Authors: Martha Powell, Future Science Group
Onchocerciasis, also termed river blindness, is a disease caused by the parasite Onchocerca volvulus and is the second most common cause of blindness due to infection. This neglected tropical disease is currently treated by the mass drug administration of ivermectin, with annual, community-directed treatment being carried out in high burden regions.
However, this approach has its challenges; control programs can be disrupted or delayed due to resource limitation or instability, in addition, cross-border foci make logistics challenging . The drug itself also has downfalls; ivermectin suppresses the production of microfilariae by female worms but it doesn’t target adult worms, moreover, parasites have a low susceptibility to ivermectin when onchocerciasis is co-endemic with loiasis, and finally there is potential for the emergence of resistant parasite strains .
Some of these difficulties could be addressed with new drugs or drug combinations with higher effect for the parasite – leading us to ask, what new treatments are currently in the clinical pipeline?
New compounds for mass drug administration is one strategy to tackle onchocerciasis. However, there is a very specific target-product profile; these compounds need to have treatment regimens and safety profiles suitable for large-scale distribution, in addition to appropriate efficacy profiles .
In June 2018 the US FDA approved moxidectin as the first new treatment for onchocerciasis in 20 years. Research on moxidection was initiated by the Special Programme for Research and Training in Tropical Diseases (TDR) in the late 1990s. The drug went through animal studies before clinical development was initiated in partnership with the pharmaceutical company Wyeth, the owner of moxidectin at the time.
After completing Phase I and II studies, Wyeth was acquired by Pfizer (NY, USA), discontinuing the collaboration and sparking the search for a new donor. In 2014 the Medicines Development for Global Health (MDGH; Victoria, Australia) agreed to partner with TDR to initiate Phase III trials for this drug .
The FDA approval followed priority review and was based on data from a controlled double-blind Phase III trial carried out in the Democratic Republic of Congo, Ghana and Liberia, which demonstrated that moxidectin was superior to ivermectin in suppressing microfilariae [3,4]. Although approved, moxidectin is not yet in use, as Mark Sullivan, Founder and Managing Director of MDGH, explained: “The FDA registration is a real achievement but we still have a number of steps to go until African countries can use moxidectin to accelerate elimination of this disabling disease – and we are counting on TDR and the river blindness research and control communities to work with us” .
Ivermectin and albendazole
Albendazole is an anthelmintic that has been investigated in combination with ivermectin. A Phase III trial was completed by University Hospitals Cleveland Medical Center (OH, USA) assessing this regimen in 2016, comparing ivermectin and albendazole in combination with ivermectin alone .
The trial enrolled adults between 18 and 60 years in Ghana, measuring the presence of fertile female O. volvulus worms in skin nodules before and after treatment. The results demonstrated that a single 400 mg dose of albendazole combined with ivermectin resulted in no greater reduction in macrofilaricidal activity compared to ivermectin alone. However, the findings suggested that the combination therapy suppressed embryogenesis more than the standard-of-care .
Based on this result, there is now an ongoing Phase III trial from the University Hospitals Cleveland Medical Center examining the efficacy of combination therapy versus ivermectin alone in sterilizing adult worms. This study will also investigate whether ivermectin and albendazole given twice a year is superior to ivermectin once or twice a year . This trial is larger than the previous one, at 375 participants compared with 272, and participants will be followed for 36 months following treatment. Completion is estimated to be imminent.
The compound emodepside – by contrast to ivermectin and moxidectin – is a macrofilaricide, targeting adult worms . The substance is used in veterinary medicine and preclinical studies have demonstrated its effectiveness against O. volvulus. As a result of this Astella (Tokyo, Japan) have granted Bayer (Leverkusen, Germany) the rights to develop this drug, with the hope that a success could significantly shorten the duration of treatment for onchocerciasis .
For clinical development Bayer partnered with the Drugs for Neglected Diseases initiative (DNDi; Geneva, Switzerland) in 2014 and a Phase I trial was completed in March 2017. In the trial, which comprised 79 healthy male participants, emodepside was assessed for safety, tolerability and pharmacokinetics. In addition, exploratory investigations of the bioavailability of the drug when administered as tablets and the effect of food were carried out . The DNDi reported that multiple ascending dose studies would be carried out in 2018 and the results for these are awaited .
Wolbachia organisms are crucial to the survival of adult Onchocerca, therefore the other line of investigation for new treatments is to combine antibiotics targeting Wolbachia with antifilarials such as ivermectin, causing both direct and indirect macrofilarial death.
Ivermectin and doxycycline
Doxycycline has been assessed many times as to whether its combination with ivermectin could increase the effectiveness of therapy for onchocerciasis with trials producing varied results . Moreover, a 2016 Cochrane review assessed the effectiveness of doxycycline and ivermectin against ivermectin alone for onchocerciasis, identifying three randomized controlled trials with a total of 466 participants . One study assessed visual impairment at 6 months, the other two studies assessed microfilarial load in skin at a follow-up of 21 months or longer.
When combined, the studies, which were conducted across Cameroon, Ghana and Liberia, did not have a conclusive outcome. After initial results, doxycycline treatment was recommended at a dose of 200mg/day for 6 weeks for a macrofilaricidal effect, or the same dose for 4 weeks if only worm sterility were needed . There was some suggestion that 6 weeks of doxcycine followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, the review notes this is based on ‘low quality evidence’ .
Rifapentine and moxifloxacin
Rifapentine is an antibiotic that has had questionable effectiveness. In a 2007 trial no depletion of Wolbachia or microfilariae was noted after short course rifapentine alone or in combination with azithromycin [16,17]. In addition, rifapentine was studied in a 2009 clinical trial led by the AWOL consortium (Liverpool, UK) , a trial that had several outcomes. First, it demonstrated that doxycycline alone was superior to doxycycline in combination with rifapentine when administered for 6 weeks. Moreover, both of these treatments were demonstrated to be superior to rifapentine alone . Finally, the trial suggested that a 100mg/day dose of doxycycline for 6 weeks is as effective as 200mg/day if the aim is to achieve the sterility of live female worms
Despite these findings, rifapentine and moxifloxacin appears to be a promising combination, with screening in mouse models demonstrating positive results for microfilariae depletion . A Phase II trial has now been initiated in which participants will be randomly allocated to be given one of the following four treatment regimens: moxifloxacin plus rifapentine for 14 days, moxifloxacin plus rifapentine for 7 days, doxycycline 200 mg for 4 weeks or no treatment. Following the 6-month trial period all patients treated with ivermectin . Recruitment of patients began in October 2018 and the trial is expected to run through until December 2019 .
Doxycyline, albendazole and minocycline
A randomized, open-label pilot trial published in 2017 provided other potential avenues of promise for targeting O. volvulus via Wolbachia. The study assessed five different regimens: doxycycline 200mg/day for 4 weeks, minocycline 200mg/day for 3 weeks, doxycycline 200mg/day for 4 weeks plus albendazole for 3 days, doxycycline 200mg/day for 3 weeks, and finally albendazole for 3 days .
The study, which comprised of 156 participants, followed patients for 6 months before assessing filarial load. The results confirmed what earlier studies had suggested; that 4 weeks of doxycycline was sufficient for Wolbachia depletion and the desired parasitic effects . However, the more intriguing findings were regarding albendazole and minocycline. The data suggested a synergistic effect of albendazole when combined with doxycycline, moreover, minocycline for 3 weeks appeared to have a stronger potency than the same length regimen of doxycycline. The authors do caution that these are preliminary results, and that confirmation will be required via a full randomized, controlled Phase II trial .
There are other new prospects on the horizon for the treatment of onchocerciasis. For example, in January 2019 researchers from the Liverpool School of Tropical Medicine and the University of Liverpool (both UK) have identified an optimized a compound, AWZ1066S, which is the first novel, fully synthetic and rationally designed anti-Wolbachia drug .
However, other drugs have also fallen by the wayside; flubendazole, a drug approved in 1980 for the treatment of gastrointestinal nematode infections in human and veterinary medicine, was picked back up as a potential compound for onchocerciasis, paving the way for clinical development. However, in early 2017, after assembling the preclinical data, Janssen Research and Development (NJ, USA) determined the risk–benefit ratio for flubendazole was insufficient to continue development .
Progress has been seen in the bid to eliminate onchocerciasis – but could new drugs help us get there faster? And which drugs will come to the fore?
Let us know your thoughts in the comments below.
You might also like:
- Kussel AC. Research for new drugs for elimination of onchocerciasis in Africa. J. Parisitol. Drugs Drug Resist. 6(3), 272–286 (2016).
- Moxidection – a new drug for onchocerciasis. www.who.int/tdr/research/ntd/onchocerciasis/moxidectin/en/ (Accessed on 28th January 2019).
- Opoku N, Bakajika DK, Kanza EM et al. Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind Phase 3 trial. The Lancet. 392(10154), 1207–1216 (2018).
- Medicines Development Limited. Study evaluating orally administered moxidectin in subjects with Onchocerca volvulus https://clinicaltrials.gov/ct2/show/NCT00300768 NLM identifier: NCT00300768
- First new treatment for river blindness approved by U.S. FDA in 20 years. www.who.int/tdr/news/2018/moxidectin-approved-as-treatment-for-river-blindness/en/ (Accessed on 28th January 2019).
- University Hospitals Cleveland Medical Center. IVM alone vs ALB and IVM against onchocerciasis. https://clinicaltrials.gov/ct2/show/NCT03238131 NLM identifier: NCT03238131
- University Hospitals Cleveland Medical Center.Comparison of ivermectin alone with albendazole (ALB) plus ivermectin (IVM) in their efficacy against onchocerciasis. https://ichgcp.net/clinical-trials-registry/NCT03238131 NLM identifier: NCT03238131
- University Hospitals Cleveland Medical Center. Efficacy of ivermectin and albendazole against onchocerciasis in the Volta Region, Ghana. https://clinicaltrials.gov/ct2/show/NCT02078024 NLM identifier: NCT02078024
- Bayer and DNDi sign first agreement to develop an innovative oral treatment for human river blindness. www.dndi.org/2014/media-centre/press-releases/pr-bayer-filaria/ (Accessed on 28th January 2019).
- River blindness. http://pharma.bayer.com/en/commitment-responsibility/neglected-diseases/river-blindness/ (Accessed on 28th January 2019).
- Drugs for Neglected Diseases. First-in-man trial of empepside (BAY 44-4400). https://clinicaltrials.gov/ct2/show/NCT02661178 NLM identifier: NCT02661178
- Portfolio: emodepside.www.dndi.org/diseases-projects/portfolio/emodepside/ (Accessed on 28th January 2019).
- Klarmann-Schutz U. Current research landscape in onchocerciasis. Clinical research in onchocerciasis. Onchocerciasis research network and DNDi stakeholder event. Kampala, Uganda, 3–4 October 2018.
- Abegunde AT, Ahuja RM, Okafor NJ. Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis. Cochrane Database Syst. Rev. doi:10.1002/14651858.CD011146.pub2 (2016).
- Hoerauf A. Filariasis: new drugs and new opportunities for lymphatic filariasis and onchocerciasis. Opin. Infect. Dis. 21(6), 673–681 (2008).
- Richars FO Jr, Amann J, Arana B et al. No depletion of Wolbachia from Onchocerca volvulus after a short course of rifampin and/or azithromycin. J. Trop. Med. Hug. 77(5), 878–882 (2007).
- Centers for Disease Control and Prevention. Clinical trial of rifampin and azithromycin for the treatment of river blindness. https://clinicaltrials.gov/ct2/show/NCT00127504 NLM identifier: NCT00127504
- University of Bonn. Comparison of doxycycline alone vs doxycycline plus rifampicin in their efficacy against onchocerciasis. isrctn.com/ISRCTN68861628 (Accessed on 28th January 2019).
- University Hospital Bonn. The efficacy of rifapentine plus moxifloxacin against onchocerciasis: a randomized, open label pilot trial. http://www.isrctn.com/ISRCTN43697583 (Accessed on 28th January 2019).
- Klarmann-Schutz U, Specht S, Debrah AY et al. Comparison of doxycycline, minocycline, doxycycline plus albendazole and albendazole alone in their efficacy against onchocerciasis in a randomized, open-label, pilot trial. PLoS Negl. Trop. Dis. 11(1), e0005156 (2017).
- Imperial College London.Elephantiasis and river blindness could be eliminated faster with new molecule. imperial.ac.uk/news/189806/elephantiasis-river-blindness-could-eliminated-faster/ (Accessed on 28th January 2019).
- Geary TG, Mackenzie CD, Silber SA. Flubendazole as a macrofilaricide: History and background. PLoS Negl. Trop. Dis. 13(1): e0006436 (2019).