Studying influenza and cell intrinsic immunity @BiochemOxford (Masters student)
United Kingdom
Joined March 2020
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I feel like some very interesting therapeutics lie in the complement system. Not directly acting on it or its effectors, but utilizing it as a signal to trigger the activation of a manufactured protein. Let the body figure out where your drug needs to be activated
Karl Doberman if he had VC money
Warhound, the brain child of Ben Lamm and Palmer Luckey, emerges from stealth to genetically engineer dogs for military and law enforcement.
spr.ly/6011BHZNMF
You cannot make any reasonable conclusions by comparing the HR of the neoadjuvant vs INTerpath trial. Different cohorts, different end points, different questions!
But you would be valid in asking: is a better alternative to a $400k vaccine just administering pembro earlier? $MRNA should absolutely run a trial for this.
Pembro before surgery + after surgery vs vaccine + pembro after surgery
Sid retweeted
$MRNA back to reality.
$MRNA with the single most hilarious possible outcome in this study. EFS HR 0.58. Down the the hundredth, EXACTLY what *NEO*-adjuvant treatment with pembro yielded against adjuvant pembro (the nerfed comparator $MRNA studied against) in SWOG S1801.
What does this mean in English? $MRNA’s drug is showing the exact same benefit versus adjuvant pembrolizumab as NEOadjuvant pembrolizumab did.
Even more simply? If you just give patients a few doses of the pembrolizumab BEFORE you cut their cancer out, you do what $MRNA does for you, except with just the free tumor that’s already inside your body. No need to pay for this $400K drug.
And this makes rational sense, right? The whole point of $MRNA’s vaccine is to produce stuff that looks like the tumor.
You know what looks A LOT like the tumor does? THE FREAKING TUMOR!!!!!!
Absolutely poetic that $MRNA produced the EXACT HR benefit as neoadjuvant pembro did. Truly, the most hilarious possible outcome.
Now can we move on from this bullshit? $MRK and $MRNA should feel free to study their vaccine against the REAL standard of care now - NEOadjuvant immunotherapy.
From my perspective, this has been total fugaze, and an amateurish pump and dump worthy of much lesser enterprises.
Incredible! The expanse of our imagination is truly the only limit to progress. Once the thought has formed, it’s only a matter of time before it’s made into a reality. So many examples of this across our history. From a tunnel across the English Channel to vaccines to alchemy!
Last month, we demonstrated high-rate alchemy: turning mercury into real, stable gold, beating CERN’s record by a factor of 10.
Last week, we enriched isotopes in the world’s most powerful plasma centrifuge, beating the Soviet record that stood for 40 years.
Now, we’re building a fusion reactor in San Francisco to achieve record power density.
Are there ways in which biotech can help end of life patients, aside from the obvious? How useful are we outside of a therapeutic context?
I don’t know if this already exists, but a Twitter account that tweets like it exists in Biotech Twitter during 2021 or something. We need to be reminded of the opinions we held
Boring, next
What is AI really capable of in bio?
To separate hype from reality, we spent 3 months working firsthand with @AnthropicAI's internal research model to see if it could create an experimental scorpion antivenom.
Introducing Citrini Therapeutics.
citriniresearch.com/p/citrin…
Sid retweeted
pretty crazy molecule. very keen to see it work in the clinic. a lot of acting/ counteracting MoAs built in one here.
the thing about a steroid payload is you get way way way less action per mg by coupling them to an antibody. stoichiometrically, you can think of needing typically thousands of steroid molecules per antibody by mass to have an effect.
so you need incredibly powerful steroids to have comparable efficacy to something like prednisone. their GRM payload must be very potent but even then with a DAR4, hard to know if they really do a lot, but that's also kind of the point, you have a more localized delivery via an antibody conjugated delivery. very interesting chemistry and balance being struck.
then ADCC via afucosylation also an interesting choice. will hit cells hard, but I would be quite worried about IRRs and heme tox. this is also where the GRM comes into play, chill out the reaction a bit, keep it on task, and don't nuke the entire immune system.
it's like going long on CD19 with shares, call options and a hedge via puts.
tough indications though, safety has to be kind of flawless.
I'd looked pretty extensively at the steroid conjugated ADC space. not a lot of players. if this one works out expect a ton of interest, but it will be tough to fast follow with novel steroids and coupling chemistries
There are no antibody-drug conjugates (ADCs) for autoimmune disorders... yet.
AbbVie have a CD19-targeting ADC that delivers a glucocorticoid specifically to B cells.
In trials for lupus and Sjogren's, it works in 3 ways:
1) Deliver steroid to CD19+ B cells, reducing systemic toxicity.
2) Induce B cell apoptosis.
3) Further deplete B cells through antibody-mediated cytotoxicity.
Sid retweeted
So what did VERDICT show? In short, it basically says....Endoscopic remission is the endpoint that GI docs should be targeting when treating UC patients.
The study directly showed that achieving endoscopic remission was associated with fewer UC-related complications than even achieving symptom free status.
So if a patient is telling their GI doc "I literally have zero symptoms of ulcerative colitis", based on these VERDICT data, that is still not the target of treatment. The patient needs to be treated to the point that they have ENDOSCOPIC remission with zero evidence of disease upon endoscopy...not just "symptom free" clinical remission.
GI docs have had the suspicion that endoscopic remission was the key endpoint in UC (hence why I have often said it is some GI docs' "favorite" endpoint over clinical remission that is often the primary endpoint in P3s). Guidelines have advised treating to ER based on expert consensus that this might be what matters most.
The VERDICT data today settle that debate. The key endpoint isn't clinical remission (or, even histologic remission) - it is endoscopic remission.
Sid retweeted
There are no antibody-drug conjugates (ADCs) for autoimmune disorders... yet.
AbbVie have a CD19-targeting ADC that delivers a glucocorticoid specifically to B cells.
In trials for lupus and Sjogren's, it works in 3 ways:
1) Deliver steroid to CD19+ B cells, reducing systemic toxicity.
2) Induce B cell apoptosis.
3) Further deplete B cells through antibody-mediated cytotoxicity.
Life span extension research will take a similar path to cancer treatment. I’m not sure if we will ever end up discovering a Keytruda equivalent for aging or if such a thing even exists.
But I’m fairly certain that life span extension will be approached from a highly personalized standpoint, even more so than cancer.
There is now an added benefit now to personalized cancer therapy clinics, who will be well positioned to capture this market
Sid retweeted
$PRME Regulation can make or break a thesis in bio. Between 2024-2026, the FDA has been overhauling how it evaluates genetic medicines and platform technologies like Prime editing, creating a potential tailwind for this type of tech.
Roughly 95% of rare diseases still have no approved treatment. Instead of forcing ultra-rare programs into slow, legacy clinical trial models designed for mass-market pills, the FDA has announced several policy changes to modernize the process:
• Plug-and-Play Platform Reuse (May 2024 & Summer 2026)
Once a delivery vehicle or manufacturing method (like a standardized LNP or AAV vector) is approved, sponsors no longer have to start from scratch. Under Section 506K and recent genome-editing guidance, companies can cross-reference prior safety, biodistribution, and manufacturing (CMC) data across different drug candidates using the same platform.
• Single-Arm Approvals for Ultra-Rare Diseases (Sept 2025)
For severe genetic conditions affecting less than 1,000 U.S. patients, randomized placebo trials are practically impossible. Building on previous policy, the FDA’s Rare Disease Evidence Principles (RDEP) now permit full marketing approval based on a single-arm trial, provided it’s backed by clear natural history data and confirmatory biomarker readouts.
• Mutation Bundling via Draft "Plausible Mechanism" (Feb 2026)
Gene editing therapies often target distinct, patient-specific mutations within the exact same gene. Under the Plausible Mechanism Framework, sponsors could bundle multiple mutation-specific editors into a single trial and BLA under a master protocol. In addition, new mutation variants could potentially be added post-approval without requiring full-scale clinical trials.
• Restored Non-Dilutive Capital & Division-Wide Alignment (2026)
Congress and the White House reauthorized the Rare Pediatric Disease Priority Review Voucher (PRV) program, restoring an asset historically worth about $100M+ in cash upon approval. Capping this off, the FDA’s recent rare disease framework whitepaper standardizes Bayesian stats and flexible CMC inspections across all CDER and CBER review divisions to eliminate inconsistent standards.
In short, for modular genetic medicines with hard biomarker readouts, the FDA is starting to dismantle the traditional 10-year development gauntlet in favor of a faster, capital-efficient, plug-and-play framework. While some of these shifts are still in a draft or non-binding guidance status, they're shaping up to be a regulatory sweet spot for therapies like prime editing that directly repair a root genetic mutation and deliver objective, binary biochemical proof.
$PRME The FDA's new Rare Disease Framework Initiative is well-timed for Prime, especially considering their $108.8M in cash as of Q2 (runway into 2027).
Roughly 30M Americans have a rare disease ($997B annual burden), yet only about 5% have an approved therapy. Historically, the FDA’s 18+ rare disease programs were applied unevenly across review divisions (for example, the FDA rejecting uniQure’s plan to file a single-arm BLA in Huntington’s and mandating a sham-surgery trial).
The new framework aims to fix this division-by-division inconsistency by calibrating evidence and manufacturing rules to what is realistically attainable in small populations. This initiative caps a 13-month wave of CBER and CDER reforms to make regulatory flexibility the default norm.
Here are 4 ways the FDA's 2025–2026 rare disease overhaul could directly impact Prime:
1) De-Risking PM359's 1H 2027 BLA
While seeking a CGD partner to focus capital on in vivo liver programs, Prime is advancing PM359 (granted RMAT in June) toward a 1H 2027 BLA on Phase 1/2 data.
Unlike Huntington's (which has about 40,000 U.S. patients), p47phox CGD affects fewer than 1,000 U.S. patients and has a clear biochemical readout in functional neutrophil activity (exceeding 20% restores immune function, and PM359 hit 69–83% in NEJM). This checks every box of the FDA's Rare Disease Evidence Principles (RDEP) criteria for a single-arm filing.
2) Removing CMC Bottlenecks & Unlocking a $100M+ PRV
Historically, ex vivo stem cell therapies have been delayed by manufacturing (CMC) hurdles rather than clinical efficacy. Pairing the framework's risk-based CMC rules with CBER's Jan 2026 policy (dropping the 3-PPQ-lot mandate and allowing concurrent batch release and post-approval spec tweaks) could sharply cut the time and cost to make PM359 BLA-ready.
With Rare Pediatric Disease status (recently extended by Congress through 2029), approval also unlocks a Priority Review Voucher (PRV) worth $100M–150M+ in non-dilutive cash.
3) Scaling the "Universal Liver LNP" Platform
PM577a (Wilson disease, H1069Q), its R778L follow-on, and PM647 (AATD, PiZ) share the same GalNAc Universal Liver LNP and Prime Editor mRNA, swapping only the guide RNAs (pegRNA/ngRNA). Two 2026 FDA policies turn this modularity into a major moat:
• Platform Data Reuse (June 2026 Guidance): Safety, biodistribution, and CMC data from PM577a (first patient dosed Oct 5) can be reused across programs (evidenced by PM647 clearing its IND on Sept 24, just two months after PM577a).
• Mutation Bundling (Feb 2026 Plausible Mechanism Framework): Editors targeting different mutations in the same gene (like Wilson's ATP7B variants or Cystic Fibrosis CFTR variants) can be tested under one master protocol, bundled into a single BLA, and expanded to rarer variants.
4) Fast-Tracking 2027 Liver Readouts via Biomarkers
Instead of waiting 5–10 years for clinical cirrhosis or emphysema outcomes, the framework supports accelerated registration using direct mechanistic biomarkers:
• PM577a (Wilson): Measuring how effectively the liver clears copper into bile (via 64Cu PET imaging), blood ceruloplasmin (copper-carrying protein) levels, 24-hr urinary copper, and chelator withdrawal.
• PM647 (AATD): Restoring normal M-AAT protein levels and reducing toxic Z-AAT protein accumulation.
In short, the FDA is systematically removing the biggest historical roadblocks in gene editing for rare diseases, giving Prime a faster, clearer, and more capital-efficient path to validate its platform and monetize its pipeline.
Great article! Isn’t a very easy fix for publication slop to just read the papers? Surely this is already done by people on hiring/grant committees.
I agree that “the paper” has become an oversubscribed metric. It’s a surrogate for the research quality, among other things. But, quality isn’t present in AI generated papers, at least in what I’ve read. So what benefit does it confer to those who use it to pump out publications?
At some point the economics of it stop making sense. Why would you keep paying for tokens and publication fees if your papers don’t lead to meaningful career growth?
Some of my thoughts about the surge in AI-generated papers, why this feels like a completely new kind of problem, and what this means for how we evaluate science in biology.
Out now in PLOS Biology:
journals.plos.org/plosbiolog…
Sid retweeted
2024 to present, went down a rabbit hole of proxy documents from all the mergers and acquisitions in bioland after @daphnezohar tweet. To try to see if I can find any insights into what the turnaround period could be or what the outcomes may look like. I&I , Onco , rare disease and neuro been the hottest areas, will that continue?
Nephrology have the most parties interested 16 per deal n=2. (Also why $vera m&a will have legs) Actually read below with the graphics in the subtweets that will be easier and better.
Findings:
The first mover usually loses once a second bidder appears. In the 18 competitive deals the first party to name a price won only 44% of the time. $nvs took $trml, $rgls and $mor from earlier bidders; $pfe took $mtsr from $nvo; $mrk took $cdtx from Company D and Terns from Party C.
•Competitive processes run on a clock the company sets. Process letters with bid deadlines ($dcph, $akro, $cdtx, $trml, $mrus) and a best and final round are the standard tools. $cdtx committee added a rule that the winner had to clear the next bid by 5% or the top two went another round.
•Single bidder deals price the gap with CVRs instead.CVRs appear in a larger share of single bidder deals; with no second bidder, the contingent payment is how the board closes a valuation gap (Poseida, $etnb , $verv, $bpmc, $aclx, $apls).
•Exclusivity is a prize, not a default. It is granted in a similar share of both groups, and when it is granted it is usually short and bought with a price step ($dawn got $1 more for 8 days; $mor got $57 for exclusivity to Jul 11; $swtx got $50 instead of $49). Deals that refused exclusivity entirely did not give up any bump.
•Competition does not make deals slower from first price. Median first price to signing is similar in both groups. What stretches competitive deals is the longer run up: more parties approached and more diligence before the board lets prices crystallise.
More insights below..
Deals announced in Nov would have most likely had their 1st offer late Sept or Oct.
