andrew

Biomed PhD. Thoughts posted are my own and should not be taken as financial advice - DYOD

[andrew @thecellengineer]

$CABA ripping 30% on news of insider buys. Cat might be out of the bag, but I suspect this will trickle back to $2.5 bc of the pre-funded warrants. Lots of intrinsic and competitive risk but at <300M mc I still see a strong setup with upcoming catalysts. My pick for biosquidgames

[andrew @thecellengineer]

@financebully @a_a_free @Lord_of_Biotech The clinical superiority is precisely what I believe justifies the long thesis. I think it gives an edge for capturing market share quickly in ISM and will lead to a longer therapeutic duration in 2l gist than typically modeled.

[andrew @thecellengineer]

I think bezu could overtake ayva quicker than some expect. The side effects for ayva are nasty and this patient community is tight-knit. I think word will spread quickly and organically. As for 2l gist, I agree that $3b peak sales is unrealistic - I'm modeling ~$2.2 bn global peak and that is with flawless execution. The push into 1L is an interesting development and it sounds like a lot of off-podium talk with KOLs at ASCO is pushing COGT to consider how to get 1L beyond just exon 9.

[andrew @thecellengineer]

I like $cogt selling into the ayvakit launch for two reasons. 1) $bpmc laid a lot of the ground work of specialist education, KIT testing, and referral pathways. The 25% CAGR in ISM diagnoses 2019-2024 they helped create is now being amplified by $sny support. 2) bezu has a compelling value prop versus ayva for both providers and patients. Ayva's CNS permeability and promiscuity result in CNS side effects for over 50% of patients - cognitive impairment including memory loss, confusion, trouble thinking. This is the main reason why the 25mg dose is what's approved for ISM despite 200mg being the EC90. Providers are literally prescribing 25mg and then titrating up to achieve symptom improvement while avoiding edema and CNS effects which appear ~50mg - a very tight window. Bezu has zero CNS effects at EC90 (not BBB permeable) and is creating in complete resolution of detectable disease for some ISM patients within 6 months. Patients are going to love it and can easily understand why it's better. Plus COGT's GIST and ISM sales forces are actually one unit as specialists for both indications practice at the same medical facilities.

[andrew @thecellengineer]

Also note the delay in B cell depletion for no-PC. Interesting to see given the CAR T expansion happens more or less around the same time as PC patients shown in image above

[andrew @thecellengineer]

$CABA hot take on new slides & Jeffries call.

tl;dr clear accretion to NPV despite market reaction. Myositis PoS up on data - main risk is SA design. JDM data looks encouraging. SSc moves from blue sky to base case. No-PC SLE data is positive incremental signal. Downside of few meaningful catalysts left this year - FDA clarity on SA design is a possible big one. Unlikely to see much if any further no-PC data until it is mature enough to comment on selected dosing and preliminary safety and efficacy with durability. The work CABA continues to advance is medically transformative and potentially immensely valuable. Let’s see how the market absorbs the data.

Pros:
- No-PC SLE/LN — IMO this data looked encouraging and perhaps is the biggest derisking factor for long-term value creation. Granted, just 2 patients. The SLE patient had deep B cell depletion and then LN patients had 90% reduction in B cells levels. LN is a tough nut to crack but… look at the patient’s starting level of B cells relative to every other patient’s(!) (including other LN with PC) - it’s top-3 highest. PC is probably doing some debulking work that creates a more hospitable environment for CAR T expansion - the data show a possible ~10 day delay in B cell depletion for no-PC SLE/LN and pemphigus relative to the rest of dataset. Regardless, this data is a significant pieces of evidence that PC isn’t required for B cell reset in patients with more systemic autoimmune conditions. It wouldn’t shock me to see >>50% of LN/SLE patients have deep B cell depletion w/o PC at higher doses. BAFF also suggest this could be overcome with higher dose.
- Myositis and scleroderma data are strong. They are disease modifying in way current and imminent therapies aren’t. Especially compelling as a product in juvenile DM and scleroderma where disease severity will organically drive adoption.
- The JDM data increase PoS for PRV voucher (worth ~$100M)
- In SSc the improvement on FVC will be the recitation endpoint and could be first in class as a disease modifying therapy - stopping or reversing respiratory decline rather than slowing it. Huge for these patients as they have usual life expectancy in the 2-3 year range. Encouraged by the 12 patients evaluated - signals demand that should keep the 24pt registrational trial enrollment on track.
- Management is laying the ground work with payer engagement for DM and SSc commercial launches. We’re told that 52wk durability for TIS improvement is the minimum and 78wk is ideal. The durability is maturing with 3 pts showing sustained durability out to a year and one pt with a durable response out to 80wk. The TIS metric is a bit noisy - lots of ups and downs but every 6/6 patients (including juv DM) with mod/major improvement at 16wk held through at least 32 wks. Not only does this data derisk P3 approval, it suggests RESE-CEL strongly aligns with payer incentives.

Cons:
- The registrational myositis trial requires 14 DM patients and 3 ASYS. Enrollment is quietly filling but no indication from management on actual numbers. Possible delay flag.
- The no-PC data will require higher dosing of RESE-CEL for desired response/durability in SLE/LN and potentially DM, SSc, MG - this could produce unforeseen safety issues. Any serious signals would challenge the outpatient GTM strategy for most indications.
- Few anticipated 2026 catalysts. A rerate, deal, or FDA commentary on SA registrational design would be pleasant surprises but not forecasted.

[andrew @thecellengineer]

LN no-PC starting B cell count was quite high

[andrew @thecellengineer]

@Investorclimber Bad macro day for biotech. Will take time to digest the good data unfortunately

[andrew @thecellengineer]

@RaminNasibov

[andrew @thecellengineer]

@bryan_johnson @_katetolo Bring back international travel by boat.

[andrew @thecellengineer]

I'm excited to see more FROs like https://t.co/fCsjNeJvji and industrial policy like NSF's X-Labs.

Modern biotech increasingly benefits from industry-grade datasets, tooling, and engineering that are not easily produced by even the best NIH-backed academic collaborations and don't align with a VC thesis.

[andrew @thecellengineer]

Agree blina dosing wasn't optimized for AID, but IV infusion saturated drug exposure so I'm not convinced extended PK solves the durability issue.
The published CLN-978 readouts are B-cell depletion and preclinical, not durability. Blina-treated patients also looked great at 3mo, and healthy cynos are easier than inflamed SLE patients. Durability is a 12mo+ question. We will certainly see more at EULAR.
For what it's worth, I hope AID patients get many options for treatment and that CGEM / TCE approach ultimately succeeds. Realistically though, it isn't trivial to just add indications and outcompete on market share when being years behind. Eventually, if TCE is durable, then sure.

[andrew @thecellengineer]

Agree completely. I love the vision for a future without cardiovascular disease, but Repatha only treating a couple million patients over 11 years of approval is a harbinger of the difficulty getting payers to authorize. 30% of PCSK9 claims are denied. I’m closely watching enlicitide’s (probable) launch later this year, as if a macrocyclic drug can’t get decent market share, how will a gene therapy?

[andrew @thecellengineer]

@ladanuzhna I’m excited by the science and potential health benefits (I have hypercholesterolemia). We’ve had approved PCSK9 inhibitors for over a decade. Single digit of eligible patients have been treated. 1 in every 3 prescriptions rejected by insurance. We need better access

[andrew @thecellengineer]

This is great scientific innovation but we NEED access innovation.

We’ve had FDA APPROVED PCSK9 inhibitors since 2015, yet of the 80M Americans with elevated cholesterol <3M have recieved this therapy ever. That is 9 of 10 not getting treatment.

Gene therapy is harder.

[Afshine Emrani MD FACC @afshineemrani]

1/5
I'm a cardiologist. I have spent twenty years watching cholesterol destroy arteries, trigger heart attacks, and kill people I care about.
Today, Eli Lilly presented data that may begin to end that era.
VERVE-102. A single infusion. One dose. It uses base editing to permanently turn off the PCSK9 gene in your liver.
Presented today at the European Atherosclerosis Society Congress:
88% reduction in PCSK9.
62% reduction in LDL cholesterol.
Sustained up to 18 months.
No treatment-related serious adverse events.
One infusion. Not daily pills you forget to take. Not monthly injections. One dose — and your cholesterol may stay low for the rest of your life.

[andrew @thecellengineer]

@garrytan Gary, this is great scientific innovation but we NEED access innovation.

We’ve had FDA APPROVED PCSK9 inhibitors since 2015, yet of the 80M Americans with elevated cholesterol <3M have recieved this therapy ever. That is 9 of 10 not getting treatment.

Gene therapy is harder.

[andrew @thecellengineer]

@MasalaFry69 @Radion_Popalzai @EricTopol @NEJM @skathire This isn’t evidence that supports a harmful phenotype from depletion of LDL via PCSK9. The Dallas Heart Study is more direct

[andrew @thecellengineer]

@EricTopol @NEJM @skathire Remarkable, but patients should be able to gain access before sig disease. Prior auth = clinical ASCVD + LDL >100 on MT therapy?
That sucks.
COGs are good but will $LLY set a price that payers can tolerate? Huge TAM so maybe 10x haircut from typical gene therapy pricing?

[andrew @thecellengineer]

@MichaelAlbertMD Remarkable, but patients should be able to gain access before sig disease. Prior auth = clinical ASCVD + LDL >100 on MT therapy? That sucks.

COGs are good but will $LLY set a price that payers can tolerate? Huge TAM so maybe 10x haircut from typical gene therapy pricing?

[andrew @thecellengineer]

@cremieuxrecueil Love to see next-gen PCSK9 therapies like this and Merck's enlicitide advancing toward approval, but insurance coverage is going to be a bitch or going out of pocket will substantially limit who can access these amazing preventative medicines.