eIisa

This is a beautiful way to visualize the pathophysiology. B cells at different stages of differentiation occupy different compartments, express different surface markers, and drive different pathologies. Based on this biology, it'd make sense that (for example) lupus would respond best to anti-CD19 therapies, while Sjögren’s would respond best to anti-BCMA -- though how that shakes out in trials isn't fully known.

How many of these have genuinely new mechanisms? By my count, 23. Vepdegestrant – first PROTAC Daraxonrasib – first multi-selective RAS inhibitor Oveporexton – first orexin receptor agonist Baxdrostat – first aldosterone synthase inhibitor Atacicept - first dual BAFF/APRIL inhibitor Icotrokinra – first IL23 receptor antagonist Apitegromab – first myostatin activation inhibitor Pivekimab sunirine – first CD123 ADC Gedatolisib – first combined pan-PI3K and mTORC1/2 inhibitor Brepocitinib – first combined TYK2/JAK1 inhibitor Bulevirtide – first NTCP inhibitor (blocks hepatitis D entry receptor) Islatravir – first nucleoside reverse-transcriptase translocation inhibitor Rusfertide – first hepcidin mimetic Zilganersen - first GFAP-targeting antisense therapy Garetosmab - first activin A-neutralising antibody Zilurgisertib – first ALK2/ACVR1 kinase inhibitor Pegzilarginase – first arginase-1 enzyme replacement therapy Pritelivir – first HSV helicase–primase inhibitor Relacorilant – first glucocorticoid receptor antagonist to improve chemotherapy sensitivity Tavapadon - first selective D1/D5 agonist Tividenofusp alfa – first TfR-mediated IDS enzyme delivery Centanafadine – first triple noradrenaline/dopamine/serotonin reuptake inhibitor Tiratricol – first thyroid hormone analogue that works independently of MCT8

How ARPA-H is planning to cut clinical trial times from 10+ years to <4 years: 1. 'Phaseless' clinical trials - move towards replacing phase 1 → 2 → 3 with adaptive trials that can cut failed drugs (or advance good ones) faster. 2. Simulate trial outcomes before starting, with digital twins - to reduce reliance on large control groups. 3. AI agents for trial operations. 4. Turn ordinary hospitals into reusable clinical trial sites, and gets AIs to flag eligible trials to doctors and patients.