Pyronaridine Artesunate (Pyramax®)
Today, artemisinin-based combination therapy (ACT) is the treatment of choice for acute malaria, as prescribed by the World Health Organization (WHO) in 2001. In early 2006, WHO urged the malaria community to stop the production and use of monotherapies. This counsel has been fully supported by MMV.
ACTs come in many shapes, sizes, and dosages: some require administration of several tablets more than once a day, or for longer than three days; some do not have patient-adapted pediatric formulations; and some are unaffordable and thus inaccessible to the vulnerable populations of malaria-endemic countries. Many currently-marketed ACTs continue to be given in co-blister packs which are relatively expensive and prone to misuse. These limitations give rise to problems of compliance, which increase morbidity and mortality.
In an effort to address this critical lack of effective, affordable, easy-to-use, and accessible new antimalarial drugs, MMV launched a Call for Proposals in 2000. One of the most promising proposals accepted came from the South Korean pharmaceutical company Shin Poong Pharmaceuticals and the WHO Special Programme for Research and Training in Tropical Diseases (TDR), combining the artemisinin derivative, artesunate, with a known antimalarial drug, pyronaridine.
Pyronaridine is active against multiple chloroquine-resistant malaria in vitro and in vivo models. It was used for almost 20 years as monotherapy to treat malaria in the Hunan and Yunan provinces in China, where it was discovered in the 1970s. As the drug has not been used outside China, the rapid development of resistance once it is combined with artemisinin is less likely. Studies conducted by Loorsewaan1, Ringwald 2, and others, demonstrated that pyronaridine was an effective antimalarial drug in both African and Asian patient populations. Pyronaridine artesunate (Pyramax) is being developed as a 3-day treatment for acute uncomplicated malaria caused by Plasmodium falciparum or Plasmodium vivax. It is presented in two fixed-dose formulations: the tablet formulation contains 180:60 mg pyronaridine artesunate for patients over 20 kg; and the pediatric formulation, in granular form, contains 60:20 mg pyronaridine-artesunate for infants over 5 kg.
Securing good stability is a critical measure of success in the development of artemisinin-based fixed-dose combinations, given that artesunate is very unstable when exposed to light, humidity, and high temperatures. Shin Poong developed a novel formulation technology to protect artesunate from pyronaridine and also to increase the stability of the combination. Once produced, Pyramax tablets and granules will have a shelflife of three years, which is longer than for other artesunate combinations and will be a key advantage in developing countries where storage facilities are not impervious to heat, light and humidity.
The Pyramax project has been a leading example of virtual drug development within MMV’s portfolio and could well be one of MMV’s first-to-market products. A rigorous and exhaustive development programme was designed and undertaken, ensuring that Pyramax was subjected to international regulatory standards at the manufacturing, nonclinical nonclinical, and clinical levels (GMP/GLP/GCP). The combination drug will be distributed to the public and private sector at an affordable price. Commercial scale manufacturing will take place in an EU GMP facility currently under construction in South Korea specifically for the product.
The early promise of Pyramax in terms of efficacy, safety and tolerability from a large Phase II dose-finding trial in eight sites spread over six countries in Africa and South-East Asia, is now to be confirmed in Phase III pivotal trials in malaria patients which were implemented in the beginning of 2007. These trials will study the use of Pyramax in patients with both Plasmodium falciparum and Plasmodium vivax malaria.
The Pyramax team
By focusing on quality, deliverables, and world-class expertise, the pyronaridine artesunate team, comprising MMV, Shin Poong Pharmaceuticals and the University of Iowa, has achieved an efficient and cost – effective means of virtual drug development. The Chair of the Product Development Team is Professor Larry Fleckenstein of the University of Iowa.
The Pyramax team are grateful to the skills and dedication of the scientists at the clinical sites who have worked on the Phase I and Phase II trials : Prof. I J Jang, Seoul National University, South Korea ; Prof. S Looareesuwan, Mahidol University, Thailand; Prof. O Gaye, University of Dakar, Senegal ; Dr. E Tjiitra, National Malaria Control Programme, Indonesia ; Dr. D Socheat, National Malaria Control Programme, Cambodia; Dr. B Kalifa, Farafenni Hospital, The Gambia ; Dr. P Piola, Mbarara Hospital, Uganda, and Prof. Kremsner, Albert Schweitzer Hospital, Lambaréné, Gabon.