Jason

- notes from an amateur biotech investor

[Jason @jasmarce]

Apologies if this point has already been made elsewhere, but I think it is worth emphasizing that, since December 2024, $QURE has consistently maintained that the FDA views cUHDRS as an intermediate clinical endpoint reasonably likely to predict efficacy. TFC, by contrast, is viewed as a direct measure of clinical benefit, which is why the FDA recommended it as the primary endpoint for the confirmatory trial.

It is also helpful to consider the original design of the clinical program. The Phase I/II trial was intended as a dose-exploration study to inform a registrational trial. After one year of blinded follow-up in the low- and high-dose cohorts, the plan was to make a go/no-go decision on further development. In that context, using cUHDRS as the primary endpoint made sense as it could provide an early indication of clinical benefit that would ultimately be confirmed in a longer Phase III trial.

Ultimately, that benefit was not observed during the relatively short one-year follow-up period. Management commentary prior to the two-year high-dose data also suggested limited enthusiasm for further investment in the program, with the company indicating that it would initiate Phase III only if it could secure a partner. Given the one-time administration and the commitment to long-term follow-up inherent in gene therapy programs, continuing to follow treated patients did not require the incremental cost associated with ongoing dosing. It was only after the two-year high-dose data that the company pivoted toward pursuing accelerated approval.

With that context, I think the company's messaging should be emphasizing that cUHDRS serves an important purpose in providing an interim indication of whether a benefit exists, while TFC is the more meaningful long-term measure of clinical benefit. Intermediate clinical endpoints and biomarkers such as NfL are ultimately intended to predict efficacy on clinical outcomes. Once long-term clinical-outcome data are available, cUHDRS and NfL should therefore be viewed as supportive evidence, particularly when they are directionally consistent and do not contradict the TFC results.

cUHDRS is the primary endpoint, and as a result, the headline of press releases and articles, largely as an artifact of using a Phase I/II dose-finding study to support accelerated approval. As longer-term follow-up accumulates, however, and the focus shifts toward success in a confirmatory trial, real-world clinical benefit, and payer reimbursement, TFC should sit above cUHDRS in the hierarchy for assessing meaningful benefit to patients. Prioritizing cUHDRS over TFC at that stage would be somewhat analogous to prioritizing PFS over OS, which I know VP would not approve of.

[Jason @jasmarce]

I think one possible explanation for the difference in magnitude of VOC reduction despite Hb induction for PKR activators compared to HbF inducers is the effect on deformability in the deoxygenated state. If PKR activators don��t increase deformability in that state to the same magnitude they do in the oxygenated state it might make sense that there’s a higher rate of VOC compared to HbF inducers despite Hb increases. I haven’t kept up with the latest mitapivat data but that was my concern with etavopivat.

[Jason @jasmarce]

FDA wouldn’t have accepted them into the START program if they didn’t see a significant unmet need and the development plan and timelines were detailed in the application. The feedback they received in June detailed the safety database size required, I think it would be pretty unexpected for them to turn around and ask for a larger n on the basis of efficacy. If animal data is sufficient to prove increase in FXN is reasonably likely to show clinical benefit and the agency gave them written response indicating they are open to the use of skin FXN concentrations as a RLSE, I don’t know how you can look at today’s data and not think they will likely see it as sufficient for AA. https://t.co/FjsjAmPkMH

[Jason @jasmarce]

$LRMR feel free to call me a bag holder, but I still think this gets AA. If the FDA had instructed them to stop dosing or make any changes to the protocol for 2-17 year olds I would be more concerned.

[Jason @jasmarce]

Here’s how I’m thinking about it in terms of the data:
1. skin FXN – reasonably confident in this based on prior data
2. lipid data (when available later this year) – company said FDA has been impressed with what they’ve seen so far and FDA has specifically called this out as data of interest in correspondence, need to replicate early improvements over longer term/larger n
3. safety data – last update was clean, no updates in the interim and FDA has allowed them to continue to dose <18 year olds, so reasonably confident there
4. functional data for ambulatory subset and/or <18 year olds subset (if available) – mFARS read through to confirmatory trial endpoint
5. overall functional data – strong trends would help preempt any concerns with payer coverage, negative trend surprise may impact AA

From AA perspective, as long as there isn’t a surprise negative trend on the overall functional data, I think this will get approved if they show the majority of patients >50% of normal FXN and there are no sig safety concerns.

The company said in their first meeting with FDA in late 2023 on surrogate endpoints and use of FXN for AA the FDA confirmed that (1) there was an unmet need despite Omav approval and (2) animal data is sufficient to prove increase in FXN is reasonably likely to show clinical benefit and human data is not required for proving that.

In the March 2025 Leerink call, pre the regulatory update disclosure, the company said when they applied for the START program they outlined plan of filing for AA and timelines for filing, requirements for AA to be discussed with FDA and timelines for when data would be available and they were accepted into the program. They also said in March 2025 they were in the process of dialogue under the START program on using FXN as a surrogate endpoint to support AA and that animal data could be used in place of clinical outcomes such as mFARS or survival.

In the June 2025 reg update they confirmed that the 50mg animal exposure data was provided to the FDA and FDA acknowledged overlap with human exposure data in their written response and were happy to see exposures animals that had adequate distribution that were similar to levels in humans. They also reiterated there was no discussion on requirement of functional data in the BLA filing for AA, and that the FDA had reviewed their briefing package, are open to using skin FXN as a surrogate endpoint, and had made the comment that the company had “pretty much done all the work.” So I think we can reasonably confident they are satisfied with the animal data package provided and skin FXN as being sufficient for AA.

For me, baseline positive in this update is majority of patients >50% of normal skin FXN, clean safety, and confirmation of timelines ($7-8). If we get a breakdown by ambulatory/non-ambulatory and age groups any strong positive trends on mFARS for ambulatory/<18 groups is incremental positive ($10-12), and strong overall functional positive trends on mFARS/9HPT are a home run ($15+). If there’s a sell off on overall functional data that is mixed/slightly positive but not outright negative and skin and safety data is good I’d likely think that’s a buying opportunity. If they get AA, I think there will be sufficient pressure from the community to cover it while the confirmatory trial is run that I'm not as concerned with that.

Separately, and this is complete speculation, I’ll also mention that when they did a raise at the end of July, Deerfield took down 50% of the offering, greater than their current % ownership at the time so they increased their overall stake. Last offering 2/2024 at $8.74 they were allocated 25% of the offering, so maybe a bit of a make good in advance of data. Obviously, you can make the opposite argument and say a raise before data could show a lack of confidence though.

[Jason @jasmarce]

https://t.co/zWMCbCBsUw is a great resource to find well-vetted organizations for causes that you'd like to support and understand the work that they do. @adamfeuerstein @bradloncar and any others involved in biotwitter, if you can help amplify this., I'd be very grateful.

[Jason @jasmarce]

With all the recent large moves in biotech $XBI $QURE $ABVX $NKTR, I think this is a great opportunity to mention to all in the biotwitter community to please consider a donation to the organizations like https://t.co/eGQfAOTW2p that do the important work to support the people

[Jason @jasmarce]

that are impacted by these diseases. It can be easy to get caught up in the ups and downs of symbols on our screens and lose focus on those that are affected by these diseases.

[Jason @jasmarce]

@Prof_Oak_ but based on the language in 5.3 maybe FDA didn’t agree with it and/or didn’t find it necessary to include a cutoff

[Jason @jasmarce]

@Prof_Oak_ Seems a bit surprising that there’s no language in the indication around a cutoff for a certain AAV5 neutralizing antibody titer. Matt indicated recently they were expecting one and last year said they were preparing a validated test for it

[Jason @jasmarce]

$QURE approved https://t.co/op8HYABcRM

[Jason @jasmarce]

$QURE confirmed today enrollment will resume at the higher dose after DSMB review with no significant changes to protocol beyond closer patient monitoring in the first two weeks

[uniQure @uniQure_NV]

Positive news on our AMT-130 #genetherapy trial for #huntingtonsdisease: Following a comprehensive review, the DSMB has recommended that we resume patient enrollment at the higher dose in our ongoing European Phase Ib/II study. https://t.co/AnZMuGUnDX

[Jason @jasmarce]

$QURE a few interesting updates posted to Clinical Trials in advance of the update from meeting with the DSMB this quarter. 9/8 Matt said the investigation was completed at WF HC conference.

[Jason @jasmarce]

Today the US trial entry was updated to add the surgical adaptive expansion cohort and lists the dose as high dose (6x10^13 gc/subject.)
https://t.co/1FV46gikMk

[Jason @jasmarce]

@drug_smolecules @Biohazard3737 @ErikOtto2 @bio_clouseau They floated idea that anti-drug antibodies could potentially decrease clearance in NHPs. If they're able to resume dosing even with 25/50mg and get to 4wk and eventually 12+ seems like they should be able to more definitively say if there's accumulation similar to NHPs or not

[Jason @jasmarce]

@drug_smolecules @Biohazard3737 @ErikOtto2 @bio_clouseau Do you think there's no scenario where it accumulates in NHPs but doesn't in humans? They started with less frequent dosing in Phase 1 due to accumulation seen in tox studies but increased to qd with 100mg because the levels were dropping off with 50mg.

[Jason @jasmarce]

@Sports_bios For FA probably also will get an update from $LRMR on if there’s any possibility to get the hold removed as they’ll likely receive the minutes from their Type C meeting this month

[Jason @jasmarce]

@JohnsHopkins2 @bio_clouseau but remains to be seen if there’s actually any translatability to volumetric MRI and other outcomes.

[Jason @jasmarce]

@JohnsHopkins2 @bio_clouseau In the minipig model 25-30% CSF decrease equated to ~75% reduction in the deep structures. The way they’ve been talking I think this far exceeds what they were looking for with the low dose so that’s positive