Kidney Week

Abstract: TH-PO412

First-in-Human Study of an mTORC1-Selective Inhibitor 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

• Dinh, Alex, Janssen Research and Development LLC, Raritan, New Jersey, United States

Alex Dinh,

• Dishy, Victor, Janssen Research and Development LLC, Raritan, New Jersey, United States

Victor Dishy,

• Waggoner, Jason R., Janssen Research and Development LLC, Raritan, New Jersey, United States

Jason R. Waggoner,

• Csonka, Dénes, Janssen Research and Development LLC, Raritan, New Jersey, United States

Dénes Csonka,

• Shi, Yifan, Janssen Research and Development LLC, Raritan, New Jersey, United States

Yifan Shi,

• Gonzalez-Villalobos, Romer Andres, Janssen Research and Development LLC, Raritan, New Jersey, United States

Romer Andres Gonzalez-Villalobos,

• Bukanov, Nikolay O., Janssen Research and Development LLC, Raritan, New Jersey, United States

Nikolay O. Bukanov,

• Magnone, Maria Chiara, Janssen Research and Development LLC, Raritan, New Jersey, United States

Maria Chiara Magnone,

• Breyer, Matthew Douglas, Janssen Research and Development LLC, Raritan, New Jersey, United States

Matthew Douglas Breyer,

• Tobin, James F., Janssen Research and Development LLC, Raritan, New Jersey, United States

James F. Tobin,

• Wendel, Susan C., Janssen Research and Development LLC, Raritan, New Jersey, United States

Susan C. Wendel,

• Makimura, Hideo, Janssen Research and Development LLC, Raritan, New Jersey, United States

Hideo Makimura,

Background

There are no disease modifying therapies currently available for patients with autosomal dominant polycystic kidney disease (ADPKD). The mechanistic target of rapamycin complex 1 (mTORC1) is a protein kinase complex and key regulator of cellular metabolism and proliferation that promotes cyst formation and growth. We are developing a mTORC1-selective inhibitor to slow kidney disease progression in patients with ADPKD while reducing the incidence of mTORC2-associated toxicities that have limited other rapalogs in ADPKD clinical trials. In addition to demonstrating selectivity for mTORC1 inhibition over mTORC2 inhibition, our compound has previously been demonstrated to reduce disease burden in ADPKD animal models. The objective of this first-in-human study was to assess the safety, tolerability and pharmacokinetics of single ascending doses of our compound in healthy adult volunteers.

Methods

In this double-blind, single ascending dose (SAD) study, we enrolled healthy adult volunteers into 4 sequential ascending dose cohorts. Subjects were randomized to receive our compound or placebo. Safety, tolerability and pharmacokinetics were assessed at baseline and at multiple timepoints after dosing.

Results

In this SAD study, our compound was safe and well tolerated at all dose levels examined. All adverse events related to our compound were mild. Concentrations of our compound increased with increasing doses.

Conclusion

Our compound was safe and well tolerated after a single dose in healthy volunteers. A planned phase 1b, multiple ascending dose study in patients with ADPKD will evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics with repeated doses of our compound.

Funding

• Commercial Support – Janssen R&D