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European Biopharmaceutical Review

Biting Back

The fight against malaria has gained recent prominence with the announcement of the partial success of the RTS,S vaccine (1). This is a great step forward in disease prevention, particularly for the most vulnerable populations, and it has raised hopes once again that this disease is both curable and preventable.

The global strategy to tackle the disease has been extremely successful, as evidenced by a 40% reduction in mortality over the last 10-15 years (2). However, in excess of 500,000 malaria deaths still occur, of which nearly 90% are in sub-Saharan Africa, in children aged five and under (78% of the total). Despite the advances, malaria is still on the global health agenda, as indicated through endorsement by the World Health Assembly’s Global Technical Strategy for (eradication of) Malaria 2016-2030 (3).

This successful approach has been – and continues to be – multi-faceted, and includes vector (mosquito) control, vaccine development and drug treatment. But there are some significant challenges ahead. Vector control is becoming less effective as mosquitoes develop resistance to the most commonly used insecticides, and vaccines – potentially lifesaving for children through a reduction in the risk of developing severe malaria – are still in development and may not confer full protection. Effective drug treatment remains the cornerstone of immediate malaria control, and considerable advances have been made in the world of small molecule drug development in the last five years, although resistance is still a major concern.

Development Challenges


The predominant hurdle the malaria community faces continues to be avoidance of the selection of resistance by Plasmodium. The emergence of resistance has long since rendered chloroquine- and sulfadoxinepyrimethamine- based treatments less effective against P. falciparum, which is responsible for the majority of deaths. Somewhat worryingly, recent evidence indicates the emergence of resistance against artemisinin-combination theraphies (ACT) in Mekong Delta countries, such as Cambodia, Laos, Myanmar, Vietnam and Thailand (4). This is potentially catastrophic and threatens to reverse the advances made globally in combating malaria over recent decades.

Combination therapy is the most logical way forward in developing new treatments, but traditional drug discovery and development routes to the clinic mean this will be very challenging, both scientifically and economically. Normally, single agent drugs are developed in isolation to address the disease and then added on to, or replace, existing combination treatments. This will not solve the long-term objective of avoiding resistance if monotherapy treatments continue to be developed in isolation.

Desirable Characteristics

The target profile for a new drug in any existing or de novo combination therapy will be to have a rapid killing profile (TCP1) to replace the endoperoxide combination component of the ACT, as well as a long-lasting effect (TCP2) (5). A new mode of action should be a prerequisite and, potentially, provide additional efficacy against multiple stages of the parasite lifecycle – specifically gametocytocidal or hypnozoiticidal activity (TCP3). This is still the expectation of the ideal single agent, but the strategy to develop combinations from the outset means that partner drugs could have very different characteristics, thereby providing this coverage of target profiles. Ideally, each partner drug would operate via a different mode of action but contribute to an overall profile having these various characteristics, which would be key to avoiding the emergence of resistance.

From a drug discovery perspective, lead molecules (or hits) have been identified using high-throughput phenotypic screens with some considerable success – and a number of potential drugs are being developed as a consequence (6). A target-based approach is still appropriate, although there is a lack of well-validated targets upon which to base any screens. The accessibility of omics technology will be vital to provide greater understanding of targets that will enable the discovery of next-generation anti-malarial drugs. Progress has been made across industry and academic collaborations to augment such research efforts, and this has been facilitated through access to the vast compound libraries within companies. One such library was made available to the scientific community in the hope that this would encourage research groups to pick up on and develop series based on some of the 13,000+ identified hits (6).

To assist in this global exercise, a number of assays have been developed in parallel that enable the characteristics of a hit or series across the whole parasite lifecycle to be assessed. Generation of this data will be key to selecting the right drugs as part of any combination moving forward.

Treatment Profile


Current gold-standard treatments are based on ACT regimens, so the focus over the coming years is, at the very least, to replace the artemisinin component to counteract the emergence of resistance. However, in reality, the entire combination needs to be replaced; therefore, any new single agent drug must have an entirely novel mode of action and would need to be developed as de novo combinations – and not as single agents for add-on or replacement in existing combination treatments where resistance may already be an issue. This is the only way to avoid the emergence of resistance for future generations.

The ultimate goal is to have a single dose combination cure that provides symptomatic relief quickly, and gives total parasite cidality or clearance within a few days. Furthermore, the combination should provide a level of transmission blocking potential and a degree of prophylaxis. In order to achieve this, single agents will still need to be progressed far enough in the preclinical and clinical area to demonstrate their anti-malarial properties, but pragmatically, the earlier evaluation of potential combinations will be of paramount importance.

Preclinical Assets

The increasing portfolio of potential assets in early preclinical stages provides the community with a new set of drugs to evaluate. In the normal course of drug development, this would require considerable economic resources but, in recent years, a human challenge model has been developed that avoids having to conduct a full Phase 1 and 2a clinical trial (7).

This challenge model offers the field a great opportunity, and enables novel assets and mode of action to be assessed rapidly for clinical efficacy against low-level parasitemia in healthy volunteers. The readout has enabled a number of potential drugs to be progressed further with significantly more confidence into pivotal Phase 2 trials.

Funding Research

Funding for malaria research and prevention has increased dramatically over the last dozen years, resulting in a concomitant 25% fall in new cases and an estimated 40% decrease in number of deaths.

Ongoing drug research efforts across the globe are sponsored mainly through governmental and philanthropic routes and have led recently to the progression of new small molecule drugs that are being assessed in early clinical trials. The cost of conducting trials is far greater than preclinical testing, so one of the greatest economic challenges is to maintain funding for basic malaria discovery and research, while enabling continued progression of early clinical assets.

Considering the global impact of such a disease, the level of research funding is perhaps disproportionate compared to other therapeutic areas offering a greater economic return on investment. The reality is that any medicine developed de novo still incurs similar costs, as it has to meet stringent criteria in terms of risk/benefit, safety and clinical efficacy and – particularly in neglected diseases – affordability.

Winning Support

In uncertain economic times, pharmaceutical companies have had to reduce their efforts in neglected conditions. The knock-on effect has been to reduce opportunities for scientists to see their drug discovery efforts mature through early-stage preclinical and clinical development. The onus is left on non-governmental organisations and funding bodies to coordinate very complex collaborative agreements with the few industrial partners that remain engaged, to bring some industrial rigour and delivery to assets that are progressed.

There has been a huge desire to fund malaria research, but there is, unfortunately, an ever-decreasing field of suitable industry partners. The Bill and Melinda Gates Foundation has been at the forefront of a number of initiatives through support of various bodies such as the Global Fund, Malaria for Medicines Venture (MMV) and the WHO via RollBack Malaria. There are also other considerable funding streams, including government contributions to the Global Fund, and grants via national research councils and charitable agencies, like the Wellcome Trust.

The remit of such organisations is to eradicate the disease, and much of the money made available is for a wide range of disease prevention and treatment initiatives. In the area of drug R&D of new medicines (other than vaccines), MMV plays a crucial role coordinating the global emerging drug portfolio through its collaborative network of industrial and academic partners.

What Next?


Irrespective of the funding challenges, drugs for the next generation of new anti-malarial treatments with novel mode of action seem to have arrived. These will not only be replacements for artemisinin itself, but also form the basis of de novo combination treatments, which will be needed for disease eradication through complete avoidance of the emergence of resistance.

The malaria drug discovery community has available some good molecules to develop, uniquely translational animal models of the disease, and access to a fairly robust early clinical challenge model. These afford the opportunity to evaluate combinations in advance of costly and complex clinical trials.

Malaria inflicts a huge economic burden on African countries; thus, any approach will require a sustained commitment – not only in terms of R&D, but also through the implementation of control strategies. While it is a corporate responsibility to use expertise to bring forward new medicines, it should be remembered that these developing nations are important emerging markets in the long-term. There needs to be continued high-level support to protect society and global health, as well as all the children that malaria kills.

References


1. Schwenk RJ and Richie TL, Protective immunity to pre-erythrocytic stage malaria, Trends in Parasitol 27: pp306-314, 2011
2. Visit: www.rollbackmalaria.org
3. WHO Malaria, Report by the Secretariat, Draft global technical strategy: Post 2015, 2015
4. Dondorp AM et al, Artemisinin resistance in Plasmodium falciparum malaria, New Engl J Med 361: pp455-467, 2009
5. Burrows JN et al, TCP1, 2 and 3 relate to target compound profile characteristics, Malaria Journal 12: p187, 2013
6. Gamo FJ et al, Thousands of chemical starting points for antimalarial lead identification, Nature 465(7,296): pp305-310, 2010
7. McCarthy JS et al, A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs, PLoS One 6(8): e21914, 2011

Note
The views expressed herein are the author’s alone and should not be attributed to the company or its clients.


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John Haselden is Vice President and Head of GlaxoSmithKline’s (GSK’s) malaria discovery group within the Diseases of the Developing World Division, based in Spain. Previously, he was Head of Investigative Preclinical Toxicology at the Drug Safety department in the UK. John completed his PhD in Biochemistry at the University of London in 1992, and has since been working for GSK and its heritage companies. He has degrees in Pharmacology and Toxicology, and is a visiting professor at Imperial College London, UK.
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