Eli Lilly and Company / Rigel Pharmaceuticals, Inc.

Inflammatory/autoimmune diseases (peripheral RIPK1) and neurodegenerative diseases (CNS-penetrant RIPK1)

6.7M US cases/yr · $70.0B Global autoimmune biologics + neurodegenerative drug spending 2021 (USD MM) · 16000 US patients with ALS

Disease Overview

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a master regulator of necroptosis, an inflammatory programmed cell death pathway, and also drives apoptosis and inflammatory cytokine production via downstream NF-κB and MAPK signaling. Pharmacologic RIPK1 inhibition has potential applications across immune-mediated inflammatory diseases (rheumatoid arthritis, ulcerative colitis, psoriasis) and neurodegenerative diseases including amyotrophic lateral sclerosis (ALS, ~16,000 US patients), Alzheimer's disease (~6.7 million US patients in 2022), and multiple sclerosis (~1 million US patients). The combined US prevalence across the lead RIPK1 indications exceeds 25 million if including the broader autoimmune basket. Standard of care for autoimmune indications is biologic-dominated (TNF inhibitors, IL-23, JAK inhibitors); ALS therapy is limited to riluzole (Rilutek, 1995), edaravone (Radicava, 2017), and the more recent Relyvrio/AMX0035 (sodium phenylbutyrate-taurursodiol, approved Sep 2022, withdrawn April 2024 after Phase 3 PHOENIX failure) and Qalsody/tofersen (antisense SOD1, accelerated approval April 2023). Alzheimer's disease has anti-amyloid antibodies (Leqembi/lecanemab Eisai-Biogen, July 2023; Kisunla/donanemab Lilly, July 2024), but these provide modest cognitive benefit (~25-35% slowing) with substantial ARIA risk and infusion burden. RIPK1 inhibition offers an oral, mechanism-distinct alternative.

Competitive Landscape

At deal date (Feb 2021), the RIPK1 inhibitor competitive landscape was led by Sanofi/Denali Therapeutics, which had announced a $1.075 billion partnership in October 2018 covering Denali's CNS-penetrant RIPK1 inhibitor SAR443060/DNL747 (Phase 1b in ALS and Alzheimer's, discontinued for off-target rodent toxicity in 2021) and the next-generation backup SAR443122/DNL758/eclitasertib (Phase 2 in cutaneous lupus and ulcerative colitis). GlaxoSmithKline GSK2982772 (peripheral RIPK1, Phase 2 in psoriasis, RA, ulcerative colitis — discontinued 2020 for insufficient efficacy). Roche/Genentech RG6346 (CNS RIPK1, preclinical). AbbVie advanced ABBV-668 (Phase 1). Other necroptosis/inflammation pathway competitors include AstraZeneca AZD0530, Astex/Otsuka ASTX027 (RIPK2). Rigel's lead asset R552 was a peripheral, non-CNS-penetrant RIPK1 inhibitor in Phase 1 development for psoriasis and RA, while CNS-penetrant Rigel candidates remained discovery-stage. The Lilly-Rigel deal ($125M upfront + $835M milestones = $960M) gave Lilly worldwide rights for inflammatory and CNS indications, with Rigel retaining co-development rights for inflammatory/autoimmune. The R552 program produced positive psoriasis Phase 2 data in 2024 but Lilly elected not to advance to Phase 3, returning rights to Rigel in March 2025.