FDA Advisory Committee recommends against approval of Tolvaptan for polycystic kidney disease

As noted in a previous posting, Tolvaptan, a vasopression type-2 receptor antagonist, currently approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia, is also being developed for the treatment of autosomal dominant polycystic kidney disease (ADPKD).  Otsuka pharmaceuticals had sponsored a development program,  including a phase 2 and a recently completed phase 3 (TEMPO 3:4) study in 1445 patients, the results of which were published in New England Journal of Medicine  and summarized in this forum (see here).

On April 12, 2013, the FDA granted priority review for Tolvaptan’s New Drug Application (NDA) (see press release).  On April 30, 2013, following the review of the data from the Tolvaptan TEMPO study in ADPKD, the FDA issued a Drug Safety Communication on possible liver injury with Tolvaptan. The specific warning is as follows: [Samsca treatment should be stopped if the patient develops signs of liver disease. Treatment duration should be limited to 30 days or less, and use should be avoided in patients with underlying liver disease, including cirrhosis. Patients should be aware that Samsca may cause liver problems, including life-threatening liver failure, and should contact their health care professional to discuss any questions or concerns about Samsca].  The company updated the Samsca label to indicate that the drug should be limited to 30 days and that it is no longer indicated in patients with cirrhosis (see here).  As a result of these new findings, which had not been seen in patients treated with Tolvaptan for hyponatremia, the FDA sought the advice of an advisory committee prior to a final decision on possible approval.

On August 5, 2013, the FDA Cardiovascular and Renal Advisory Committee evaluated the data submitted by the sponsor in patients with ADPKD.  The materials submitted (briefing package, FDA summary) are available at the FDA website.  Following review, the Advisory Committee voted 9 to 6 against approval of Tolvaptan for the treatment of ADPKD.  The panel cited excessive dropouts and limited efficacy in slowing progression of renal disease, despite reductions in kidney volume and pain.  The overall risk was assessed to be higher than the benefit observed, despite a high unmet medical need in this patient population.  Additional information can be found here and at Medpage Today.  See also Otsuka press release.


There have been very few drugs approved for the treatment of kidney diseases (see here). Many drugs that appeared to show promise in animal models, have failed to show efficacy in human kidney diseases.  The traditional outcomes such as doubling of serum Cr or time to dialysis require many years in a disease with relatively slow progression such as ADPKD.  The decision to move tolvaptan forward for the treatment of ADPKD was in part due to prior efforts by the renal community with support from NIDDK and the PKD Foundation.  The formation of the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP Consortium), led to longitudinal studies aiming to establish changes in kidney volume as a surrogate endpoint for the clinical studies of ADPKD. Therefore, we must congratulate the sponsor and the investigators for undertaking such a risky clinical development program.  Whatever the final FDA decision, the PKD community has benefited from the acceptance of renal volume as an endpoint in studying progression in ADPKD.  Another important effort in this direction is the recent formation of the PKD Outcomes Consortium Project (PKDOC), which is an ongoing project supported by the PKD Foundation, academic nephrologists, pharmaceutical representatives and the FDA.  I had the privilege of being involved in this effort.

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