Investigational drug tafenoquine (GlaxoSmithKline) seemed effective and generally well-tolerated in clinical trials designed to evaluate the therapy as part of a radical cure for Plasmodium vivax malaria in patients age 16 and older, according to released by the FDA prior to an advisory committee meeting on Thursday.
Studies found "a statistically significant treatment effect for the proposed regimen" of tafenoquine for the radical cure of malaria when comparing the therapy to chloroquine alone. A separate study comparing tafenoquine to chloroquine plus primaquine seemed to produce similar results, "supporting the efficacy of [tafenoquine,]" FDA staff said.
Moreover, the drug was generally well-tolerated in safety studies and studies of healthy volunteers, though some safety concerns were raised about safety of the drug in patients with anemia.
Members of the Antimicrobial Drugs Advisory Committee will be asked to vote on whether there is "substantial evidence" that tafenoquine is effective and whether evidence is "adequate" that the drug is safe. They may also offer recommendations on labeling and additional studies that should be performed.
Tafenoquine, a synthetic analog of primaquine, was granted orphan drug and breakthrough therapy designations for the radical cure of P. vivax malaria. Because it "has slow clearance of blood stage," according to the briefing material, the proposed regimen is administration of the drug on day 1 or 2 of chloroquine therapy.
The primary endpoint of the trials was relapse-free efficacy 6 months post-dosing, and treatment success was defined as parasite numbers below the level of detection in a thick blood smear that remained undetectable in a second smear 6 to 12 hours later, and no P. vivax asexual stage parasites within 6 months.
One two-part study was a randomized, double-blind clinical trial, including a dose-ranging trial. Four of six groups evaluated tafenoquine in varying doses after subjects were initially treated with chloroquine, one group examined primaquine after chloroquine therapy and one group examined treatment with chloroquine only as a "control" group.
"Although the first part of the study was designed to find the optimal dose to evaluate in Part 2, the selected 300 mg [tafenoquine] single dose given with [chloroquine] did demonstrate significant efficacy compared with [chloroquine] alone," FDA researchers wrote.
Part 2 of the study confirmed "a clinically and statistically significant reduction in the risk of recurrence at 6 months in the [chloroquine + tafenoquine] arm compared with [chloroquine] treatment alone."
A third study randomized patients to receive either chloroquine plus tafenoquine or chloroquine plus primaquine (the "control" group). FDA researchers confirmed that the two treatments "produced similar results in parasitic clearance and clearance time," though they noted that the non-inferiority margin of chloroquine plus tafenoquine regimen could be 16% worse than chloroquine plus primaquine. Nevertheless, they concluded that "the study provides supportive evidence of efficacy."
Safety was evaluated in the three trials, plus three healthy volunteer studies that provided information on tafenoquine alone, without chloroquine. FDA researchers found it was "generally well-tolerated," with a safety profile similar to 8-aminoquinoline, primaquine. In addition, there was "no evidence" that tafenoquine exacerbates the adverse effects of chloroquine.
There were two cases of hypersensitivity noted in a healthy volunteer study. FDA researchers also wrote that patients should have G6PD testing done before starting tafenoquine to avoid the risk of hemolytic anemia and the drug should not be prescribed to patients with G6PD enzymatic activity <70% of normal. They added that "safety data are negligible" in patients with G6PD enzymatic activity 40%-60%.
"Monitoring of hematologic parameters in patients with vivax malaria who are treated with [tafenoquine] 300 mg + [chloroquine] is warranted, especially in patients anemic at baseline," they wrote.
FDA researchers added that tafenoquine has not been studied in pregnant or lactating women, should not be used in this population due to risk of acute hemolytic anemia in the fetus or breastfed infant and is contraindicated in pregnancy.
The FDA is not obliged to follow advisory committee recommendations but it usually does.