Currently, primaquine is the only treatment available to prevent the relapse of Plasmodium vivax malaria. However, as per the primaquine label and WHO recommendations, it is administered once daily for 14 days – a regimen that is hard for patients to comply with, meaning that many are not cured. A single-dose treatment with the potential to improve patient compliance would positively impact P. vivax control and elimination efforts.
MMV and GlaxoSmithKline (GSK) have partnered to develop tafenoquine – a potential new single-dose cure to prevent the relapse of P. vivax malaria. In late 2017, registration dossiers were submitted to two stringent regulatory authorities (SRAs), representing a key milestone in the development programme of this important new treatment.
Anna Thomas and Robert Stocken discuss the potential impact of tafenoquine in the management of P. vivax malaria, and explain the next steps for achieving regulatory approval and country registration.
1. What is special about tafenoquine?
Anna: If approved, tafenoquine would be the first-ever single-dose treatment to target the dormant relapsing form of P. vivax malaria, with the potential to significantly improve patient compliance and effectiveness outcomes compared with primaquine.
2. Can you tell us about the regulatory review process for tafenoquine?
Anna: In 2013, the US Food and Drug Administration (FDA) granted tafenoquine a ‘breakthrough therapy’ designation whereby a drug is subject to regulatory measures designed to accelerate the development and review of drugs for serious or life-threatening diseases.
MMV and GSK’s regulatory strategy for tafenoquine was discussed and agreed upfront with two SRAs – the US FDA and the Australian Therapeutic Goods Administration (TGA). Phase III studies have been successfully completed in adults and adolescents over 16 years of age (the target age group for initial registration) supporting submission to these SRAs in 2017. In parallel, a paediatric study is underway to collect data to support subsequent approval of tafenoquine in children.
3. What specific challenges have you overcome with tafenoquine?
Robert: In each endemic country, regulatory requirements and approval timelines vary considerably. To expedite completion of the tafenoquine phase III clinical development programme, we worked closely with the study investigators, as well as with local regulatory and clinical personnel, on the planning and implementation of each study. However, in some regions, such as Asia, we encountered challenges with patient recruitment. To address this, we reached agreements with the FDA and TGA regarding the required number of patients in phase III studies both in total and in each region, so as not to delay the overall marketing application timeline.
4. What are the next steps for tafenoquine?
Robert: In late 2017, GSK and MMV submitted a new drug application to the FDA and a marketing authorization application (MAA) to the TGA. The next step is providing high-quality responses to satisfy questions that these SRAs have regarding the data package.
Anna: Once SRA registration is obtained, MAAs will be filed with the regulatory authorities of P. vivax endemic countries. The associated regulatory dossiers are currently being prepared.
Of note, as with primaquine, tafenoquine could induce haemolysis in patients who have a deficiency in glucose-6-phosphate dehydrogenase (G6PD) enzyme activity, meaning that patients need to be tested for G6PD activity before being given tafenoquine. To facilitate the safe deployment of the treatment, work is therefore ongoing to develop a point-of-care diagnostic test for G6PD deficiency.
Finally, a phase IIIb study has started in Indonesia to assess the co-administration of an artemisininbased combination therapy (ACT) for blood-stage treatment of P. vivax infection with tafenoquine. It is hoped that the results from this study will lend support to achieving registration in some of the countries that currently recommend use of an ACT instead of chloroquine for the management of P. vivax blood-stage infection.
5. Can you tell us about the working relationship between MMV and GSK?
Robert: MMV is a great partner and we have good synergy in our working relationship. The tafenoquine joint project team, which includes representatives from the two organizations, meets regularly both virtually and in person. It is this joint team that is working closely together on the FDA and TGA review processes and development of regulatory responses. In addition, MMV provides valuable advice on how to facilitate access to the newly registered medicine in malaria-endemic countries to ensure the best possible patient outcomes – an area in which they have extensive expertise.