Tafenoquine, a potential next-generation anti-relapse medicine for P. vivax malaria, successfully completed a Phase IIB trial in 2013. In that trial, a 300 mg single dose of tafenoquine plus chloroquine provided better protection from P. vivax relapse than chloroquine alone. In addition, the US FDA granted tafenoquine Breakthrough Therapy designation – one of its newest initiatives aimed to accelerate the development and review times of drugs for serious or life-threatening diseases. Tafenoquine entered Phase III in April 2014 and was awarded MMV's Project of the Year.
MMV's Jörg Möhrle & Wiweka Kaszubska talk about the challenges, the partnership and what the future holds.
Dr Jörg Möhrle, Former Project Director for Tafenoquine
1. According to Dr JP Kleim, Project Leader, GlaxoSmithKline, the biggest challenge in the development of tafenoquine was ensuring patients return for follow-up. What challenges stand out for you?
To help speed the development process we designed an innovative, seamless Phase IIB/Phase III protocol. This concept has been employed for cancer but never for malaria so it was challenging to explain it to some of the regulatory agencies, particularly as the historical perception of P. vivax malaria is that of a benign disease. Before starting the Phase IIB study there were only a few patients that had been treated with a single dose of tafenoquine to eliminate P. vivax hypnozoites, so embarking on the development programme required a great deal of confidence.
Another challenge was deciding where to conduct the trial. First, as we chose to treat the P. vivax blood stage with chloroquine (standard of care against chloroquine-sensitive strains of P. vivax) we could only go to countries which use chloroquine as first-line treatment. Second, different strains of P. vivax around the world, leading to different rates of relapse, would imply different follow-up times for the trial. Unfortunately, data on relapse rates from around the world are limited. We made our selection based on available data and on the advice of the investigators from the countries with the greatest burden of P. vivax disease.
2. What is the significance of the Phase IIB results?
We now know from the Phase II trial that a single dose of 300 mg of tafenoquine protected around 90% of patients from relapse. For the purpose of statistical analyses, before the trial, we decided that the efficacy of tafenoquine combined with chloroquine would have to be 30% better than chloroquine alone, in the end it was 50% better. As a consequence, the level of confidence that we will be successful in Phase III, both among the team and the wider malaria community, is much higher than before. So now, we have a huge amount of momentum and a clear pathway to complete development, and if successful, registration with a stringent regulatory authority and in endemic countries.
Dr Wiweka Kaszubska, Project Sponsor for Tafenoquine
1. What is the significance of the US FDA Breakthrough Therapy designation?
This designation offers us the possibility to get tafenoquine to patients quicker. First of all, the FDA will review the marketing application in 6 months’ time instead of the standard 10 months; and provide guidance to ensure an efficient development programme. Second, we will then be able to progress earlier with registrations in endemic countries or additional studies to support these registrations.
2. What are the next steps for tafenoquine?
The Phase III trial began in April 2014 and is expected to run until the end of 2015. We will thereafter complete the submission of the regulatory dossier. In the meantime, MMV/GSK’s access and product management team are laying the groundwork for endemic-country access, where we will see the real impact of the medicine. This includes ensuring enough evidence is generated to support the inclusion of tafenoquine as well as an appropriate G6PD diagnostic test in the WHO malaria treatment guidelines. The access team is also evaluating how to improve the supply chain in disease-endemic countries to ensure the availability of tafenoquine together with a G6PD test.While the current formulation is expected to be used by adults and adolescents, we are also progressing our plans to develop a formulation for children.