Bernard Pécoul

Fexinidazole – A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness

Background Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. Methods and Findings Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC50 against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a Cmax of 500, 14171 and 13651 ng/mL respectively, and an AUC0–24 of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. Conclusions The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

New, Improved Treatments for Chagas Disease: From the R&D Pipeline to the Patients

Endemic throughout Latin America with a prevalence rate of approximately 1.4%, Chagas disease (CD) is estimated to kill 14,000 people every year, which is more people in the region each year than any other parasite-born disease, including malaria [1],[2]. Brazilian physician Carlos Chagas first described CD exactly a century ago [3], and its socioeconomic impact makes it the most important parasitic disease in the Americas [4]. Estimated to infect somewhere between 8 to 14 million people, CD both afflicts the poor and, like other neglected tropical diseases, “promotes poverty” [2],[5]. Through its impact on worker productivity, and by causing premature disability and death, CD annually costs an estimated 667,000 disability-adjusted life years lost [1],[6]. In the case of Brazil alone, losses of over US

The drug and vaccine landscape for neglected diseases (2000-11): a systematic assessment.

1.3 billion in wages and industrial productivity were due to the disabilities of workers with CD [7]. CD is an important public health issue, both in Latin America and increasingly around the world: the infection rate in endemic areas is estimated to be 1.4% [8], with geographic variation from 0.1% to 45.2% [9]. Vectorial transmission has been significantly reduced due to control efforts like the Southern Cone Initiative [10],[11] and others [11],[12]. However, there are areas producing new cases such as regions untouched by vector control efforts [13], special areas with non-domiciliated triatomine [14], and the Amazon region with recent cases reported via oral transmission and by wild triatomine [15]. And still to this day, millions of patients remain without adequate treatment for this silently debilitating and potentially fatal disease. Although no official global figures exist, it is estimated that no more than 1% of those infected are believed to receive any treatment at all. An increasing number of CD patients are also seen in non-endemic, developed countries because of globalization and the movement of unknowingly infected people from Latin America to other parts of the world [16],[17],[18]. The appearance of Trypanosoma cruzi in blood banks in the United States has led the Food and Drug Administration (FDA) to recently issue a draft guidance on CD screening [19].

''Manifesto'' for Advancing the Control and Elimination of Neglected Tropical Diseases

BACKGROUND In 1975-99, only 1·1% of new therapeutic products had been developed for neglected diseases. Since then, several public and private initiatives have attempted to mitigate this imbalance. We analysed the research and development pipeline of drugs and vaccines for neglected diseases from 2000 to 2011. METHODS We searched databases of drug regulatory authorities, WHO, and clinical trial registries for entries made between Jan 1, 2000, and Dec 31, 2011. We defined neglected diseases as malaria, tuberculosis, diarrhoeal diseases, neglected tropical diseases (NTDs; WHO definition), and other diseases of poverty according to common definitions. FINDINGS Of the 850 new therapeutic products registered in 2000-11, 37 (4%) were indicated for neglected diseases, comprising 25 products with a new indication or formulation and eight vaccines or biological products. Only four new chemical entities were approved for neglected diseases (three for malaria, one for diarrhoeal disease), accounting for 1% of the 336 new chemical entities approved during the study period. Of 148,445 clinical trials registered in Dec 31, 2011, only 2016 (1%) were for neglected diseases. INTERPRETATION Our findings show a persistent insufficiency in drug and vaccine development for neglected diseases. Nevertheless, these and other data show a slight improvement during the past 12 years in new therapeutics development and registration. However, for many neglected diseases, new therapeutic products urgently need to be developed and delivered to improve control and potentially achieve elimination. FUNDING None.

An unfolding tragedy of Chagas disease in North America.

Neglected tropical diseases (NTDs) are the most common infections of the worlds poorest people and the leading causes of chronic disability and poverty in low- and middle-income countries [1]–[3]. NTDs (Table 1) especially affect children and young women of reproductive age [4], and consequently deprive them of their health and economic potential [3]. NTDs also impair agricultural productivity and are an important reason why the worlds poorest 1.4 billion people who live below the poverty line cannot escape destitution and despair [3]. Despite the devastating effect of these diseases on health and development, with evidence that their global burden is as great as that of any other serious disease [1]–[3], financial support for control and elimination efforts, as well as research and development (R&D), have been inadequate [2], [5]. Indeed, in Millennium Development Goal 6 (to “combat HIV/AIDS, malaria and other diseases”), NTDs were not even specifically mentioned but merely considered as part of the “other diseases” [6]. However, policy makers are slowly beginning to appreciate the importance of NTDs. Table 1 Neglected tropical diseases. The World Health Organization (WHO) has a new Department of Neglected Tropical Diseases, and WHO-TDR (Special Programme for Research and Training in Tropical Diseases) has a new 10-year strategic plan with support from UN agencies, member states, and private philanthropies. At the same time, funding for integrated NTD preventive chemotherapy control from the governments of the US and UK has increased dramatically and is approaching US

New Drugs for Neglected Diseases: From Pipeline to Patients

100 million annually, while support remains strong for product development partnerships from the Bill & Melinda Gates Foundation, Medecins Sans Frontieres (MSF), and a few European governments. Recently, the new Director of the US National Institutes of Health, Francis Collins, has targeted NTDs as a research priority, and the UK charity Wellcome Trust has agreed with the multinational pharmaceutical company Merck & Co. to allocate substantial funds for a joint, not-for-profit research center in India to develop inexpensive “antipoverty” vaccines against neglected diseases [7], [8]. Additional efforts to combat NTDs are also being shared among major multinational pharmaceutical companies (i.e., Novartis, GlaxoSmithKline, Pfizer, Sanofi-Aventis, Merck & Co.) and others who have also committed resources and made investments in research and development for these conditions. Thus, although at present only about 10% of the global funds required for preventive chemotherapy and NTD mass drug administration have been committed, and although R&D for NTDs has not even reached the so-called 10/90 gap [9], (meaning only 10% of available global R&D spending is committed for diseases that disproportionately affect 90% of the world living in low-income and middle-income countries), there is cautious optimism that such disparities could diminish in the coming decade. With a combination of funds from the group of eight (G8) nations, emerging economies (e.g., Brazil, India), multinational companies, and private philanthropic sources, together with a community of scientists, physicians, and other healthcare workers, global public health experts and policy makers committed to NTDs have begun to deliberate about how future resources and investments should be best allocated, particularly in terms of an appropriate balance between implementation and R&D. The leadership of key international agencies such as WHO, ministries of health in disease-endemic countries, and the communities themselves is key to achieve any ambitious strategy. With a global dialogue now underway, this is an appropriate time to present an eight-point manifesto (“a public declaration of motives and intentions by a government or by a person or group regarded as having some public importance” [2], [11]) for NTDs.

The BENEFIT Trial: Where Do We Go from Here?

In North America, Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi) was first reported in Mexico in 1940 [1] and in the United States in Texas in 1955 [2]. However, based on ancient mummified remains discovered in the Rio Grande Valley, human T. cruzi infection has been present in North America since prehistoric times [3].

Eliminating the Neglected Tropical Diseases: Translational Science and New Technologies

The Drugs for Neglected Diseases Initiative is a new, public- sector organization dedicated to drug discovery

Pediatric HIV--a neglected disease?

In the next five years, we can now project that 200,000 people living with Chagas disease will die from heart disease and related complications. We urgently need to redouble our efforts to identify and treat young people who are still in the early stages of their illness, but ultimately we need to find better treatments and new cures. According to recent estimates, there are 5.7–9.4 million people living with Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi), a neglected tropical disease and leading cause of heart disease and cardiomyopathy, especially in Latin America and the United States [1,2]. Today, less than 1% of people infected with T. cruzi have access to diagnosis and treatment [3], a consequence of the fact that Chagas disease mostly affects those living in extreme poverty and in marginal surroundings. This finding is especially sad given new information by the World Health Organization (WHO) stating that more than one-half of Chagas disease sufferers live in Latin America’s three wealthiest countries—Argentina, Brazil, and Mexico [1]. Moreover, there are hundreds of thousands of infected people living in the US, with emerging evidence for significant T. cruzi transmission in Texas [4,5]. In this sense, Chagas disease represents one of the Western Hemisphere’s greatest health disparities. Moreover, in recent years we also have seen the globalization of Chagas disease to Spain and elsewhere in Europe and worldwide [6]. For years, the community of scientists, physicians, and other health care providers and Chagas disease patients has been awaiting the results of the Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial, which was designed to evaluate the safety and efficacy of benznidazole in patients with Chagasic cardiomyopathy [7]. Approximately 20%–30% of T. cruzi-infected individuals progress to Chagasic cardiomyopathy, a debilitating heart condition associated with conduction disturbances, heart failure, and sudden death. While it is established that benznidazole is effective in curing Chagas disease patients during their early acute phase [8–11], very few individuals are diagnosed at this stage of the disease. The BENEFIT trial aimed to determine if the 1.17 million people now living with Chagasic cardiomyopathy (WHO estimate [1]) might also experience improved clinical outcomes or even cures with benzimidazole treatment. Unfortunately, the answer appears to be “no.” Compared to a placebo control, benznidazole did not result in a statistically significant improvement in cardiac clinical outcomes. Although the study was not sufficiently powered to show incremental benefits in cardiac outcome (on the order of 5%–15%), it is clear that our current strategies for antiparasitic chemotherapy need to be revisited for patients with evidence of Chagasic heart disease. But there is additional bad news—the BENEFIT trial found that in both treated and placebo arms (comprising almost three thousand patients), 17%–18% died over a five-year time frame, most from cardiac complications [7]. If we extrapolate from the WHO estimate, this means that roughly 200,000 people will die from Chagasic cardiomyopathy over the next five years. To put this number in perspective, it is almost identical to the number of women living in the US who will die from breast cancer over the same period [12]. Whereas breast cancer is now linked with a highly successfully and accomplished advocacy and awareness campaign that promotes early detection and treatment, as well as research and development (R&D) into an exciting portfolio of new and innovative therapies, we are now facing almost the opposite situation with Chagas disease and cardiomyopathy. Today, there are few advocates for the millions of Chagas disease sufferers mostly living in poor and marginalized conditions. As a result, the vast majority have no access to diagnosis and treatment, and far too little is invested into R&D for new drugs, vaccines, and other tools (including tests for cure). From our perspective, the BENEFIT trial is a wake-up call to aggressively pursue a global initiative of diagnosis, treatment, and research, emphasizing the following specific points:

Research in complex humanitarian emergencies: the Médecins Sans Frontières/Epicentre experience

Today, the World Health Organization recognizes 17 major parasitic and related infections as the neglected tropical diseases (NTDs). Despite recent gains in the understanding of the nature and prevalence of NTDs, as well as successes in recent scaled-up preventive chemotherapy strategies and other health interventions, the NTDs continue to rank among the world’s greatest global health problems. For virtually all of the NTDs (including those slated for elimination under the auspices of a 2012 London Declaration for NTDs and a 2013 World Health Assembly resolution [WHA 66.12]), additional control mechanisms and tools are needed, including new NTD drugs, vaccines, diagnostics, and vector control agents and strategies. Elimination will not be possible without these new tools. Here we summarize some of the key challenges in translational science to develop and introduce these new technologies in order to ensure success in global NTD elimination efforts.