Safety and efficacy of the choline analogue SAR97276 for malaria treatment: results of two phase 2, open-label, multicenter trials in African patients

Abstract

BackgroundMalaria remains one of the most important infectious diseases. Treatment options for severe malaria are limited and the choline analogue SAR97276A is a novel chemical entity that was developed primarily as treatment for severe malaria. Before starting clinical investigations in severely ill malaria patients, safety and efficacy of SAR97276A was studied in patients with uncomplicated malaria. Here, we summarize two open-label, multi-center phase 2 trials assessing safety and efficacy of parenterally administered SAR97276A in African adults and children with falciparum malaria.Results Study 1 was conducted in Burkina Faso, Gabon, Benin and Tanzania between August 2008 and July 2009 in malaria patients in an age de-escalating design (adults, children). A total of 113 malaria patients received SAR97276A. Adults were randomized to receive a single dose SAR97296A given either intramuscularly (IM) (0.18 mg/kg) or intravenously (IV) (0.14 mg/kg). If a single dose was not efficacious a second adult group was planned to test a three dose regimen administered IM once daily for 3 days. Single dose SAR97276A showed insufficient efficacy in adults (IM: 20 of 34 cured, 59%; and IV: 23/30 cured, 77%). The 3-day IM regimen showed acceptable efficacy in adults (27/30, 90%) but not in children (13/19, 68%). SAR97276A was well tolerated but no further groups were recruited due lack of efficacy. Study 2 was conducted between October 2011 and January 2012 in Burkina Faso, Gabon and Kenya. SAR97276A administered at a higher dose given IM was compared to artemether–lumefantrine. The study population was restricted to underage malaria patients to be subsequently enrolled in two age cohorts (teenagers, children). Rescue therapy was required in all teenaged malaria patients (8/8) receiving SAR97276A once daily (0.5 mg/kg) for 3 days and in 5 out of 8 teenaged patients treated twice daily (0.25 mg/kg) for 3 days. All patients (4/4) in the control group were cured. The study was stopped, before enrollment of children, due to lack of efficacy but the overall safety profile was good.ConclusionsMonotherapy with SAR97276A up to twice daily for 3 days is not an efficacious treatment for falciparum malaria. SAR97276A will not be further developed for the treatment of malaria. Trial registration at clinicaltrials.gov: NCT00739206, retrospectively registered August 20, 2008 for Study 1 and NCT01445938 registered September 26, 2011 for Study 2.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-017-1832-x) contains supplementary material, which is available to authorized users.

Scoping Review of Antimalarial Drug Candidates in Phase I and II Drug Development

“…Nearly half of these studies recruited Australian populations ( n = 12). Studies were conducted in healthy volunteers ( n = 8) ( 17 , 25 , 30 ), induced blood-stage malaria (IBSM) subjects ( n = 7) ( 12 , 14 , 15 , 18 , 21 , 23 ), a combination of healthy volunteers and IBSM subjects ( n = 5) ( 20 , 26 – 28 ), and malaria patients ( n = 8) ( 13 , 16 , 19 , 22 , 24 , 29 ). Of the studies involving IBSM subjects and malaria patients, in only four studies were antimalarial drug candidates for treating P. vivax evaluated ( 14 , 16 , 22 , 24 ).…”

“…Of the studies involving IBSM subjects and malaria patients, in only four studies were antimalarial drug candidates for treating P. vivax evaluated ( 14 , 16 , 22 , 24 ). Among studies in malaria patients, six studies involved adults ( 13 , 16 , 19 , 22 , 24 ), while the remaining two studies recruited both adults and children ( 29 , 31 ).…”

“…Detailed summaries of PK-PD data were available from 24 open-access published manuscripts for 17 antimalarial drug candidates, with 1 study also providing deidentified individual participant data (IPD) ( 23 ). In addition to summaries of PK-PD data, deidentified IPD can be requested through the Clinical Study Data Request repository ( n = 1) ( 25 ) or by contacting the corresponding authors ( n = 2) ( 28 , 29 ). Of 12 completed, unpublished studies, deidentified IPD sharing was available for three studies through the Clinical Study Data Request repository or stated by the investigators as available upon reasonable request.…”

“…Most of the published studies investigated oral antimalarial drug candidates, with the exception of two studies in which candidates were delivered by an intravenous or intramuscular route ( 25 , 29 ) (Table S2 in the supplemental material). Antimalarial drug candidates were tested as single doses ( n = 20) ( 12 , 14 – 23 , 25 – 28 , 30 – 32 , 34 , 35 ), 3-day regimens ( n = 2) ( 13 , 33 ), and both single doses and 3-day regimens ( n = 2) ( 24 , 29 ). The majority of antimalarial drug concentrations were measured in plasma ( n = 22) ( 12 , 14 – 35 ).…”

Histone deacetylase inhibitors with high in vitro activities against Plasmodium falciparum isolates collected from Gabonese children and adults

“…Additionally, the natural P. falciparum population is constantly exposed to host factors including antimalarial drug pressure and is therefore genetically highly diverse, and parasites may be intrinsically heterogenous in their susceptibility towards the molecule 29,30 . An additional layer of complexity results from clinical trials reporting different drug efficacies (of non-HDACi) against P. falciparum infections in adults and children 31–33 . These differences are mostly attributed to the partial immunity that is developed by the populations living in malaria endemic regions after multiple P. falciparum infections 34,35 .…”