Kidney Week

Abstract: FR-PO0098

First-in-Human Pregnancy-Associated Plasma Protein A Inhibition Achieves Insulin-Like Growth Factor Binding Protein 4 (IGFBP-4) Pathway Modulation in Healthy Volunteers and Patients with ADPKD: Results from Phase 1

Session Information

• ADPKD and Cystic Kidney Disease - 2
  October 23, 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

• Mäki-Petäjä, Kaisa M., AstraZeneca R&D Cambridge, Cambridge, England, United Kingdom

Kaisa M. Mäki-Petäjä, PhD

• Ingelsten, Madeleine, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden

Madeleine Ingelsten, MS, MSc, PhD

• Mbuguiro, Wangui, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, United States

Wangui Mbuguiro, PhD

• Alluri, Ravindra Varma, AstraZeneca R&D Cambridge, Cambridge, England, United Kingdom

Ravindra Varma Alluri, PhD

• Vildhede, Anna, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden

Anna Vildhede, PhD

• P, Samuel Gideon George, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden

Samuel Gideon George P, PharmD

• Chu-Martin, Tzu-Chun, AstraZeneca R&D Boston, Boston, Massachusetts, United States

Tzu-Chun Chu-Martin, MS, PhD, MPH

• Gasparyan, Samvel B., AstraZeneca R&D Boston, Boston, Massachusetts, United States

Samvel B. Gasparyan, PhD

• Zhou, Alex Xianghua, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden

Alex Xianghua Zhou, MS, PhD

• Murray, Thomas V., AstraZeneca R&D Cambridge, Cambridge, England, United Kingdom

Thomas V. Murray, PhD

• Jones, Christopher, AstraZeneca R&D Cambridge, Cambridge, England, United Kingdom

Christopher Jones

• Mansoury, Kamran, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, United States

Kamran Mansoury, MSc

• Newgreen, Donald T., AstraZeneca R&D Cambridge, Cambridge, England, United Kingdom

Donald T. Newgreen, PhD

• Gonzalez-Villalobos, Romer Andres, AstraZeneca R&D Boston, Boston, Massachusetts, United States

Romer Andres Gonzalez-Villalobos, MD, PhD

• Chebib, Fouad T., Mayo Clinic in Florida, Jacksonville, Florida, United States

Fouad T. Chebib, MD, FASN

• Hofherr, Alexis, AstraZeneca R&D Gothenburg, Mölndal, Västra Götaland County, Sweden

Alexis Hofherr

Background

Autosomal dominant polycystic kidney disease (ADPKD) is characterised by progressive renal cyst growth, and current treatment options are limited. Preclinical data implicate pregnancy-associated plasma protein A (PAPPA) as a driver of cyst expansion via increased local IGF-1 activity through IGF-binding protein 4 (IGFBP4) cleavage. AZD1613 is a human monoclonal antibody inhibitor of PAPPA. We report initial Phase 1 results on its safety, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers (HVs) and adults with ADPKD.

Methods

A randomised, single-blind, placebo-controlled Phase 1 trial, with single ascending dose (SAD) cohorts in HVs and on-going multiple ascending dose (MAD) cohorts in ADPKD patients (PIONEER-PKD / NCT06995820). Assessments included safety/tolerability, PK, immunogenicity, and a PD biomarker of PAPPA activity (circulating cleaved IGFBP4), plus exploratory kidney injury markers, and height-adjusted total kidney volume (htTKV) in patients.

Results

In HVs (8 SAD cohorts, n=64), AZD1613 was safe and well tolerated: no serious adverse events (SAEs) or discontinuations, and no clinically significant laboratory, vital sign, or ECG changes. AZD1613 exhibited dose-proportional PK and dose-dependent suppression of cleaved IGFBP4 which lasted >100 days, confirming sustained PAPPA inhibition. Population PK/PD modelling was performed using the HV SAD data to characterize exposure-response and inform dose selection for the patient MAD study. In the patient MAD study, doses were selected to achieve sustained reductions of cleaved IGFBP4 while ensuring predicted exposures remain within the established safety margins. Safety in patients is expected to be similar to that observed in HVs, with no SAEs, no discontinuations due to adverse events, and no renal safety signals observed to date.

Conclusion

AZD1613 demonstrated a favourable safety profile and dose-proportional PK in both HVs and ADPKD patients. Sustained PAPPA target engagement establishes clinical proof of mechanism in humans, while exposure–response analyses will inform dose selection for subsequent studies. Together, these Phase 1 findings underscore PAPPA inhibition as a potential therapeutic approach for ADPKD.

Funding

• Commercial Support – AstraZeneca