Rintatolimod for Chronic Fatigue Gets FDA Panel's 'No' Vote

Miriam E. Tucker

December 21, 2012

A federal advisory panel voted 8 to 5 against the approval of rintatolimod for the treatment of chronic fatigue syndrome.

The Arthritis Advisory Committee split 4 to 9 against the adequacy of the data supporting efficacy and also 4 to 9 against the adequacy of the safety data. However, the panel reversed 8 to 5 in favor of the drug's safety profile overall, given the severity of the illness and what some panel members felt was the absence of a serious safety signal.

The majority of panel members said that at least a single additional randomized controlled study was needed before the drug could be approved.

Rintatolimod, manufactured by Hemispherx Biopharma Inc under the proposed trade name Ampligen, is a synthetic, double-stranded ribonucleic acid injectable agent that appears to act as an immune modulator.

There are currently no approved drugs for the treatment of chronic fatigue syndrome, defined as a "complex, debilitating disorder of unknown etiology characterized by profound fatigue lasting for 6 or more consecutive months that is not improved by bed rest and that may be worsened by physical or mental activity," said Theresa M. Michele, MD, clinical team leader, Division of Pulmonary, Allergy, and Rheumatology Products, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA).

Data Deficiencies

Rintatolimod has a long regulatory history with the FDA. Hemispherx had originally submitted a new drug application for the drug in 2007 on the basis of studies dating back to 1991, which the FDA had refused because of "numerous deficiencies" in both safety and efficacy data, including lack of dose-ranging studies, database discrepancies, statistical plans inconsistent with the protocols, and lack of carcinogenicity data, Dr. Michele said.

The company resubmitted the application in April 2008 and the FDA accepted it for review. This time, in November 2009, the FDA issued a complete response action, meaning that they did not approve it, again because of deficiencies in both safety and efficacy data. The agency then asked Hemispherx to conduct at least a single additional controlled clinical trial showing a convincing effect in the target population.

Instead, in August 2012, the company submitted additional post hoc analyses from the original clinical trials from the original submission with justification for each deficiency, which company officials summarized at the hearing.

The data included 2 primary randomized, double-blind controlled studies, one (502) enrolling 92 patients and lasting 24 weeks, the other (516) including 234 patients and running 40 weeks. Primary efficacy endpoints were Karnofsky Performance Scale scores for study 502 and exercise treadmill duration for 516.

Data for the safety analysis included a total of 737 patients exposed to rintatolimod in those and other trials, including an open-label extension of study 516. In both studies, the drug was delivered intravenously twice weekly.

The manufacturer and the FDA disagreed on many aspects of the data analysis, particularly with regard to whether the primary endpoint had been met, given that the company had changed its method of statistical analysis from what had been specified in the original protocol.

In addition, in study 502, the manufacturer and the FDA disagreed regarding the statistical implications of excluding 7 patients who could not complete the treadmill test because of illness severity.

According to Hemispherx Medical Director David R. Strayer, MD, the mean increase from baseline on exercise treadmill testing in study 516 was 95.7% with rintatolimod vs 28.2% with placebo, giving a statistically significant P = .047. However, that difference was achieved without performing log transformation, which had been part of the original protocol.

The FDA did agree with the company that some of their post hoc analyses reached statistical significance, such as the proportion of patients achieving at least 25% clinical improvement (39% vs 24%; P = .025). However, the FDA also cited numerous safety concerns about the data, including signals for thrombosis, major cardiac events, malignancy, liver function abnormalities, infections, and autoimmune diseases. Infusion reactions were also more common with rintatolimod than placebo, raising the question of unblinding, FDA reviewer Janet Maynard, MD, said.

Risk-Benefit at Issue

The hearing was notable for its unusually long public comment period, lasting nearly 2 hours compared with the usually 30 to 60 minutes for most FDA hearings. A majority of the 31 speakers were patients with chronic fatigue syndrome and their family members, many of whom had participated in the trials and described how the drug had dramatically improved their daily function. Alaine Perry, MPH, the patient representative on the panel, also spoke movingly about the effect of the disease on her life and her willingness to accept less-than-perfect data for the possibility of improved function.

Several of the panel members who voted in support of the drug's safety profile said that this testimony convinced them that informed patients would be willing to accept the risks of the drug, which Perry explained she viewed as far less severe than the disease itself. In addition, a couple of participants noted that because the drug is administered intravenously, patients would likely be under closer monitoring than with an oral medication.

Still, the panel majority cited too many problems with the current data to support licensure at this time.

Anthony Komaroff, MD, Simcox/Clifford/Higby Professor of Medicine at Harvard Medical School, Boston, Massachusetts, voted no on both efficacy and safety. "As a physician who has cared for many of these patients for nearly a quarter of a century, nothing would please me more than solid evidence of an effective therapy, but I think there are enough questions about the conduct of the studies that it does not meet the standard of adequate evidence."

Jacqueline Gardiner, PhD, MPH, professor emeritus in the Department of Pharmacy at the University of Washington, Seattle, also voted no on both questions: "What I would like to see going forward is a good deal of effort put into using the existing data if possible to identify subgroups in which small studies could be initiated that might shed light on who is best able to respond to this compound and begin to focus the effort on those people."

Participants in FDA advisory committee meetings are vetted for conflicts of interest and waivers are granted if necessary. No waivers were granted for this meeting.