SILVER SPRING, Md. -- An FDA advisory committee has declined to endorse an expanded indication for tolvaptan (Samsca) to treat autosomal dominant polycystic kidney disease (ADPKD).
The agency's voted 9-6 on Monday against recommending approval of tolvaptan for use against the rare disease that causes a proliferation of kidney cysts, resulting in grossly enlarged kidneys.
Panel members echoed concerns FDA reviewers had expressed in advanced of the meeting, namely, that judging efficacy from the single trial supporting the treatment is difficult because of missing data.
Furthermore, it was tough to balance the drug's various safety issues including liver toxicity with the unmet need that ADPKD patients face.
"I felt that the benefit was real but very small. The risk was real but large," Stuart Rich, MD, cardiologist at the University of Chicago Pritzker School of Medicine, said. "In balance, I felt the risk was too high given the marginal benefit."
Gains in total kidney volume were higher for patients treated with placebo than for those on tolvaptan (5.5% per year versus 2.8% per year, P<0.001), a randomized, controlled trial of 1,445 patients showed.
The trial revealed a four-fold increase in incidence of liver injury among patients taking tolvaptan compared with controls. However, a sizable portion of trial enrollees dropped out of the 36-month trial (23% of those on tolvaptan and 14% of placebo patients) and were never followed up on, reviewers noted.
With such a sizable amount of efficacy and safety data missing, depending on what assumptions would be made for the missing patients. The FDA had wanted a P-value less than 0.01 with only one trial in support of the approval.
Tolvaptan was approved in 2009 to treat low serum sodium levels, but manufacturer Otsuka America Pharmaceutical is seeking to expand its indication to treat patients with ADPKD. There are no approved products for slowing the progression of kidney disease in patients with ADPKD, and the FDA granted orphan drug status for tolvaptan in April 2012 for that indication. Tolvaptan is a selective vasopressin V2-receptor antagonist that targets cyst growth and formation.
Many committee members agreed the drug was effective in reducing kidney size and pain, but differed in their opinion as to what extent. Patients on the drug slowed glomerular filtration rate (GFR) by 4.3 mL/min/1.73m2 compared with 5.4 mL/min/1.73m2 in patients taking placebo, the FDA said.
"For me, this small change in GFR is not convincing and I have a major issue with the efficacy of the drug and slowing progression of renal disease," said Vasilios Papademetriou, MD, staff cardiologist at the Veterans Affairs Medical Center in Washington, who voted against approval.
Scott Emerson, MD, PhD, professor of biostatistics at the University of Washington in Seattle, took exception to the proposed indication of slowing kidney disease, saying evidence didn't support it.
Committee members generally agreed that the studied population was acceptable despite the FDA's concerns that it didn't include patients with more advanced stages of kidney disease making it difficult to project the drug's impact on end-stage renal disease.
The FDA admitted Monday it didn't know how to study the disease and the drug's safety and efficacy when the trial started.
Despite that, Bob Temple, MD, the FDA's deputy director for clinical science, said the agency told the company it needed some secondary endpoint and couldn't rely solely on drop in kidney size to determine efficacy.
For committee chair Michael Lincoff, MD, vice chair of cardiovascular medicine at the Cleveland Clinic, simply reducing patients' kidney size was meaningful without other secondary endpoints.
"In and of itself, reducing size is a clinical benefit as well," said Lincoff, who voted for approval.
The panel members also agreed that the FDA's proposed risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) wouldn't be overly burdensome should the drug gain approval. The FDA is proposing a REMS that includes provider and pharmacy certification and monthly patient monitoring for the first 18 months of treatment.
The FDA decision on the drug is due Sept. 1. The agency isn't obligated to follow the advice of its advisory committees but usually does.