An advisory committee to the US Food and Drug Administration (FDA) voted 9 to 6 not to recommend tolvaptan (Otsuka Pharmaceutical Company, Ltd) for the indication of slowing kidney disease in adults at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).
"I think the evidence is promising, but on balance, the risk–benefit ratio wasn't there. For a medication that's going to need to be taken lifelong, you don't have long enough follow-up data in the early disease or good data in later disease," Linda F. Fried, MD, MPH, chief of peritoneal dialysis at Veterans Affairs Pittsburgh Healthcare System and a professor of medicine, epidemiology, and clinical and translational science at the University of Pittsburgh in Pennsylvania, said during the meeting.
ADPKD is a progressive disease in which bilateral fluid-filled cysts compress normal kidney tissue and blood vessels, resulting in ischemia, inflammation, fibrosis, and progressive nephron loss. Clinical manifestations include hematuria, infections, pain, hypertension, albuminuria, and renal insufficiency.
There were an estimated 116,228 cases of ADPKD in the United States in 2009, qualifying it as an orphan disease. There are currently no treatments to address the underlying cause of ADPKD. Tolvaptan blocks the kidney V2 receptor, resulting in decreased water reabsorption and decreased cyst growth and fibrosis.
The panel reviewed data from a randomized, double-blind, placebo-controlled, multicenter phase 3 trial conducted in 1445 adults (961 of whom received tolvaptan, and 484 placebo) with ADPKD and relatively preserved renal function (an estimated glomular filtration rate of ≥60 mL/minute by the Cockcroft-Gault equation) who were considered at risk for rapid disease progression on the basis of a total kidney size of 750 cc or larger.
Patients were given a split-dose regimen starting at 45/15 mg twice daily and titrated at weeks 1 and 2 to 60/30 mg and 90/30 mg if tolerated.
Patients were seen at weeks 1, 2, and 3/end of titration and every 4 months from month 4 until month 36/early termination. Magnetic resonance imaging evaluations of kidney volume were done at baseline and months 12, 24, and 36 (±2 weeks)/early termination. Those who discontinued the study drug were followed-up by telephone and did not undergo assessment of serum creatinine levels, blood pressure, or kidney volume. Many on the committee thought this was a weakness of the study.
Unacceptable Surrogate Endpoint
The primary endpoint was the rate of total renal volume change; the FDA did not consider this to be an acceptable surrogate endpoint. The first secondary endpoint was time to multiple ADPKD clinical progression events (progressing hypertension, severe renal pain, worsening albuminuria, and worsening renal function). The FDA considered this the key efficacy endpoint. The first noncomposite secondary endpoint was renal function.
Tolvaptan reduced the rate of total kidney volume growth by about half compared with placebo (2.78% vs 5.61%/year) for a difference of 2.71%/year (P < .0001), a 49.2% reduction of growth rate.
Hazard ratios (HRs) were 0.865 (95% confidence interval [CI], 0.775 - 0.965; P = .0095) for time to multiple ADPKD progression events, 0.386 (95% CI, 0.263 - 0.566; P < .0001) for worsening renal function, 0.642 (95% CI, 0.466 - 0.887; P = .0071) for renal pain, 0.942 (95% CI, 0.814 - 1.090; P = .4223) for worsening hypertension, and 1.037 (95% CI, 0.837 - 1.284; P = .7420) for worsening albuminuria.
The difference between treatment groups in the rate of loss of renal function was about 1 mL/minute per 1.73 m2 per year. Because of missing data, the size of this effect was unclear.
Drug-Induced Liver Injury Concerning
There were 3 "Hy's Law" cases of drug-induced liver injury in the tolvaptan group, and none in the placebo group. Patients in the tolvaptan group had a 4-fold higher incidence of significant alanine transaminase elevation compared with those in the placebo group. Patients did not progress to liver failure.
Other adverse events included skin neoplasms (basal cell carcinoma and malignant melanoma), glaucoma, hypernatremia with potentially clinically significant increased sodium levels (>150 mEq/L), increased uric acid, gout, and dehydration.
More patients in the tolvaptan group (7.7%) permanently discontinued treatment in the first 28 days because of polyuria, nocturia, pollakiuria, and polydipsia compared with those in the placebo group (1.0%).
As of March 31, 2012, 2 deaths were reported, both of which were unlikely related to tolvaptan (1 self-inflicted gunshot wound, 1 subarachnoid hemorrhage).
"I think they met the ground rules that were established by the FDA in the first place," A. Michael Lincoff, MD, vice chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine, director of C5Research, an interventional cardiologist in the Sydell and Arnold Miller Family Heart & Vascular Institute, and a professor of medicine at the Cleveland Clinic in Ohio, said.
The disease's orphan status and the fact that ADPKD is a difficult disease deserve consideration, Dr. Lincoff said. "Those facts, coupled with the fact that it would be a difficult but probably doable [risk evaluation mitigation strategy] in a very motivated population, I thought on balance this was worth approval."
Several individuals with ADPKD made impassioned pleas for the committee to approve tolvaptan during the open public hearing portion of the meeting.
"To dismiss all of the comments and testimony of all the patients that are actually living with this is difficult, and I think that ultimately it's the patient's decision," temporary voting member Susan Broyles, RN, a patient representative from Fort Worth, Texas, said of her vote in favor of recommending tolvaptan.
The voting members have disclosed no relevant financial relationships.
FDA Cardiovascular and Renal Drugs Advisory Committee Meeting. Silver Spring, Maryland. August 5, 2013. Briefing information
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Cite this: Tolvaptan Not Recommended for ADPKD - Medscape - Aug 06, 2013.