Abstract: TH-PO426
Development Program of 2-deoxy-D-glucose (2DG) for the Treatment of ADPKD
Session Information
- Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Yu, Alan S.L., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Chiaravalli, Marco, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
- Federici, Matteo, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
- Vivian, Carolyn J., University of Kansas Institute for Advancing Medical Innovations, Kansas City, Kansas, United States
- Weir, Scott J., University of Kansas Institute for Advancing Medical Innovations, Kansas City, Kansas, United States
- Boletta, Alessandra, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of fluid-filled kidney cysts due to abnormal epithelial proliferation. We have demonstrated that ADPKD cyst epithelial cells undergo metabolic reprogramming with increased aerobic glycolysis (Warburg effect) and so are exclusively dependent on glucose for energy production. This can be exploited to treat ADPKD using an analog of glucose, 2-deoxy-D-glucose (2-DG), that inhibits glycolysis. We have shown that 2DG is effective at slowing cyst growth in both rapid and slowly progressive mouse PKD models. 2DG has previously been tested in over 200 normal human volunteers and cancer patients in both single and continuous daily dosing for up to 3 months and shown to be safe and well tolerated at doses up to 45 mg/kg/day.
Methods
We now present a new development program to advance 2DG for treatment of ADPKD. Preclinical investigational new drug (IND)-enabling activities are underway or will begin soon, including refinement of the dose-response relationship, chronic GLP toxicology studies in rodent/non-rodent species, synthesis of GMP-grade batches of drug product, and discussions with regulatory authorities.
Results
Our first-in-human study is proposed to be a multicenter Phase 1B uncontrolled, multiple ascending dose clinical trial. ADPKD patients aged 18–60 yr with eGFR >60 mL/min/1.73 m2 will be enrolled in cohorts of 3 and administered single daily oral doses of 2DG for 2 weeks. The primary objective will be to assess the safety and tolerability of 2DG in ADPKD patients and to determine a recommended Phase 2 dose. The secondary objectives will be to determine the pharmacokinetics of 2DG and to identify candidate metabolic response biomarkers in patient blood and urine.
Conclusion
The results of this study will determine whether it is justified to proceed to a clinical proof-of concept study, and will also inform the design of such a trial.
Funding
- Other U.S. Government Support