Ketohexokinase Inhibition in Hereditary Fructose Intolerance (KHKi in HFI)

Short-term Safety and Efficacy of Ketohexokinase Inhibition in Patients With Hereditary Fructose Intolerance

Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism. Patients with HFI develop acute abdominal pain, nausea, vomiting, hypoglycemia and proximal tubular dysfunction upon consumption of a fructose containing food product. In rare cases, (prolonged) fructose consumption can even lead to liver and kidney failure. Patients with HFI are therefore treated with a lifelong fructose-restricted diet. Animal studies have shown that the clinical manifestations of HFI are abrogated upon inhibition of ketohexokinase (KHK), the enzyme that catalyses the first step in fructose metabolism.

Recently, PF-06835919, a KHK inhibitor (KHKi), was developed as a new treatment for non-alcoholic fatty liver disease. The compound was well tolerated in several phase II clinical trials.

It is hypothesized that PF-06835919 is also effective in patients with HFI.

Study Overview

• Status: Completed
• Conditions: HFI
• Intervention / Treatment: Drug: PF-06801591

Detailed Description

Rationale: Hereditary fructose intolerance (HFI) is a rare inborn error of metabolism. Patients with HFI develop acute abdominal pain, nausea, vomiting, hypoglycemia and proximal tubular dysfunction upon consumption of a fructose containing food product. In rare cases, (prolonged) fructose consumption can even lead to liver and kidney failure. Patients with HFI are therefore treated with a lifelong fructose-restricted diet. Animal studies have shown that the clinical manifestations of HFI are abrogated upon inhibition of ketohexokinase (KHK), the enzyme that catalyses the first step in fructose metabolism.

Recently, PF-06835919, a KHK inhibitor (KHKi), was developed as a new treatment for non-alcoholic fatty liver disease. The compound was well tolerated in several phase II clinical trials.

It is hypothesized that PF-06835919 is also effective in patients with HFI. Objective: To study the effects of PF-06835919 on fructose tolerance and intrahepatic lipid content in patients with HFI. Study design: open-label, pilot study Study population: three adult patients with HFI will be treated with PF-06835919. Five adult healthy individuals will be included (but not be treated) as a reference. Intervention (if applicable): Patients receive once daily (in the morning) three tablets of 100 mg PF-06835919 for 9 days. They will subsequently be gradually exposed to increasing doses of either oral fructose or glucose (in a blinded fashion). Healthy individuals will only undergo oral fructose exposure, as a reference. Main study parameters/endpoints: Intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (at baseline and completion), intestinal fructose tolerance (after oral fructose in comparison to oral glucose), hepatic fructose tolerance (serum glucose and phosphate after oral fructose in comparison to healthy individuals) and renal fructose tolerance (urinary glucose, phosphate, pH and amino acids after oral fructose in comparison to healthy individuals). Nature and extent

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6202AZ
      • Maastricht University Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participants are able to provide signed and dated written informed consent prior to any study specific procedures
• Use of effective contraception (only applicable to premenopausal women; a pregnancy test will be performed in these women at baseline)
• Aged ≥ 18 years

Exclusion Criteria:

• Diabetes mellitus
• Pregnancy
• Patients with congestive heart failure and/or severe renal and or liver insufficiency
• Uncontrolled hypertension
• Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the investigator which would possibly hamper our study results
• Use of drugs that inhibit organic anion transporting polypeptide B1 (OATPB1) transporters (e.g. rifampicin, gemfibrozil, ciclosporine, erythromcyin and clarithromycin)*
• Treatment with irinotecan* Any contra-indications for MRI scanning*

• Subjects who do not want to be informed about unexpected medical findings

  • Exclusion criterion for HFI patients only.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HFI patients; HFI participants will receive PF-06835919 for 9 days. Dosage; once daily 300 mg PF-06835919 in the form of 3 tablets, oral.	Drug: PF-06801591; Active ketohexokinase inhibitor; Other Names: KHKi
No Intervention: Healthy controls; Healthy controls will receive no intervention, but a single fructose tolerance test.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intestinal Fructose tolerance,	a visual analog scale from 1-10 for abdominal pain will be used. Additional every 5 minutes the participant will be asked if he/she is nauseous, and more, less or similar nauseous as 5 minutes before.	9 days
Intestinal Fructose tolerance,	Every 5 minutes the participant will be asked if he/she is nauseous, and more, less or similar nauseous as 5 minutes before.	9 days
Renal Fructose tolerance	Urinary pH	9 days
Renal Fructose tolerance	Glucose content, mmol/L	9 days
Renal Fructose tolerance	Phosphate content mmol/L	9 days
Renal Fructose tolerance	Amino acid content mmol/L	9 days
Hepatic fructose tolerance	Serum glucose levels, mmol/L	9 days
Hepatic fructose tolerance	Serum phosphate levels, mmol/L	9 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intrahepatic lipid content	measured using 1H-MRS at baseline and completion	9 days
Blood pressure	measured at baseline and completion. Both systolic and diastolic pressure will be assessed	9 days
Glycosylated transferrin	measured at baseline and completion.	9 days

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Pfizer
• Investigators: Principal Investigator: Patrick Schrauwen, PhD, Maastricht University

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2023
• Primary Completion (Actual): November 30, 2023
• Study Completion (Actual): November 30, 2023

Study Registration Dates

• First Submitted: May 15, 2023
• First Submitted That Met QC Criteria: October 16, 2023
• First Posted (Actual): October 18, 2023

Study Record Updates

• Last Update Posted (Estimated): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Fructose Metabolism, Inborn Errors; Fructose Intolerance
• Other Study ID Numbers: NL83631.068.23 / METC23-006

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data can be obtained with the PI on request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No