Will AN15368 be the final 'kiss of death' against the silent and silenced Chagas disease?
Despite burgeoning vector control challenges and the drawbacks of current treatments for Chagas disease, a novel therapeutic holds promise in combating a long neglected parasite.
When presented with the words ‘assassin’, ‘kiss’, and ‘neglect’, one can be forgiven for imagining a certain agent of espionage, famed in the works of British novelist Ian Fleming. Few would associate such words with the potentially life-threatening vector-borne disease: Chagas. Perhaps fewer still are aware of the Chagas disease burden experienced by around 7 million people throughout Central and Latin America suffering from the region’s biggest parasitic disease killer. Here, the causative disease agent is a protozoan parasite, famed for its deadly and asymptomatic disease presentation, and the vehicle of transmission the aptly named ‘assassin’ or ‘kissing’ bug.
Image credit: James Gathany/CDC, 2005
Chagas can be understood as a silent and silenced disease: silent, as the infected majority have no or mild disease presentation (asymptomatic), and silenced, as the disease burden disproportionately affects populations of lower socioeconomic status. These populations are silenced as their voices repeatedly receive less attention in spaces of government, policy, and research and development decision making, resulting in situations where access to healthcare and disease diagnostic budgets remain inadequate to support the population’s public health demands.
“The parasite (Trypanosome(s)) is transmitted by the assassin bugs, with bites being colloquially termed the ‘kiss of death’: ‘kiss’ as the insects prefer to feed on the soft, delicate skin of the lips, and ‘death’ as untreated infections are lifelong and potentially life threatening.”
The parasite (Trypanosome(s)) is transmitted by the assassin bugs, with bites being colloquially termed the ‘kiss of death’: ‘kiss’ as the insects prefer to feed on the soft, delicate skin of the lips, and ‘death’ as untreated infections are lifelong and potentially life threatening. Unlike other vector-borne diseases, such as malaria which is spread via the bite from infected mosquitos, Chagas disease occurs when assassin bug faeces contaminated with trypanosome parasites gain entry to the host, where they replicate once established. Entry occurs when the parasites cross through skin abrasions, bite site wounds (from scratching the bite), or via the conjunctivae.
Large-scale disruption and elimination of Chagas disease has primarily focused on controlling the kissing bug vector populations through community and household insecticide spraying programmes. A successful such programme was the Southern Cone Initiative. The control programme covers seven countries, and in the nine years since its initiation, new cases of Chagas have fallen by an average of 94% through reducing kissing bug populations. Despite these achievements, the success of Chagas disease control is threatened by the ongoing emergence and spread of insecticide-resistant kissing bugs, and more intriguingly, household invasion of kissing bugs typically known for spreading Chagas disease among wild animals (armadillos, bats, and opossums) that then spread the disease to humans. This process has been driven by habitat destruction, such that both kissing bugs and the wild fauna are spatially associated with humans, increasing Chagas spread. Additionally, Chagas disease transmission can also occur through further routes including congenital transmission (from mother to child), through blood transfusions, organ transplantation, and via ingestion of food or drink contaminated with kissing bug faeces and/or bodies, all of which are compounded by the fact that the silent nature of the disease makes diagnosis difficult.
Image credit: Kay DeWitt/CDC, 1965
With successful vector control limiting the disease spread, few attempts have been made to innovate the treatment options for patients suffering Chagas, such that half a century since their introduction, benznidazole and nifurtimox remain the only viable treatment options available for patients suffering from Latin America’s most prominent Neglected Tropical Diseases (NTDs). A combination of continued neglected status and supply chain management has meant that clinicians and community health care workers are forced to administer these compounds, despite the high frequency of adverse side effects observed in patients experiencing chronic disease. The concerns with the treatment supply chain are well voiced, with NGO and advocacy group ‘Uniting to Combat Neglected Tropical Diseases’ reporting that fewer than 1% of patients can access Chagas treatments globally. These issues alone do not drive neglected status, with additional categorisation down to the silenced nature of the disease, put compassionately by Professor Fausto Pinto (Current World Heart Foundation President) who pronounced Chagas “affects the most neglected populations in the world. Often, people living with Chagas disease have no access to healthcare, nor a political voice”.
Despite the neglected tropical disease categorisation, severe adverse side effects of existing treatments and continued spread of kissing bugs throughout Latin America, a recent treatment breakthrough has been discovered after nearly 50 years of sub-standard treatment options. This exciting breakthrough re-ignites discussions around the possibility of new Chagas control and management. The evidence, published in Nature Microbiology introduces a novel class of compounds that could prove to be the first acceptable, effective, and safe therapeutics for Chagas disease in close to five decades. Perhaps the days of the assassin's lethal kiss are finally over?
“the success of Chagas disease control is threatened by the ongoing emergence and spread of insecticide-resistant kissing bugs”
The therapeutic in question, AN15368, has been developed by international research teams, and belongs to a new class of compounds termed benzoxaboroles. These benzoxaborole compounds have been studied for their antiparasitic properties against other tropical diseases, including Plasmodium falciparum (malaria parasite). In these studies, significant reductions in the numbers of infecting parasites have been reported. These results are of interest against the Chagas parasite and it has been proposed that the lead compound AN15368 acts against the trypanosome parasite through a prodrug mechanism. This means that the compound, once initially administered, cannot directly exhibit therapeutic effects and must first be processed into the pharmacologically-active compound internally. Once processed, the now active AN15368 compound functions to kill the trypanosomes by way of interrupting the replication and survival abilities of the parasite.
“Perhaps the days of the assassin’s lethal kiss are finally over?”
Initial results appear hopeful that the quest to combat this silent disease may be on the horizon, with the first test of cure study in non-human primates boasting 100% cure rates after just 60 days post AN15368 administration. To put these results in context: another study which followed standard nifurtimox treatment cure rates for chronic Chagas sufferers found that cure rates were as low as 7% following traditional treatments. That is why the AN15368 findings are significant: for nearly 50-years Chagas disease patients have had limited to no choice in tolerating severe treatment side effects, whilst only getting a fraction of the drug's potency. The AN15368 study’s authors remark that: “The observed 100% cure with AN15368 in macaques harbouring long-term [Chagas] infections with genetically diverse parasite lineages. . .bodes well for the potential safety and efficacy of AN15368 in humans”. It is important to also recognise that whilst these initial trial results are exciting and timely, these trials were first conducted in mice and non-human primates, so results boasting total Chagas cure rates (100%) must be taken with a pinch of salt. However, we can remain optimistic that the next and continued stages for AN15368 development are to progress the drug through clinical trials to determine the efficacy and drug safety in humans.
“The AN15368 drug alone won’t be sufficient in quashing Chagas transmission, but its inclusion into the portfolio of control measures will have a measurable impact across endemic regions.”
With current reliance on toxic benznidazole and nifurtimox treatments, and with no clinically approved vaccines available, calls to innovate the treatment options available to those suffering Chagas could not be more timely. The AN15368 drug alone won’t be sufficient in quashing Chagas transmission, but its inclusion into the portfolio of control measures will have a measurable impact across endemic regions. It’s unlikely at this stage to determine whether “the final kiss of death” is one, two, or perhaps more than ten years away. However, the portfolio of Chagas control measures is in a very strong position, with groups such as Drugs for Neglected Disease initiative (DNDi) delivering their first-ever paediatric benznidazole regimen; the Pan American Health Organization (PAHO) and Unitaid’s five-year partnership pledge to scale-up regional and national efforts to eliminate mother-to-child transmission of Chagas disease; and the tantalising glimpse of a therapeutic vaccine candidate against Chagas.
“international collaboration is vital: when a platform from which to preach successes are encouraged, breakthroughs in treatment options for neglected tropical diseases will flourish”
Whilst all these exciting discoveries and pledges are welcomed, it’s vitally important to understand the context to which Chagas is placed. During his address at WHO World Chagas Disease Day 2022, Dr Ghebreyesus reinforced that Chagas disease “is curable with early treatment. . .but this depends on early case detection”, which is why the theme of 2022 was to tackle the Chagas fight by first “finding and reporting every case”. Chagas disease elimination as a public health problem is achievable, but this can only occur with the combination of early case detection and then the application of efficacious treatments. Additionally, international collaboration is vital: when a platform from which to preach successes are encouraged, breakthroughs in treatment options for neglected tropical diseases will flourish. This case in point is expanded in “Under the Big Tree”, where author Ellen Agler (CEO, The End Fund) exquisitely justifies, as she phrases, that treatment for NTDs are a “best buy for global health”; they are inexpensive yet yield “educational, medical, financial, and moral benefits” in return.
For many years neglected disease status, suboptimal treatment options, and growing insecticide resistances perpetuated the Chagas disease burden and has stalled any elimination campaigns, preventing that “final kiss” from becoming a reality. This being said, the preliminary success achieved with benzoxaborole compound AN15368 provides an exciting glimpse into how providing platforms to showcase neglected tropical disease breakthroughs, coupled with investment, will open the discussion to the possibility of endemic Chagas disease elimination by 2030.
For more information on Chagas Disease news and disease control programme management head to:
Chagas Coalition: https://www.coalicionchagas.org/
Uniting to Combat Neglected Tropical Diseases: https://unitingtocombatntds.org/ntds/chagas-disease/