6-week Safety and PD Study in Adults With NAFLD

• Placebo (Drug): 0 mg
• PF-06835919 Low Dose (Drug): 75 mg once daily
• PF-06835919 High Dose (Drug): 300 mg once daily

Primary outcomes

• Percent Change From Baseline in Whole Liver Fat at Week 6 [Baseline and Week 6]: The percent change from baseline in whole liver fat at Week 6 was assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF). MRI-PDFF generates measures of the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF was calculated as follows: Whole Liver PDFF= PDFFs for (Segment I+Segment II+Segment III+Segment IVa+Segment IVb+Segment V+Segment VI+Segment+VII+Segment VIII) / (number of segments assessed). The same segments were to be used at both baseline and post-baseline time points in the calculation of whole liver PDFF to derive the percent change from baseline. The values of whole liver PDFF ranges from 0 to 100 and higher values represent higher liver fat.

Secondary outcomes

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Baseline up to Day 77 (28-35 days post last dose)]: All-causality adverse events (AEs) were any untoward medical occurrence in a study participant who administered a product or medical device, the event need not necessarily have a causal relationship with the treatment or usage. Treatment-related AEs were any untoward medical occurrence in a study participant who administered a product or medical device, the event needed to have a causal relationship with the treatment or usage. A TEAE was defined as any event not present prior to the initiation of the treatments or any event already present that worsens in either intensity or frequency following exposure to the treatments.
• Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria [Baseline up to Day 56 (Week 8)]: The vital sign categorical criteria included: Sitting DBP (diastolic blood pressure) millimeter of mercury (mmHg) Change >= 20 mmHg increase Sitting SBP (systolic blood pressure) (mmHg) Change >= 30 mmHg increase Sitting DBP (mmHg) Change >= 20 mmHg decrease Sitting SBP (mmHg) Change >= 30 mmHg decrease Sitting DBP (mmHg) Value < 50 mmHg Sitting Pulse Rate (bpm) Value < 40 bpm or Value > 120 bpm Sitting SBP (mmHg) Value < 90 mmHg
• Number of Participants With Post-dose ECG Data Meeting Categorical Criteria [Baseline up to Day 56 (Week 8)]: The ECG categorical criteria included: PR Interval (msec) percent (%)Change >= 25% increase when baseline >200 or >=50% increase when baseline <=200 QRS Interval (msec) %Change >= 50% increase QTcF Interval (Fridericia's Correction) (msec) increase 30 <= Change < 60 or Change >= 60 PR Interval (msec) Value >= 300 QRS Interval (msec) Value >= 140 QTcF Interval (Fridericia's Correction) (msec) 450 <= Value <480 or 480 <=Value <500 or Value >= 500
• Number of Participants With Laboratory Abnormalities [Baseline up to Day 56 (Week 8)]: Below parameters were evaluated for laboratory tests: Hemoglobin, Hematocrit, Erythrocytes, Ery. Mean Copuscular Volume, Ery. Mean Copuscular Hemoglobin, Ery. Mean Corpuscular HGB Concentration, Platelets, Leukocytes, Lymphocytes, Neuprophils, Basophils, Eosinophils, Monocytes, Bilirubin, Direct Biliirubin, Indirect Bilirubin, Aspartate Aminotransferase, Alanine Aminotransferase, Gamma Glutamyl Transferase, Alkaline Phosphatase, Protein, Albumin, Albumin, Blood Urea Nitrogen, Creatinine, Urate, Sodium, Potassium, Chloride, Calcium, Bicarbonate, Glucose-Fasting, pH, Urine Glucose, Ketone, Urine Protein, Urine Hemoglobin, Urobilinogen, Urine Bilirubin, Nitrite, Leukocyte Esterase, Urine Erythocytes, Urine leukocytes, Hyaline Casts, Urine Creatinine.

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* BMI at least 28 kg/m2
* Type 2 diabetes and/or metabolic syndrome

Exclusion Criteria:

* Liver disease
* Type 1 diabetes
* Recent heart attack or stroke
* Inability to have an MRI scan

Participant flow

Outcome results

• Percent Change From Baseline in Whole Liver Fat at Week 6 (Primary), Mean, Percent Change: Placebo -7.97 +/- 24.521; PF-06835919 75 mg 2.84 +/- 22.246; PF-06835919 300 mg -25.43 +/- 22.434 (p 0.1654)
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Placebo 5; PF-06835919 75 mg 4; PF-06835919 300 mg 5
• Number of Participants With Post-dose Vital Signs Data Meeting Categorical Criteria (Secondary), Count of participants, Participants: Placebo 1; PF-06835919 75 mg 0; PF-06835919 300 mg 1
• Number of Participants With Post-dose ECG Data Meeting Categorical Criteria (Secondary), Count of participants, Participants: Placebo 0; PF-06835919 75 mg 0; PF-06835919 300 mg 0
• Number of Participants With Laboratory Abnormalities (Secondary), Count of participants, Participants: Placebo 9; PF-06835919 75 mg 8; PF-06835919 300 mg 8

Adverse events

Time frame: Baseline up to Day 77 (28-35 days post last dose)

Other adverse events by term

• Results publication: Hong JG, Trotman J, Carbajal Y, Dey P, Glass M, Sclar V, Alter IL, Zhang P, Wang L, Chen L, Petitjean M, Bhattacharya D, Wang S, Friedman SL, DeRossi C, Chu J. Mannose reduces fructose metabolism and reverses MASH in human liver slices and murine models in vivo. Hepatol Commun. 2025 Mar 21;9(4):e0671. doi: 10.1097/HC9.0000000000000671. eCollection 2025 Apr 1. PMID 40116750
• Results publication: Kazierad DJ, Chidsey K, Somayaji VR, Bergman AJ, Birnbaum MJ, Calle RA. Inhibition of ketohexokinase in adults with NAFLD reduces liver fat and inflammatory markers: A randomized phase 2 trial. Med. 2021 Jul 9;2(7):800-813.e3. doi: 10.1016/j.medj.2021.04.007. Epub 2021 Apr 27. PMID 35590219

• Study Protocol (PDF, 2017-06-29)
• Statistical Analysis Plan (PDF, 2017-11-07)

• Pfizer CT.gov Call Center, Study director, Pfizer