Adding “Filaricide” to the Gleevec Portfolio

(See the major article by O'Connell et al on pages 684–93.) Although great strides have been made in reducing the incidence and public health impacts of many parasitic infections in the past 2 decades, much work needs to be done to accelerate achievement of the Millennium Development Goals as interpreted in the 2012 London Declaration, a gathering of leaders from governments, nongovernmental institutions and major pharmaceutical companies that calls for the elimination of a number of helminth infections of humans by 2020 [1, 2]. The targeted infections include many so-called neglected tropical diseases, caused primarily by nematodes. Of particular interest are filariases, systemic diseases caused by parasitic nematodes that have been targeted for control for several decades; these diseases include onchocerciasis (“river blindness”), due to Onchocerca volvulus, and lymphatic filariasis (LF, or elephantiasis), caused primarily by Wuchereria bancrofti [3]. These filariae infect >100 000 000 persons, with a billion or so residing in areas at risk for transmission. They are vector-borne infections, arising from the transfer of infectious larvae to humans by the bite of black flies in the genus Simulium (onchocerciasis) or by a variety of mosquito species (LF). These filariases are characterized by the presence of adult parasites residing in nodules, some palpable under the dermis and some deeper (O. volvulus) or in lymphatic vessels (LF species). Fertilized female parasites release thousands of larvae (microfilariae [mf]) that inhabit the skin (onchocerciasis) or the blood (LF), where they can be ingested by an appropriate arthropod vector, undergo additional development, and be reintroduced to a new host in a subsequent bite. Human filariases have been subjected to control campaigns for several decades. The campaign against onchocerciasis, originally based on vector control, expanded in 1987 to rely primarily on annual or semiannual treatment with ivermectin, a drug originally developed for veterinary use by Merck in the 1980s [4–6]. Ivermectin has been donated by Merck for human use as a yearly or twice-yearly oral dose that removes mf from the skin over the course of a few days and prevents the release of new mf by adult female parasites for ≥6 months. Because the mf stage is responsible for the pathology of onchocerciasis, this regimen leads to a marked reduction in disease in treated patients and cessation of transmission of all filariases in treated areas. The implementation of this strategy in mass drug administration (MDA) campaigns has led to remarkable success in the control of onchocerciasis in many areas of the world, including the nearly complete eradication of the parasite from foci in South and Central America [4–10]. Campaigns against LF, which rely on yearly or semiannual MDA programs using diethylcarbamazine plus albendazole or ivermectin plus albendazole in onchocerciasis-endemic regions, where diethylcarbamazine is contraindicated, have also made great strides toward elimination in many areas of the world [11]. Although LF elimination programs are thought to have the potential for success based on current MDA programs [12], several factors continue to make elimination of onchocerciasis from Africa via a microfilaricide-only strategy a challenging proposition, especially in the time frame posed by the Millennium Development Goals [4, 5]. The least tractable problem is the long life span of the adult parasites in humans; the limits are imprecisely known, but it is clear that it is at least a decade. Because ivermectin MDA campaigns do not have acute lethal effects on the adults, such control programs must be long term (≥10 years). Another important fact is that onchocerciasis overlaps geographically with infection by another filariid parasite, Loa loa [4, 5]. Individuals bearing high loads of L. loa mf (eg, >30 000/mL) are at risk for serious adverse central nervous system events after ivermectin administration, and MDA campaigns have been accordingly restrained in coendemic areas. Finally, as control programs succeed, it becomes progressively more expensive to extend yearly MDA interventions to areas with low incidence of infection. The lowest population incidence that can safely be assumed to present no risk of reemergence is not known; data from Ecuador indicate that migration of 4 persons to a cleared or naive area that harbors a highly competent Simulium species can lead to the establishment of a new focus (C. D. M., unpublished observations). These factors conspire to make development of a macrofilaricide for onchocerciasis a matter of considerable urgency. These considerations have led to the conclusion that elimination of onchocerciasis from Africa would be greatly facilitated if a safe and effective macrofilaricidal compound could be rapidly introduced into the equation [5, 13–17]. The macrofilaricidal activity of extended regimens of doxycycline, which targets the symbiotic Wolbachia bacteria that are essential for viability of these filarial pathogens, is well known [18] and has proved useful in the field. However, the extended course needed (approximately 4 weeks) leaves room for the introduction of other drugs that achieve efficacy in shorter regimens that are more compatible with use in the field, especially in remote areas. This is the need addressed in a new study by O'Connell et al in this issue of the Journal of Infectious Diseases [19], which reports for the first time that the well-known Abl kinase inhibitor imatinib (Gleevec) and 2 analogues have antifilarial activity in culture at concentrations in the range of those attained during treatment of patients with cancer. The discovery of anthelmintics in general and macrofilaricides in particular is difficult. Filarial nematodes cannot be continuously maintained in culture, and neither O. volvulus nor W. bancrofti infects common laboratory model hosts, nor can they be acquired for phenotypic screens. Surrogate parasite species in model hosts are therefore needed for drug screening, and so few clinically validated macrofilaricides are available that it has been difficult to optimize these models. Given this background, random screening of chemical libraries for new macrofilaricides faces daunting odds for success. Recent emphasis has instead been placed on repurposing compounds with known mechanisms of activity for use in chemotherapy of filarial and other parasitic infections [15, 20–23]. Compounds to be evaluated in such highly targeted screening programs may come from collections of already-approved drugs screened in phenotypic assays or from bioinformatics-based approaches in which druggable parasite proteins are screened against collections of chemicals that act on homologous proteins in humans; these screens preferably include compounds that have been approved or have accumulated considerable preclinical information and entered advanced development in a company before being dropped (not for safety concerns, obviously). The enormous advantage of this strategy is that the path to registration for use in filariases can be very short, minimizing the risk of additional investment and limiting the time to introduction to the field. Kinases became of great interest as drug targets with the discovery and development of imatinib for cancer chemotherapy. Early skepticism that medicinal chemistry could not distinguish among adenosine triphosphate–binding domains of kinases sufficiently well to generate selective inhibitors was disproven, and efforts to expand the library of mammalian kinase inhibitors expanded accordingly. The realization that parasites, including parasitic helminths, express homologues of these kinases motivated O'Connell and colleagues [19] to assay several clinically approved inhibitors of Abl kinases (imatinib, dasatinib, and nilotinib) for activity in culture against the filarial nematode Brugia malayi (which, in addition to being a valuable laboratory model, does infect humans and is a cause of LF). Their results are highly encouraging: adult parasites can be killed in culture by concentrations of these drugs that could be achieved during high-dose therapy for cancer [19]. These results have been expanded in subsequent work showing that imatinib can cause detectable reductions in motility of adult B. malayi over the course of 24 hours [24]. These results are bolstered by work on a phylogenetically distant parasite, the trematode Schistosoma mansoni, which establishes chronic infections in the mesenteric vasculature. Imatinib also has profound effects on the shape and viability of this parasite [25, 26], albeit with slightly less potency than observed by O'Connell et al [19]. Importantly, follow-up studies from the same group provided convincing evidence that these effects are attributable to action through the Abl kinase homologue [27]. Although repurposing of drugs is a very important route to the discovery of new treatments for neglected diseases, the first step should be to confirm that the activity is indeed mediated through action at the presumed (homologous) target and not through nonspecific or off-target effects, especially at concentrations >10 µmol/L, at which nonspecific actions become increasingly likely. Intriguingly, imatinib also has effects on the free-living nematode Caenorhabditis elegans [28]. The Abl kinase homologue in this model organism acts in an antiapoptotic pathway; inhibition of Abl kinase activity by RNA interference leads to increased apoptosis after radiation exposure, an effect mediated by p53. This effect is phenocopied by exposure to imatinib. Imatinib is considerably more potent in C. elegans than in B. malayi or S. mansoni, with a median effective concentration of 20 nmol/L. Data on viability of C. elegans were not included in this report, and it is possible that the pharmacology of imatinib differs in different physiological contexts. Indeed, O'Connell et al [19] show that the relative abundance of the Abl kinase homologue in the life stages of B. malayi is not correlated with potency of imatinib. Additional studies on B. malayi could validate that the effects of imatinib on viability are mediated by action on the Abl kinase homologue as supporting data for understanding the results of clinical trials in humans. Where next with imatinib and filariases? Obtaining preclinical efficacy data in an animal model could prove challenging; imatinib failed to show efficacy in a mouse model of schistosomiasis [29], traced to the inhibitory effects of albumin and α1-acid glycoprotein, at least in part due to the drug-binding properties of these proteins. The absence of preclinical efficacy data would not preclude testing imatinib in human cases, but clinical trials are, themselves, quite challenging to organize. We lack validated biomarkers that are highly correlated with adult worm burden for macrofilaricidal drug efficacy trials, and access to the numbers of patients needed to conduct dose-ranging efficacy studies is also limited. Perhaps the drug could be used to treat immigrants or infected travelers returning to the United States or other centers, monitoring adulticidal efficacy by monitoring mf counts after treatment, but such a choice would have to be made knowing that a 4-week regimen of doxycycline has already been shown to be safe and effective for this indication. For field use, it seems likely that the cost of imatinib may limit wide distribution. In addition, its more potent activity against mf (at least in culture) suggests that its use in loiasis-endemic regions would be restricted. Nonetheless, should a short course of imatinib be shown to be highly efficacious against O. volvulus in patients, it could have real value in treating end-stage cases in controlled areas or cases in areas with low incidence or where control is impeded by unrest or disaster. This strategy will require adoption of a diagnostic test of sufficient quality and value to enable a “test and treat” rather than an MDA approach. It is encouraging that research is now being devoted to such assays, and it is to be hoped that progress will be rapid in this regard. Of course, operational and management support will be of critical importance in introducing new strategies, including a macrofilaricide, to achieve the goals of control and elimination programs [5, 17]. It is important to place imatinib in perspective with regard to other late-stage repurposing efforts. Focused screening of a library of approved drugs identified auranofin as a potential lead for the treatment of filarial infections (as well as other human parasitoses) [30]. This drug is sometimes used for the treatment of arthritis and is believed to act with some selectivity on antioxidant systems, which are found in some helminth and protozoan parasites [30]. Clinical trials are planned with auranofin for onchocerciasis [31], the results of which may influence prospects for trials of imatinib. Similarly, flubendazole is undergoing preclinical development by Johnson & Johnson [32]; this drug has potent and highly efficacious macrofilaricidal activity when given parenterally; the repurposing effort is focused on developing a formulation that can provide high oral bioavailability and efficacy. At least when dosed parenterally, flubendazole does not exhibit microfilaricidal activity, making it an appealing possibility for use in loiasis regions [33]. Finally, the Drugs for Neglected Diseases initiative, in partnership with Bayer, the United States Agency for International Development, and the Bill and Melinda Gates Foundation, has identified the veterinary anthelmintic emodepside as a candidate for repurposing for human use in filariases [34, 35]. This drug has very potent activity against a variety of filariae in culture and in animal models but is also microfilaricidal. None of these candidates should be considered a “magic bullet” for the treatment and elimination of human filariases, but each has undeniable potential to contribute to the resolution of these diseases. Indeed, it should be hoped that we can amass an arsenal of drugs that can be used with specific success in the many areas and situations that challenge the eradication of these pathogens from the world [17]. The report by O'Connell et al [19] encourages us to search more broadly for near-at-hand candidates that can quickly be developed to enable achievement of the ambitious goals delineated in the Millennium Development Goals. It is convincing proof-of-concept for the repurposing strategy, and the community eagerly awaits progress in its development. Potential conflict of interest. Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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