Why inhibit Ketohexokinase (KHK) to treat NASH?

Anjani Shah, PhD, Senior Conference Director for Cambridge Healthtech Institute spoke on the phone March 6, 2019 with Kendra K. Bence, PhD, Senior Director, Metabolism, Internal Medicine Research Unit (IMRU), at Pfizer to learn more about Dr. Bence's presentation Targeting Fructose Metabolism: Update on KHK Inhibitor for NASH that will be delivered at CHI’s Targeting NASH conference September 17-18, 2019 in Boston. Excerpts from their conversation are below.

Q: What is ketohexokinase and why is it a NASH ‘target’?

A: Ketohexokinase (KHK) helps break-down the fructose component of sugar. KHK catalyzes the phosphorylation of fructose to fructose-1-phosphate (F1P), the first step of fructose metabolism.

By inhibiting KHK, less sugar is metabolized into fat. Because excessive fat accumulation in liver cells increases the risk of progression from simple fatty liver to NASH, decreasing the amount of fat stored in liver cells is likely to ameliorate the symptoms of NASH.

Q: Is there only one type of KHK in the body?

A: There are two isoforms of KHK, KHK-A and KHK-C. Fructose is primarily metabolized by KHK-C as it has both a higher affinity and capacity for fructose compared to KHK-A. Thus, fructose is metabolized at sites where KHK-C is expressed including the liver, kidney and intestine.

Q: What are the challenges of inhibiting KHK?

A: Since KHK is a high capacity enzyme, you need to hit the enzyme hard. I will highlight some technical details in my presentation which describe how the compound was discovered.

Q: What data will you present?

A: Efficacy of KHK inhibition in preclinical NASH rodent models will be presented, along with data in normal human subjects demonstrating target engagement. Additionally, recent results from our Phase 2A study will be summarized. Following a 6 week administration in subjects with nonalcoholic fatty liver disease, Pfizer’s Ketohexokinase inhibitor PF-06835919 reduced liver fat as measured by magnetic resonance imaging-proton density fat fraction, and was safe and well-tolerated.

Q: Who else is working on KHK inhibitors and what else in the lipid metabolism pathway is showing promise for NASH?

A: The inhibition of KHK for the treatment of NASH represents a ‘first in class’ mechanism. In the area of lipid metabolism, triglyceride production is also being targeted as a treatment for NASH. For example, DGAT2 is a molecule in that pathway that several companies are targeting.

Read more about lipid metabolism and NASH in Bence's review article.

About Kendra K. Bence, Ph.D, Senior Director of Metabolism, Internal Medicine Research Unit, Pfizer, Inc.

Dr. Bence leads research and discovery efforts in the NAFLD/NASH and metabolic disease therapeutic areas for the Pfizer Internal Medicine Research Unit. She leads a talented team of scientists focused on developing a deep understanding of the biological mechanisms underlying metabolic dysfunction and fatty liver disease, with the goal of identifying novel ways to treat and eventually prevent these metabolic diseases. She is also the Internal Medicine representative to the Pfizer WRD Post-Doctoral Program and has a strong commitment to training and mentoring the next generation of scientists. Dr. Bence has a long-standing interest in the pathogenesis of metabolic disease. She received her B.A. in Biology from Colgate University, and her Ph.D. in Physiology and Biophysics from the Weill Cornell Medical College of Cornell University. Dr. Bence conducted her post-doctoral work at Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, where she became interested in the role of cellular signaling in the regulation of metabolism. Following her post-doctoral fellowship, she joined the University of Pennsylvania as an Assistant Professor and was subsequently promoted to Associate Professor with tenure. While at Penn she served as the Director of Academic Enrichment for the Institute for Diabetes, Obesity and Metabolism (IDOM), and served on the American Diabetes Association and NIH grant review panels. She continues to serve on the SBIR-NIH study section panel.