Tolvaptan OK Would Require Unusual Tolerance Of Drug-Induced Liver Injury

FDA advisory committee briefing docs indicate odds stacked against Otsuka’s tolvaptan kidney disease indication without better efficacy data to counteract drug-induced liver injury risk.

FDA would have to accept an incidence of liver injury that is considerably higher than what it has typically allowed to approve Otsuka Pharmaceutical Co. Ltd.’stolvaptan for kidney disease patients, the agency indicates in briefing documents released ahead of the drug’s Aug. 5 advisory committee review.

FDA’s Cardiovascular and Renal Drugs Advisory Committee will be asked to weigh in on this risk, along with a proposed risk evaluation and mitigation strategy (REMS) and multiple issues with the drug’s pivotal trial, including design, statistical analyses, and efficacy data, before voting on whether tolvaptan should be approved to slow kidney disease in adults at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). ADPKD, a genetic disease that can lead to kidney failure, has no approved treatments.

Tolvaptan is likely to cause liver failure in about 1 in 3,000 patients based on the numbers of patients who experienced hepatocellular liver injury in the company’s sole Phase III trial, FDA said. This number far exceeds the incidence of drug-induced liver injury (DILI) seen in products removed from the market due to hepatotoxicity.

Most of the drugs withdrawn from the market for hepatotoxicity have caused death or transplantations at frequencies in the range of ≤1 per 10,000, the agency said. Only two marketed drugs have the high incidence of liver injury expected to be seen with tolvaptan’s use in kidney disease – Actelion Ltd.’s Tracleer (bosentan) for pulmonary hypertension and isoniazid (now generic) for tuberculosis.

The safety concerns coupled with FDA’s critique of the sponsor’s efficacy data indicate the drug may be destined for a “complete response.”

FDA reviewers expressed concerns about tolvaptan’s development program, particularly the design of its sole Phase III study, which used a primary endpoint that is not accepted by the agency. There were also issues with the patient population studied, statistical analyses utilized to analyze trial data, the large number of study dropouts and missing data. These concerns leave the agency dissatisfied with the drug’s efficacy data, but such concerns could have been sufficient for approval with a “reassuring” safety profile, FDA said.

However, the expected frequency of liver injury requiring liver transplant or resulting in death tip the scales toward a recommendation against the drug’s approval at this time, agency reviewers indicate. “If tolvaptan’s safety profile had been reassuring, we think the available data, despite the aforementioned limitations, might have been sufficient to support approval,” the briefing documents say.

Short-Term Risk Period Could Mitigate Concerns …

FDA said if it could be confident the period of liver injury risk was limited to a relatively short timeframe early in the course of treatment, it might be easier to mitigate the concern in the postmarket setting. However, Otsuka has only limited data in subjects exposed to the drug for an extended duration (about 740 subjects were exposed for 36 months in the pivotal trial) and thus it is unknown if the risk is limited to a finite period.

Ongoing clinical trials could provide further insight into DILI risk associated with tolvaptan, the agency said, but it also acknowledged that given the expected frequency of severe livery injury it is unlikely to understand the true nature of the risk until the drug is widely used in more patients post approval.

FDA has for the time being allowed tolvaptan, marketed as Samsca to treat clinically significant hypervolemic and euvolemic hyponatremia (low sodium levels in the blood), to remain on the market following the liver injuries seen in the kidney disease study. However, it issued a drug safety communication April 30 that said treatment should be limited to 30 days – a fix that could not work for ADPKD because of the need for long-term treatment (Also see "FDA Panel To Weigh Unmet Need Vs. Liver Injury With Samsca Kidney Indication" - Pink Sheet, 21 Jun, 2013.).

… But Better Efficacy Data May Have to Do

Given the limitation of assessing DILI in the premarket space, FDA’s briefing materials indicate it may be willing to allow commercialization of the drug, if the company can provide additional efficacy data that could reduce some of the current uncertainty about its benefit. This data could potentially come from Otsuka’s ongoing extension trials or possibly a new trial in patients with lower levels of kidney function than were evaluated in the Phase III trial.

“We believe such data would provide the information necessary for patients to make a properly informed decision about whether to use the therapy. We also believe it would place us in a better position for making decisions in the post-marketing setting about withdrawing the drug from the market should cases of severe liver injury be seen or possibly scaling back on the proposed measures to mitigate risk should the safety experience support the decision to do so,” clinical reviewers Nhi Beasley and Aliza Thompson concluded.

The review staff raised numerous concerns about the current efficacy data.

For starters, the primary endpoint of total kidney volume is not currently accepted as a surrogate endpoint and is not acceptable for approval. The trial’s first secondary endpoint – the time to multiple ADPKD clinical progression events (progressing hypertension, severe renal pain, worsening albuminuria and worsening renal function) – was deemed to be an acceptable endpoint and was considered the key efficacy endpoint by the agency. However, the p-value for this composite secondary endpoint did not meet the significance level of 0.01 that the agency wanted, according to FDA’s statistical analysis. Otsuka contends its endpoint did meet this significance level.

“Treatment effects also varied greatly across the components of the composite, further complicating interpretation of the endpoints results,” FDA reviewers added.

And the findings are also affected by the high number of study dropouts, particularly in the treatment arm: 23% of tolvaptan patients and 14% of placebo patients. Otsuka’s prespecified primary analysis of the composite secondary endpoint “does not adequately” address the problem of the missing data that resulted, FDA said.

Because of the missing data, the size of the effect on renal function remains unclear, FDA said, even though the totality of the evidence indicates the drug has activity in treatment of the renal manifestations of the disease and the drug was shown to be effective in slowing the rate of loss of renal function in the study population.

Further, because the subjects enrolled in the Phase III study were generally remote from end-stage renal disease, FDA said treatment effects on this clinical outcome were not directly observed and the effect on renal function observed in the Phase III trial was small and would not be considered clinically meaningful in itself.

In the trial population studied, FDA said it would predict an approximately four-year delay in the time to end-stage disease and in the best case, a patient who starts therapy young with relatively preserved kidney function might prevent the need for dialysis some 40 years in the future. But whether these projections are accurate is unknown, it added.

Combined with its efficacy concerns, FDA also asked for a stricter REMS than Otsuka proposed.

Tolvaptan has been given orphan designation in the indication and is undergoing a priority review. It has a Sept. 1 user fee action goal date.