ADPKD is the most common inherited genetic kidney disease, caused by mutations in the PKD1 or PKD2 genes that lead to formation and progressive growth of fluid-filled cysts in kidneys.1 ADPKD is an autosomal dominant genetic disease; therefore, each child from a patient who has this genetic disorder has a 50% chance of inheriting the faulty gene and developing the disease.2

The genetic defect leads to increased glucosylceramide synthase (GCS) activity and results in a local accumulation of glycosphingolipids in the kidney.3,4 This abnormal accumulation of glycosphingolipids promotes the development of fluid-filled cysts that increase total kidney volume (TKV), reduce kidney function and often lead to kidney failure or end-stage kidney disease (ESKD).3

Venglustat is an investigational oral glucosylceramide synthase inhibitor (GCSi). Its effect on the accumulation of glycosphingolipids in the kidney is being studied.

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Sanofi Genzyme CommitmentSanofi Genzyme has pioneered the development and delivery of therapies for patients affected by rare and debilitating diseases for over 30 years. With a focus on rare diseases, multiple sclerosis, immunology, oncology, and rare blood disorders, we are dedicated to making a positive impact on the lives of patients and families we serve. This goal guides and inspires us every day.

Venglustat is investigational and has not been approved by the US Food and Drug Administration (FDA) or any other regulatory agency worldwide for the uses under investigation.

MAT-US-2100241, v.1.0 Exp date: 01/19/2023

1. Spithoven EM, Meijer E, Boertien WE, Sinkeler SJ, Tent H, de Jong PE, Navis G, Gansevoort RT. Tubular Secretion of Creatinine in Autosomal Dominant Polycystic Kidney Disease: Consequences for Cross sectional and Longitudinal Performance of Kidney Function Estimating Equations. Am J Kidney Dis. 2013;Sep;62(3):531-40. doi: 10.1053/j.ajkd.2013.03.030. 2. Autosomal dominant polycystic kidney disease. NIH. https://rarediseases.info.nih.gov/diseases/10413/autosmal-domi-nant-polycystic-kidney-disease. Accessed April 27, 2020. 3. Sun Y, Zhou H, Yang B. Drug discovery for polycystic kidney disease. Acta Pharmacologica Sinica. 2011;32(6):805-816. doi:10.1038/aps.2011.29. 4. Haas, M. PKD: cease and de-cyst. Science-Business eXchange 3, 785 (2010). https://doi.org/10.1038/scibx-.2010.785. 5. Venglustat – Sanofi Genzyme. https://adisinsight.springer.com/drugs/800036945. Accessed April 27, 2020. 6. FDA clinical trial (NCT03523728): https://www.clinicaltrials.gov/ct2/show/NCT03523728?term=EFC15392&rank=1. Accessed April 27, 2020. 7. EudraCT:2017-004084-12: https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004084-12/DE//. Accessed April 27, 2020.

STAGED-PKD

This Phase 2/3 trial is an international, multicenter, randomized, double-blind, placebo-controlled, two-stage study to characterize the efficacy, safety, tolerability, and pharmacokinetics of venglustat in patients at risk of rapidly-progressive ADPKD.

The primary objective of Stage 1 is to determine the effect of venglustat on the rate of TKV growth. The primary objective of Stage 2 is to determine the effect ofvenglustat on the rate of kidney function (eGFR) decline.

Secondary objectives of Stage 1 include rate of change in eGFR, and of Stage 2 include rate of change in TKV and change in urine osmolality. Secondary objectives in both stages also include evaluating plasma concentration of venglustat, safety/tolerability profiles of venglustat, and any impact on nocturia.6,7

Randomized patients will receive a once-daily oral venglustat dose for 24 months, or a once-daily oral placebo dose for 24 months. Patients who complete the 24-month treatment period will enter a 1-month follow-up period after their last venglustat dose.

Stage 2 key inclusion criteria*

18–55 years of age

Mayo Imaging Classification of ADPKD class 1C, 1D or 1E

eGFR between 30-89.9 mL/min/1.73m2

Stable treatment regimen of antihypertensive therapy for at least 30 days prior to screening visit for hypertensive patients

Able to read, comprehend, and respond to the study questionnaires

Ineligible for tolvaptan, according to treating physician

A complete list of eligibility requirements are listed at:www.clinicaltrials.gov (Identifier: NCT03523728); andwww.clinicaltrialsregister.eu (EudraCT Number: 2017-004084-12)

*Stage 1 enrollment is complete and is ongoing.

Study To Assess Glucosylceramide synthase inhibitor (Venglustat) Efficacy, Safety and Tolerability in ADPKD

• For inquiries in the Americas, email: medinfo@genzyme.com

For more information contact medical information:

Sanofi GenzymeCambridge, Massachusetts, USA

MAT-US-2100241, v.1.0 Exp date: 01/19/2023