Dr Anja Stirnweiss1, ANNA MILLS1, MARIA KERFOOT1, ARON CHAKERA1,2, CLARISSA MCDONAGH1, BRIDGET FLIS1, NATALI VASILEVSKI1, AUDREY CHAMBERLAIN1, ADAM MARTIN1, SUBRATA DAS1, GENEVIEVE SYN1, LINDA DE CASTRO1, ALEXANDER DE BONT1, DEAN DE ALVIS1, JESSICA STEVENSON1, ASHWARYA KUNDU1, SRI MUDUMBA1, PAULA CUNNINGHAM1
1PYC Therapeutics, Nedlands, Australia, 2Sir Charles Gairdner Hospital, Perth, Australia
Biography:
Dr Anja Stirnweiss is a biomedical scientist with deep expertise in molecular biology, cancer biology, and immunology. She has led and contributed to research programs targeting rare diseases such as NUT midline carcinoma. As Principal Scientist at PYC Therapeutics, she plays a pivotal role in bridging research and clinical application, overseeing the design and execution of preclinical and early clinical development programs. Dr Stirnweiss works cross-functionally to ensure scientific rigor in therapeutic development, supporting regulatory, translational, and external collaboration efforts.
Aim:
To assess PYC-003 efficacy in upregulating PC1 protein in in vitro Autosomal Dominant Polycystic Kidney Disease (ADPKD) models and establish its pharmacokinetic profile in preclinical species, aiming to optimise safety and probability success in clinical trials.
Background:
ADPKD is a genetic disorder affecting 1 in 1,000 people, often leading to kidney failure, with no disease-modifying treatments available. About 80% of cases are caused by mutations in the PKD1 gene, leading to insufficient PC1 protein in renal cells. PYC-003 is a peptide-conjugated antisense oligonucleotide designed to upregulate PC1 protein, targeting the root cause of ADPKD.
Methods:
Preclinical data for PYC-003 include in vitro studies using ADPKD cell lines and 3D cyst models, and in vivo safety evaluations across species, including a Pkd1 knockout mouse model. These studies assess the effects of PYC-003 on PC1 protein expression and cyst growth. Findings supported the safety and dosing strategy for its ongoing clinical evaluation in a single ascending dose study in healthy volunteers and ADPKD patients.
Results:
PYC-003 increased PC1 expression (1.2-fold) in WT9-7 cells and inhibited cyst formation while reducing cyst area in a patient-derived 3D model. Moreover, PYC-003 exhibited uniform distribution to all cyst-derived cells in a cystic mouse model following a single injection. Notably, GLP safety studies in non-human primates established a No Observed Adverse Effect Level (NOAEL) of 12 mg/kg, with kidney medulla and cortex drug exposure significantly exceeding anticipated efficacious doses.
Conclusion:
PYC-003 demonstrates significant disease-modifying potential for ADPKD. Its ability to upregulate PC1 protein, inhibit cystogenesis in vitro, and achieve uniform distribution at effective concentrations within the target kidney tissue in vivo highlights its potential to address the root cause of the disease.