Kidney Week

Abstract: TH-PO0184

Preclinical Safety and Pharmacokinetic Characterization of Oral 2-Deoxyglucose Supporting First-in-Human Trial Design in ADPKD

Session Information

• ADPKD and Cystic Kidney Disease - 1
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)

Authors

• Federici, Matteo, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Matteo Federici, PharmD, PhD

• Vivian, Carolyn J., The University of Kansas Medical Center, Kansas City, Kansas, United States

Carolyn J. Vivian

• Boletta, Alessandra, IRCCS Ospedale San Raffaele, Milan, Lombardy, Italy

Alessandra Boletta, PhD

• Weir, Scott J., The University of Kansas Medical Center, Kansas City, Kansas, United States

Scott J. Weir, PharmD, PhD

• Yu, Alan S.L., The University of Kansas Medical Center, Kansas City, Kansas, United States

Alan S.L. Yu, MBChB

Background

2-Deoxyglucose (2DG), a competitive inhibitor of intracellular glucose metabolism, is under development as an oral treatment for autosomal dominant polycystic kidney disease (ADPKD). Oral 2DG at 100 mg/kg retarded disease progression in slow progressive mouse models, corresponding to a Human Equivalent Dose (HED) of 8 mg/kg per FDA allometric conversion. Establishing a safe human starting dose required comprehensive preclinical safety and pharmacokinetic (PK) characterization across multiple species.

Methods

Safety pharmacology studies assessed CNS, respiratory, and cardiovascular function in rats and dogs. GLP 28-day repeat-dose oral toxicity studies were conducted in rats and dogs, with exploratory toxicity studies in mice up to 26 weeks. PK plasma profiles were measured by LC-MS/MS after single and repeated dosing. Allometric scaling of rat and dog PK data predicted human steady-state clearance and systemic exposure. The Maximum Recommended Starting Dose (MRSD) was derived per FDA guidance from the No Observed Adverse Effect Level (NOAEL) of the most sensitive species with a 10-fold safety factor applied to the HED.

Results

No adverse CNS or respiratory effects were observed in rats up to 800 mg/kg; single doses up to 360 mg/kg produced no adverse cardiovascular effects in dogs. Species-specific effects were noted: mice and dogs tolerated high doses well, while the 28-day rat study showed mild adverse cardiac effects at ≥200 mg/kg with evidence of recovery. In the 28-day dog study, the NOAEL was 240 mg/kg (HED=129.6 mg/kg) with no cardiac findings. The rat was the most sensitive species, with a NOAEL of 125 mg/kg (HED=20 mg/kg). Based on this, the predicted human systemic exposure at the MRSD of 2 mg/kg (8.51 h*µg/mL) was approximately one-tenth of the rat NOAEL exposure, defining our starting dose. Oral PK profiling showed rapid absorption (T_max=0.3–0.5h), less-than-dose-proportional exposure, and minimal accumulation with once daily dosing. Allometric scaling predicted a human steady-state oral clearance of 235 mL/h/kg.

Conclusion

The preclinical safety and PK data support an oral MRSD of 2 mg/kg for the 2DG Phase 1b dose-escalation trial in ADPKD, with a ceiling dose of ~32 mg/kg set below the published human Maximum Tolerated Dose of 45-63 mg/kg. Safety, tolerability, and PK findings will guide dose selection for subsequent efficacy clinical studies.

Funding

• Other U.S. Government Support