GSK ends its antifolate drugs Lapdap and Dacart

GlaxoSmithKline pulled Lapdap (chloroproguanil-dapsone) from the market and ended the development of Dacart (Lapdap+artesunate) after phase III trials of the drugs showed significant hemoglobin reductions in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Patient’s with G6PD deficiency have weaker red blood cell membranes which can rupture when exposed to oxidative stress caused by certain drugs including the antimalarial primaquine. The sudden hemolysis and loss of hemoglobin can lead to severe anemia which may require blood transfusions. 10-25% of people in sub-Saharan Africa are G6PD deficient because, like the various hemoglobinopathies such as sickle cell, G6PD deficiency protects against severe malaria.

Kenya was the only market where Lapdap was being sold and GSK was developing Dacart with the Medicines for Malaria Venture (MMV), an interesting public private partnership model which seeks to mitigate some of the financial risks associated with drug development (well illustrated in this case). Still, it’s an unfortunate development to lose treatment options, but there were other concerns with these drugs. While Lapdap and Dacart’s toxicity in certain patients are well acknowledged, their cross resistance with another antifolate, sulphadoxine-pyrimethamine (SP), is a significant impediment as well. SP, which also inhibits folic acid synthesis, has been used worldwide for decades and SP resistant strains exist in many places in sub-Saharan Africa. The same molecular mechanisms which confer SP resistance, point mutations in the dhfr and dhps genes, confer Lapdap resistance. Thus, the therapeutic life of Lapdap and Dacart would be compromised in areas with preexisting SP resistance. Research by Dr. Alisa Alker (a former mentor of mine) and others have shown the presence of these mutations in sub-Saharan Africa whose prevalence would have rapidly increased in the face of increased drug pressure. Lapdap and Dacart are gone, but they may have not been the best of options in the first place.

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