Tarius SAC Tracker®


Background Analysis: US FDA Advisory Committee to Review Proposed Malaria Treatment by GlaxoSmithKline – JUL 12, 2018 (AMDAC)


The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Thursday, July 12, 2018 to discuss a new drug application (NDA) for tafenoquine tablets, sponsored by GlaxoSmithKline Intellectual Property Development Ltd. (GSK), for the proposed indication of the radical cure (prevention of relapse) of Plasmodium vivax  (P. vivax) malaria.

Indication Background

Description of Indication

Malaria is a mosquito-borne disease caused by a parasite. Symptoms include fever, chills, and flu-like illness. If untreated, the disease can lead to severe complications and death. According to the US Centers for Disease Control and Prevention (CDC), in 2016, an estimated 216 million cases of malaria occurred worldwide and 445,000 people died, mostly children in the African Region. In the US, about 1,700 cases of malaria are diagnosed each year, usually related to immigrants and travelers.

After an infected mosquito bite, P. vivax parasites can lie dormant in the liver, where they are called hypnozoites. From the liver, hypnozoites can periodically reactivate, causing relapses.

Most drugs used in malaria treatment are active against the parasite forms in the blood and include: chloroquine; atovaquone-proguanil (Malarone®); artemether-lumefantrine (Coartem®); mefloquine (Lariam®); quinine; quinidine; doxycycline (used in combination with quinine); clindamycin (used in combination with quinine); and artesunate (not licensed for use in the US, but available through the CDC malaria hotline).

Another drug, primaquine, is active against hypnozoites. Notable safety considerations with primaquine use include that it should not be taken by pregnant women or by people who are deficient in G6PD (glucose-6-phosphate dehydrogenase). In addition, the clinical development and use of primaquine has been subject to some controversy. Critics of the drug have questioned the ethics of its clinical trials, which studied its use in the treatment of military personnel. Also, there are media reports about severe neurotoxic effects experienced by a subset of patients who took primaquine.

 Product Background

Description of Product

GSK proposes to market a 150 mg tablet formulation of tafenoquine. The company proposes its use for radical cure (prevention of relapse) of P. vivax malaria patients aged 16 years and older. Tafenoquine and primaquine are both derivatives of 8-aminoquinoline and show activity against the P. vivax lifecycle, including hypnozoites. However, tafenoquine is proposed for administration as a single-use oral dose, whereas FDA-approved labeling for primaquine advises oral, daily dosing over 14 days. GSK believes tafenoquine dosing will improve compliance. Another potential benefit of marketing an additional 8-aminoquinoline drug is mitigation of drug resistance.

Tarius note: Subsequent to this meeting, on July 26, 2018, the AMDAC will review another tafenoquine NDA by a different sponsor, 60 Degrees Pharmaceuticals, LLC (60 Degrees). 60 Degrees is proposing to market a 100 mg tablet for the prevention of malaria in adults for up to 6 months of continuous dosing.

Clinical Trials of Proposed Indication

The NDA submission includes Phase III data from the GATHER and DETECTIVE studies, which were conducted in malaria-endemic countries covering South America, Asia, and Africa. Comprehensive data and company and FDA analyses of the clinical development program will be presented in meeting materials posted by the FDA two days prior to the meeting. The meeting materials will be summarized on the day they are posted, in our subsequent report, the Briefing Summary. Presented below is information from the tafenoquine clinical development program (CDP), based on company press releases.


(Study number: TAF112582, ClinicalTrials.gov ID: NCT01376167)

DETECTIVE was a double-blind, double-dummy phase III study evaluating the efficacy, safety, and tolerability of tafenoquine in 522 patients with P. vivax malaria. Patients were randomized to receive either a single-dose (1-day) of tafenoquine (300 mg), a 14-day course of primaquine (15 mg), or placebo, with all patients also receiving a 3-day course of chloroquine to treat the acute blood stage of the infection.

The study met its primary endpoint, showing that a statistically significant greater proportion of patients treated with tafenoquine (60%) remained relapse-free over the 6-month follow-up period than patients on placebo (26%), with an odds ratio for risk of relapse vs. placebo given with chloroquine of 0.24, p<0.001.

Further, a statistically significant greater proportion of patients treated with 14 days of primaquine (64%) were relapse-free over the 6-month follow-up period than patients on placebo (26%), with an odds ratio vs. placebo when given with chloroquine of 0.20, p<0.001.

The frequency of adverse events was 63% for the tafenoquine group, 59% for the primaquine group, and 65% for the chloroquine group. The frequency of serious adverse events was 8% for the tafenoquine group, 3% for the primaquine group, and 5% for the chloroquine group.


(Study number: TAF116564, ClinicalTrials.gov ID: NCT02216123)

GATHER was a study in 251 patients investigating a single-dose of 300 mg tafenoquine on levels of hemoglobin (a protein in red blood cells that carries oxygen) when compared to a 14-day course of 15 mg primaquine, with all patients also receiving a standard 3-day course of chloroquine. The incidence of decline in hemoglobin (the primary endpoint) was very low and similar between the two treatment groups (2.4% for patients receiving tafenoquine and chloroquine vs. 1.2% for patients receiving primaquine with chloroquine), with the difference in proportions (95% CI) of 1.23% (-4.16%, 4.98%).  No patient required a blood transfusion.

The frequency of adverse events was 72% for the tafenoquine group and 75% for the primaquine group. The frequency of serious adverse events was 4% for the tafenoquine group and 1% for the primaquine group.

Adverse events from the headline data from both studies were consistent with the known safety profile of tafenoquine. The proportion of patients experiencing adverse events and serious adverse events during the 6-month study was similar for tafenoquine, primaquine, and chloroquine alone.

Regulatory Background

US Regulatory Background

July – PDUFA date (estimated)

November 28, 2017 – GSK announced the submission of NDA 210795.

Breakthrough Therapy Designation, Priority Review

Ex-US Regulatory Background

December 14, 2017 - GSK announced the submission of a regulatory application to the Australian Therapeutic Goods Administration (TGA)

What’s Next?

Tarius will send a Briefing Summary after briefing materials are posted to FDA’s website (typically within 2 days of the meeting). This report will provide a summary of the FDA and the Sponsor’s briefing materials.

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: GlaxoSmithKline Intellectual Property Development Ltd. Drug Name: tafenoquine Drug Class: antibiotic Indication: radical cure (prevention of relapse) of Plasmodium vivax malaria

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.