In the Journals

Fosmidomycin-piperaquine appears safe, effective against malaria

A combination regimen of fosmidomycin-piperaquine that is being developed in response to increasing resistance to artemisinin-based therapy for uncomplicated Plasmodium falciparum was well-tolerated and led to rapid parasite clearance in adults and children, according to results of a phase 2 proof-of-concept study.

Fosmidomycin is an aminopropylphosphonic acid that was first developed in the 1970s as an antibacterial agent, according to Ghyslain Mombo-Ngoma, MD, MSc, PhD, head of the clinical operations department at the Medical Research Center of Lambaréné in Gabon, and colleagues. It has been assessed in several studies over the past 15 years as monotherapy or in combination with clindamycin or artesunate for uncomplicated P. falciparum malaria. Fosmidomycin was associated with poor efficacy and prolonged parasite clearance in at least one of these studies, the researchers reported. However, Mombo-Ngoma and colleagues noted that combining the agent with piperaquine could increase its efficacy.

“The combination of fosmidomycin and piperaquine represents a novel approach to the chemotherapy of malaria,” the researchers wrote in Clinical Infectious Diseases. “It possesses different modes of action and different biochemical targets, with fosmidomycin exerting rapid blood schizonticidal activity and piperaquine providing prolonged post-treatment prophylaxis.”

For the phase 2 trial, a twice-daily, 30-mg/kg dose of fosmidomycin and once-daily, 16-mg/kg dose of piperaquine was administered for 3 days to 100 adult and pediatric patients from two regions in Gabon that are “highly endemic” for malaria, according to the researchers. The primary efficacy endpoint was the per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) at day 28.

The researchers reported that all 83 patients with available data who completed the treatment had PCR-corrected ACPR 28 days after treatment. The median time to rapid parasite clearance was 36 hours (interquartile range, 6-60), and time to fever clearance was 12 hours (IQR, 6-48). Asexual parasitemia occurred in 14 patients between days 28 and 63. However, PCR results showed that all infections were new.

In a safety analysis, researchers identified 97 adverse events in 55 patients. Most events were mild or moderate and involved the gastrointestinal tract, such as vomiting and abdominal pain (24%), upper and lower respiratory tract (24%), skin lesions (13%) or were systemic (12%). However, ECG results revealed prolonged QT corrected (QTc) intervals in two young patients aged 5 years. They researchers said the events were brief and did not require hospitalization.

“In conclusion, the combination fosmidomycin-piperaquine has demonstrated high efficacy in the treatment of uncomplicated P. falciparum malaria in adults and children in Gabon,” they wrote. “The combination was well-tolerated, with the majority of adverse events being transient and mild to moderate in severity. However, QTc prolongation was the most important safety finding warranting further studies, including at least an [artemisinin-based combination therapy] comparator group, pharmacokinetic-pharmacodynamic assessments, and other potential partner drugs.” – by Stephanie Viguers

Disclosures: Mombo-Ngoma reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.

A combination regimen of fosmidomycin-piperaquine that is being developed in response to increasing resistance to artemisinin-based therapy for uncomplicated Plasmodium falciparum was well-tolerated and led to rapid parasite clearance in adults and children, according to results of a phase 2 proof-of-concept study.

Fosmidomycin is an aminopropylphosphonic acid that was first developed in the 1970s as an antibacterial agent, according to Ghyslain Mombo-Ngoma, MD, MSc, PhD, head of the clinical operations department at the Medical Research Center of Lambaréné in Gabon, and colleagues. It has been assessed in several studies over the past 15 years as monotherapy or in combination with clindamycin or artesunate for uncomplicated P. falciparum malaria. Fosmidomycin was associated with poor efficacy and prolonged parasite clearance in at least one of these studies, the researchers reported. However, Mombo-Ngoma and colleagues noted that combining the agent with piperaquine could increase its efficacy.

“The combination of fosmidomycin and piperaquine represents a novel approach to the chemotherapy of malaria,” the researchers wrote in Clinical Infectious Diseases. “It possesses different modes of action and different biochemical targets, with fosmidomycin exerting rapid blood schizonticidal activity and piperaquine providing prolonged post-treatment prophylaxis.”

For the phase 2 trial, a twice-daily, 30-mg/kg dose of fosmidomycin and once-daily, 16-mg/kg dose of piperaquine was administered for 3 days to 100 adult and pediatric patients from two regions in Gabon that are “highly endemic” for malaria, according to the researchers. The primary efficacy endpoint was the per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) at day 28.

The researchers reported that all 83 patients with available data who completed the treatment had PCR-corrected ACPR 28 days after treatment. The median time to rapid parasite clearance was 36 hours (interquartile range, 6-60), and time to fever clearance was 12 hours (IQR, 6-48). Asexual parasitemia occurred in 14 patients between days 28 and 63. However, PCR results showed that all infections were new.

In a safety analysis, researchers identified 97 adverse events in 55 patients. Most events were mild or moderate and involved the gastrointestinal tract, such as vomiting and abdominal pain (24%), upper and lower respiratory tract (24%), skin lesions (13%) or were systemic (12%). However, ECG results revealed prolonged QT corrected (QTc) intervals in two young patients aged 5 years. They researchers said the events were brief and did not require hospitalization.

“In conclusion, the combination fosmidomycin-piperaquine has demonstrated high efficacy in the treatment of uncomplicated P. falciparum malaria in adults and children in Gabon,” they wrote. “The combination was well-tolerated, with the majority of adverse events being transient and mild to moderate in severity. However, QTc prolongation was the most important safety finding warranting further studies, including at least an [artemisinin-based combination therapy] comparator group, pharmacokinetic-pharmacodynamic assessments, and other potential partner drugs.” – by Stephanie Viguers

Disclosures: Mombo-Ngoma reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.