Abstract
Severe malariaEven with the best available treatment, the mortality from severe Plasmodium falciparum malaria remains high. Typical features at death are high parasite loads and obstructed micro- vasculature. Infected erythrocytes (IE) containing mature parasites bind to the host receptor heparan sulfate, which is also an important receptor for merozoite invasion. To block merozoite invasion has not previously been proposed as an adjunctive therapeutic approach but it may preclude the early expansion of an infection that else leads to exacerbated sequestration and death.Sevuparin in phase I studyThe drug sevuparin was developed from heparin because heparan sulfate and heparin are nearly identical, so the rationale was that sevuparin would act as a decoy receptor during malaria infection. A phase I study was performed in healthy male volunteers and sevuparin was found safe and well tolerated.Sevuparin in phase I/II clinical studyA phase I/II clinical study was performed in which sevuparin was administered via short intravenous infusions to malaria patients with uncomplicated malaria who were also receiving atovaquone/proguanil treatment. This was a Phase I/II, randomized, open label, active control, parallel assignment study.Sevuparin was safe and well tolerated in the malaria patients. The mean relative numbers of ring-stage IEs decreased after a single sevuparin infusion and mature parasite IEs appeared transiently in the circulation. The effects observed on numbers of merozoites and throphozoites in the circulation, were detected already one hour after the first sevuparin injection. Here we report the development of a candidate drug named sevuparin that both blocks merozoite invasion and transiently de-sequesters IE in humans with P. falciparum malaria.Trial registrationClinicalTrials.gov NCT01442168
Highlights
Severe malaria due to P. falciparum claims 430,000 lives annually, despite the use of the best anti-malarial medications currently available [1]
In a phase I study conducted in healthy male volunteers we found sevuparin to be safe and well tolerated at the dose levels studied, the data of which are to be found in S2 Supportive Information
As the dose 6.0 mg/kg 6 q6h did give higher activated partial thromboplastin time (APTT) values than the lower doses and in one patient APTT was up to 120 seconds 1 hour after the dose (ULN = 33 sec), the Data Safety Monitoring Board (DSMB) considered the risk of adverse events was potentially increased and recommended that the study should continue to part 2 with 3.0 mg/kg sevuparin q6h
Summary
Severe malaria due to P. falciparum claims 430,000 lives annually, despite the use of the best anti-malarial medications currently available [1]. The effects have not been possible to reproduce in humans infected with P. falciparum likely because the hosts, the parasites and the pathology that bring about severe malaria are only partially alike in animals and man [5,6,7,8]. We hypothesized that ring stage parasitemia in P. falciparum infected humans is maintained by an asynchronous rupture of schizonts, the subsequent invasion of erythrocytes by merozoites and the development of the parasites into ring- and adhesive trophozoite stage IE. Heparin has been found to reduce the mortality from severe P. falciparum malaria if it was given as an adjunct to anti-plasmodial drugs, but its use was stopped because of the risk of hemostatic disorders [14,15,16]. Preclinical investigations have demonstrated that sevuparin, an acidic, negatively charged, antiadhesive polysaccharide drug manufactured from heparin with eliminated antithrombin (AT) binding site, affects both merozoite invasion and sequestration of IE
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