Anvisa releases new medicine to treat malaria

A new treatment, which can eliminate the parasite with just one dose, will be an alternative to the standard primaquine, that should be given for 7 or 14 days

The National Health Surveillance Agency (Anvisa) approved on October 30 the registration for the single-dose drug Kozenis (tafenoquine succinate) for the treatment of malaria. Kozenis has been registered by the GSK pharmaceuticals and will be marketed in 150mg tafenoquine packs with two units. tafenoquine is an effective drug to fight the parasite Plasmodium vivax. The new drug, which can eliminate the parasite with just one dose, should facilitate patient compliance and will be an alternative to standard treatment with primaquine, given for 7 or 14 days.

Brazil has become the first malaria-endemic country to approve tafenoquine, which represents one of the most significant advances in malaria treatment in the world in the last 60 years. The Research Director of the Tropical Medicine Foundation, Dr. Wuelton Marcelo Monteiro, explains that before the drug is made available to the population, a study will be conducted to explore the feasibility of its use in conjunction with the Glucose-6-Phosphate Dehydrogenase (G6PD) enzyme test performed at the time of patient care. “Economic studies will also be conducted to see if the new treatment will be cost-effective. In a while we will have information that will support the Ministry of Health in expanding the use of taphenoquine throughout the country”, he says.

According to the researcher of the Tropical Medicine Foundation Doctor Heitor Vieira Dourado (FMT-HVD) from Manaus, Dr. Marcus Lacerda, a key safety issue regarding the use of primaquine and tafenoquine is the pre-administration evaluation of these G6PD enzyme activity, whose deficiency occurs in about 5% of the population. “Its deficiency can be verified by methods with varying costs and complexities. Ideally, we would have an effective and reliable test that can be applied in malaria-endemic regions, usually with high temperatures and high humidity levels, without relying on highly skilled human resources and costly infrastructure. Thus, the so-called rapid tests (RDT) become an important tool”, he says.

Qualitative RTDs available for G6PD use 30% of normal enzyme activity as a threshold above which the reading is normal G6PD. This cutoff point is appropriate for men; however, using the same test, a substantial number of heterozygote females (with G6PD activity between 30 and 70% of normal) would be classified as normal, developing a type of severe and acute anemia called acute hemolytic anemia if receiving primaquine or tafenoquine. With primaquine regimens, which require repeated dosing for 7 to 14 days, the drug may be discontinued if, in a person not known to be G6PD deficient, hemolysis occurs. However, with tafenoquine, given its pharmacokinetic characteristics, once a single dose is administered, there is no known antidote and therefore hemolysis would continue.

Thus, patients with G6PD enzyme activity <70% of normal should not receive a standard tafenoquine regimen. For this reason, it is mandatory that an evaluation of G6PD enzyme activity be performed prior to the pre ion of these drugs. Some quantitative point-of-care devices are under current validation and should be available in the field soon. The TRuST study has as one of its main objectives to evaluate the use of such tafenoquine pre-use rapid tests in real life scenarios. The first quantitative point-of-care G6PD test was provisionally approved in July 2019 by the Expert Review Panel for Diagnostics (ERPD). This achievement came from the work of the global nonprofit health organization, PATH, in partnership with SD Biosensor (global diagnostic company), in collaboration with MMV and GSK.

Tafenoquine is expected to be incorporated into the Unified Health System (SUS), however, one of the main concerns of its use, as well as primaquine, is its potential to cause hemolysis in patients with G6PD deficiency. Thus, prior to the incorporation of the drug into the SUS, the Ministry of Health (MS), in partnership with other institutions, such as Doctor Heitor Vieira Dourado Tropical Medicine Foundation and Fiocruz, along with MMV, will conduct drug feasibility studies with a rapid test for G6PD deficiency in Manaus and Porto Velho in a real life setting. The TRuST study is expected to have results in early 2021 and will assist the Ministry of Health in decision-making regarding drug implementation in the endemic regions of malaria vivax in the country.

“Once SUS is found to be able to effectively absorb the use of RDTs in the population where tafenoquine is indicated, and patient safety is maintained, incorporation of the drug into the malaria therapeutic armamentarium makes it viable. It is important to clarify, however, that primaquine should not be abandoned, as it is still useful in cases where tafenoquine has no application”, notes Dr. Lacerda.

Tafenoquine is generally well tolerated, as are the other antimalarials. However, the new drug should not be given to women who breastfeed a child who has not been tested. The drug should not be used in patients under 16 years of age either, as there are no clinical studies in this age group yet. “It is still necessary to wait for the results of this age group so that in the future there is sufficient information on the safety of the drug in smaller patients”, points out Dr. Monteiro.

Asymptomatic people may also be treated with tafenoquine, if the test for G6PD deficiency is previously checked and the individual has enzyme activity above 70%. Dr. Lacerda explains that asymptomatic individuals are the great bottleneck in malaria propagation cycle. Once infected but without symptoms, one does not seek treatment. According to him, the identification of this population should be performed actively, that is, by conducting testing in a healthy population. Several studies have sought to evaluate different strategies for identifying this group. However, there are still no cost-effective methods for this.

Tafenoquine X Primaquine

Dr. Monteiro details that the tafenoquine molecule is a modification of primaquine. This modification allowed tafenoquine to remain in circulation for a much longer time. Thus, in a single dose, it enables radical healing and may facilitate adherence to treatment, which is an important step in malaria elimination efforts. Treatment with primaquine in Brazil usually lasts 7 days, and many patients stop taking the drug soon after their symptoms have stopped, after 2 or 3 days of treatment, without a complete elimination of parasites in the liver. “tafenoquine, developed by GSK and MMV, is approved by Anvisa with the indication for radical cure (relapse prevention) of Plasmodium vivax malaria in patients 16 years of age and older receiving Chloroquine as therapy for acute infection by P. vivax”, he adds.

Why only now has Brazil approved the use of taphenoquine

The use of tafenoquine, with or without other medicines, to eliminate with Plasmodium, is not new. The substance was developed 30 years ago in the United States, but testing did not proceed at the time. The drug approval process lasts years of research. It begins with laboratory development and reaches its final stage by conducting studies of tolerability, safety and efficacy in humans.

tafenoquine is a primaquine-like drug that was synthesized in the 1970s at the Walter Reed Army Institute of Research (WRAIR) in the United States as part of an antimalarial drug development program started in the previous decade. However, over the past ten years, a partnership between the non-governmental organization Medicines for Malaria Venture (MMV) and British pharmaceutical GlaxoSmithKline, with support from the Bill and Melinda Gates Foundation, has enabled the clinical phase of studies in Peru, India, Vietnam, Ethiopia and Brazil, in the cities of Porto Velho (RO) and Manaus (AM), which culminated in this recent approval.

These studies, conducted in endemic countries for Plasmodium vivax malaria, started in 2012, showed that the single dose of tafenoquine was safe and effective in radically curing this type of malaria, i.e., the drug was effective in attacking dormant forms of P. vivax and keep the patient free of further relapses for the next six months at a rate similar to primaquine. After releasing data from these studies to the US drug regulatory agency, tafenoquine was first approved in July 2018 by the US Food and Drug Administration, and in September 2018 by the Australian Agency. Therapeutic Goods Administration. Regulatory requests are being submitted in other countries with endemic malaria.

Such regulatory approvals were based on efficacy and safety data from a comprehensive global clinical development program for radical cure of P. vivax, conducted in nine countries with endemic malaria, including Brazil, at the Dr. Heitor Vieira Dourado Tropical Medicine Foundation, which signaled a positive risk/benefit profile for the proposed indication. With the approval by Anvisa, Brazil became the first country with endemic malaria to regulate tafenoquine as a medication to be made available to the population. “Other countries in Latin America, such as Peru, are already going in the same path. This way, the endemic countries of this continent are taking a huge step towards the elimination of malaria”, concludes Dr. Monteiro.

To Dr. Lacerda, the recent approval of tafenoquine is an important step towards the elimination of malaria in Brazil and worldwide. “Being able to ensure the patients adherence to the complete treatment, that is, that one takes the medication still in the health unit, under the supervision of the health team, is only possible with the single dose medicine. However, because of its hemolytic potential, we need to ensure patient safety, and this will only be possible through real-life assessment of the feasibility of using RDTs to assess G6PD deficiency”, he adds. Also, according to the researcher, it is necessary to continue seeking advances in the study of different ways to eliminate the disease, either by treatment strategies or with new drugs. “I still believe in the eradication of malaria. We have advanced more and more in control and some countries have already reached elimination status. We know that despite phases of epidemic control seen in past periods, the resurgence of major epidemics in the Amazon region and around the world has only occurred due to decreased investment in research and development in this field. Therefore, although tafenoquine has been approved by Anvisa, much remains to be studied to ensure patient safety in real-life scenarios of drug use”, he concludes.

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