PF-05175157 / Pfizer - LARVOL DELTA

Low phosphorus increases hepatic lipid deposition, oxidative stress and inflammatory response via Acetyl-CoA carboxylase-dependent manner in zebrafish liver cells. (PubMed, Fish Shellfish Immunol) - "PF-05175157 also relieved the LP-induced oxidative stress and inflammatory response. Overall, these findings suggest that ACC is a promising target for treating LP-induced elevation of lipid deposition in ZFL, and can alleviate oxidative stress and inflammatory response."

Journal • Inflammation • AMPK • FAS • FASN

Inhibition of ACC causes malformations in rats and rabbits: comparison of mammalian findings and alternative assays. (PubMed, Toxicol Sci) - "Following positive predictions of developmental toxicity in alternative in vitro assays (positive in murine embryonic stem cell [mESC] assay and rat whole embryo culture, but negative in zebrafish), developmental toxicity (growth retardation and dysmorphogenesis associated with disrupted midline fusion) was observed with the oral administration of the dual ACC1 and 2 inhibitor, PF-05175157, in Sprague Dawley rats and New Zealand White rabbits. The results of these studies are presented here to make comparisons across the assays, as well as mechanistic insights from the mESC assay demonstrating high ACC expression in the mESC and that ACC induced developmental toxicity can be rescued with palmitic acid providing supportive evidence for DNL pathway inhibition as the underlying mechanism. Ultimately, while the battery of alternative approaches and weight-of-evidence case were useful for hazard identification, the embryo-fetal development studies were necessary to inform the..."

Journal • Acne Vulgaris • Dermatology • Diabetes • Hepatology • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Type 2 Diabetes Mellitus

[VIRTUAL] Inhibition of Acetyl-CoA Carboxylase in Acutely Injured Tubular Cells Exacerbates DNA Damage and Mitochondria Fission in Diabetic Nephropathy (KIDNEY WEEK 2020) - "Cisplatin-injured HK2 cells were treated with an ACC inhibitor, PF-05175157 (ACCi) or a carnitine palmitoyltransferase 1 inhibitor, etomoxir (CPT1i) and examined for DNA damage and mitochondria fission. Increased levels of p-ACC were associated with increased tubular injury and fibrosis in human DN. P-ACC in injured renal epithelial cells permitted b-oxidation of acyl-CoA in damaged mitochondria and enhanced mitochondrial fission resulting in DNA damage plausibly from reactive oxygen species. Prevention of mitochondrial overload of acyl-CoA is a potential therapeutic target to mitigate mitochondria damage and DNA damage after ATI in DN."

Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Infectious Disease • Metabolic Disorders • Nephrology • Renal Disease • KIM1

Optimizing the Benefit/Risk of Acetyl-CoA Carboxylase (ACC) Inhibitors Through Liver Targeting. (PubMed, J Med Chem) - "Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a non-human primate model."

Benefit-risk assessment • Journal • Hepatology • Metabolic Disorders • Non-alcoholic Steatohepatitis

A 6-Week Study To Determine The Safety And Effect Of An Investigational Drug Given With Canagliflozin In Adults With Type 2 Diabetes Mellitus Taking Metformin (clinicaltrials.gov) - P2; N=8; Terminated; Sponsor: Pfizer; N=60 -> 8

Enrollment change • Biosimilar • Diabetes

Study Of Safety, Tolerability And Effects Of PF-05175157 In Adults With Moderate To Severe Acne Vulgaris (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: Pfizer; Not yet recruiting -> Withdrawn

Trial withdrawal • Biosimilar • Chronic Kidney Disease • Immunology

Study Of Safety, Tolerability And Effects Of PF-05175157 In Adults With Moderate To Severe Acne Vulgaris (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: Pfizer; N=60 -> 0

Enrollment change • Biosimilar • Chronic Kidney Disease • Immunology

DE NOVO LIPOGENESIS IS CRITICAL FOR PLATELET PRODUCTION; THE LIVER DIRECTED ACC INHIBITOR PF-05221304 FOR THE TREATMENT OF NASH SHOWS IMPROVED PLATELET SAFETY PROFILE OVER SYSTEMIC ACC INHIBITION (AASLD 2019) - "These studies demonstrate that ACC and DNL play a critical role in thrombopoiesis and that strategies that enhance inhibitory activity in liver (the pharmacological site of action) relative to bone marrow are necessary for an adequate safety profile of DNL inhibitors for the treatment of NASH."

Clinical

Targeting host metabolism by inhibition of acetyl-Coenzyme A carboxylase reduces flavivirus infection in mouse models. (PubMed, Emerg Microbes Infect) - "...Considering the central role of acetyl-Coenzyme A carboxylase (ACC) on fatty acid metabolism, we analyzed the effect of three small-molecule ACC inhibitors (PF-05175157, PF-05206574, and PF-06256254) on the infection of medically relevant flaviviruses, namely West Nile virus (WNV), dengue virus, and Zika virus...This study constitutes a proof of concept of the reliability of ACC inhibitors to become viable antiviral candidates. These results support the repositioning of metabolic inhibitors as broad-spectrum antivirals."

Journal • Preclinical