Effects of ACC Inhibitor on Lipid and Lipoprotein Metabolism

NCT04395950 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: AAAS9106
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of this study is to assess the effects of an investigational drug, PF-05221304 (PF'1304) on the way the liver handles fat. The planned study will identify why the fat in the blood increases at the same time this drug reduces fat in the liver. The study will have two treatment periods of 6 weeks each, separated by a 3 week rest period with no treatment. The subjects will receive the active drug in one of the 6 week treatment periods and a placebo in the other 6 week period. The investigators will know when the subjects are receiving active treatment or placebo, but the subject will not know.

Conditions

NASH (Nonalcoholic Steatohepatitis); NAFLD (Nonalcoholic Fatty Liver Disease)

Keywords

NASH; NAFLD; non-alcoholic steatohepatitis; liver disease

Outcome Measures

Primary Outcomes (2)

• Rate of Secretion (also called production-PR) of VLDL TG (mg/kg/day)

  This is also called the production rate of very low density lipoprotein (VLDL) triglycerides (TG).

  Up to 20 weeks

• Fractional Clearance Rate (FCR) of VLDL TG (pool/day)

  This is obtained from the modeling of enrichment data obtained by mass spectrometry.

  Up to 20 weeks

Study Arms (2)

PF-0522130

ACTIVE COMPARATOR

PF-05221304 10 mg daily (two 5mg tablets daily in the morning).

Drug: PF-05221304

Placebo

PLACEBO COMPARATOR

Placebo (two tablets daily in the morning).

Drug: Placebo

Interventions

PF-05221304 DRUG

PF-05221304 10 mg daily (two 5mg tablets daily in the morning for 6 weeks)

Also known as: PF1304

PF-0522130

Placebo DRUG

Placebo two tablets daily in the morning for 6 weeks

Also known as: Placebo tablets

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Body mass index (BMI) of ≥ 25 kg/m2 but \< 40 kg/m2 and at least 2 of 5 traits of metabolic syndrome (fasting blood glucose \>100 mg/dl or diagnosis of diabetes mellitus; BP \>130/85; fasting TG \>150 mg/dl; HDL cholesterol \<40 mg/dl for men and \<50 mg/dl for women; waist circumference \>101 cm for men and \>89 cm for women).
• NASH will be defined as a FibroScan® of CAP \>280 db/m and \>7 kPa, OR demonstrated by liver biopsy, plus:
• ALT \> ULN but \< 5 X ULN.
• FIB4 score \<3.5 (see below)
• BP of ≤ 160/100 mmHg.
• Alkaline phosphatase ≤ ULN.
• Total bilirubin ≤ ULN (unless the subject has Gilbert's syndrome, a benign genetic problem where bilirubin is not conjugated normally and indirect bilirubin (unconjugated bilirubin increases) in which case direct bilirubin must be ≤ ULN with total bilirubin \> ULN).
• Platelet count ≥ LLN (155,000/mm3).
• Albumin ≥ LLN (3.0 g/L).
• INR ≤ 1.3.
• Fasting serum triglycerides ≤ 350 mg/dL either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. They may be receiving statins if the dose has been stable for at least 3 months.
• Subjects may have diabetes but must have an HbA1C ≤ 8.0% with glycemic control either non-pharmacologically managed or pharmacologically managed with stable doses of up to 3 oral agents for at least 6 months. Subjects taking a stable dose of long-acting insulin or an injectable GLP-1 inhibitor may be enrolled at the discretion of the investigators.
• No changes in drugs affecting blood lipid or glucose or insulin levels will be permitted during the study without approval by the investigators.

You may not qualify if:

• Individuals with a history of plasma TG \>1000 mg/dl and/or pancreatitis.
• Females of childbearing potential.
• Chronic kidney disease defined by estimated glomerular filtration rate \< 30 ml/min/1.73 m² by the modification of diet in renal disease equation.
• Documented chronic hepatitis B or C. Subjects with hepatitis C are eligible provided there is proof of sustained virology response (SVR) for ≥ 3 years.
• History of active malignancy within 5 years (subjects with non-melanoma skin cancer may be included).
• Any other disease, condition, or laboratory value that, in the opinion of the principal investigator or clinical study team would place the subject at an unacceptable risk or interfere with the evaluation of the investigative product.
• History of organ transplantation (other than corneal).
• History of hepatobiliary malignancy even if subject "cured".
• Pancreas divisum or a congenital abnormality of the pancreas
• History of pancreatic surgery.
• Subjects taking anti -coagulants or anti-platelet agents other than 81 mg ASA daily.
• Treatment with immunomodulators.
• Drugs associated with acute pancreatitis as asparaginase, azathioprine, didanosine, mecaptourinol, mesalamine, opiates, pentamidine, pentavalent anti-monials, valproic acid, and rifampin.
• a = the major clearance mechanism of PF-05221304 is active uptake into liver (mainly via hepatic transporters OATP1B1/1B3) followed by hepatic carbonyl reductase 1, 11b-hydroxysteroid dehydrogenase, and CYP 3A4/5-mediated metabolism. It is anticipated that potent OATP inhibitors may increase plasma concentrations of PF-05221304. As such, subjects treated with clinically relevant OATP inhibitors will be excluded from this study.

Sponsors & Collaborators

• Columbia University: lead
• Pfizer: collaborator

Related Publications (9)

• Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab. 2011 Sep;22(9):353-63. doi: 10.1016/j.tem.2011.04.007. Epub 2011 May 26.

  PMID: 21616678 BACKGROUND

• Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005 May;115(5):1343-51. doi: 10.1172/JCI23621.

  PMID: 15864352 BACKGROUND

• Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab. 2003 Nov;29(5):478-85. doi: 10.1016/s1262-3636(07)70061-7.

  PMID: 14631324 BACKGROUND

• Kim CW, Addy C, Kusunoki J, Anderson NN, Deja S, Fu X, Burgess SC, Li C, Ruddy M, Chakravarthy M, Previs S, Milstein S, Fitzgerald K, Kelley DE, Horton JD. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017 Aug 1;26(2):394-406.e6. doi: 10.1016/j.cmet.2017.07.009.

  PMID: 28768177 BACKGROUND

• Goedeke L, Bates J, Vatner DF, Perry RJ, Wang T, Ramirez R, Li L, Ellis MW, Zhang D, Wong KE, Beysen C, Cline GW, Ray AS, Shulman GI. Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents. Hepatology. 2018 Dec;68(6):2197-2211. doi: 10.1002/hep.30097.

  PMID: 29790582 BACKGROUND

• Reyes-Soffer G, Moon B, Hernandez-Ono A, Dionizovik-Dimanovski M, Jimenez J, Obunike J, Thomas T, Ngai C, Fontanez N, Donovan DS, Karmally W, Holleran S, Ramakrishnan R, Mittleman RS, Ginsberg HN. Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans. Sci Transl Med. 2016 Jan 27;8(323):323ra12. doi: 10.1126/scitranslmed.aad2195.

  PMID: 26819195 BACKGROUND

• Ramakrishnan R, Ramakrishnan JD. Using mass measurements in tracer studies--a systematic approach to efficient modeling. Metabolism. 2008 Aug;57(8):1078-87. doi: 10.1016/j.metabol.2008.03.011.

  PMID: 18640385 BACKGROUND

• Hellerstein MK, Neese RA. Mass isotopomer distribution analysis at eight years: theoretical, analytic, and experimental considerations. Am J Physiol. 1999 Jun;276(6):E1146-70. doi: 10.1152/ajpendo.1999.276.6.E1146.

  PMID: 10362629 BACKGROUND

• Caulfield MP, Li S, Lee G, Blanche PJ, Salameh WA, Benner WH, Reitz RE, Krauss RM. Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis. Clin Chem. 2008 Aug;54(8):1307-16. doi: 10.1373/clinchem.2007.100586. Epub 2008 May 29.

  PMID: 18515257 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Liver Diseases

Condition Hierarchy (Ancestors)

Fatty Liver; Digestive System Diseases

Study Officials

• Henry Ginsberg, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 15, 2020
• First Posted: May 20, 2020
• Study Start: December 1, 2020
• Primary Completion: August 19, 2021
• Study Completion: August 19, 2021
• Last Updated: August 25, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share