Dboy

[mike @mike98572986]

$qure $clpt

Thought this was interesting regarding Tabrizi, I knew she was doing young adult studies but I didn’t know they had already 4 years of brain image data on them. Why is this interesting? I keep going back to, how in the world can Tabrizi be so confident that Amt 130 is working?

Because Tabrizi has been looking at the before and after of the amt 130 patients brain images. She has a good idea what is happening on the images. She knows what typically 4 years of progression on a mri scan looks like. I’m talking about the amt 130 patients but I’m sure this additional data is also giving her unique insights. If you don’t want to read, watch video 1

Who is likely the biggest expert on what progressive HD looks like on a MRI over time?

Tabrizi has been generating HD natural history imaging data across multiple cohorts for nearly two decades.

The skeptic will say CED makes this entirely mute, I think to be fair there isn’t a crapload of literature out there about this topic and we could likely argue this point for days. The facts are AMT-130 trial took baseline MRI before surgery, so they have a pre-CED structural baseline. There is absolutely no question that CED can impact this, the true question is whether Tabrizi can truly separate disease progression after the CED procedure on the images. I highly recommend video one below, clearly she “believes” she can tell the difference. Time will tell whether she is correct on those interpretations.

Tabrizi was the lead investigator on all 3 studies.

When she looks at an AMT-130 patient’s 3 or 4 year MRI, she’s not just reading it in isolation, she’s comparing it against:

Her own internal model of expected natural progression from TRACK HD and Track On

The HD-YAS presymptomatic trajectory data she’s actively generating and been studying.

For example, her most recent paper on the topic of pre symptomatic

“Importantly, over the 4.5-year study period, the HD gene-expanded group showed no signs of decline in any movement, thinking or behavioural function. However, subtle changes in brain scans and spinal fluid measures designed to detect the earliest molecular changes in the brain, indicate that the neurodegenerative process has already started.”

If an AMT-130 patient’s striatal volumes are holding relative to what 4 years of natural history should look like, Tabrizi would be among the first and most qualified people on earth to recognize that signal.

Having tracked premanifest and early manifest striatal volumes over years of natural progression, she can distinguish between transient post surgical structural changes and long term neurodegenerative atrophy. When reviewing an AMT-130 patient's 3 or 4 year post dosing MRI, she can compare the observed striatal volume against both her internal models of expected natural history and the premanifest trajectory data from HD-YAS. Her expertise allows her to identify whether the striatal structures are holding their volume relative to the progressive atrophy expected in untreated natural history, providing a crucial clinical assessment of whether the therapy is effectively preserving target brain tissue

Video quote below

“I will also share that out of UCL which is a University College London uh Dr. Sarah Tabrizi’s lab has been doing
the HD young adult study and they have it's an observational study that they've been doing now for I think four
They showed their four-year data where they've been able to look at some small changes within the brain of how the putamen if I can say it correctly, of how um some of these things are changing. So their hope is in that the next couple of years there could be a therapy that's developed now that they could then move into this population of um earlier sign either early symptoms or you know ideally pre-symptomatic”

Tabrizi looking at brain image

https://t.co/vbacWf8aW5

Hd video with quote about Tabrizi-35 minute in

https://t.co/rslRhx94W0

https://t.co/La9b8N1FLt

[Harpoon Harry @oshea9_harry]

Chemo free complete response obtained by Candel, years ago!

https://t.co/jK2dGfr7U9

The complete responder in the CAN 3110 trial: This patient had recurrent glioblastoma after initial surgery, chemoradiation, and temozolomide.

In the repeat dosing cohort, they received multiple injections of CAN-3110 with no concurrent chemotherapy.

Serial biopsies over months showed the virus triggering a strong immune attack, ultimately replacing tumor cells with immune cells and achieving a complete pathological response.

This highlights CAN-3110’s potential as a chemo-free viral immunotherapy at the point of treatment.

[mike @mike98572986]

$clpt $cadl at Jefferies

Not bad not bad..

I think equally exciting but in an earlier stage of development, which is called linoserpaturev, formerly known as CAN-3110. It's a different mechanism of action. It's also a viral
immunotherapy, but this is a true oncolytic virus, but it's a next generation replication-competent herpes simplex virus that has been designed to replicate specifically in the tumor while sparing the healthy tissue. We tested in probably the most difficult to treat form of cancer, which is recurrent glioblastoma. We've seen beautiful effects where we see even after a single injection, doubling of expected median overall survival. We've studied the molecular and immunological changes. We published this in "Nature," and more recently, we presented data where we injected this multiple times, each preceded by a brain biopsy. We've learned a lot about the tissue response in the brain of patients to linoserpaturev. We published this in Science Translational Medicine. We are on the cover.

I think we've shown there the first pathological complete response in history in recurrent glioblastoma. This is a big unmet need, big commercial opportunity in an area that has been a graveyard for the industry, where we are planning now a randomized controlled phase Il study.

[mike @mike98572986]

$clpt

Very nice

Prescriptive Approach to Convective Perfusion of the Bilateral Thalami for Gene Therapy

Systematic convective delivery to the thalamus ensures consistent perfusion and enhances both accessibility and procedural uniformity across surgeons and institutions. This methodology reduces the learning curve for convective perfusion and will permit practitioners to implement the technique more efficiently and effectively.

https://t.co/1TweerGCaQ

Lonser, Russell R. MD1,2; Elder, J. Bradley MD1,2; Damante, Mark A. MD1,2; Gray, William MD3; Zabek, Mirek MD4; Rabon, Matthew BEng5; Cooper, David L. MD6

[Peter Mantas @peter_mantas]

$IONS readout soon could be interesting. Original post below.

[mike @mike98572986]

$clpt Irraflow

Joe might just be a genius.

[mike @mike98572986]

$qure $clpt

Schedule of the meeting today

https://t.co/i2bUkB2at7

[Longroader @Longroaderstar]

$qure

Setting the stage. AMT-130.

https://t.co/bVEQabn0ac

[mike @mike98572986]

$qure $clpt

Definitely a lot going on today

OTP TOWN HALL: BEST PRACTICES FOR PREPARING BLA SUBMISSIONS FOR CELL AND GENE THERAPY PRODUCTS

https://t.co/eqXO0cyWZ0

[mike @mike98572986]

$clpt

Interesting….

[DesertDweller_ROAR_4_A_CURE_4_HD @DesertDweller93]

All interested in @uniQure_NV $QURE AMT130, clear your schedule for this meeting today live streamed on YouTube. Looks like @Christina4HD and @KarlMiran will be on the agenda between 1:15-2:15 EST. They get 5 minutes to speak, and panel can ask follow up questions according to the agenda.

https://t.co/BYLWMbGLOD

[mike @mike98572986]

$qure $clpt

The groups expressed dissatisfaction with the prior leadership under Marty Makary. The meeting emphasized trust-building as Diamantas seeks a permanent role and aims for a collaborative approach with stakeholders.

The meeting, confirmed by a government official, addressed concerns and sought to build support for treatments catering to small patient populations.

as Diamantas listened to concerns and reinforced the agency's dedication to advancing rare disease therapies.

Attendees urged Diamantas to provide greater regulatory clarity and predictability. While no commitments were made, discussions underlined the need for innovative approaches to clinical trials and enhanced public engagement, as emphasized by a spokesperson for the Foundation for Angelman Syndrome Therapeutics.

https://t.co/TkN9fSJoug

[mike @mike98572986]

$qure $clpt

As far as I can tell, this is a new FDA page… I could be wrong though but I think it is.. once again, possibly a page that has been there and I have never seen it. Way back page acts like it is new also. If this is new this is big, do what you will.

CBER Biological Product Approvals that Used Real-World Evidence

https://t.co/vAp4Jkfyrb

@peter_mantas @biggercapital @DesertDweller93

[Banana Oncology @Banana_Oncology]

How it feels on BioX last 24 hours $ABVX

[Adam May @A_May_MD]

I keep hearing people referring to "7" cases of cancer in the high dose arm for $ABVX. I get it - that's what they technically showed in the table, but in observing a lot of conversation about this I gather that people don't actually realize what really matters there. I am strongly of the opinion that there are really only 2 malignancy cases that matter for adjudication - the prostate cancer and breast cancer cases.

I initially started talking about these cases as "the 2" cases from the very beginning because I assumed that everyone would be on the same page that these were the only 2 that mattered...but I've found that people really are considering this as a case of *7* full blown malignancies in the 50mg arm...This is just not correct.

Let's break this down.

First of all, they're counting "colonic dysplasia" in this table as one of the "malignancies". I cannot stress this enough: Colonic dysplasia is, by definition, LITERALLY not cancer. This is actually an unequivocal point that I don't understand how it could even be up for debate.

"Dysplasia" is a "precancerous" lesion. Cervical dysplasia, colonic dysplasia, melanocyte dysplasia. Terms exist for these PREcancerous findings because they are, by definition NOT CANCER (otherwise, if they were cancer, we'd call them cervical cancer, colon cancer, and melanoma)...

Dysplastic lesions, not being cancer, often regress on their own or simply never evolve into cancer, staying in the "dysplastic" state until death. However, if they *do* become cancer, they do so through a process that is called "malignant transformation". Literally, something that is NOT malignant TRANSFORMS into something that is.

Why did the ABVX management team include this in the list of "malignancies"? Honestly, I don't know. I think it is an evident mistake, and a strong piece of evidence that they didn't think they'd actually have to explain away a "cancer signal" in this dataset because their analysis of the data told them that there isn't one. If they were worried that the market was going to interpret these data as a catastrophic malignancy risk (which, make no mistake, is what the current low $70s price tag is assuming), they would've likely adjudicated this more thoroughly and left the "malignancy" that is by definition NOT malignancy off of the "malignancy" table...

So that is tossed out easily IMO. 6 cases left now. 4 of those are NMSC (non-melanoma skin cancer). I gather that people are dramatically overestimating what a diagnosis of NMSC means. Far be it from me to minimize NMSC (since it is what I treat for a living as a dermatologist), but guys....this is NOT in the same category as ANY other malignancies. NMSC is a milder category of its own, and I don't mean that as a matter of opinion. Literally, "non-NMSC malignancies" is a distinct endpoint used to gauge risk of "serious" malignancies in clinical trials. NMSCs are left out of that category because they almost never are "serious" - certainly almost never life threatening.

Here's an exercise anyone can do to drive this point home. Google, or ask an LLM "what are the 10 most common cancers in the United States?". They are all going to give you the same answer: Breast & prostate will be the top 2 at slightly >300,000 cases/year.

So breast and prostate are the #1 and #2 most common cancers according to every source...except, those sources either ignore completely or footnote at the bottom that there is a type of cancer 15x more common...NMSC!!!

The point? Ubiquitously, NMSC isn't even included on the list of "most common cancers" because they're frankly in a separate category altogether from cancers like breast and prostate. It actually is controversial whether or not it is even possible for basal cell carcinoma to metastasize, and (aside from transplant patients), CSCC is almost never fatal unless left ignored/untreated for years (people ignoring a giant bleeding skin cancer is perhaps more common than you'd think, but not happening in any clinical trial patients).

These 4 50mg NMSC cases (vs 1 in the placebo group) are a not representative of serious malignancy risk even if the market is acting as if they are...they are absolutely in milder a category all their own, and lumping these all together is a mistake.

Again, if people think these 4 NMSC cases are some scary life threatening event, they're just flat out wrong. There are >15x more cases of NMSC than breast cancer in the US/year, yet >10x more breast cancer deaths occur in the US per year.

Again, not to minimize my own career too greatly, but almost *always* NMSC are removed by VERY simple, ~10 minute procedures under local anesthesia. Cutting out (or scraping away) the lesion typically takes me around 60 seconds, and the bulk of the procedure is actually spent stitching the patient back up. Drive yourself to the office, drive yourself home, local anesthesia, under an hour, you're cured. Hell, in many places in Europe it is actually standard practice to not even "treat" a basal cell carcinoma! On many body locations they are simply biopsied, and once diagnosed they are considered cured by the biopsy itself!

It has become very clear to me that people are thinking that these NMSC cases are highly relevant cases of severe, potentially fatal cancer. They simply are not. There are *millions* of these in the US per year and most are treated with <15 minute procedures. These are in a TOTALLY different, far less serious category of "cancer".

So again, why wasn't $ABVX prepared to discuss/explain this? I legitimately think they did not expect to need to. They may have overestimated the market's knowledge here and underestimated its potential for a knee-jerk reaction to the "C-Word". It's a mistake, yes, but it ultimately doesn't change the profile of the drug.

So, I think we have compelling cases to write off the colonic dysplasia (literally not cancer) and NMSC cases, as I have usually found to be standard in these situations.

That leaves the breast and prostate cancer cases. Again, the otherwise #1 and #2 most common cancer types...funny how that worked out! I sincerely do not believe that these two cases alone represent a signal against 0 in the placebo arm. This is textbook small sample statistical noise, ESPECIALLY for a drug with no mutagenic risk AND no immunosuppression (literally, HOW would this drug even be causing cancer then???).

However, clearly the market will want more info here on these two cases.

Hopefully the market will wake up to the points above (that $ABVX and I mistakenly thought were obvious) highlighting that the colonic dysplasia and NMSC cases can be almost completely written off. After that, hopefully $ABVX can give us more info on these two "legit" cancer cases (breast and prostate).

Yes, they should've been ready to do so on the call. they messed up, but let's see what the details show. Some are saying we will see updates sooner than the October conference like they initially guided for on the call (at which point they clearly did not expect the market to be freaking out at all).

After that, we also need to see the data from the 50mg "escape/placebo" arm that was not part of the primary efficacy analysis. That's is own topic of conversation, but that could significantly rewrite the narrative (now that $ABVX is aware a narrative needs to be rewritten after it got away from them).

I think the market thinks they are hiding these "escape/placebo" arm 50mg patients' data. I believe they were just totally caught off guard by the market's reaction to the "cancer signal" here and didn't think they'd need to have that dataset ready to prove there's no cancer risk (they thought the initial dataset spoke for itself...I agree, but so far the market clearly doesn't).

There should be several hundred patients worth of extra 50mg patients in that group. Ideally they can move up the release of that dataset to help qualm the market's fears and try to prove they aren't trying to hide anything there. Depending on the sample size there, we should very likely expect a few "cases" there too, but if the rate comes in lower than the original 50mg data we got, this narrative could snap back rapidly. Let's hope!

[mike @mike98572986]

$qure $clpt

Full disclosure, this article says it’s new, maybe it’s old news but it says exclusive and 3 hours ago, so not 100 percent sure, sounds like new news but it says can’t find this out anywhere else and maybe just reposting of old news.

The Food and Drug Administration on Tuesday will issue draft guidance for how companies developing cell and gene therapies can rely on existing scientific knowledge to avoid unnecessary tests and speed up the development process, the agency exclusively told Axios.

•The new FDA guidance outlines how this prior knowledge can be used so that companies aren't essentially starting from scratch each time they develop a new product.

•Using prior knowledge "may be particularly helpful in the context of [genome editing] products intended to treat rare diseases, many of which may be serious and life threatening," the FDA writes.

•The industry complained that the agency repeatedly went back on what it had previously told companies about drug reviews and standards.

And while FDA officials publicly spoke of regulatory flexibility and a vision of bringing new therapies to market faster, the agency's real-world requirements of specific companies were frequently accused of being unnecessarily onerous

https://t.co/i2IAKHIOJv

[mike @mike98572986]

$qure $clpt

There it is

[Yair Einhorn @yaireinhorn]

The Baker Brothers - or under its official name “Baker Bros. Advisors LP”, is by far the biggest “Healthcare only” investment firm in the BioTech and Pharma ecosystem - managing $28.1B of Assets Under Management (AUM) 🧵👇. Just for comparison - the second biggest investment firm - orbimed - is far behind with “only” $20.6B of assets under its management. The story of the “Baker Brothers” is a story of both patience and persistence that played a huge rule in their biggest investment ever - Seagen (formally known as Seattle Genetics). Julian and Felix Baker began investing in Seagen in 2003 when they made their initial investment while the company had no drugs on the market and was barely breaking even. In order to strengthen the company’s leadership Felix Baker joined Seagen's board of directors and played a leading role in its long-term strategy. Up until 2023 the investment firm maintained its high conviction and substantial stake and took part in the company’s strategic plans and operations. In March of 2023 $PFE announced an all-cash acquisition of Seagen for $43 billion or $229 per share - one of the biggest M&A deals ever made in the BioTech and Pharma ecosystem. In December of that year the deal was officially closed and the Baker Brothers received $10 billion in cash for their stake in the company. This was and still is one of the largest single Return on Investment (ROI) in BioTech history. A truly remarkable story!

[Simon Collings @sr_collings]

Arsenal have a strong foundation to build off, and this summer should be about evolution - not revolution - for Mikel Arteta’s side.

Piece looking at what next for the Gunners:

https://t.co/t8I3WyxRS3

[mike @mike98572986]

$qure $clpt

Interesting comments by @TracyBethHoeg , obviously by being head of Cder she had no involvement in Uniqure but interesting to me that she called it out in her article, is she trying to distance herself from those decisions at the FDA?

“Here are press releases on Zycubo for Menkes Disease, Avlayah for Hunter Syndrome and leucovorin, based on a literature review, for CFD-FOLR1. I was not involved in uniQure and Replimune decisions.”

“At NORD and Rare Disease Day at HHS, I connected with a number of rare disease patient advocates, including for Huntington’s disease, whom I remain in contact with through today as well as U Penn researchers.”

https://t.co/BTux9sqkTq