Pfizer Discontinues KHK Inhibitor PF-06835919 in NASH Pipeline Following Phase 2 Trial

Compiled & Translated by | Fan Dongdong

Following the completion of Phase II clinical trials, Pfizer recently dropped the ketohexokinase (KHK) inhibitor PF-06835919 from its NASH pipeline. Previously, Pfizer had already decided to halt the development of two NASH therapeutic candidates, including PF-05221304 and a DGAT2 inhibitor.

The ketohexokinase (KHK) inhibitor PF-06835919 has entered clinical development, driven by evidence that fructose consumption can lead to metabolic disorders such as nonalcoholic steatohepatitis (NASH). The conversion of fructose by ketohexokinase marks the initiation of a metabolic cascade; therefore, Pfizer posits that inhibiting this enzyme may represent a therapeutic strategy for NASH. This hypothesis is further supported by animal studies, in which mice deficient in this enzyme were protected against fructose-induced obesity and nonalcoholic fatty liver disease (NAFLD). NAFLD encompasses a spectrum of disorders characterized by hepatic fat accumulation, while NASH, a more aggressive form of NAFLD, involves liver inflammation and may progress to organ damage or failure.

To this end, Pfizer initiated a placebo-controlled Phase 2a trial involving 164 subjects in 2019 to evaluate the effects of the ketohexokinase (KHK) inhibitor PF-06835919 on total liver fat and average blood glucose levels in patients with NAFLD and type 2 diabetes. The trial has now concluded, and Pfizer has discontinued the development of PF-06835919.

Notably, Pfizer is not the only company to encounter setbacks in NASH development. In recent years, Genfit and NGM Biopharmaceuticals have also experienced late-stage clinical trial failures. Many drug candidates have been plagued by adverse events; for instance, certain therapies have induced pruritus severe enough to force patients to withdraw from the trials.

Additionally, Pfizer recently disclosed further changes to its NASH pipeline. The combination trial of utomilumab and Yescarta, initiated in collaboration with Gilead’s Kite Pharma in 2018, has also been terminated. The study was primarily designed to evaluate the therapeutic efficacy of Pfizer’s CD137 agonist in combination with CAR-T cell therapy for patients with large B-cell lymphoma. Other discontinued programs by Pfizer also include a HER2 antibody-drug conjugate and a therapeutic cancer vaccine.

Pfizer also announced details regarding the progress of its COVID-19 protease inhibitor currently under development. Pfizer expects to initiate a Phase 2/3 clinical trial of PF-07304814 in hospitalized patients in the third quarter of this year. Another candidate, PF-07321332, entered Phase 2/3 studies this month, focusing on high-risk non-hospitalized adults. Pfizer anticipates obtaining Phase 2/3 trial data in the fourth quarter.

Source: Pfizer dumps mid-phase NASH prospect, slew of early efforts in Q2 clear-out