Tim

Markets, biotech, energy and occasionally questionable theories.

[mike @mike98572986]

$qure $clpt

Regenxbio ceo cc call today

God Bless America and Amt 130

One of the easiest situations I have ever seen.

@Christina4HD @laurencurehd @hthurgood @JRenz0418 @peter_mantas @Tim_Corr @zugmanfabio @tishmitten @biggercapital

[BioSpace @biospace]

The seven proposals in the Bio Advance plan include easing clinical trial starts, boosting manufacturing and establishing a new White House office to coordinate the government’s biotech policy.

https://t.co/SpRPZH6QAE

[Christina D @Christina4HD]

Thank you, @FDA_KyleD and @FDA, for recognizing the urgency facing rare disease families and advancing a framework that reflects the complexities of diseases like Huntington’s disease.

The HD community has contributed decades of natural history data, clinical trial participation, and documented risk tolerance. We welcome Priority Review of AMT-130’s BLA, but continue to advocate for CNPV consideration.

If a promising gene therapy for a fatal, relentlessly progressive disease does not warrant consideration for every appropriate expedited pathway, what does?

The success of regulatory reform will be measured not by the hope it promises, but by the patients it reaches while there is still time.

Our community has done its part. Now we look to the FDA’s leadership to ensure that urgency is translated into meaningful action.

💙💜

#HuntingtonsDisease
#RareDisease

[Martin Varsavsky @martinvars]

Huntington's disease has been passed from parent to child for as long as anyone has kept records, and medicine has never had a treatment that slows it. Today that could start to change.

The FDA accepted uniQure's application for AMT-130, a one-time gene therapy for Huntington's, and gave it Priority Review. A decision is due by May 1, 2027. uniQure is a gene therapy company based in Amsterdam and Lexington, Massachusetts.

The therapy is given once, through MRI-guided neurosurgery, directly into the striatum, the part of the brain the disease damages first. It carries a small piece of RNA that silences the huntingtin gene. In the Phase I/II study, patients on the high dose saw their disease progress 75% more slowly over three years on the main clinical scale than 940 closely matched patients from Enroll-HD, a natural history registry. Daily functioning declined 60% more slowly.

Every child of a parent with Huntington's has a 50% chance of inheriting it. I've spent ten years building fertility companies, and for these families one of the few tools so far has been IVF with genetic testing of embryos, so the gene stops with them. That protects the next generation. It does nothing for the parent who already carries it. A therapy like this is the missing half.

I also like how the evidence was built. The comparison came from years of data that patients and families gave to a registry, long before any drug existed. At Certuma we have met with the FDA too, and I've learned how much careful evidence like this moves a regulator.

Congratulations to the uniQure team and to every family who joined these trials.

For generations, a Huntington's diagnosis came with a known ending. Now there is a date on the calendar.

[mike @mike98572986]

$qure $clpt

in minipigs, by 44% at the protein level after 12 months- preclinical for amt 130

https://t.co/NSrQeIq8CO

[Nyah Phengsitthy @nyahphengsitthy]

Mikhail: “Files get submitted on a weekly, monthly basis...but we should not also forget the files that we have open because we don't want to lose these opportunities. So we have a bit of catch up to do.”

[Nyah Phengsitthy @nyahphengsitthy]

“We are at a moment where we need to move from an incremental sort of progress to a true transformational effort ... it's moving at a pace that is incredibly fast and we need to be able to catch up with this," Mikhail said, in regards to advancing rare disease solutions.

[National Organization for Rare Disorders (NORD) @RareDiseases]

During our 2026 #NORDSummit FDA Rare Disease Regulatory Roundtable, moderator Amy Comstock Rick asked the Directors of #FDA CDER, CBER, and CDRH: Where can patient voices make the most difference?

Center for Devices and Radiological Health (#CDRH): Identifying unmet needs, prototyping #MedicalDevices, involving patients in design of clinical trials to maximize participation and efficacy, gauging product quality once released

Center for Biologics Evaluation and Research (#CBER): Risk-benefit analysis of #GeneTherapy, defining acceptable outcomes and meaningful clinical endpoints

Center for Drug Evaluation and Research (#CDER): Patient-focused drug development meetings help explain which symptoms needs to be treated and which do not

[National Organization for Rare Disorders (NORD) @RareDiseases]

During a #NORDSummit panel on moving "Beyond One Disease at a Time: The Future of Individualized Genetic Therapies," Apriligen CEO @Nicholas_Vita had insightful words for #pharma investors:

"What #healthcare investors should be asking is, how do I generate the best risk-adjusted return? And you can't do it anywhere else the way you can in #RareDisease. And that's the argument we should be making with investors, because when you have the regulators giving you tailwinds that have never existed before, when you have the scientific community coming up with innovation like they never have before."

#Investment #GeneTherapy

[Tim @Tim_Corr]

@mahesh_shenai

[mike @mike98572986]

$qure $clpt

Bye bye

Warden Capital Q3 2026 Letter
Says no thanks to @mahesh_shenai theory of Uniqure manipulating the data with proof. The same paper also says no thanks to placebo on tfc. Keep up the good work Mr Neurosurgeon with your odd and baseless theories. I guess they manipulated it also?

“However, dropouts progressed faster according to some end points (eFigure 4), which could influence later observations and potentially explain the slightly slower progression observed in some end points, particularly in the cUHDRS score (Figure 4E).”

Warden capital thoughts

And speaking of drags, the biggest weakness this quarter came from Uniqure, which dropped significantly on a bit less clean than ideal 4 year results6. Much ink has been shed on this elsewhere, but my quick view is that the 4 year data is actually quite good in an absolute sense and in my view removes some of the tail risks on the drug approach not working longer term7. The trial did miss statistical significance on its 4 year target indication of cUHDRS, with 44% slowing but did hit statistical significance on the 4 year TFC with 61% slowing (these are two different ways to measure disease progression). The reason for the miss though was not the patients rate of decline accelerating significantly, but instead the natural history comparator looking much better making the slowing look relatively smaller. This appears to be very likely due to the sickest patients dropping out of the natural history control group as it becomes more difficult to travel to the testing centers and take the tests, which makes the natural control group look better than a typical patient pool.8
This isn’t just random speculation, we actually have excellent data to support just this conclusion from Roche’s failed Huntington’s trial. Roche made the data available and several scientists wrote a good paper which showed in detail how the patients who dropped out of the trial were progressing 50% faster than those who stayed, which made the end year readings look artificially better than the full patient pool, because the worst patients dropped out.

Link to the paper is here, but what is really interesting are the supplements which you’ll need to download separately.

So I would say my confidence this drug works is pretty high now. However I do not know what the FDA will do & there is definitely some risk they ask for a phase 3 trial, which isn’t the end of the world but would likely hit the stock price. But on the whole I would lean towards FDA granting approval next year as is with a confirmatory trial. This is for several reasons - the 3 year data is good, which is the basis of their submission (and indeed it got better in the recent release with more patients hitting 3 years), I think the FDA will understand this drop out issue, and most importantly, the FDA seems to prefer TFC as a measure of disease progression anyways, as this is what they are going to require the confirmatory trial’s endpoint would be. It would be strange if the FDA decided TFC is the proper end point, but then didn’t approve when the 4 year TFC was very good. But you never know in bioland!

Original paper

https://t.co/7KXV1zcAId

@Christina4HD @laurencurehd @Tim_Corr @peter_mantas

[mike @mike98572986]

$qure $clpt

I think the true question also is, where is this same energy when other drugs get approved with similar or more costs with less benefits?

I don’t see Prasad, Koka or @mahesh_shenai barking up a storm on marginal products. Makes you truly wonder, I haven’t heard @mahesh_shenai go after other drugs, you probably could pull up 10 approvals in the last couple years that would make you shake your head yet all that energy is strictly on one drug. Again, I am not saying they should or shouldn’t be approved, what I am saying is where is that same energy?

You have to truly ask yourself, why is this neurosurgeon spending hours of his day bashing just one program? Huge bias and it’s personal to them. His wife got the axe due to the relationship with Prasad, this is why this guy has such strong opinions on just 1 program in this world.

[Christina D @Christina4HD]

@mahesh_shenai, Although we have never met, I addressed Dr. Mallika Mundkur at the @FDA's CNPV public meeting, whom I understand is your wife.

After reading nearly 20 of your posts concerning Huntington’s disease (HD) and AMT-130, I have to ask: Are you evaluating the totality of the evidence, or predominantly searching for reasons to discount it?

You repeatedly express hope that you will someday treat Huntington’s disease patients. But how much direct experience have you had with our community? Have you spent meaningful time with symptomatic patients across disease stages, witnessed their progressive neurological decline, or spoken with families about their risk tolerance?

I ask because I have.

HD has devastated three generations of my family. My grandmother died after years of suffering. Her chorea was so severe that she wore padded mittens for nearly four years to prevent her involuntary movements from dislodging her feeding tube.

I was nearly my daughter’s age when my grandmother developed symptoms. Now both my daughter and son are watching their grandfather and aunt experience the same disease. My father is in the middle stages of Huntington’s disease, while my aunt is further along in its devastating progression. As a mother, I live with the painful reality that my children may one day witness this same deterioration in me—or, even more heartbreaking, experience it themselves.

What I witnessed as a little girl, my children are witnessing today. Different generations, the same devastating cycle we are desperately trying to break.

The psychological consequences are equally profound. A fellow Michigander and HD advocate recently lost her father to suicide. Another Michigan chapter board member nearly lost her niece, and several HD friends have lost loved ones to suicide. Suicide risk among people with Huntington’s disease is substantially higher than in the general population.

Why? Imagine caring for someone you love while witnessing years of relentless neurological deterioration, all while knowing you could face the same fate. And even if you escape inheriting the mutation, you may carry the lifelong burden of survivor’s guilt as those you love continue to suffer. This is the profound, multigenerational trauma of Huntington’s disease.

More than 40,000 Americans live with HD, and over 200,000 are at risk. Those figures do not include the countless caregivers and relatives whose lives are also affected.

Your anecdote about a surgeon with another movement disorder reinventing his professional life was particularly revealing. When I read it, I immediately questioned your firsthand understanding of HD.

HD does not afford patients the luxury of simply reinventing their lives. It progressively damages the brain circuits responsible for cognition, judgment, behavior, movement, and independence. Symptoms can worsen over 10–25 years, gradually taking away the ability to work, communicate, maintain relationships, swallow, walk, talk, and care for oneself.

The ability to reinvent one's life requires precisely the neurological capacities HD progressively destroys. HD takes away the ability to meaningfully participate in life altogether.

The 2024 HD Symptoms and Treatment Impact Survey found that nearly three-quarters of respondents would accept treatment risks for five years without progression, while approximately 35% would accept risks for even three years.

Three more years raising children. Five more years working, communicating, remembering, and living independently. More birthdays, graduations, and time with family.

Then consider the economic consequences of inaction. Over 10–25 years, HD families will face neurologists, psychiatrists, hospitalizations, expensive chorea and psychiatric medications, physical and occupational therapy, speech and swallowing therapy, mobility equipment, home modifications, specialized residential care, and eventually around-the-clock assistance.

HD removes two people from the workforce: the patient and the family member who becomes their caregiver. Families lose wages, insurance benefits, retirement savings, and years of financial security. Many conventional care facilities lack the specialized neurological and behavioral resources required for HD, leaving families with limited options.

These costs accumulate across households, employers, Medicare, Medicaid, disability programs, and society.

When evaluating the risks and costs of treatment, why is the cost of inaction so often treated as though it were zero?

If AMT-130 meaningfully preserves independence, the potential economic and societal benefits deserve consideration.

You have described yourself as one of approximately 80 U.S. neurosurgeons with expertise relevant to this procedure. If AMT-130 does not meet your personal threshold for clinical adoption, that is your judgment. But your threshold is not the FDA's regulatory standard, nor should it determine the choices available to every informed patient and qualified physician.

Other neurosurgeons may recognize the broader significance of this investigational gene therapy. If its clinical benefits are confirmed, AMT-130 could help transform how we approach inherited neurodegenerative disorders beyond HD.

Regarding surgical risk, stereotactic neurosurgery has been performed in humans since 1947. Trial experience suggests the procedure has generally been tolerated.

But the question is not whether neurosurgery carries risk. It does. The question is whether those risks are acceptable relative to the potential benefit for patients facing a progressive, fatal disease without an approved disease-modifying treatment.

Your professional risks and our personal risks may look entirely different.

For you, this is a discussion of procedural complications, evidence, and professional responsibility. For us, it is progressive neurological deterioration, dependency, and premature death.

The reported AMT-130 findings, including favorable Total Functional Capacity trajectories compared with external controls, deserve serious consideration. TFC measures employment, financial management, domestic responsibilities, daily living, and care requirements. It measures the independence HD progressively takes away.

Scientific skepticism is essential, but it must be applied symmetrically.

Our community has also been wounded by regulatory rhetoric. @VPrasadMDMPH, your wife’s former boss, recently compared patients pursuing unproven treatments to a drowning person reaching for a blade. Regardless of the intended scientific warning, such language risks reducing informed, deeply personal benefit-risk decisions to acts of desperation, overlooking the devastating consequences patients and families face without treatment.

Our willingness to accept uncertainty is not desperation. It reflects a rational understanding of what HD will otherwise take from us.

Imagine watching someone you love progressively lose the ability to think, communicate, walk, swallow, or even recognize the people they love most. Now imagine living with the knowledge that the same devastating disease could one day affect you, your children, your siblings, or generations of your extended family. This is the reality of Huntington’s disease.

What would a few additional years together mean? What would you do to break the cycle?

I am not asking you to abandon scientific standards. I am asking you to recognize that the consequences of waiting are as real as the risks of treatment.

The absence of treatment is not the absence of risk. It is continued disease progression, escalating dependency, enormous psychological and economic suffering, and irreversible neurological loss.

You may see an investigational neurosurgical procedure that has not met your preferred evidentiary threshold. We see a potential opportunity to preserve the ability to think, communicate, work, love, and remain present in our families' lives.

We are asking for scientific judgment that accounts for the full reality of Huntington’s disease.

P.S. Go Blue! 〽️💙💛

#HuntingtonsDisease
#RareDisease

[Senate Aging Committee @SenateAging]

Part of caring for America’s aging population is making sure that more Americans are given the opportunity to grow old.

Under Chairman @SenRickScott’s leadership, the Senate Aging Committee is proud to fight for the tens of millions of Americans living with a rare disease. The FDA’s action is a great step forward to help ⬇️

[mike @mike98572986]

$qure $clpt

Holy shit!!!
3 back to work!!!
Game on boys!!
September 23rd presentation.

Here it is, the full presentation we have all been waiting for from that bearish lady known as Sarah Tabrizi!

Regarding tfc

“Actually at our site and a couple of sites, in the US, we have patients with early disease, early symptomatic disease, I have a IT consultant who gave up work and took medical retirement because he couldn’t manage his job at a high level. He is in this trial and he went back to work. I have never seen anyone with HD go back to work. Actually 2 people in the US have gone back to work, one is a doctor and has gone back to work.”

Regarding tfc, they are improving.

“This isn’t driven by any outlier, regarding chudrs at 3 years, they are all similar.”

The data shows you can slow it but you cannot stop it.

Regarding tfc
“This is the datapoint the FDA loves because it is function.”

“Tox in pre-clinical identified a wide safety margin.”

They anticipate following the patients for “10” years.

Quite a few of the sham developed problems due to the fake surgery.

6 of the 10 were no longer eligible after the one year to cross after the 1 year due to striatum deterioration.

My personal understanding were 2 but who am I to argue with Tabrizi.

Listen to her comments on NFL

“It was safe.” Most AE’s were related due to the very long surgery.

“It is a small number treated.”

She said she saw the data with the additional 3 and the data looks even better. Specifically talking about the 3 year combined.

Placebo can last up to 24 months.

With an external comparator you need at least 3 years.

Effect size likely not 75 percent, it’s more likely to be 50 percent.

Long surgery is a massive challenge. It’s long and boring.

We now know what to target now and how.

Tabrizi is now going after stage 0 patients, age 20.

@peter_mantas @Tim_Corr @DesertDweller93 @Prof_Dollar @biggercapital @laurencurehd @Christina4HD @JRenz0418

https://t.co/74iENOKIdQ

[mike @mike98572986]

$qure $clpt

Serious question here, how do we explain the exact starting point track hd tfc 12.2, amt 130 was 12.2 on the high dose starting.

2024 decision modeling analysis using TRACK HD data estimated a 36 month TFC change of −1.989 for the TFC 11–13.

AMT-130 high dose: −0.27 tfc at 36 months, n=15

We can agree this isn't 100% like for like, but the starting TFC is remarkably similar, and the populations are in a comparable early functional range

You have that plus the 2000 study of 575 patients with baseline showing per year 0.97 points loss for tfc 7-13. Check out all the studies below.

Historically, patients with higher baseline TFC have generally shown faster TFC decline than patients with lower baseline TFC.

Uniqure had a loss of 0.37 points at 4 years.

The updated Enroll-HD external control shows −0.94 TFC points at 48 months, while the earlier Enroll-HD control produced approximately −1.24 points. Again, I ask here, are these aggressive or conservative control numbers? Where are all the 2 year, 3 year, 4 year studies in hd showing anything like these numbers?

2024 track hd study

https://t.co/4y5K9OThYf

2000 study
Tfc 7-13
0.97 per year

https://t.co/HkBSnEuluy

The CREST-E study of creatine for Huntington disease: A randomized controlled trial

N 278
Starting baseline 10.18

Estimated placebo TFC decline was 0.70 points/year; the trial was designed for up to 48 months but was stopped early, with only 36 participants having ≥4 years of primary outcome data.

https://t.co/84Lg1aHGUZ

https://t.co/E9ZRYsO0EH

2CARE study
609 participants
Starting baseline 10.9
0.83/year

only 34% of participants had completed 5 years of follow-up at the time of study termination, although 91% had completed at least 1 year of follow-up and 69% had completed 3 years

https://t.co/Upq6aZjaDi

@peter_mantas @Tim_Corr @laurencurehd @Christina4HD @JRenz0418 @DesertDweller93

[Tim @Tim_Corr]

$QURE

Three HD abstracts at ISPOR Europe Nov 8–11, Vienna:

Patients: 60.8% work productivity impairment once diagnosed

Caregivers: 60.5% work impairment, QoL 5.5/10

EU5 ex-payers (independent Precision AQ survey): 60% yes in principle to reimbursing pre-symptomatic gene therapy

https://t.co/8J4A3wi8KA

https://t.co/EqpEdduqwP

https://t.co/1AchourRYG

[Tim @Tim_Corr]

$QURE
There is also another interesting presentation at the annual ERN-RND (rare disease conference) October 9-10th

Ralf Reilmann inventor of Q-Motor is giving a presentation titled “Natural History Studies as Historical Control Data in Trials — Problems and possible Solutions.”

https://t.co/fqRrMXKGtl

[Tim @Tim_Corr]

$QURE
Here is another presentation at the upcoming movement disorder conference October 5th.
https://t.co/rMWzbFjKiw

[mike @mike98572986]

$qure $clpt per @Tim_Corr

Nice

Uniqure just addressed 2 problems today, see unlocked abstracts, what hd patients consider meaningful and why people drop out of trials, might want to read the conclusions of the abstracts.

https://t.co/7Ror8DZsMA

https://t.co/nQjJFjQDU9

[Tim @Tim_Corr]

$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.

[mike @mike98572986]

$qure $clpt

Got some DM’s about whether I think Uniqure will meet the deadline.

I personally think so but I think your guesses are as good as mine. I would assume the FDA is looking at the 4 year data and is talking about what the confirmatory trial is going to look like. This is by far the most likely thing that is going on.

My personal opinion is I think the FDA will say, dose 200 people and track them. I still believe the 4 year data is going to be extremely good. If the FDA has in hand good 4 year data, mri images, q-motor scores, I think you can honestly say all options are on the table here. If something came on health wise that is a whole different discussion, that would change this situation quite a bit, I don’t believe that is what is happening here but at the end of the day that is not impossible.

Will you panic if they miss the deadline and don’t hear from them?

Nah, I am not doing anything until I hear from the company, I don’t care if they miss the deadline and I get smoked near term. I am not selling out because they missed a deadline, you just don’t truly know what discussions are happening behind closed doors. Matt could also be waiting for the FDA to decide what the confirmatory trial is going to look like and wants to be on the call with that information.

If we want to go extreme unlikely scenario but not impossible, Uniqure actually could technically get full approval instead of aa at the end of the day. This sounds like crazy talk especially after the week we just had but hear me out. The bears will laugh me out of the room on this one but that is okay.

I think full approval is a possibility, obviously not a likely one but with all the new things the fda is talking about, you technically could get it. Not to mention all the political stuff and the signal this shows to the rare disease community. You would need the Q-motor data to be good, 4 year data, mri images, nfl. You would need all of those to align. That is a hell of a data package at that point. This is indeed crazy talk but it isn’t 0 percent. All those 4 things are not impossible for Uniqure to have and therefore you can’t put 0 percent probability on that scenario playing out. Uniqure would apply under AA just like FAYUVI did and when decision time comes they technically could grant traditional approval.

I don’t delete posts because if I am wrong I need to eat it, I have been wrong before and I am sure I will be wrong again in the future. A lot of shorts if wrong will just delete their posts and act like it never happened, that is weak, own your opinion and live with it either way. Whether right or wrong, stick to what you believe is happening and own the consequences either way. That is the way.