Two fixed-dose antimalaria treatments to become available in 2006

January 2006

WASHINGTON — Two new simplified, nonpatented malaria treatments are expected to become available in the second half of 2006, the Drugs for Neglected Diseases initiative (DNDi) announced at a briefing at the 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene held here.

Artesunate-amodiaquine (AS/AQ, Sanofi-Aventis) and artesunate-mefloquine (AS/MQ, Far-Manguinhos) are fixed-dose, artemisinin-based combination therapies (ACTs).

“These two new fixed-dose combinations have been adapted to patients’ needs — they are more affordable and easier to use,” said Bernard Pecoul, MD, MPH, executive director of DNDi. “The fact that they are not under patent removes a significant barrier to their availability and should serve as a model for future drug development for neglected diseases.”

Both coformulation AS/AQ and AS/MQ will cost about half of what the current treatments cost and each will converge two tablets into one, making for a more simplified dosing regimen and therefore ensuring better patient compliance.

Because increasing resistance has rendered common antimalarials, like chloroquine, ineffective, WHO has recommended the use of ACTs since 2001. To date, 43 sub-Saharan countries have adopted ACTs in their malaria treatment protocols, but only 15 have actually begun to implement the change and only a handful have done so on a national level. The use of AS/MQ combinations for malaria treatment is particularly recommended in Southeast Asia and several Latin American countries, according to a release.

Simplified and affordable

The new formulation consists of six tablets over a course of three days (two tablets once a day) instead of the current recommendations of four to eight tablets a day for three days.

AS/AQ and AS/MQ will also be available in a low-dose pediatric formulation of one smaller tablet a day for three days. In addition, the tablets are water soluble to facilitate absorption for younger children.

“In our projects worldwide, MSF [Médecins Sans Frontières] has seen that patients urgently need safe, effective, affordable malaria treatments, and a fixed-dose combination leads to better adherence,” said Unni Karunakara, MD, medical director of the MSF’s Campaign for Access to Essential Medicines. “Today, even though many countries have changed their national protocols to ACT, very few patients are actually receiving the treatment. The problem in tackling malaria now is no longer medical, technical or scientific, it is political.”

High cost and procurement problems on the local and regional levels have prevented access to ACTs. However, the cost of the AS/AQ and AS/MQ could be 50% less than the cost of existing ACTs. The target price for the new AS/MQ formulation is estimated at $2 to $2.50 for adults and $1 to $1.50 for children. For the AS/AQ formulation, the target price will be less than $1 for adults and $0.50 for children.

“We have to find ways to make the price of these new medicines, and ACTs in general, comparable to the cost of chloroquine,” said Nick White, professor of tropical medicine at Oxford University. “A subsidized fund could be one solution, but it is clear that the international community has to take immediate steps to fund the fight against malaria with medicines that work.”

These nonpatented products double as public goods, according to DNDi’s Web site. This ensures its availability at the most competitive price for patients and will make them readily available for malaria treatment.

In September, DNDi presented completed results of phase-3 clinical trials of AS/MQ at the 16th International Congress for Tropical Medicine and Malaria Medicine conference, held in Marseille, France.

The study, conducted in Thailand, included children and adults.

Cure rate high

The results of the 500 patient clinical studies found that the cure rate at day 63 for patients taking the AS/MQ and existing separate tablet formulations is very high and similar in both groups: 94.1% for the fixed-dose combination and 92% for the separate tablet formulation.

Findings also indicated that AS/MQ and the existing formulation have similar safety profiles, with low and comparable rates of minor adverse events such as dizziness, lack of appetite, headaches and sleep disturbance. The most commonly reported adverse event for mefloquine is early vomiting, and it was lower in the AS/MQ regimen (3%) than in the separate tablet formulation (8.4%).

“This is good news for patients and for the fight against malaria as this new fixed drug combination is effective, safe, easier to use and better tolerated than the loose formulations,” White said in a statement.

A double-blind, randomized, controlled phase-3 trial of AS/AQ is ongoing in Burkina Faso. Target enrollment for this trial is 500 children younger than 5 years, and so far researchers screened 662 children, 70% of whom are enrolled for up to 28 days of follow-up, according to an abstract presented at the International Congress for Tropical Medicine and Malaria Medicine.

Results of this trial are expected to be available by March 2006, according to a DNDi spokesperson.

DNDi’s development strategies

WHO estimates that about 100 million patients each year could benefit from AS/AQ. This formulation will be primarily used in sub-Saharan Africa, Indonesia and other countries such as India, according to DNDi.

For AS/MQ, Far-Manguinhos — Brazil’s state pharmaceutical company — is responsible for registering the product in Brazil and other Latin American countries.

The target countries for AS/MQ distribution include areas of Southeast Asia, such as Vietnam, Laos, Cambodia and Thailand, and areas of Latin America, such as Peru, Bolivia, Colombia, Venezuela and Brazil. More than 2 million malaria cases occur each year in Southeast Asia and more than 200,000 cases occur in Latin America. Availability of AS/MQ in East Africa is still under consideration, due to the increasing prevalence of multidrug resistance.

For AS/AQ development being produced by Sanofi-Aventis, the company is responsible for the development, specifically for filing the dossier with regulatory agencies and for attaining WHO prequalification. The company plans to sell the drug at cost to governments, international organizations and nongovernment organizations to assist in facilitating antimalaria treatment access to those countries most afflicted by malaria, according to DDNi. Sanofi-Aventis has agreed to deliver a nonpatented product.

Far-Manguinhos is responsible for registering the product in Brazil and other Latin American countries.

For more information:

• White N. New fixed-dose artemisinin combination therapies to treat falciparum malaria. Symposium 42. Presented at: 54th Annual Meeting of the American Society of Tropical Medicine and Hygiene; Dec. 11-15, 2005; Washington.
• Ashley E. Exploring combination therapies to increase efficacy of drugs for neglected disease. Presented at: 16th International Congress for Tropical Medicine and Malaria; Sept. 11-15, 2005; Marseilles, France.
• Ashley E, Phaiphun L, Barends M. Safety and efficacy of a new artesunate-mefloquine coformulation for the treatment of acute, uncomplicated falciparum malaria, a randomized trial. Abstract Q178. Presented at: 16th International Congress for Tropical Medicine and Malaria; Sept. 11-15, 2005; Marseilles, France.
• Sirima SB, Tiono AB, Gansane A, et al. Safety, efficacy and pharmacokinetics of artesunate and amodiaquinein fixed formulation vs loose formulation in the treatment of mild and uncomplicated malaria. Abstract Q177. Presented at: 16th International Congress for Tropical Medicine and Malaria; Sept. 11-15, 2005; Marseilles, France.
• Please visit the Drugs for Neglected Diseases initiative Web site at www.dndi.org.