Efficacy and safety of the glucagon receptor antagonist PF-06291874: A 12-week, randomized, dose-response study in patients with type 2 diabetes mellitus on background metformin therapy.

AIMS: To conduct a dose-response assessment of the efficacy and safety of the glucagon receptor antagonist PF-06291874 in adults with type 2 diabetes (T2DM) using stable doses of metformin. MATERIALS AND METHODS: This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM who were receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60 or 100 mg once daily) for 12 weeks. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and safety endpoints were assessed at baseline and post baseline. RESULTS: Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol), and for FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycaemia was low and was similar between groups receiving PF-06291874 and placebo. Small, non-dose-dependent increases in LDL cholesterol (<10%) and blood pressure (BP) (systolic BP > 2 mm Hg; diastolic BP > 1 mm Hg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L vs placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L vs placebo); these were not associated with bilirubin changes. Small increases were observed in body weight (< 0.5 kg) in each PF-06291874 group vs placebo. CONCLUSIONS: In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non-dose-related increases in BP, lipids and hepatic transaminases were observed.

Once-weekly administration of a long-acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non-human primates.

AIMS: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of PF-05231023, a long-acting fibroblast growth factor 21 (FGF21) analogue, in obese people with hypertriglyceridaemia on atorvastatin, with or without type 2 diabetes. METHODS: Participants received PF-05231023 or placebo intravenously once weekly for 4 weeks. Safety (12-lead ECGs, vital signs, adverse events [AEs], laboratory tests) and longitudinal weight assessments were performed. Blood samples were collected for pharmacokinetic and pharmacodynamic analyses. Cardiovascular safety studies were also conducted in telemetered rats and monkeys. Blood pressure (BP; mean, systolic and diastolic) and ECGs were monitored. RESULTS: A total of 107 people were randomized. PF-05231023 significantly decreased mean placebo-adjusted fasting triglycerides (day 25, 33%-43%) and increased HDL cholesterol (day 25, 15.7%-28.6%) and adiponectin (day 25, 1574 to 3272 ng/mL) across all doses, without significant changes in body weight (day 25, -0.45% to -1.21%). Modest decreases from baseline were observed for N-terminal propeptides of type 1 collagen (P1NP) on day 25, although C-telopeptide cross-linking of type 1 collagen (CTX-1) increased minimally. Systolic, diastolic BP, and pulse rate increased in a dose- and time-related manner. There were 5 serious AEs (one treatment-related) and no deaths. Three participants discontinued because of AEs. The majority of AEs were gastrointestinal. PF-05231023 increased BP and heart rate in rats, but not in monkeys. CONCLUSIONS: Once-weekly PF-05231023 lowered triglycerides markedly in the absence of weight loss, with modest changes in markers of bone homeostasis. This is the first report showing increases in BP and pulse rate in humans and rats after pharmacological administration of a long-acting FGF21 molecule.

Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study.

AIMS: The aim of the present study was to evaluate the pharmacokinetics/pharmacodynamics (PK/PD), safety and tolerability of single intravenous (IV) doses of PF-05231023, a long acting fibroblast growth factor 21 (FGF21) analogue being developed for the treatment of type 2 diabetes mellitus (T2DM). METHODS: T2DM subjects (glycosylated haemoglobin: 7.0-10.5%; on stable metformin therapy and/or diet and exercise) were randomized to receive a single dose of placebo or PF-05231023 (0.5-200 mg). Safety evaluations were performed up to 14 days after dosing. PK and PD endpoints were measured and a PK/PD model was developed for triglyceride - an early marker of drug activity. RESULTS: No antidrug antibody or serious adverse events (AEs) were observed. The most frequent AEs were gastrointestinal but were generally mild. Plasma PF-05231023 levels peaked immediately post-IV dosing, with mean terminal half-lives of 6.5-7.7 h and 66.5- 96.6 h for intact C- and N-termini, respectively. Intact C-terminus exposures increased proportionally with increasing dose, whereas N-terminus exposures appeared to trend higher than dose-proportionally. Although no apparent effect on plasma glucose was seen, dose-dependent decreases in triglyceride were observed, with a maximum reduction of 48.5 ± 10.0% (mean ± standard deviation) for the 200 mg dose compared with a reduction of 19.1 ± 26.4% for placebo, demonstrating proof of pharmacology. Moreover, a reduction in total cholesterol and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol were observed in the high-dose groups. CONCLUSIONS: Single IV doses of PF-05231023 up to 200 mg were generally safe and well tolerated by subjects with T2DM. The observed early sign of pharmacology supports further clinical testing of PF-05231023 upon repeated administration.

Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial.

BACKGROUND: Increased consumption of the lipogenic sugar fructose promotes the current epidemic of metabolic disease. Ketohexokinase (KHK) catalyzes the first committed step in fructose metabolism. In animal models, KHK inhibition decreases hepatic de novo lipogenesis and steatosis and corrects many metabolic abnormalities associated with insulin resistance. The consequences of inhibiting fructose metabolism in humans have not been tested. This randomized, double-blind, placebo-controlled, phase 2a study (NCT03256526) assessed the effect of the reversible KHK inhibitor PF-06835919 on metabolic parameters in participants with non-alcoholic fatty liver disease (NAFLD). METHODS: Adults with NAFLD (>6% whole liver fat [WLF] by magnetic resonance imaging-proton density fat fraction) received once-daily oral placebo or PF-06835919 75 mg or 300 mg for 6 weeks. Randomization (1:1:1) was via computer-generated randomization code with random permuted blocks. Endpoints included WLF (primary endpoint), safety/tolerability, and metabolic parameters. FINDINGS: Overall, 158 participants were screened and 53 randomized; 48 completed the trial (placebo, n = 17; PF-06835919 75 mg, n = 17; PF-06835919 300 mg, n = 14). Compared with placebo, significant reductions in WLF were observed in participants receiving PF-06835919 300 mg (difference of -18.73%; p = 0.04), but not with 75 mg. In addition, inhibition of KHK resulted in improvement in inflammatory markers. The incidence of treatment-emergent adverse events (AEs) was low and similar across treatment groups (26.3%, 23.5%, and 29.4% of participants in the placebo and PF-06835919 75 mg and 300 mg groups, respectively). No serious AEs were reported. CONCLUSIONS: Data suggest that KHK inhibition may be clinically beneficial in the treatment of adults with NAFLD and insulin resistance. FUNDING: This study was sponsored by Pfizer Inc.

A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the glucagon receptor antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus.

AIMS: The glucagon receptor antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. METHODS: After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150mg once daily for 28days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. RESULTS: Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8mg/dL and in FPG from 27.1 to 57.2mg/dL after 28days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3×upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. CONCLUSIONS: PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4weeks of dosing in subjects with T2DM.