Two Natural Capital

Bit of a different piece this week. Wrote on the potential of degraders in treating Fibrolamellar carcinoma, a rare, fusion-driven, cancer that currently doesn't have compelling treatments beyond surgery. FLC is caused (and driven by) the DNAJ-PKAc fusion protein, which can't be hit with a kinase inhibitor because of how crucial wild-type PKAc is to cells (Blueprint did have a candidate here, but ended up abandoning it). In theory DNAJ-PKAc could be hit directly if you could find a unique binding pocket (say, via chemoproteomics). There's also some fascinating PROTAC work here from Dialectic Therapeutics, although its FLC study is currently suspended. twonaturalcap.com/p/degrader…

$RVMD developing a catalytic RAS inhibitor is just so cool. World of sub-stoichiometric small molecules continues to grow

Comparing the Excellergy pre-clinical data against Lycia's is pretty wild. Lycia reduces basophil FcεR1 expression by ~50%, Excellergy by 95%(!)......

Interesting how large the delta is between Immunovant and Lycia sizing the Graves Disease population......Lycia puts the number at ~3mm, or >3x greater

Wild stuff - very cool effort to expand the PROTAC E3 ligase universe

How do you value $lyca's allergy efforts when Excellergy exists....

Does anyone have strong views on $TNGX? Weird mix of specialist ownership plus high short interest

Lysosomal-degradation approaches are a bit odd in that the early papers are about more effectively hitting cancer targets or proteins implicated in Alzheimer's but now there's a lot of focus on treating food allergy. Seems to be a bit of an underwhelming pivot? (Although perhaps that's an uncharitable take and IgE clearance profits will in turn fund more exciting work)

Why isn't $BCAX way oversold? Will Genmab just dominate?

Is Vicinitas Therapeutics still going? Deubiquitinating proteins is a pretty cool idea

Lycia Tx on the benefit of TRAbs depletion over FcRn inhibition in Grave's Disease $lyca

Very interesting that first-generation LYTACs are actually not catalytic, unlike PROTACs & MGDs. From $lyca therapeutics' S1: "These degraders shuttle target proteins to the lysosome, where both the target and the classic LYTAC degrader are broken down. Classic LYTAC degraders are designed for targets that have low concentrations or slow resynthesis rates, or for situations where intermittent depletion is preferred."

Better Call Saul ending is fantastic. Not unlike the end of Crime and Punishment

Enjoyable interview from @ldtimmerman with the fmr CEO of Arvinas and co-founder of Halda Tx (acquired by J&J for 3bn) Includes a fun digression on Arvinas trying to figure out why their androgen receptor PROTAC wasn't working well in wild-type patients timmermanreport.com/2026/10/…

Anyone have strong opinions on $IONS ION582 candidate? Seems like it's in trouble unless Ultragenyx's Aspire trial had unusually high placebo rates. What am I missing?

It's a shame Hume formulated his epistemology before beyond rule of 5 molecules came about. Would've been a nice illustration of what he was trying to get at