Abstract: TH-PO447
Investigational New Drug (IND)-Enabling Studies to Support the Development of 2-Deoxy-D-Glucose (2DG) for the Treatment of ADPKD
Session Information
- Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Federici, Matteo, IRCCS Ospedale San Raffaele, Milano, Italy
- Weir, Scott J., University of Kansas Institute for Advancing Medical Innovations, Kansas City, Kansas, United States
- Vivian, Carolyn J., University of Kansas Institute for Advancing Medical Innovations, Kansas City, Kansas, United States
- Yu, Alan S.L., University of Kansas Medical Center Department of Internal Medicine, Kansas City, Kansas, United States
- Boletta, Alessandra, IRCCS Ospedale San Raffaele, Milano, Italy
Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of fluid-filled cysts due to abnormal epithelial proliferation. We have demonstrated that ADPKD cyst epithelial cells undergo metabolic reprogramming, which can be targeted using 2DG. Our preclinical data indicate that 2DG retards the disease progression in PKD models. Previously tested in >300 individuals, 2DG showed to be safe at 45-63 mg/kg/day. We have designed a Phase 1b clinical trial to evaluate safety/tolerability in ADPKD patients assuming a ceiling dose of 32 mg/kg/day. We now present our development program and the IND-enabling studies required to support this clinical trial
Methods
Our program was discussed in a pre-IND meeting with the FDA. The purpose was to reach agreement on chemistry, manufacturing, and controls (CMC) and nonclinical studies to be completed prior to the IND submission. We manufactured a GMP batch of 2DG drug substance, with ongoing stability testing. Nonclinical GLP studies are being conducted in two species to determine the toxicity/toxicokinetic profile of 2DG when administered by oral gavage. The studies include dose escalation to determine the maximum tolerated dose followed by 7-day repeat-dose to assess tolerance, 28-day repeat-dose toxicity, safety pharmacology on CNS, respiratory, cardiovascular systems, and genotoxicity studies
Results
The FDA generally agreed with our development program and gave helpful recommendations to optimize the nonclinical plans. The GMP batch passed all quality controls for release. Preliminary data showed stability at least up to one year. In the dose escalation study 2DG resulted well tolerated at single dose up to 1,600 mg/kg in the rat and 480 mg/kg in the dog (human equivalent dose of ~256 mg/kg). Transient clinical signs were observed only at 1,600 mg/kg in rats. No major gross findings at necropsy in both species. Bacterial reverse mutation test showed negative mutagenic response.
Conclusion
Our hypothesis is that 2DG will be an effective and safe treatment for ADPKD. The results from current nonclinical studies, along with CMC information and clinical trial plans, will be ultimately included in the IND submission to seek FDA approval for initiating the clinical study. Future efforts will focus on securing funds for the clinical trials.
Funding
- Other U.S. Government Support