close to this. Read the papers why. A new study has revealed why some people with Huntington disease develop symptoms 10 to 12 years earlier and experience a more aggressive form of the disease. “The mutational expansion seems to be selective for the brain,” Hayden said. “That may help explain why Huntington disease, even though the mutation is in every cell, is fundamentally a brain disease.” The findings suggest blood tests are not a reliable indicator of the disease unfolding inside the brain, which is an important consideration for future Huntington disease research and clinical trials. In conclusion, we show that the HD genetic modifier with the largest magnitude of effect, the CAG-CCG LOI, is associated with an increased proportion of large somatic expansions in HD striatal MSNs, lower MSN counts, and earlier loss of D2 MSNs of the indirect pathway. Peripheral blood DNA does not capture increased somatic expansion in MSNs, suggesting that blood DNA is a poor biomarker for disease-relevant somatic expansion in HD-affected neurons. While the underlying mechanism by which the CAG-CCG LOI modifier influences somatic expansion remains unresolved, our results suggest HD pathogenesis can be modified through introducing local genetic changes to the HTT CAG repeat region that alter its expansion in vulnerable cell types in the human brain. Our study further underscores the need for cell-type-specific studies across other repeat expansion disorders that preferentially affect specific neuron populations. @peter_mantas @DesertDweller93 @Tim_Corr @biggercapital news.ubc.ca/2026/09/why-some… cell.com/neuron/fulltext/S08…

We are pleased to see these four @US_FDA senior leadership appointments at such a critical time for people living with rare diseases. Stability, certainty and strong leadership are essential to advancing regulatory science. Rare diseases are a significant #PublicHealth issue affecting more than 30 million Americans, most of which have no approved therapy. NORD looks forward to working with our new leaders to advance innovation and ensure the needs of people living with #RareDiseases remain at the forefront of the #FDA’s work.

$QURE In my last post I said I was more interested in what FDA does next. Yesterday’s appointments are worth thinking about. Why make the acting center heads permanent before the next commissioner even takes over? I would think a commissioner looking to change direction would want a say in who runs those centers. Maybe Overton already agrees with these choices. That would make me more comfortable too. My read is the administration is reassuring the market, patients and advocates that the more flexible FDA is here to stay. Keeping that direction seems to matter more to them than who sits in the commissioner’s chair.

$qure $clpt A blast from the past, it’s funny to look back, was an interview in 2019 on what Uniqure thought from Joseph Higgins. They knew exon 1 did something but they definitely didn’t know the full ramifications of HTT1a, they specifically called out the smaller toxic fragments but no way did they know that by going after the smaller toxic fragments they would hit gold with htt1a. If this drug truly works better than 99.9 percent of people think it might, Gillian Bates video is a master class on why that might be. We will find out very soon, a lot of anecdotes and at the end of the day pre-clinical is pre-clinical but if it translates to humans Chdi, researchers and the patients deserve a lot of credit here by not only finding it but the courage to take part in a trial. Minute 33 and minute 50, these are mice but if something truly special is happening in humans this is the thesis. piped.video/live/iQwv3Yx2Lu8 “And that exon-1 fragment is now known to be one of the primary reasons that patients with high number of repeats have an earlier onset, because this toxic exon-1 fragment is more common when there's a larger repeat. It also is in patients with a lower number of repeats, but it seems to be at higher levels than those that have higher number of repeats. So the therapy is treating not only the full length mutant huntingtin protein, but also the smaller toxic fragments. Which is something very unique about this therapy compared to other therapies.” “We did show in an animal model of Huntington's disease that when we treated with this drug AMT-130, that we had a restoration of neuronal function in the brain. And that’s a pretty amazing result. Usually you don't see that. So what that suggests is that when we treat patients or treat mice at least at an early stage, that the neurons are sick and there's a possibility they could be rescued. So that was a really important part of our preclinical data, and we hope that by doing this in patients we may see the same thing.” “but now with better neuroimaging techniques you can target areas of the brain within 0.1 millimeters. So the delivery is another advancement in the last 30 years that has coincided with betterment in gene therapy, AAV vectors and also our understanding of those mechanisms. So the time is right for this type of thing, especially Huntington's disease because of those three different fields coming together, neuroimaging, better delivery system and understanding the molecular neurobiology.” “So the neuropathology starts there, affects the medium spiny neurons. So I know in animal models that when we inject in those areas, and not only in Huntington's but with other diseases that start very specific areas of the brain, we're able to reverse the neuropathology and actually ameliorate the phenotype in these animal models. So getting it and delivering it to the right spot is critically important, and understanding the neuropathology is critically important.” huntingtonstudygroup.org/wp-… @peter_mantas @Tim_Corr @DesertDweller93

If you’re wondering why $QURE is down after filing the BLA, here’s my opinion on it (worth exactly what you paid for it). The last time QURE really moved on something the company itself did was the September data. Since then the big moves have come from the FDA. November rug pull. March Type A. Then the big reversal in June after the Type B. To me June was the real BLA catalyst. That was when FDA went from questioning whether the 3-year data could even support a filing to allowing QURE to move forward and getting aligned on the basic confirmatory trial: randomized AMT-130 vs SOC, no sham. We also started hearing more from management about how they could deal with SOC patients dropping out once AMT-130 is commercially available, including potentially using Enroll-HD as a supplement if attrition becomes a problem. I don’t think we know exactly what FDA has agreed to there yet, but clearly they have discussed the issue. That was a massive change from where we were a few months earlier. The stock rerated in June because the FDA changed the story. So when QURE actually filed the BLA this week, what really changed? Not much. It was obviously an important milestone, but the big regulatory change had already happened. That’s also why I’m not convinced good 4-year data moves the stock as much as people expect. Bad 4-year data would obviously matter a lot. But if it shows what I think it will, continued efficacy and maybe even better separation with time, then it mostly confirms the story we already have. I’m more interested in what FDA does next. How fast do they accept the filing? If they do it well inside the 60-day window, I think that matters. Does AMT-130 get a CNPV? And there is one company catalyst that I think is getting overlooked: the peer-reviewed manuscript. Sung seemed pretty excited about it in his recent presentation and hinted there is a lot more in the full dataset than what we have seen in the topline. We already know imaging/sensitivity work should be in there. Now EHDN also has a presentation specifically on 3-year Q-Motor outcomes after AMT-130. Maybe Q-Motor is in the manuscript, maybe it isn’t. But it makes me wonder what else is sitting in that dataset that QURE hasn’t really shown us yet. That’s why I think the manuscript could actually be more interesting than the 4-year topline. Four-year data probably tells us whether the same story is still holding up. The manuscript may show us there was more to the story the whole time. For the last year the market hasn’t really cared when QURE tells us FDA agrees with them. It moves when FDA tells us FDA agrees with them.

FDA Convening RISE to the Challenge: Statistical Considerations for Rare Disease Clinical Investigations September 29, 2026 — 9:00AM–4:30PM healthpolicy.duke.edu/sites/…

Here is some information to consider when thinking of $QURE confirmatory trial. In the June 2026 Leernik note management stated they already had discussions with the FDA on potential dropouts and have plans to "impute missing data and/or ENROLL HD could potentially be used as an external control comparison. On the Q2 earnings call Dr. Walid said that would use statistical techniques and in agreement with the FDA about how to deal with drop outs. And look at this talk on October 24th at EHDN that is on using external data in clinical trials with partial or no Internal Control I think the FDA and the company have come up with a way that ensures scientific rigor but will use external control data if it is needed.

There is a lot of negativity surrounding the confirmatory trial set up for $QURE. I think we need to give the HD community more credit for what they are willing to endure to get to their ultimate goal. A European Huntington Association survey of 525 people found high motivation to participate in HD research, with altruistic reasons outweighing reasons not to participate. Another study specifically looking at genetic interventions found 80% of respondents willing to participate, with the single most important stated motivation being gaining knowledge for future generations. pmc.ncbi.nlm.nih.gov/article… pmc.ncbi.nlm.nih.gov/article…