K777 for the Treatment of Chagas' Disease, IND-enabling Studies and IND Submission

Sponsor: Drugs for Neglected Diseases Initiative (DNDi)

Location(s): United States


Chagas Disease remains a major health problem in Latin America due to lack of an effective preventative vaccine and inadequate treatments post-infection. Thus, there is a desperate need for new drugs to treat this debilitating Disease. K777 is a vinyl sulfone cysteine protease inhibitor which irreversibly inhibits cruzain, a key protease required for viability of Trypanosoma cruzi, the parasite responsible for Chagas Disease. K777 is a novel chemical entity originally identified at University of California San Francisco by screening cysteine protease inhibitors against T. cruzi infected macrophages and evaluating growth inhibition of intracellular amastigotes. K777 has since been shown to be efficacious in models of acute and chronic Chagas Disease in both mice and dogs. K777 is non-mutagenic, has an acceptable PK profile, and has been shown to be well tolerated in animal safety studies. K777 has now progressed into IND-enabling studies, recently completing a 14 day GLP toxicity study in rats. Upon completion and approval of the K777 Investigation New Drug (IND) application, the First in Man Phase I dose escalation clinical trial to assess safety, tolerability and pharmacokinetics after a single oral dose will be conducted in the United States in healthy volunteers. On September 15, 2009 the FDA formally reviewed the proposed IND package for K777 in a type B pre-IND meeting. This proposal is designed to complete all remaining requirements as agreed by the FDA to fulfill the K777 IND package and allow K777 to move into clinical trials. The goals of this grant include production of 1.5 kilograms non-GMP as well as 1.5 kg GMP quality drug substance to complete activities required for the Pre- IND program and the planned Phase I clinical study. Efforts will include salt selection, analytical development of methods for release testing, and development of a reference standard. Additionally, a suitable Formulation will be developed, including placebo, for use in preclinical in vivo toxicity/pharmacokinetics and safety testing, as well as in the clinical setting. Once drug substance has been produced and a clinical Formulation determined, we will perform studies necessary to enable appropriate design of the IND-enabling non-human primate (NHP) 28-day toxicity study, including a pharmacokinetics study, evaluating one IV dose and two oral doses using the clinical Formulation and a dose-range finding study in non-human primates, comparing three dose levels once daily as well as one cohort in divided doses to determine if bid dosing has an advantageous pharmacokinetic profile. We will then perform the IND-enabling 28-day toxicity study in the non-human primate. Finally, we will perform a mass balance study of K777 in rodents using radiolabeled compound to more fully understand routes of clearance of K777. An IND application will be compiled upon completion of this work, and submitted to the FDA in order to allow initiation of human clinical trials.

 New drugs to treat Chagas Disease, a neglected tropical Disease, are urgently required. Current medicines do not cure the Disease and have numerous severe side-effects. K777 is a new chemical that has demonstrated the ability to improve and cure Chagas Disease in animal models. This proposal is designed to complete all remaining requirements as agreed with the FDA to allow K777 to move into clinical trials.