SILVER SPRING, Md. -- An FDA advisory committee voted to recommend approval of single-dose tafenoquine (GlaxoSmithKline) in patients 16 and older for the "radical cure" (prevention of relapse) of malaria, finding both substantial evidence for efficacy and adequate evidence for safety.
The vote on the evidence for efficacy was unanimous (13-0), while the evidence for adequate safety also sailed through (12-1), with one dissenting vote designed to signify the need for ongoing post-marketing studies and surveillance.
Although the FDA's Antimicrobial Drugs Advisory Committee discussed the need for a G6PD test prior to the drug, as well as two episodes of psychiatric-related adverse effects in the studies, the committee ultimately concluded tafenoquine was largely safe in the indicated population.
Committee members characterized their feelings about the drug's efficacy as "a slam dunk," with "highly consistent" data. Others cited the need for additional therapies to treat Plasmodium vivax malaria other than primaquine, which has been on the market since the 1950s.
"We treat HIV and tuberculosis with multiple drugs all the time. Malaria, we have so much disrespect for it that we still treat it with a single drug that we hope is going to stick around for 50 or 60 years," said committee member Peter Weina, MD, of Walter Reed National Medical Center in Bethesda, Maryland.
Thomas Moore, MD, of the University of Kansas in Wichita added, "it's nice to bring malaria treatment into the 21st century."
Tafenoquine was recommended as a single 300-mg dose as part of a "radical cure" for P. vivax malaria, which can cause relapses months or years after the primary infection. Committee members were mostly impressed with the three randomized trials that examined efficacy, though they pointed out that the trials only examined one dose of the drug, and there were still lingering questions about repeat dosing. Another question was how the drug would be used in patients with severe P. vivax malaria.
Public comment about the drug was generally supportive, with Larry Slutsker, MD, of global health organization PATH in Seattle, pointing out that most of the progress made against malaria in the past decade was against P. falciparum malaria, not P. vivax, and called it a "potentially game-changing opportunity in [P. vivax] malaria."
He added that the opportunity for a "radical cure" for this type of malaria "would have a major impact on reducing [P. vivax] transmission" and could help "end the potential for ongoing transmission."
Geoffrey Dow, PhD, founder and CEO of 60 Degrees Pharmaceuticals, which has its own , also made a presentation during the public comment section.
Dow urged the committee not to be swayed by reports "on social media" and avoid putting specific neuropsychiatric warnings on the drug, which could greatly limit its marketability.
But another presentation from Remington L. Nevin, MD, executive director of the Quinism Foundation, a non-profit organization, warned about the neurotoxicity of 8-aminoquinolines such as tafenoquine. Nevin recommended a boxed warning with restricted distribution and a phase IV study commitment if the drug were to be approved.
Safety of tafenoquine received much discussion -- and a separate presentation from the FDA addressed the concerns about neurotoxicity through a single-dose study in rats and a multiple-dose study where young animals were dosed and then followed. They concluded that tafenoquine was "not associated with any drug-related neurobehavioral or histopathology findings in either study."
Committee chairperson, Lindsey Baden, MD, summed up the discussion about safety, noting that it was "largely reassuring" that the drug's safety profile looks broadly similar to primaquine. He also cited potential warnings about use in patients with anemia, and said the drug should not be given without determining a patient's G6PD status. Baden added that the drug also needs to be studied more in different populations, such as the elderly, those with comorbid conditions and pediatric populations.
Post-marketing studies were recommended to address concerns with side effects related to psychosis, anemia or nausea. Baden added that, "fear of a safety concern is not a reason not to move forward with a therapy that has efficacy for a disease of real consequence."
The one dissenting vote for evidence of adequate safety came from consumer representative Michele Orza, ScD, of Patient-Centered Outcomes Research Institute in Washington D.C.
"I was reacting largely to the word adequate," she said. "I have some remaining concerns about the long-half life [of tafenoquine] and when it gets out into settings out there globally that are much less controlled than the U.S., there should be a lot more attention paid to post-marketing studies and surveillance."