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May 26, 2011

Background

It is estimated that nearly one million people worldwide (and possibly as many as three million) die of malaria annually with most deaths occurring among children under the age five ¹⁾. Malaria occurs predominantly in developing countries and is considered a neglected tropical disease. Cerebral malaria occurs in approximately 10% of malaria cases and is associated with a 25-50% mortality within 24-48 hours ^{2, 3)}.

Chloroquine, an agent used in the treatment of malaria for several decades has become less effective, and in some areas chloroquine resistant parasites have climbed to 90% of cases ⁴⁾. Resistance to the newer agent artemisinin has also been described ⁵⁾. Given the widespread prevalence of malaria and the resistance observed with available drugs, the availability of newer agents for its treatment is extremely urgent.

Although prolonged malaria infections can result in mortality due to anemia, the most severe clinical manifestations of malaria are mainly caused by an exaggerated host immune response to the Plasmodium infection rather than a direct effect of the blood parasites ⁶⁾. Indeed, there is currently consensus that malaria is a disease where a strong proinflammatory response is responsible for the severity of clinical manifestations ⁶⁾. Patients severely afflicted by Plasmodia, experience extremely high systemic cytokinemia, high fever, paroxysms, renal failure, and ultimately death ³⁾. Cerebral malaria typically presents with generalized convulsions and coma progressing to death ³⁾.

Technology development

TLRs constitute a family of innate immune receptors that are critical for proinflammatory cytokine production during microbial challenges ⁷⁾. Eisai has pioneered the discovery of novel drugs interacting with TLRs. Eritoran, a TLR4 antagonist, is currently in Phase III studies for the treatment of severe sepsis. Since TLR9 has been shown to play a role in animal models of malaria and in the pathogenesis of human disease, Eisai therefore initiated the discovery of TLR9 modulators.

Eisai developed E6446, an orally active TLR9 antagonist. The effects of E6446 were tested in several animal infection models in collaboration with Federal University of Minas Gerais (Dr. Ricardo Gazzinelli) and University of Massachusetts (Dr. Doug Golenbock).

P. chabaudi malaria model, E6446 prevented spontaneous release of proinflammatory cytokines triggered in response to infection in vivo and by splenocytes in vitro. Treatment with E6446 significantly suppressed the hyper-responsiveness of cells from P. chabaudi-infected mice after in vitro stimulation with various TLR ligands. In addition, Treatment with E6446 prevented mortality in P. chabaudi-infected mice which are hyper-responsive to challenges with endotoxin. In P. berghei ANKA cerebral malaria model, Mice infected with P. berghei develop seizures and paralysis, resulting in ~ 75% mortality by day 10-15 post infection. Prophylactic treatment with E6446 reduced the frequency of death due to cerebral malaria to 20%, and suppressed the formation of cerebral vascular lesions and leakage of vascular contents into the brain.

Selected References

• 1)
  World Health Organization, Fact Sheet No.94, April 2010
• 2)
  Krishnan, A. et al. Crit Care Med 2003; 31:2278-84
• 3)
  Newton, C.R.J.C. et al. N. J. Neurol. Neurosurg. Psychiatry 2000 69:433-441
• 4)
  Djimdie, A.A. et al. FEMS Immunology & Medical Microbiology, Special Issue: Neglected Tropical Diseases. Volume 58, Issue 1, pages 113-118, February 2010
• 5)
  Dondorp et.al. Nature Reviews Microbiology 8, 272-280 (April 2010)
• 6)
  Artavanis-Tsakonas K, et al. Clin Exp Immunol. 2003 Aug;133(2):145-52.
• 7)
  R. Medzhitov, et al. N Engl J Med 343, 338 (Aug 3, 2000)