Shorter Treatment Time For Chagas Could Blunt Kissing Bug Disease
Executive Summary
Chagas is in the spotlight with Novartis, Bayer and DNDi running different trials designed to tackle the neglected tropical parasitic disease.
A two-week course of drugs for treating patients with Chagas disease, instead of the current 60-day regimen, could be just as effective and safer, according to a new study which researchers believe could change the paradigm for treatment of the debilitating and potentially fatal insect-borne illness.
The BENDITA study was led by the not-for-profit Drugs for Neglected Diseases Initiative (DNDi) and carried out at sites in Cochabamba, Tarija and Sucre in Bolivia. It tested six treatment arms with a variety of lengths and dosages of benznidazole, the drug most commonly used to treat Chagas, both as monotherapy and in combination with Eisai Co. Ltd.'s investigational antifungal fosravuconazole.
Some 80% of the patients assigned to the group which took the standard dose of 300mg/day of benznidazole, but for two weeks instead of the standard eight weeks, showed no sign of the parasite in their blood six and 12 months after finishing the treatment. A similar result was observed in the group that took the standard eight-week treatment.
Significantly, DNDi noted, none of those in the two-week reduced duration group interrupted treatment. On average, 20% of patients who followed the standard course of treatment with benznidazole abandoned it due to side effects such as gastric intolerance, rashes or neuromuscular problems.
The side effects associated with benznidazole have "often discouraged some people from seeking treatment and healthcare workers from recommending it,” said Joaquim Gascon, principal investigator in the trial and director of the Chagas Initiative at the Barcelona Institute for Global Health. A fellow investigator, Faustino Torrico, president of the CEADES Foundation in Bolivia, added, "We’ve shown shorter treatment could be just as effective, and much safer. This could change the paradigm for Chagas treatment, by improving adherence and encouraging wider adoption by the medical community."
The results "bring new hope for people living with this silent disease and could change the reality of access to treatment in endemic countries. With a much simpler treatment regimen, there is no excuse for not treating people with Chagas,” added Sergio Sosa Estani, head of the Chagas clinical program at DNDi.
Chagas is caused by the parasite Trypanosoma cruzi and transmitted to humans via the feces and urine of kissing bugs or triatomines. According to the World Health Organization, 8 million people are infected worldwide, mainly in Latin America where one quarter of the population is potentially at risk of contracting a disease which causes incapacity and more than 10,000 deaths per year. International travel and migration has meant that Chagas is increasingly a global health issue – according to the Centers for Disease Control and Prevention, in the US an estimated 300,000 people are infected with T cruzi.
As the disease typically remains asymptomatic for years after infection, most people with Chagas are unaware of their condition, noted DNDi, and for 30-40% of people infected, most will suffer cardiac damage, often leading to sudden death or progressive heart failure.
Novartis Tests Entresto For Chagas Cardiomyopathy
It is against this background that Novartis AG has announced that as well as joining the Global Chagas Disease Coalition as a member, it is preparing a study to test its heart failure blockbuster Entresto (sacubitril/valsartan) versus enalapril in around 900 patients with chronic Chagas cardiomyopathy. Recruitment is planned to commence this year and the Swiss major noted that it will be "the first definitive morbidity and mortality study to assess a potential therapy for cardiac disease in this underserved patient population."
The primary endpoint is time to occurrence of a composite of cardiovascular events, including death or first hospitalization due to heart failure. Novartis said that the study followed an exploratory analysis from the PARADIGM-HF trial on which the appproval of Entresto was based which suggested the drug may have beneficial effects in people with chronic Chagas cardiomyopathy and heart failure with reduced ejection fraction.
The company added that it was also "working with stakeholders in endemic countries to co-develop tailored access-to-medicine programs and health system strengthening strategies to help ensure lower-income patients suffering from chronic Chagas cardiomyopathy can benefit from the best available treatment." In addition, Novartis pointed out that its proteasome inhibitor LXE408 was recently advanced as a promising drug candidate for the treatment of visceral leishmaniasis and "this novel mechanism of action is also being explored for other indications, including Chagas."
Bayer Pediatric Study A Success
There are currently only two drugs available to treat the disease – benznidazole and nifurtimox – and the latter was discovered by Bayer AG which first introduced the drug in Argentina (marketed as Lampit) in the 1970s, and shortly afterwards in other Latin American countries. Now the German major has presented positive data from the first part of a Phase III study of nifurtimox in pediatric patients at a Chagas conference in Barcelona.
The 330-patient study met its primary endpoint, which was the serological response at one year after end of treatment, by demonstrating superiority of 60-day nifurtimox treatment compared with historical placebo control. The study was conducted at sites in Argentina, Bolivia and Colombia between 2016 and 2018.
For the trial, Bayer developed a new formulation of both the 30mg and 120mg tablets, which can be dissolved in water to form a slurry when administered to children to allow for dosing accuracy and administration to those who have difficulty swallowing tablets. Jaime Altcheh of the Ricardo Gutierrez Children's Hospital in Buenos Aires and coordinating investigator of the trial, was quoted by Bayer as saying that "an adequate dispersable formulation of nifurtimox is a big step forward toward achieving the goal of treating all infected children. Early treatment after infection is very important to prevent manifestation of the disease in adulthood."
So progress is being made and pharma has been doing the right thing in an area of great unmet need but not a lucrative one. For example, since 2002 Bayer has been providing the WHO with nifurtimox free of charge, as well as financial resources for logistics and distribution and funding awareness, education and training programs, plus surveillance activities.
However much is still to be done and Bayer noted that today, less than 1% of people infected with Chagas worldwide are treated due to low disease awareness and limited access to treatment.