Sharing some of my diligence regarding $PEPG, which helps explain why I remain quite bullish into the 10mg / kg MAD readout. I may share more if I have time to get the rest into a distributable format and think it adds something. The headline takeaway is twofold. One, I think the outlier in the 5mg / kg MAD has little bearing on its chances of EDODM1 continuing to show best in disease efficacy in the higher MAD cohorts like it showed it in the SAD cohorts. Two, I think the EDO51 safety data and how it has tracked with EDODM1 substantially increases the likelihood there will be no SAEs at the 10mg / kg MAD dose for EDODM1, and EDODM1 will deliver a strong and commercially competitive safety profile. $PEPG is a one drug company, early stage, and the most advanced drug in its class. So, efficacy and safety risks will always exist and can never be fully ruled out. If EDODM1 fails, it's over and the stock will be crushed, albeit perhaps some value can still be extracted from the remaining cash balance given the heavy institutional ownership and sway over management. This remains a very risky investment. However, if it's successful, I would say that it is at least a 10x return from current levels, possibly a good bit more, especially with a buyout premium, and I think the probability of a strong 10mg / kg MAD make the company highly compelling at currently trading levels if position is appropriately sized. Thread below:

Time for a portfolio update. TL;DR $ABVX and $NKTR seriously tanked the portfolio since the last one ($TENX was also an L but that was a small position so was quite a small contribution). $PEPG, $QURE, and $IVA are really critical readouts coming up in the next few weeks that are likely to move the portfolio substantially, one way or another. Wanted to put out where things sit ahead of then for accountability As noted previously, majority of capital was committed many months after each portfolio's start date, so start dates are somewhat misleading in that regard (e.g. for WSLS II about 40% of capital...a lot of it $ABVX post-cancer freakout... committed from May 2026 onwards). Probably going to combine them into one and have a better display layout when I have time, don't really want to do a more classic time weighted approach here bc I think that would paint a rosier view of performance than is warranted. _______________________ Re $ABVX, my brilliant strategy of loading up time and again since Fall 2025 with more and more non-biotech allocated capital because hey the market will totally figure it out this time and you know I think I'll be able to flip that into other positions with readouts further out, plus its really derisked and probably getting bought anyways, and where else can you find an opportunity like that in the market has all worked out about as well as you would think...pretty terribly. WSLS II in particular is really living or dying by the VAX at the moment. However, I have continued to hold basically my full position, with the exception of selling a small silver to get a little tax loss harvesting motion going (cope) and free up a little capital for some diversification in an ugly market and to play a few nearer term binaries. I made a judgment call on $NKTR pricing dynamics that there was a reasonable probability there would be little buying support after it nose dived following off treatment data based on the broader market conditions, the apparent lack of confidence in management across the Street and the lack of near-term catalysts, and closed out a big part of the position. I took that capital and did the following: I took a position in $ZURA on the basis of Adam's really thoughtful work. All of the arguments made sense to me for why IL-17A was the critical driver of Bimzelx's superior efficacy. However, I became concerned about tibulizumab's IL-17A target engagement in vivo. Briefly, my concern arises from the fact that a) tibulizumab's binding affinity is 14pM to ixekizumab's 1.8pm in vitro b) I think there is a risk that the very high concentrations of BAFF in vivo relative to IL-17A further interfere with target engagement w/ IL-17A, perhaps as may have happened with sonelokimab and IL17-F, recognizing $ZURA's bispecific has two ends so this view is predicated on things like aggregation dynamics, membrane bound BAFF etc and c) the only in vivo metric of target engagement w/ IL-17A I have been able to find across the IL-17A antibodies / small molecules is an increase in Total - IL17A and cosentyx and tibulizumab show a similar ~50x ish increase (see 2020 article in Dermatology) (investors.zurabio.com/static…, onlinelibrary.wiley.com/doi/…). Increase in Total IL17-A is a really imperfect metric, and is highly susceptible to measurement error at baseline, differing clearance rates, etc. which could all seriously mess with results. However, collectively that represented too much risk for me to want to take on, especially given the important upcoming binaries with 10mg / kg MAD for $PEPG, $QURE's BLA filing decision, and $IVA (more on that later). So, I sold the position for a tiny gain. Depending on how $ZURA reads out, might be back in for SSc. I went back into $MAZE in reasonable size. I opened a position in $IVA (some brief commentary here: xitter.cf/WaveStrumLS/status/211…) I went back into $PCVX after it dumped into the 60s following data. I opened a position in $MDGL. The thought process with $PCVX and $MDGL was basically these late stage companies got torched from their highs in a manner somewhat akin to $ABVX. If you believe this reflects short term pricing dynamics that don't reflect underlying value (degrossing, etc.) but have hit quality names really hard, at some point that will turn around and so you’ll get more of a return than you should for a company at this stage, while not exposed to drug failure / trial risks the same way. For $MDGL, I also used it as somewhat of a hedge against $IVA. If $IVA fails and sentiment swings back in favor, I expect $MDGL will rise and hopefully offset some of the $IVA loss. If $IVA succeeds, my hope is that it will have relatively minimal impact next to the $IVA gains. I further increased my $QURE position after the 4 year data. I have written about this elsewhere but the likelihood that this is having disease modifying effect is near certain in my opinion based on the totality of data. If that's true, I think it should be approved. As mentioned, if $PEPG, $IVA and $QURE do what I hope they do in the next few weeks, we hopefully will be back on a good growth path with the port. If not, that will suck. I do continue to believe for all the many reasons previously discussed that $PRME has the kind of upside potential to be a true marquee VC style investment wherein everything else could get crushed and, if it reaches its full potential, the portfolio still delivers beats the market over the long-term. (And as always, I think its very derisked at this price sans a black swan safety event given the $VERV acquisition at the depths of the bear market for 1 - $1.3Bn, the actual platform nature of the technology, the evolving FDA approval environment that favors said platform, etc.) I was in and then out of $DFTX, decided I liked other opportunities better

To be fair, Dean Kamen dropped out of WPI and is one of the most prolific medical inventors / entrepreneurs in US history first.global/dean-kamen/

Yet ANOTHER datapoint indicating $QURE 's AMT-130 has disease modifying effect. Look at the drop off in cUHDRS in those who did not complete Week 101. Data point after data point after data point all point in the same direction. And, the most notable data point of them all remains the updated 3-year data showing highly stat sig 80% slowing on cUHDRS and the stat sig TFC on both 3 AND 4 year, DESPITE the presence of dropouts in the control arm even at 3 year which of course will bias towards being the worst progressors.

Okay boys who is the asshole that went levered long $MRNA into ESMO and now has to sling their long book to cover? That’s what’s happening right? Right!?!?!? Hashtag always be coverin' $ABVX

I think $PRAX is fairly likely to end up in the news in future years. The Phase III studies were 8 weeks and 12 weeks respectively. That’s very short. The drug is a once daily oral drug. Easy to take. Nevertheless, 35% and 38% of patients dropped out of the Phase III study vs. 5% on placebo. The most notable complaint was brain fog. I cannot tell you how poorly set up these studies are to detect “brain fog” in a quantitative way beyond self-report. Same holds true for cognitive impacts or really any other deleterious brain insults in the short-term, and they of course can say nothing about the long-term. However, “brain fog” and a 35-38% drop out rate w/ a 30%+ delta over placebo is a MAJOR red flag that there’s something going on here that patients really don’t like, and it comes on quickly. This delta is particularly concerning because there are a lot of mechanistic reasons to worry about what this type of inhibition in the brain does long-term. One warning sign I would look for is elevated conversion rates to PD. Long-term follow up studies really should be run. Actually pretty concerned about this given how prevalent ET is. Though, beta-blockers are bad news for the brain too.

This is actually one of the better biological uses of LLMs in the near-term with tangible benefit. There is a LOT of biological data (quantitative and qualitative) from different sources on purportedly the same topic, and organizing in a digestible and interrogable format which dataset says what and what evidence the dataset actually provides, and then synthesizing a more accurate map of the topic with reference to source evidence is actually quite useful in generating new ideas, insights and understandings of the topic and understandings of the holes that need to be filled in. Need to cross-check and verify the output is correct of course, but this does streamline a process that has tangible benefit and the ability of LLM's to code a great visualization and investigation structure is real

Excellent. Legend. Dave is based. Unironically, one great marker of a high quality CEO is whether they have the balls to speak authentically as an actual individual rather than in corporate HR blabber, take some (thoughtful, divergent, and well reasoned) stands, and be unfazed by ruffling some feathers and pissing people off while doing so. That has been gone from corporate America for a long time outside of a few standouts, Elon, Jamie (to a degree), etc. Need more of it. And, probably one of the reasons Lilly is mogging so many insufferable groupthink bores across the rest of Pharma Now, fire up the jet and acquire my extraordinarily heavy bags Dave.

We need an F1 but for Roadsters

RT x 1000

What a beast, what a fucking beast. Great man theory embodied. The West lost touch with its intrepid daring, grand vision, and authentic cool in peak woke and the decades long build up therein. Few have done more than @elonmusk to bring it back Inspiring.

The lack of correlation between alpha-synuclein pathology and PD stage is especially topical given the $ARWR news today. It is a scientific achievement to deliver any molecule to the brain in sufficient quantities to have a clinical effect. It is a hard to do. However, the target you are hitting obviously determines whether or not the drug works and these proteinopathy based models of both AD (beta-amyloid / tau) and PD (alpha-synuclein) are based on garbage science and even worse reasoning. This is why these protein targeting drugs either keep failing, or have extremely limited clinical benefit over the duration studied with big questions about whether the decline then accelerates after a short-term period of minimal benefit (donanemab and lecanemab) and how the data for clinical benefit has been interpreted. I think it is highly likely that MAPT will just be yet another busted target. Maybe this will be an important trigger for the field to finally move on to looking for new ideas. neurology.org/doi/10.1212/WN…

Excellent news for $MRNA. Not only will it cure all cancer, it will take all market share. Price target 2 trillion