Lilly drops 2nd program against NASH target that caught Pfizer’s eye

Lilly drops 2nd program against NASH target that caught Pfizer’s eye

Eli Lilly’s second stab at developing a KHK inhibitor in diabetes and nonalcoholic steatohepatitis (NASH) is over. Fifteen months after dropping its first candidate, Lilly has kicked the second program from its phase 1 pipeline, dealing another blow to a target that has attracted the attention of Pfizer.

KHK, also known as ketohexokinase, modulates the effect fructose has on human metabolism. Inhibiting the enzyme could cut the amount of sugar that is converted into fat and the amount of fat that is stored in the liver, thereby potentially lowering the risk of NASH development, treating symptoms and providing weight benefits.

Pfizer has led the way in the space, moving a KHK inhibitor, PF-06835919, into the clinic in 2016 and going on to link the molecule to significant reductions in whole liver fat in a midphase study. But Lilly has stayed tucked in behind its rival and at one point had two KHK inhibitors in phase 1 development.

The first program fell in October 2021, and it has now been joined in Lilly’s discard pile by KHK inhibitor No. 2. Lilly disclosed the removal of the one-time potential treatment of diabetes and NASH from its pipeline in its fourth-quarter results update. The removal ends a program that Lilly supported through projects such as an assessment of the prevalence of KHK gene variants and a patent filing for pyrazole compounds.

Lilly’s retreat from KHK inhibition leaves the future of the target in doubt. Pfizer ran a series of phase 1 and 2 clinical trials of PF-06835919 between 2016 and 2021, and included the asset in its NASH tie-up with Novartis in 2018. But the only study to start since 2020 is a 17-subject phase 2 trial sponsored by Maastricht University Medical Center.

The wind down in KHK inhibitor clinical trial activity dampens the chances of the target helping to unlock the NASH market, which lost some of its luster in recent years as programs across the industry have hit setbacks. Lilly remains in the race even after its retreat from KHK. Like peers such as Amgen, AstraZeneca and Johnson & Johnson, Lilly is targeting PNPLA3, and it is also studying tirzepatide in NASH.

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