Improvement of Tafenoquine Radical Cure by Combination with SJ733, a Novel ATP4 Inhibitor, for Treatment of Malaria

Technical Abstract Background. Malaria caused an estimated 249 million cases and 608,000 deaths in 2022. Most malaria is caused by either Plasmodium falciparum, which causes the most deaths, or Plasmodium vivax, which is geographically the most widespread. Although P. falciparum causes 98% of all cases, P. vivax causes 20-100% of cases in countries outside of Africa. Current WHO treatment guidelines center on the artemisinin combination therapies (ACTs). ACTs are highly effective and safe against P. falciparum malaria but do not cure the latent liver disease seen with P. vivax. Additionally, spreading resistance to both the artemisinins and their partner drugs is threating ACT efficacy. Safe and effective new treatments are needed. Drugs to treat US Service Members must be FDA approved, which most ACTs are not. Thus, developing new, FDA approved, drugs to treat malaria is essential. Relevance to the Topic Area. The topic area is the development of SJ733-based combination antimalarials as potential ACT replacements and drugs for radical cure of P. vivax malaria. This addresses the identification of novel targets for blood and liver stage malaria parasites. SJ733 is an antimalarial targeting ATP4 that is potent against all malaria species, rapidly acting, and blocks malaria transmission in mouse models. SJ733 has good oral bioavailability and pharmacokinetics consistent with a 3-dose drug. SJ733 has a strong safety pharmacology profile, low potential for drug-drug interactions, and was well tolerated in GLP toxicology studies. It is being developed under FDA IND (#126652). Phase 1 studies (ClinicalTrials.gov: NCT02661373) demonstrated SJ733 was well tolerated in oral single- dose, 3-dose, and cobicistat pharmacoboosted single-dose schedules with no SJ733-related serious adverse events, dose limiting toxicities, study discontinuations, or clinically relevant changes in vital signs or biological parameters. SJ733 pharmacokinetics showed proportional increase in AUC and Cmax up to doses of 600 mg, minimal food effect, and a median T1/2 of 20 hr. Combination with cobicistat increased Cmax and AUC 3-4 fold. A Phase 1b study showed similar safety and pharmacokinetic profiles and that a single oral dose of SJ733 (600 mg) rapidly cleared P. falciparum infection – equivalent to one dose of artesunate. A Phase 2a study (Clinicaltrials.gov: NCT04709692) demonstrated that 3 consecutive daily doses of 600 mg of SJ733 (600 mg), with or without cobicistat (150 mg) pharmacoboosting, was well tolerated with no SJ733- related serious adverse events or adverse events, dose limiting toxicities, study discontinuations, or clinically relevant changes in vital signs or biological parameters. SJ733 rapidly cleared P. vivax infection and was equally efficacious regardless of boosting. While highly effective for blood stage disease, SJ733 did not clear liver stage disease leading to the proposed trial combining with tafenoquine. Hypothesis/Objective. The clinical hypothesis is SJ733-tafenoquine combination will be a safe radical cure drug for uncomplicated P. vivax malaria. Specific aims/Study Design. The specific aim is: testing the combination of SJ733 and tafenoquine for the radical cure of uncomplicated P. vivax malaria in a proof-of-concept Phase 2b study. Clinical Impact. The proposed Phase 2b study will define safety and efficacy of the combination of SJ733 and tafenoquine for radical cure of uncomplicated P. vivax malaria in adults and establish parameters for a Phase 3 registration trial. The study will allow targeted development of SJ733 to those populations that would most benefit. In the long term, the proposed studies will enable the registration of a multi-component drug based on SJ733 as an ACT replacement. Relevance to Military Health. US Service Members deploying to malaria endemic areas are at risk for infection and severe disease because they are usually malaria naïve. There has been a steady incidence of malaria infections in US Service Members during the last decade, running between 28 and 126 cases per year, with 30-50% being P. vivax malaria. The global standard of care is the combination of chloroquine and primaquine, which is subject to chloroquine resistance and poor adherence to primaquine. Tafenoquine, which requires only one dose, has emerged as the preferred liver stage drug but does not appear to combine as well with ACTs, and has been relabeled by the US-FDA to be used only in combination with CQ for radical cure. The wide spread of CQ resistance and the potential for poor combination with ACTs both suggest that there is a need for new combination therapies for radical cure that have a fast-acting component to rapidly cure blood stage disease and a relapse preventing component. The strategic need to protect US service members against P. vivax has significant risk from both of these trends. FDA approval is required for US military use of malaria treatments and there is a need for new FDA approved antimalarial drugs that could be used for radical cure of P. vivax malaria in areas of the world with chloroquine resistance. Lay Abstract Malaria is an infectious disease caused by a single-celled parasite that is transferred between people by mosquitos. Malaria affects most of the world, especially places where the climate is warm and wet – where mosquitos that transmit malaria thrive. The disease is particularly widespread in areas around the equator including Africa, Asia, and Latin America. Three to four billion people live in areas that have malaria, and every year there are more than 200 million cases of the disease. When a person gets malaria, they have symptoms including fever, feeling tired, vomiting, and having headaches. Much like the flu, having malaria does not make one immune to getting it again, although if one does get malaria again, the symptoms are usually milder. Most healthy adults who get malaria don''t die from the disease, especially those who have had malaria before. However, some people are particularly sensitive to the disease and are much more likely to have a severe case, which can lead to seizures, coma, and death. Among those most likely to have severe disease are small children and travelers who go from a country without malaria to one with it. One group of travelers who are required to travel to countries with malaria are US Service Members. There are several drugs available to treat malaria. However, the parasite is very good at evading the effects of drugs by developing drug resistance – a fundamental ability to prevent the drug from working. Once that happens, resistance can spread rapidly and last for a long time, thus making the drugs useless in wide areas of the world. This problem is made worse by the economics of the disease: it occurs mostly in poorer parts of the world that cannot afford good medical care and new drugs. Therefore, there is a constant battle around our ability to treat malaria. We are currently in a phase of that battle where we are losing one of our best drugs in Asia and potentially in Africa. This could cause severe trouble in our ability to handle malaria if resistant parasites become common and if new drugs are not found. The US military represents a special case in how to deal with malaria. The US military often needs to send troops abroad to places where malaria exists. For example, in recent years we have had troops in Africa, Central Asia, and Southern Asia – all places where malaria exists. Because most troops are usually moving from a place without malaria to one with the disease, they may get severely ill if they do get malaria. To preserve the ability of our troops to carry out their job in conflict areas we normally use two strategies: 1) preventing mosquitos from biting troops using nets and insecticides; and 2) treating troops with antimalarial drugs before they get sick to prevent the parasite that causes the disease from being able to infect them. Despite these efforts, we still have between 20 and 130 cases of malaria in US Service Members each year. About half of those are caused by a form of malaria that not only makes them sick but also hides in their body and can cause multiple illnesses over months to years if not treated. New drugs to treat Service Members must be approved by the US Food and Drug Administration (FDA), which is unusual for antimalarial drugs that are rarely used or needed in the US. This project is aimed at developing a new drug (SJ733) for treating malaria, including the form that can hide in the body. This drug is intended to be safe for use by all travelers, including US Service Members and those who live in countries with malaria. This is a cost-efficient approach because it lets one drug be used for multiple purposes. The main work funded by this grant will be proving that the drug is safe and effective for use in patients with malaria in South America; this would lay the groundwork for it being approved by the US FDA. If the development of SJ733 is successful, it will be registered for use in the US with the FDA as an antimalarial. This would enable it to be available for use and protect our troops abroad.