Sanofi Pivotal Trial to Target Driver of Cyst Growth in PKD


If the trial is successful, venglustat could be the first treatment to target the mechanism of action in autosomal dominant polycystic kidney disease (PKD), which affects 120,000 people in the United States.

Polycystic kidney disease (PKD) affects about 600,000 people in the United States, which accounts for 5% of all cases of kidney failure. Autosomal dominant PKD (ADPKD), which affects about 120,000 people in this country and 170,000 in the European Union, is an especially devastating, painful illness. Propelled by a genetic mutation, ADPKD causes cysts to grow on the kidneys, which become enlarged as the cysts fill with fluid and take over these vital organs.

Normally the size of a fist, a kidney covered by cysts can expand beyond the size of a football and weigh more than 35 pounds. People with this condition experience intense abdominal pain, high blood pressure, infections, and kidney stones, typically starting between age 30 and 40.

ADPKD progresses at different rates in different patients; some will not need dialysis or a kidney transplant until age 70 but others whose disease is rapidly progressing may reach end-stage renal disease (ESRD) in their 50s. Until recently, there were no treatments of PKD; in August, Otsuka Pharmaceutical won approval for tolvaptan (Jynarque), which can slow the loss of kidney function by blocking water reabsorption in the kidney ducts.

But research over the past decade suggests that it’s possible to target the mechanism that triggers the growth of cysts in the first place. Sanofi Genzyme is developing a treatment to do this, and last month announced it is enrolling patients in a pivotal trial for venglustat, an investigational oral therapy that has shown promise in mouse models of blocking the substances that drive tumor growth.1

These substances, called glucosphingolipids (GSLs), are overexpressed in patients across an array of renal diseases, from diabetic nephropathy and renal cell carcinoma, as well as PKD. GSLs are known to regulate many cellular processes, including cell proliferation. A 2010 paper that explored the mechanism of blocking GSLs in mouse models discussed the idea that if the GSL metabolism is sped up, this may boost the growth of cysts in PKD; conversely, blocking this pathway could cause the cysts to stop growing or even retreat.

Describing the possible mechanisms of action in a 2016 paper, James A. Shayman, MD, wrote that so far, the experimental use of inhibitors looks promising in reversing the disease characteristics.2 He writes, that understanding the link between GSL inhibition and “reversal of either renal hypertrophy or cyst growth is more than a scientific exercise.”

This is precisely what researchers hope to see as they recruit the first patients for treatment with venglustat in a clinical trial, said Gianluca Pirozzi, MD, PhD, head of Development for Rare Diseases and the head of Translational Gene Therapy at Sanofi, in an interview with The American Journal of Managed Care®. Pirozzi, who previously led development of dupilumab (Dupixent), which blocks key immune system pathways to treat atopic dermatitis, is optimistic; he said that FDA recognizes the therapy could address an enormous unmet need. Venglustat has received Orphan Drug Designation.

Unlike tolvaptan, which Pirozzi said will relieve symptoms of rapidly progressing PKD, venglustat aims to disrupt the disease mechanism itself. If the treatment works as Sanofi hopes, the key will be to identify the 30% of PKD patients who are “rapid progressors,” whose kidney function is declining at a comparatively young age and who face years of dialysis or early death from the disease. ESRD treatment costs are rising faster than others in healthcare, to at least $90,000 per year. Those diagnosed with ESRD before age 65 become eligible for Medicare because treatment is so expensive.

Thus, for affected patients, the prospect of halting cyst growth by taking a pill once a day, “could be life changing,” Pirozzi said.

Because venglustat would need to be taken daily for the rest of a patient’s life, targeting the right population will be a major point of discussion with payers, he said.

“We need to find ways to identify who are the right patients, the fast progressors,” Pirozzi said. His recommendation would be to start treatment, “as soon as possible.”


  1. Natoli TA, Smith LA, Rogers KA. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. 2010;16(7):788-792. doi: 10.1038/nm.2171.
  2. Shayman JA. Targeting glycosphingolipid metabolism to treat kidney disease. Nephron. 2016;134(1):37-42. doi: 10.1159/000444926.

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