Hunter

In the wake of the tragic shooting that claimed the life of Alex Pretti this weekend, our prayers are with his family, the citizens of Minneapolis and local, state and federal law enforcement officers serving there. The images of this incident are deeply troubling and a full and transparent investigation of this officer involved shooting must take place immediately. The focus now should be to bring together law enforcement at every level to address the concerns in the community even while ensuring that dangerous illegal aliens are apprehended and no longer a threat to families in Minneapolis. The American people deserve to have safe streets, our laws enforced and our constitutional rights of Freedom of Speech, peaceable assembly and the right to keep and bear Arms respected and preserved all at the same time. That’s how Law and Order and Freedom work together in America.

The tragedy and chaos the country is witnessing in Minneapolis is shocking. The killing yesterday of Alex Pretti, a U.S. citizen, by ICE agents should raise serious questions within the administration about the adequacy of immigration-enforcement training and the instructions officers are given on carrying out their mission. Lawfully carrying a firearm does not justify federal agents killing an American—especially, as video footage appears to show, after the victim had been disarmed. A comprehensive, independent investigation of the shooting must be conducted in order to rebuild trust and Congressional committees need to hold hearings and do their oversight work. ICE agents do not have carte blanche in carrying out their duties.

I think this was the year I bought season tickets 🫠

Prime Medicine (public company) is now valued less than what we sold Rewrite for to Intellia ($200M). Rewrite had only raised $2M, with @CivilizationVC as sole VC - team was 5 people. Exited in under 2 years. Prime has raised >$500M... Timing is everything.

@ZachCrenshaw Peter Marsh is a childhood best friend, so the Marsh branded Pacers memorabilia has some extra nostalgia

Had this poster on my wall as a kid. Branded by the (now defunct) grocery store Marsh (RIP). To now have the Pacers going to another ECF vs the Knicks… nearly 20 years later… well, as Timothee Chalamet put it, time to “close the loop” #Cersin5

Donovan Mitchell shot 21 free throws tonight, one less than the entire @Pacers team (22), and they still won by 9.

Cavs were favored by 3-9 points in all five games of the East semis, and the @Pacers won 4-1 (incl. 3x in Cleveland) to advance to the Eastern Conference finals for the 2nd consecutive year. This team deserves some respect!

See you in New York.

Probably the best closing @Pacers team in the last 25 years. I would not want to be down 0-2 heading into @GainbridgeFH 🥶

Recent ep of @BiotechCH has a masterclass on reframing from Josh Schimmer, who clearly sees the fed funding for academia issue differently than @JMaraganore, and effectively debates w/out disagreeing 33:40-45:45 open.spotify.com/episode/4Qdv73…

Love when this happens ⁦@Pacers⁩

Lots of data circulating on concentration of VC bets into fewer, larger biotech financings. Less discussion on implications. Is this good or bad for innovation and patients? Probably bad.

I’ve been wondering about the LP perspective on VC right now. Don’t know if this is representative, but it sounds right.

Especially when you have a $40 B endowment and don’t need $9 B from the government to assure academic freedom

@LifeSciVC @davidycli @drrichjlaw I wish this were true, but the experience of founders raising right now is different. Biotech VCs doing direct investment are asking for clinical POC on Series A funds. That means you need to get to DC on Seed, forcing teams to choose targets and lead molecules often prematurely

De novo discovery to clinical data takes 4-5 years in the best case... and it's very rare for companies to raise enough to last 4-5 years. So the vast majority of new startups aren't expected to have clinical data in their first raise. In my experience, that's more typically a Series B+ question.

I love this article from Bruce. Particularly this bit; "it’s also important to remember that great companies are often born out of tougher times. Alnylam was started in the nuclear winter of 2002. Nimbus was formed in the spring of 2009, at the bottom of the markets. Kymera was being formulated in the late 2015/early 2016 bear market. The startups that are being created today – the few and the proud – will likely be the emerging stars of 2030’s." 💪🤩

@AppleHelix @LifeSciVC @endpts This is the answer. The disconnect is not sentiment vs data. There may be capital available, but not for young scientists, new founders, and good ideas from outside a venture creation fund or top academic lab that’s partnered with one. @LifeSciVC

@LifeSciVC @endpts But they invest in other VCs' in-house NewCos, often in these mega rounds.

Biotech doesn’t face an early stage funding deficit. Huge LP commitments made in past few years, VC investing is &20-25B per year. More early stage companies isn’t necessarily a good thing (see scarcity blog). Not sure what the real problem is we’re trying to solve with an early stage focused EIF-like fund. If anything, the limiting factor in biotech (vs tech) is lack of late-stage private growth capital to allow biotechs to stay private longer at escalating valuations. We have had to push emerging biotechs public to access growth capital via IPOs/FOPOs. And the public mkts are very fickle and cyclical - creating turbulence. The bigger limiting factors in biotech (since it’s not capital) include: - experienced & savvy management talent - regulatory clarity & efficiency - competitive TTPs (not hyper crowded me-tops) - global pricing power (and less differential pricing in major mkts) - IP/exclusivity timeframes - strong basic research enterprise (without reproducibility issues) - to name a few…

@SaraNayeem What advice do you have for entrepreneurs who have several investors in the data room to help push to a term sheet? Seems VCs often have little incentive to move quickly and can “browse” indefinitely. How can you create urgency / drive action?

Entrepreneurs: don’t make your process too reliant on investors being organized and proactive. E.g., if you have major clinical data coming in, don’t tell everyone who has been following your story, “we are going to upload it into the data room soon” and leave it at that. It might seem that everyone is on the edge of their seats waiting for this data, and perhaps some people are. But others might be distracted by other deals or just not following their emails as closely. I sometimes hear, “the people who get it will go look at the data.” There is some value to selecting investors based on enthusiasm, but in most cases you also want to build broad interest to maximize valuation and speed process to a close. Execs new to fundraising will often overestimate the interest level from funds after a couple of meetings, or will look at the number of funds engaged and feel they are set. Consider that typically an individual lead investor will look at 100s of deals in a year and invest in two or three (or less). So make the time to proactively set up calls to present the key elements of the data. No need to present every single piece of data on one call; rather, present enough to get them to do more work. For what you do present, shoot for comprehension, conviction, contextualization (the last one is key and where many companies stumble). Presenting data also allows you to control the narrative and address questions or limitations in the study head-on. Once investors have some enthusiasm and momentum, they’ll go in the data room and do the rest of the work themselves. If you need to prioritize the calendar, focus initially on investors who can lead (set terms) and who have shown clear interest previously. Once you have a credible lead, the deal may come together quickly.

@andrewpannu Would love to see the full landscape. From 1st principles, degraders sound great. In practice, are there really that many known, disease-relevant proteins that can’t be drugged with a small molecule, peptide, or antibody?

Pharma BD landscape within the molecular glue space With last week's Lilly / Magnet Biomedicine $1.3B deal, we're now up to 24 deals led by big pharma since 2020, totaling ~$27B in total disclosed deal values What's causing all of these companies to jump in? Some thoughts: Molecular glues, alongside PROTACs, are the two most clinically validated approaches within the targeted protein degradation (TPD) space. At a high level TPD selectively degrades disease-causing proteins by linking them to E3 ubiquitin ligases, causing the cell's own protein disposal system to eliminate them Benefits of this approach vs. traditional small molecules: • Enhanced potency at lower doses, minimizing off-target effects and toxicity concerns • Retain the favorable manufacturing economics (cost & scalability) of small molecules • Can target "undruggable" proteins that lack active binding sites thus unlocking proteins considered inaccessible to traditional pharmacology This last point is a huge opportunity. ~85% of the human proteome is considered "undruggable" to traditional biologics or small molecules. Only ~2-5% are both historically "druggable" and relevant to disease - meaning that the modern biopharma industry has largely been built on a fraction of potential targets. Expanding the druggable proteome has massive implications for treating diseases with huge unmet needs today, while opening hundreds of additional opportunities for the coveted 'first-in-class' tag. Given the magnitude of the prize, Pharma has taken a multi-faceted approach - spinning up internal development efforts + partnering to fill gaps. In addition to the points above, the pace of partnerships can likely be explained by two factors: • The TPD space is still very early (first clinical trial for molecular glues was in 2020), and so a lot of technical expertise and know-how resides in biotechs that helped push the field forward out of academia (i.e. Monte Rosa flagged their know-how around geometric deep learning at JPM 2025) • The modular nature of drug design in this space (similar to ADCs) rewards companies capable of rapid experimental iteration to identify synergistic properties - a strength of most biotechs versus Pharma Data and insights powered by @sleuthinsights. If you'd like a PDF of the graphic, want to see a full molecular glue competitive landscape or have any thoughts to add, let me know in the comments!

@lexfridman What did you feel was so disrespectful?

I regret engaging in the political dumpster fire of the Trump-Zelenskyy meeting. I simply want to do my small part in building bridges & pushing for long-lasting peace. I'll try to focus on that through long-form nuanced conversation with people on all sides. I love you all ❤️