FDA Reviewers Will Probably Not Endorse Samsca Based on Trial Results

FDA_will_not_endorse_samscaU.S. Food and Drug Administration (FDA) reviewers say they are not planning on endorsing Samsca (tolvaptan) for the treatment of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is a genetic disorder in which many cysts form in the kidneys, causing the kidneys to become enlarged.

Samsca is a selective vasopressin V2-receptor antagonist approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia. These are electrolyte disorders in which there is an imbalance in the sodium and water levels in the body. These metabolic conditions, explained PubMedHealth, can lead to a broad array of adverse health reactions.

In advance of an advisory committee meeting, the regulator’s reviewers cited missing clinical trial data, according to MedPage Today. The reviewers also indicated, in briefing documents prepared for the FDA’s Cardiovascular and Renal Drugs Advisory Committee, that the single phase III trial revealed that Samsca slowed the loss of renal function in those patients with relatively healthy kidneys but who are deemed to be at high risk of failure, MedPage Today reported. “However, because of missing data in a sizeable portion of the study population and particularly so in the tolvaptan arm, the size of the treatment effect is unclear,” FDA staff wrote in the documents for today’s meeting.

The committee will discuss trial results and vote on whether or not to recommend Samsca for slowing the progression of kidney disease in adults deemed at risk of rapidly progressing ADPKD, according to MedPage Today.

Samsca received approval in 2009 to treat low serum sodium levels; however, drug maker, Otsuka America Pharmaceutical, seeks expansion of the drug’s approval indications to treat patients diagnosed with ADPKD. The FDA granted so-called “orphan drug status” to Samsca as there are no approved products that slow the progression of kidney disease in patients with ADPKD, MedPage Today explained. Orphan status is given to drugs and biologics defined as being intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect less than 200,000 people in the United States or that affect more than 200,000 persons, but which are not expected to recover the costs of developing and marketing a treatment drug, according to the FDA

The randomized, controlled trial involved 1,445 patients and revealed that increases in total kidney volume were higher (5.5 percent annually) for patients treated with placebo when compared to the tolvaptan (2.8 percent annually); however, many trial enrollees dropped out of the trial—23 percent of the tolvaptan group and 14 percent of the placebo patients according to the reviewers, MedPage Today reported. “Some of these randomized subjects never entered into efficacy endpoints analyses; others contributed information for only a limited period of time,” the briefing documents stated. “There is no satisfactory way to account for these missing data and the applicant’s pre-specified primary analysis of the composite secondary endpoint does not adequately address the problem.”

Reviewers also expressed concern with the lack of data on patients diagnosed with more advanced stages of kidney disease, which, they said, makes it “difficult to project tolvaptan’s likely benefit in delaying the onset of end-stage renal disease,” according to MedPage Today. The reviewers also wrote that tolvaptan’s safety profile was “not reassuring.”

Meanwhile, the FDA recently warned that Samsca has been linked to serious liver injury in a clinical trial of the drug. During the trial, three cases of serious increases in hepatic (liver) enzymes were seen, said MedPage Today, previously. According to the “Dear Healthcare Provider” warning letter sent to physicians, Otsuka said that, “An external panel of liver experts assessed these three cases as being either probably or highly likely to be caused by tolvaptan. These findings indicate that Samsca (tolvaptan) has the potential to cause irreversible and potentially fatal liver injury,”

Overall, the FDA noted that Samsca carries a risk of liver injuries as well as of liver failure, a fatal condition.


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