Madrigal extended its MASH growth strategy through a second licensing deal in the metabolic dysfunction-associated steatohepatitis space. The company licensed Arrowhead’s siRNA asset targeting PNPLA3 (ARO-PNPLA3), valued at up to $1 billion, aiming to add precision genetics to complement its already approved oral therapy, Rezdiffra (resmetirom). The agreement includes a $25 million upfront payment, plus development, regulatory, and sales milestones up to $975 million. Madrigal characterized PNPLA3 as a key genetic driver of MASH in patients carrying the I148M mutation, with Phase 1 data suggesting meaningful liver fat reduction in homozygous carriers following a single dose. Madrigal’s rationale is that an siRNA mechanism could pair with Rezdiffra’s broad effects to cover additional patient subtypes. The company also signaled intent to pursue combination positioning across the MASH population and support a longer runway of differentiated therapies. Investors will likely track whether the PNPLA3 siRNA can demonstrate consistent clinical benefit beyond imaging endpoints and translate genetic stratification into measurable histology or fibrosis improvements.