PMID- 35590219
OWN - NLM
STAT- MEDLINE
DCOM- 20220523
LR  - 20220608
IS  - 2666-6340 (Electronic)
IS  - 2666-6340 (Linking)
VI  - 2
IP  - 7
DP  - 2021 Jul 9
TI  - Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and 
      inflammatory markers: A randomized phase 2 trial.
PG  - 800-813.e3
LID - S2666-6340(21)00156-2 [pii]
LID - 10.1016/j.medj.2021.04.007 [doi]
AB  - 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.
CI  - Copyright (c) 2021. Published by Elsevier Inc.
FAU - Kazierad, David J
AU  - Kazierad DJ
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA.
FAU - Chidsey, Kristin
AU  - Chidsey K
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA.
FAU - Somayaji, Veena R
AU  - Somayaji VR
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA.
FAU - Bergman, Arthur J
AU  - Bergman AJ
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA.
FAU - Birnbaum, Morris J
AU  - Birnbaum MJ
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA.
FAU - Calle, Roberto A
AU  - Calle RA
AD  - Pfizer Inc., Worldwide Research, Development, and Medicine, Cambridge, MA 02139, 
      USA. Electronic address: roberto.a.calle@pfizer.com.
LA  - eng
SI  - ClinicalTrials.gov/NCT03256526
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210427
PL  - United States
TA  - Med
JT  - Med (New York, N.Y.)
JID - 101769215
RN  - 30237-26-4 (Fructose)
RN  - EC 2.7.1.- (Fructokinases)
SB  - IM
MH  - *Fructokinases/drug effects
MH  - Fructose/adverse effects
MH  - Humans
MH  - Insulin Resistance
MH  - *Non-alcoholic Fatty Liver Disease/drug therapy
OTO - NOTNLM
OT  - Translation to patients
OT  - carbohydrate metabolism
OT  - fructose
OT  - ketohexokinase
OT  - non-alcoholic fatty liver disease
COIS- Declaration of interests D.J.K., K.C., V.R.S., A.J.B., M.J.B., and R.A.C. are 
      employees and stakeholders of Pfizer Inc.
EDAT- 2022/05/20 06:00
MHDA- 2022/05/24 06:00
CRDT- 2022/05/19 23:41
PHST- 2020/07/31 00:00 [received]
PHST- 2020/11/10 00:00 [revised]
PHST- 2021/04/06 00:00 [accepted]
PHST- 2022/05/19 23:41 [entrez]
PHST- 2022/05/20 06:00 [pubmed]
PHST- 2022/05/24 06:00 [medline]
AID - S2666-6340(21)00156-2 [pii]
AID - 10.1016/j.medj.2021.04.007 [doi]
PST - ppublish
SO  - Med. 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 
      27.