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Background Analysis: US FDA Advisory Committee to Review Proposed Malaria Treatment by 60 Degrees Pharmaceuticals – JUL 26, 2018 (AMDAC)


The US FDA has scheduled an Antimicrobial Drugs Advisory Committee (AMDAC) meeting for Thursday, July 26, 2018 to discuss a new drug application (NDA) for tafenoquine tablets, sponsored by 60 Degrees Pharmaceuticals, LLC (60 Degrees), for the proposed indication of prevention of malaria in adults for up to 6 months of continuous dosing.

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

60 Degrees proposes to market a 100 mg tablet formulation of tafenoquine. The company proposes use for the prevention of malaria in adults for up to 6 months of continuous dosing.

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 weekly oral dose for up to 6 months, whereas FDA-approved labeling for primaquine advises oral, daily dosing over 14 days.

One potential benefit of marketing an additional 8-aminoquinoline drug is mitigation of drug resistance.

Tarius note: Prior to this meeting, on July 12, 2018, the AMDAC will have reviewed another tafenoquine NDA by a different sponsor, GlaxoSmithKline Intellectual Property Development Ltd. (GSK). GSK is proposing to market a 150 mg tablet for the radical cure (prevention of relapse) of P. Vivax malaria in patients aged 16 years and older. GSK proposes a single-use oral dose.

Clinical Trials of Proposed Indication

In the announcement of the NDA submission, 60 Degrees points to an analysis of five clinical trials that assessed the safety and tolerability of tafenoquine that were published in the journal Travel Medicine and Infectious Disease (Travel Med Infect Dis. 2017 May - Jun;17:19-27. doi: 10.1016/j.tmaid.2017.05.008. Epub 2017 May 8.). According to the abstract for this publication, the authors conducted an integrated assessment of the Tafenoquine Anticipated Clinical Regimen (Tafenoquine ACR) from 5 clinical trials, including 1 conducted in deployed military personnel and 4 in non-deployed residents, which also incorporated placebo and mefloquine comparator groups. Among all subjects who had received the Tafenoquine ACR, safety findings were compared for subjects who were deployed military personnel from the Australian Defence Force (Deployed ADF) versus non-deployed residents (Resident Non-ADF). The incidence of at least one adverse event (AE) was 80.6%, 64.1%, 67.6% and 94.9% in the mefloquine, placebo, tafenoquine Resident Non-ADF and tafenoquine Deployed ADF groups, respectively. The latter group had a higher incidence of AEs related to military deployment. AEs that occurred at ≥ 1% incidence in both tafenoquine sub-groups and at a higher frequency than placebo included diarrhea, nausea, vomiting, gastroenteritis, nasopharyngeal tract infections, and back/neck pain. The authors conclude that weekly administration of tafenoquine for up to six months increased the incidence of gastrointestinal AEs, certain infections, and back/neck pain, but not the overall incidence of AEs versus placebo.

The publication references the following ClinicalTrials.Gov IDs: NCT02491606; NCT02488980; NCT02488902.

Regulatory Background

US Regulatory Background

August – PDUFA date (estimated)

December 18, 2017 – 60 Degrees announced the submission of NDA 210607

Priority Review, Fast Track

Ex-US Regulatory Background

Tarius has not found any publicly-available information regarding ex-US regulatory filings.

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: 60 Degrees Pharmaceuticals, LLC Drug Name: tafenoquine Drug Class: antibiotic Indication: prevention of 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.