MMV has long recognized that developing better medicines for children helps address the most vulnerable patient population at greatest risk of dying from malaria. The first product successfully co-developed by MMV and partners was Coartem® Dispersible, launched by Novartis in 2009. To date, 300 million treatments of this cherry-flavoured dispersible product have been distributed, making it the most widely-used quality ACT for children.
In 2015, Pyramax® granules (pyronaridine-artesunate), developed by Shin Poong Pharmaceutical and MMV, received a positive scientific opinion under Article 58 from the European Medicines Agency (EMA), becoming the second ACT specifically designed for paediatric use to receive approval from a stringent regulatory authority.
A third ACT co-developed by MMV (with Sigma-Tau) was Eurartesim® (dihydroartemisinin-piperaquine). Eurartesim was approved by the EMA in 2011 and received WHO prequalification in 2015. Its paediatric formulation has just completed clinical development and is expected to be submitted for EMA approval in 2016.
Dr Isabelle Borghini-Fuhrer and Mr Won June Chang talk about the development of Pyramax tablets and granules and the value of the partnership.
1. Dr Borghini-Fuhrer, you have led the development of Pyramax tablets and granules on behalf of MMV since 2006. What was it about the project that inspired your commitment?
IBF: Initially, I was struck by the high efficacy results demonstrated in phase II studies. With 98% cure rates, Pyramax showed tremendous potential.
Then I had the opportunity to go to Burkina Faso, where I met with doctors and malaria patients. When you make a trip like that, you quickly come to understand why we do the work we do – the need is enormous. I was impressed by the team I met and inspired by their dedication. The project became even more meaningful to me.
2. What is special about Pyramax?
WJC: It is the first ACT approved by a stringent regulatory authority (SRA) for treatment of both P. falciparum and P. vivax malaria. This is really useful in areas where both species cause infections and in particular where access to differential diagnosis is limited.
Importantly, the medicine is available in two formulations, a tablet for adults and children over 20 kg and specifically formulated, taste-neutral granules for children and infants between 5 kg and 20 kg. This child-friendly formulation helps ensure they get the full curative dose they need. Both formulations can be administered with or without food and only need to be taken once a day for 3 days, making administration and adherence easier than with current twice-daily dosing regimens.
3. What was the biggest challenge in the development of the combination and how did you overcome it?
IBF: During the phase III programme, we conducted a phase I relative bioavailability study in healthy volunteers, in which we detected a liver safety signal. We immediately put the phase III programme on hold and prepared a data package to be reviewed by a panel of the world’s top hepatic safety experts. They scrutinized the data and made the recommendation to continue the programme. This was a make-or-break moment for the Pyramax development programme. Pyramax then went on to receive positive scientific opinion from the EMA in 2012 for treatment of a single malaria episode in areas of low transmission with evidence of artemisinin resistance.
Moving forward, we designed additional studies to understand the mechanims underlying this safety signal and continued very close
monitoring of liver function in patients recruited in the trials. We also began working with the West African Network for Clinical Trials of Antimalarial Drugs (WANECAM), led by Prof. Abdoulaye Djimde, University of Science, Techniques and Technologies of Bamako, Mali. Pyramax was included as one of four antimalarials trialled in a large, phase IIIb/IV multicentre study where patients were treated with the same medicine more than once during a 2-year follow-up period. WANECAM was a 4,757-patient trial that has generated a large data set. As a result, Pyramax was shown to be as well tolerated and efficacious on re-treatment as on first administration leading the EMA to provide positive scientific opinion without geographical or dosing restrictions for both the tablet and granule formulations.
4. What was the value of the partnership with MMV?
WJC: In addition to MMV’s scientific expertise, MMV’s dedication and high-level global networks have been invaluable. MMV provided the knowhow to drive the scientific development and the coordination to manage the multi-nation clinical studies. They also provided significant support to prepare the dossier for submission to the EMA.
5. What are the next steps to ensure Pyramax granules reach as many vulnerable children as possible?
WJC: Today, the partnership is expanding beyond scientific development into patient access. We are working to support inclusion of Pyramax in WHO’s Standard Treatment Guidelines and Essential Medicines List, which will support approvals in malaria-endemic countries. At the end of February 2016, Pyramax, as a tablet formulation, had been registered in 13 malaria-endemic countries, was under review in 14, and was ready for submission in many other endemic countries. For the granule formulation, we expect either new approvals or line extension registrations in all countries that have registered the tablet.
6. How did you feel when you received the news from the EMA?
IBF: When it finally came, I was absolutely overwhelmed with joy. It was enormously satisfying to see that the EMA assessed that the data supported safety and efficacy of Pyramax on retreatment. I was also elated for the project team and happy to have played my part. In R&D you don’t often get to work on projects that make it to the end of development. I am thrilled to continue to be part of the team that will now ensure that Pyramax achieves the widest possible patient access. That’s what success is all about.