PMID- 34635855
OWN - NLM
STAT- MEDLINE
DCOM- 20211112
LR  - 20230207
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 27
IP  - 10
DP  - 2021 Oct
TI  - 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.
PG  - 1836-1848
LID - 10.1038/s41591-021-01489-1 [doi]
AB  - 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.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
FAU - Calle, Roberto A
AU  - Calle RA
AUID- ORCID: 0000-0001-6577-5657
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Amin, Neeta B
AU  - Amin NB
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Carvajal-Gonzalez, Santos
AU  - Carvajal-Gonzalez S
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Ross, Trenton T
AU  - Ross TT
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Bergman, Arthur
AU  - Bergman A
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Aggarwal, Sudeepta
AU  - Aggarwal S
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Crowley, Collin
AU  - Crowley C
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Rinaldi, Anthony
AU  - Rinaldi A
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Mancuso, Jessica
AU  - Mancuso J
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Aggarwal, Naresh
AU  - Aggarwal N
AD  - Aggarwal and Associates Limited, Brampton, ON, Canada.
FAU - Somayaji, Veena
AU  - Somayaji V
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Inglot, Malgorzata
AU  - Inglot M
AD  - Department of Infectious Diseases, Liver Diseases and Acquired Immune 
      Deficiencies, Wroclaw Medical University, Wroclaw, Poland.
AD  - Dobrostan, Wroclaw, Poland.
FAU - Tuthill, Theresa A
AU  - Tuthill TA
AUID- ORCID: 0000-0003-0170-3974
AD  - Early Clinical Development, Pfizer Inc, Cambridge, MA, USA.
FAU - Kou, Kou
AU  - Kou K
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Boucher, Magalie
AU  - Boucher M
AD  - Drug Safety Research and Development Global Pathology, Pfizer Worldwide Research 
      and Development, Cambridge, MA, USA.
FAU - Tesz, Greg
AU  - Tesz G
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Dullea, Robert
AU  - Dullea R
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Bence, Kendra K
AU  - Bence KK
AUID- ORCID: 0000-0002-5879-4726
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Kim, Albert M
AU  - Kim AM
AUID- ORCID: 0000-0002-5269-2155
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Pfefferkorn, Jeffrey A
AU  - Pfefferkorn JA
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA.
FAU - Esler, William P
AU  - Esler WP
AUID- ORCID: 0000-0003-4783-8620
AD  - Internal Medicine Research Unit, Pfizer Inc, Cambridge, MA, USA. 
      william.esler@Pfizer.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT03248882
SI  - ClinicalTrials.gov/NCT03776175
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20211011
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Placebos)
RN  - EC 2.3.1.20 (DGAT2 protein, human)
RN  - EC 2.3.1.20 (Diacylglycerol O-Acyltransferase)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
SB  - IM
CIN - Nat Rev Endocrinol. 2022 Jan;18(1):2. PMID: 34697464
CIN - Trends Mol Med. 2022 Jan;28(1):5-7. PMID: 34844875
CIN - Cell Metab. 2022 Feb 1;34(2):191-193. PMID: 35108509
MH  - Acetyl-CoA Carboxylase/*antagonists & inhibitors/genetics
MH  - Diacylglycerol O-Acyltransferase/*antagonists & inhibitors/genetics
MH  - Double-Blind Method
MH  - Drug Synergism
MH  - Enzyme Inhibitors/*administration & dosage/adverse effects
MH  - Female
MH  - Humans
MH  - Lipid Metabolism/drug effects
MH  - Liver/drug effects/*enzymology/ultrastructure
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Non-alcoholic Fatty Liver Disease/*drug therapy/genetics/pathology
MH  - Placebos
EDAT- 2021/10/13 06:00
MHDA- 2021/11/16 06:00
CRDT- 2021/10/12 06:44
PHST- 2020/09/11 00:00 [received]
PHST- 2021/08/03 00:00 [accepted]
PHST- 2021/10/13 06:00 [pubmed]
PHST- 2021/11/16 06:00 [medline]
PHST- 2021/10/12 06:44 [entrez]
AID - 10.1038/s41591-021-01489-1 [pii]
AID - 10.1038/s41591-021-01489-1 [doi]
PST - ppublish
SO  - Nat Med. 2021 Oct;27(10):1836-1848. doi: 10.1038/s41591-021-01489-1. Epub 2021 
      Oct 11.