Leukemia drug bosutinib shows promise for inherited kidney disease

Last Updated: 2017-08-30

By Reuters Staff

NEW YORK (Reuters Health) - The tyrosine kinase inhibitor bosutinib, approved for chronic myeloid leukemia, reduced kidney growth rate in patients with autosomal dominant polycystic kidney disease (ADPKD) in a phase 2 study.

ADPKD affects up to 1 in 1,000 people and is characterized by the development of cysts in the kidney and other organs, leading to gradual loss of renal function, often reaching end-stage renal disease in many cases. Current approaches to managing ADPKD are largely supportive and center on addressing hypertension and other secondary complications.

Overactivation of the Src kinase family has been associated with the development of ADPKD. Bosutinib is a second-generation inhibitor of Src and Abl family kinases developed by Pfizer, which funded the current study.

Dr. Vladimir Tesar from Charles University and General University Hospital, Prague, Czech Republic, and colleagues tested bosutinib in 169 patients with ADPKD, an estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73m2, and total kidney volume of at least 750 mL.

Patients were randomly assigned to receive to bosutinib (200 or 400 mg/day) or placebo for up to 24 months. The higher dose of bosutinib was not well tolerated, and 24 patients who initially received the 400-mg dose were later reduced to 200 mg.

The annualized rate of kidney enlargement (the primary outcome) was reduced by about two-thirds in patients on bosutinib 200 mg/day relative to those on placebo (1.63% vs. 4.74%, P=0.005) and by more than four-fifths for all patients receiving bosutinib compared with placebo (0.84% vs. 4.74%, P<0.0001).

"Notably," say the researchers, the change in median kidney volume from baseline to end of treatment was about 100 mL smaller with bosutinib 200 mg versus placebo (62.7 mL vs 168.1 mL).

The 4-component composite measure of disease progression was similar with bosutinib and placebo. There was no marked between-groups differences in annualized eGFR decline over the treatment period, they note in their August 24 Journal of the American Society of Nephrology (JASN) online report.

Gastrointestinal and liver-related adverse events were the most frequent toxicities. No new toxicities were seen relative to prior studies with bosutinib in other patient populations.

The gastrointestinal side effects (primarily diarrhea), "which were partly dose-dependent, may represent a substantial drawback for the further development of the drug for patients with ADPKD," Dr. Tesar said in a news release.

The study provides evidence that "Src kinase inhibitors may have the potential to retard growth of cysts and kidney volume in ADPKD but the long-term benefit remains to be determined," the investigators conclude in their article.

Dr. Tesar was a paid consultant of Pfizer at the time of this study, and several coauthors are employees of the company.

SOURCE: http://bit.ly/2x5ovEb

J Am Soc Nephrol 2017.