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ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials

Abstract

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study (NCT03248882) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study (NCT03776175) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging–proton density fat fraction. Dose-dependent reductions in liver fat reached 50–65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was −7.2 (−13.9, 0.0), −17.1 (−22.7, −11.1), −49.9 (−53.3, −46.2), −55.9 (−59.0, −52.4) and −64.8 (−67.5, −62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) −44.6% (−54.8, −32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was −44.5% (−55.0, −31.7) and −35.4% (−47.4, −20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.

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Fig. 1: Patient disposition.
Fig. 2: PF-05221304 monotherapy effects on liver fat, liver enzymes, NASH-related biomarkers and fasting lipids in patients with NAFLD.
Fig. 3: PF-05221304 and PF-06865571 co-administration reverses ACC inhibitor-induced SREBP-1 activation and circulating triglyceride increases in Western diet-fed rats and is more efficacious than monotherapy in the CDAHFD rat fibrosis model.
Fig. 4: PF-05221304 and PF-06865571 co-administration effects on liver fat, liver enzymes and markers of lipid metabolism in patients with NAFLD.

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Acknowledgements

These studies were sponsored by Pfizer Inc. The authors would like to thank the patients who offered their time, interest and participation as well as the staff across all sites who recruited at least one patient in the clinical studies. The authors would also like to thank colleagues at Nordic Bioscience, M. Karsdal and D. J. Leeming, for their help with analysis of the serum procollagens—Pro-C3, Pro-C4, Pro-C6 and Pro-C18—in NCT03248882; M. Birnbaum for helpful discussions; K. Kelly and D. Beebe for help with in vivo studies; J. Morin and D. Shanthappa for assistance with shear-wave elastography measurements; J. Travers and A. Robertson for histology; S. Vargas for microscopic imaging of histological sections; and P. Garnick for clinical study management. Medical writing support, under the direction of the authors, was provided by C. Cairney, CMC Connect, McCann Health Medical Communications, and was funded by Pfizer in accordance with Good Publication Practice guidelines (Ann. Intern. Med. 163, 461–464 (2015)).

Author information

Authors and Affiliations

Authors

Contributions

R.A.C., N. Amin, S.C.-G., T.T.R., T.A.T., A.B., A.M.K., J.A.P. and W.P.E. were responsible for study conceptualization. R.A.C., T.T.R., C.C., A.R., A.B., V.S., S.C.-G., G.T., R.D., K.K.B., A.M.K. and W.P.E. were responsible for study design. R.A.C., N. Amin, S.C.-G., T.T.R., A.B., C.C., A.R., J.M., T.A.T., K.K. and M.B. were responsible for data analysis. R.A.C., N. Amin, T.T.R., S.A., C.C., A.R., N. Aggarwal, M.I., T.A.T. and K.K. contributed to study conduct. All authors were responsible for data interpretation. N. Amin and T.A.T. provided resources and were responsible for project administration. N. Amin, S.C.-G. and A.B. were responsible for data curation. N. Amin and W.P.E. were responsible for funding acquisition. N. Amin was responsible for data visualization. R.A.C., N. Amin and T.T.R. were responsible for supervision. R.A.C., N. Amin, T.T.R., T.A.T. and W.P.E. wrote the original draft manuscripts. All authors reviewed and edited the manuscript and approved the final draft.

Corresponding author

Correspondence to William P. Esler.

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Competing interests

R.A.C., N. Amin, S.C.-G., T.T.R., A.B., S.A., C.C., A.R., J.M., V.S.,T.A.T., K.K., M.B., G.T., R.D., K.K.B., A.M.K., J.A.P. and W.P.E. are employees of, and might hold stock options in, Pfizer Inc. N. Aggarwal and M.I. have no conflicts of interest to declare.

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Extended data

Extended Data Fig. 1 PF-05221304 efficacy in patients with NAFLD.

MMRM analysis of percent change from baseline over time in a, CAP in the overall population (Placebo n = 55, PF-05221304 2 mg, n = 56, 10 mg n = 62, 25 mg n = 52, 50 mg n = 53) and, b, VCTE in the NASH subgroup (Placebo n = 42, PF-05221304 2 mg, n = 43, 10 mg n = 42, 25 mg n = 39, 50 mg n = 42), using FibroScan®, and in c, T-bili (Placebo n = 40, PF-05221304 2 mg, n = 42, 10 mg n = 42, 25 mg n = 39, 50 mg n = 40), and d–g, procollagen isoforms in the NASH subgroup (Placebo n = 39, PF-05221304 2 mg, n = 40, 10 mg n = 42, 25 mg n = 35, 50 mg n = 38), and h, HbA1c in patients with T2D (Placebo n = 23, PF-05221304 2 mg, n = 23, 10 mg n = 26, 25 mg n = 25, 50 mg n = 23). i, Percent change from baseline to last observation in liver fat (MRI–PDFF) versus fasting serum triglyceridesa and j, percent change from baseline in fasting serum triglycerides versus baseline fasting serum triglyceridesa. MMRM analysis of percent change from baseline over time to week 16 in the overall population in k, total cholesterol (Placebo n = 58, PF-05221304 2 mg, n = 62, 10 mg n = 62, 25 mg n = 58, 50 mg n = 59), and l, Apo E (Placebo n = 57, PF-05221304 2 mg, n = 60, 10 mg n = 62, 25 mg n = 54, 50 mg n = 56). Data in panels a–h and k–l represent LSM (80% CI) from an MMRM model. aOne patient in the PF-05221304 10 mg treatment group with a percent change from baseline to last observation in fasting serum triglycerides of 1727.9 was excluded from these graphs for visualization but was included in the analysis. This patient had a percent change in liver fat of –38.9 and fasting serum triglycerides at baseline were 104 mg/dL (1.17 mmol/L). Apo, apolipoprotein; CAP, controlled attenuation parameter; CI, confidence interval; HbA1c, glycated hemoglobin; LSM, least squares mean; MMRM, mixed-effects model for repeated measures; MRI–PDFF, magnetic resonance imaging-proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PF’1304, PF-05221304; Pro-C, procollagen type; T-bili, total bilirubin; T2D, type 2 diabetes; VCTE, vibration-controlled transient elastography.

Source data

Extended Data Fig. 2 Hepatic expression of SREBP target genes in the Western-diet rat study.

a, ACC1, b, FASN, c, SCD1, d, SREBP-1c, e, GPAT1, f, PCSK9. Data are mean (standard error) with n = 12 in each treatment group. Statistical significance based on ANOVA model adjusting for unequal variances between groups. ACC1, acetyl-coenzyme A carboxylase 1; ANOVA, analysis of variance; FASN, fatty acid synthase; GPAT1, glycerol-3-phosphate acyltransferase 1; PCSK9, proprotein convertase subtilisin/kexin type 9; SCD1, stearoyl coenzyme A desaturase 1; SREBP-1c, sterol regulatory element-binding protein 1c.

Source data

Extended Data Fig. 3 Liver fat and hepatic expression of pro-inflammatory cytokine (TNFA, IL1B, IL12A, IL12B, IFNG), anti-inflammatory cytokine (IL10), inflammatory cell infiltrate marker (CCL2, CCL11, CXCL1, CXCL9), inflammatory cell marker (CD4, CD68), and fibrogenic (ACTA2, COL1A1, COL3A1) genes in the CDAHFD rat fibrosis model relative to chow-fed rats.

a, Relative change in hepatic triglycerides (n = 12 per group). Relative expression of b, ACTA2 (n = 12 per group), c, COL1A1 (n = 12 per group), d, IL10 (control diet n = 10, vehicle n = 11, PF-05221304 n = 11, PF-06865571 n = 11, and PF-05221304 and PF-06865571 co-administration n = 10), e, CCL2 (n = 12 per group), f, CCL11 (n = 12 per group), g, TNF (control diet n = 11, vehicle n = 12, PF-05221304 n = 11, PF-06865571 n = 12, and PF-05221304 and PF-06865571 co-administration n = 11), h, CD4 (control diet n = 11, vehicle n = 12, PF-05221304 n = 11, PF-06865571 n = 12, and PF-05221304 and PF-06865571 co-administration n = 11), i, IL1B (n = 12 per group), j, CD68 (control diet n = 11, vehicle n = 12, PF-05221304 n = 10, PF-06865571 n = 12, and PF-05221304 and PF-06865571 co-administration, n = 12), k, IL12A (n = 12 per group), l, IL12B (control diet n = 11, vehicle n = 10, PF-05221304 n = 11, PF-06865571 n = 11, and PF-05221304 and PF-06865571 co-administration n = 12), m, IFNG (n = 12 per group, except control diet n = 11), n, CXCL1 (n = 12 per group), o, CXCL9 (control diet n = 12, vehicle n = 10, PF-05221304 n = 11, PF-06865571 n = 12, and PF-05221304 and PF-06865571 co-administration n = 12), p, COL3A1 (control diet n = 11, vehicle n = 12, PF-05221304 n = 10, PF-06865571 n = 11, and PF-05221304 and PF-06865571 co-administration n = 10). Data are mean (standard error). Statistical significance based on ANOVA model adjusting for unequal variances between groups. ACTA2, alpha smooth muscle actin; ANOVA, analysis of variance; choline-deficient, amino acid-defined, high-fat diet; IFN, interferon; IL, interleukin; PF’1304, PF-05221304 monotherapy; PF’5571, PF-06865571 monotherapy; PF’1304 + PF’5571, PF-05221304 and PF-06865571 co-administration; TNF, tumor necrosis factor.

Source data

Extended Data Fig. 4 Relative percent change from baseline in a, total cholesterol, b, HDL-C, and c, LDL-C at week 6, and d, liver fat as assessed by CAP over time to week 6, in patients with NAFLD.

Placebo n = 12, PF-05221304 n = 22, PF-06865571 n = 24, PF-05221304 and PF-06865571 n = 26. Data represent LSM (90% CI). Statistical significance versus placebo was pre-defined as a two-sided p value of <0.05 based on an ANCOVA model in panels a–c, and from an MMRM model with no adjustment for multiple comparisons in panel d. ANCOVA, analysis of covariance; CAP, controlled attenuation parameter; CI, confidence interval; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LSM, least squares mean; MMRM, mixed-effects model for repeated measures; NAFLD, non-alcoholic fatty liver disease; PF’1304, PF-05221304 monotherapy; PF’5571, PF-06865571 monotherapy; PF’1304 + PF’5571, PF-05221304 and PF-06865571 co-administration.

Source data

Extended Data Fig. 5 Chemical structures of a, ACC inhibitor PF-05221304 and b, DGAT2 inhibitor PF-06865571.

ACC, acetyl-coenzyme A carboxylase; DGAT2, diacylglycerol acyltransferase 2.

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Extended Data Fig. 6 Clinical study designs.

a, PF-05221304 monotherapy study design, b, steps to identifying the sponsor-defined population, based on pre-qualification and Screen 1 assessments in the PF-05221304 monotherapy study, c, PF-05221304 and PF-06865571 co-administration study design. All blood samples were collected after an overnight fast of ≥8 h. In the PF-05221304 monotherapy study, samples for clinical safety-related laboratory tests were collected at pre-qualification, Screen 1 (main study screen), baseline, and at all visits throughout the treatment and follow-up periods. Samples for exploratory biomarkers, including NASH-related biomarkers, apolipoproteins, and glycemic parameters were collected at baseline and day 1 and weeks 4, 8, 12, and 16 of treatment. Samples for fasting lipid profile and HbA1c were collected at all timepoints. Non-HDL-C was derived as total cholesterol minus HDL-C, and VLDL was calculated as triglycerides/5 and reported only when triglycerides <400 mg/dL. All other parameters were measured directly. In the 1st tier stratification of the PF-05221304 monotherapy study, patients classified in the diagnosed or presumed NASH subgroup had to have a documented liver biopsy with histological evidence of NASH within 24 months of Screen 1, or meet the following criteria at pre-qualification and again at Screen 1: liver stiffness measure ≥7.0 kPa based on FibroScan® assessment; ALT > ULN and ≤5× ULN. Patients with liver stiffness measure <7.0 kPa and ALT ≤ 1.25× ULN at pre-qualification and again at Screen 1 were classified as NAFLD with likely minimal inflammation and fibrosis. aRisk factors for NAFLD/NASH: BMI of ≥25 or ≥22.5 kg/m2 in Western or Asian sites, respectively; fasting plasma glucose ≥100 mg/dL (5.6 mmol/L); fasting serum HDL-C < 40 mg/dL (1 mmol/L) or <50 mg/dL (1.3 mmol/L) for males and females, respectively; fasting serum triglycerides ≥150 mg/dL (1.7 mmol/L); seated blood pressure ≥130/85 mm Hg; waist circumference ≥40 inches (102 cm) or ≥35 inches (89 cm) for males and females, respectively; or the use of pharmacological agents with the explicit purpose of improving glycemic control, increasing HDL-C, decreasing triglycerides, or controlling blood pressure. ALT, alanine aminotransferase; BMI, body mass index; CAP, controlled attenuation parameter; HDL-C, high-density lipoprotein cholesterol; MRI–PDFF, magnetic resonance imaging-proton density fat fraction; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PBO, placebo; PF’1304, PF-05221304 monotherapy; PF’5571, PF-06865571 monotherapy; PF’1304 + PF’5571, PF-05221304 and PF-06865571 co-administration; ULN, upper limit of normal; VLDL, very-low-density lipoprotein; wks, weeks.

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Calle, R.A., Amin, N.B., Carvajal-Gonzalez, S. et al. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat Med 27, 1836–1848 (2021). https://doi.org/10.1038/s41591-021-01489-1

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