Medicines for malaria. elimination/eradication

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Dennis Lynch
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Medicines for malaria 5 elimination/eradication Populating the pipeline With our sights firmly set on malaria elimination/ eradication, MMV s strategy has evolved.

1 Medicines for malaria 5 elimination/eradication Populating the pipeline With our sights firmly set on malaria elimination/ eradication, MMV s strategy has evolved. Our discovery work is focused on the need for novel medicines able to treat relapsing (Plasmodium vivax) malaria and block transmission. Yet at the same time we must stay a step ahead of the parasite; history tells us it is incredibly adaptable, having become resistant to each medicine sent to assail it. With these goals in mind MMV has worked with six pharma companies (GSK, Sanofi, Novartis, Pfizer, Genzyme and AstraZeneca) and numerous academic institutions (e.g. University of Cape Town (UCT), Dundee University and St Jude Children s Research Hospital) to screen more than six million compounds. This has resulted in over 25,000 promising molecules to populate the pipeline. Furthermore, in a bid to catalyse malaria and neglected disease drug discovery, MMV has launched a Malaria Box with 400 structurally diverse available compounds from this screening campaign. The MMV Malaria Box is being made to available researchers at no cost (page 35). Prof. Kelly Chibale Founder and Director of the University of Cape Town s Drug Discovery and Development Centre (H3-D), South Africa. Prof. Chibale talks about his work to discover and optimize new compounds to help populate MMV s antimalarial drug pipeline. What has been achieved to date? We have screened 40,000 small molecules from a commercial library (BioFocus). Compounds that killed the parasite and possessed the most promising properties were selected. The initial goal was to demonstrate pharmacological proof-of-concept by testing these select compounds in a laboratory model of malaria. We are now working on a series that has shown activity in a laboratory model of malaria. A single (low) oral dose of one of the front-runner compounds provided a complete cure in the model and shows potential as a clinical candidate. This is an outstanding result because clinically used drugs such as chloroquine, the artemisinins and mefloquine require multiple doses to achieve the same cure. What does South Africa bring to the table? South Africa is arguably the most technologically and economically advanced country on the African continent. We have a wealth of talent in various scientific disciplines relevant to drug discovery and a strong reputation in basic science and clinical studies for infectious diseases. The country really has a lot to offer. However, despite a number of drug discovery programmes being initiated in various institutions and organizations in South Africa in the last 5 years or so, the serious lack of a critical mass of individuals with pharmaceutical industry experience in key areas such as medicinal chemistry and drug metabolism disciplines, threatens to render current efforts unproductive. This issue is being addressed through our centre, H3-D, where we have embarked on recruiting experienced personnel from the pharmaceutical industry. What is the advantage of working with MMV on a project of this kind? MMV has a huge network of partners, which is partly what makes this project unique. We can integrate medicinal chemistry from UCT with preclinical pharmacology and drug metabolism from Monash University, Australia, and parasitology expertise from Swiss TPH. We can then screen a huge volume of compounds with engineering technology from Eskitis (Griffith University, page 33). This volume would just not have been possible a few years ago. Medicinal chemistry is about understanding what the liabilities are and how you can use chemistry to overcome them. This expert multicentre team really provides all the information that a medicinal chemist needs to determine which molecules to take forward and to move quickly. The MMV project has also been critical to building infrastructure at UCT and we are now on our way towards being able to conduct integrated antimalarial drug discovery with parasitology, medicinal chemistry and drug metabolism all at UCT. 28

Variation in parasite density throughout the lifecycle The malaria parasite is transmitted to man ( ) by a female anopheles mosquito when she takes a blood meal to feed her young.

2 Variation in parasite density throughout the lifecycle The malaria parasite is transmitted to man ( ) by a female anopheles mosquito when she takes a blood meal to feed her young. The parasites are rapidly taken up into the cells of the liver where they become schizonts (A), multiply and go on to invade blood cells. Current medicines mostly kill malaria parasites at this blood-stage, as this is when the parasite is at its most abundant (up to parasites in one person; B) and the stage that leads to clinical symptoms of malaria. Some of the blood-stage parasites develop into male and female gametocytes (see dotted line and C) which are taken up into the mosquito gut during her blood meal. In the gut these gametocytes become gametes and fuse. This is the sexual stage of the lifecycle. To eradicate malaria we also need medicines that can stop the parasite at this stage (C to F) thereby stopping transmission. This stage is also the most efficient to target as this is where the parasite density is as low as 10. Asexual stage (human blood cell) Asexual stage (human liver cell) Transmission to man Transmission to man Transmission to mosquito A Liver-stage schizonts B Blood-stage schizonts C Gametocytes D Micro- and macro-gametocytes E Ookinetes F Oocysts G Sporozoites Sexual stage (mosquito gut) Where do antimalarials act in the lifecycle? To support the elimination and eradication strategy, MMV and partners (Imperial College London, Genomics This research was not only able to tell us which in-development molecules have activity where, but by Institute of the Novartis Research screening antimalarials that are Foundation, Swiss Tropical and Public Health Institute, University of Basel and Scripps Research Institute) have currently in use, it was also able to validate screening platforms for the future. This information will be criticompleted the first comparative cal in deciding which molecules analysis of all currently available and in-development antimalarials assessing which stages they target in the parasite s lifecycle. 1 could become next-generation antimalarials and it provides us with the tools to discover further promising molecules. 1 Delves M et al. The activities of current antimalarial drugs on the life cycle stages of Plasmodium: a comparative study with human and rodent parasites. PLoS Med. (2):e (2012). 29

Stopping the relapse... We need... new medicines that are easier to take and more efficacious at eliminating the P. vivax parasite from the liver for all patients.

3 Stopping the relapse... We need... new medicines that are easier to take and more efficacious at eliminating the P. vivax parasite from the liver for all patients. Tafenoquine GlaxoSmithKline, UK Phase IIb/III Project Leader: Dr JP Kleim, GlaxoSmithKline MMV Project Director: Dr Jörg Möhrle Dr Alejandro Llanos Universidad Peruana Cayetano Heredia, Lima, Principal Investigator at the Peruvian trial site to determine the safety and efficacy of tafenoquine. Dr Llanos talks about the trial and why there is a need for new medicines to treat relapsing malaria in Peru. The long-held belief that Plasmodium vivax is benign in comparison to Plasmodium falciparum is starting to change. In addition, the dormant liverstage form (hypnozoite) of P. vivax, which can reactivate without warning leading to the feverish symptoms of malaria, remains a challenge to treat. The only approved medicine able to eliminate hypnozoites and thus provide a radical cure for relapsing P. vivax malaria is primaquine. In practice primaquine is not always efficacious. The reasons for this are not entirely clear, however, the treatment course is 14 days and so compliance is often difficult to achieve. Additionally, it is associated with potentially fatal side effects in patients who are deficient in the enzyme glucose 6-phosphate dehydrogenase (G6PD). Tafenoquine, the lead contender to replace primaquine, is currently in clinical development with MMV and GlaxoSmithKline (GSK). Studies show tafenoquine could be taken as a 1-day treatment course for liver-stage malaria a significant improvement on primaquine s 14-day course. However, the safety of tafenoquine in G6PD-deficient patients is being assessed because it comes from the same chemical family as primaquine. Trials are also underway to determine the safety and efficacy of tafenoquine for the treatment of P. vivax malaria in non- G6PD-deficient patients. This study commenced in 2011 in Peru and Thailand. What is the prevalence of P. vivax in Peru? In Peru 90% of malaria is caused by P. vivax, with approximately 22,000 cases occurring each year. Clinically speaking, we are only just beginning to understand the differences between P. falciparum and P. vivax and to make the distinction. Previously, we assumed that patients with severe symptoms were suffering from P. falciparum, but in my clinic at least eight of the last 10 patients with symptoms of severe malaria were found to have P. vivax. In fact, more than half the malaria patients we see actually have both. How is P. vivax malaria managed in Peru in terms of diagnosis and treatment? Malaria diagnosis both for P. vivax and P. falciparum is made based on clinical symptoms; in facilities with a laboratory a smear examination is conducted to identify the parasite. When a patient is diagnosed with P. vivax malaria, chloroquine plus primaquine is administered. For P. falciparum the treatment is artesunate plus mefloquine for 3 days. How can the management of P. vivax malaria be improved in Peru? With the current primaquine plus chloroquine regimen we eliminate relapse in approximately 80% of cases. In my view that is not adequate. Moreover, this varies with geography as drug resistance appears to be emerging in some areas. This could be a big problem for us in Peru if changes in climate lead to an increase in mosquitoes and therefore in malaria transmission. Additionally, the current regimen in Peru is long, which makes it difficult to ensure adherence. What we need are new medicines that are easier to take and more efficacious at eliminating the P. vivax parasite from the liver for all patients. How is the trial progressing? The trial is going well. We have already enrolled the majority of patients required by the study, but will continue to recruit for the next few months. We are aiming to determine the correct dose of tafenoquine to move to Phase III. It stands a good chance of being a great alternative to primaquine, but of course we need to wait to see the results. 30

We think the efficacy further research on relapsing of primaquine very much depends on P. vivax malaria and its treatment.

4 Colonel Bagus Tjahjono avoid using it in patients with this Indonesian Army Health enzyme deficiency. The other problem Command, Jakarta, is is that primaquine is our only tool Co-Investigator of the trials. against relapse and we don t fully He explains the need for understand it. We think the efficacy further research on relapsing of primaquine very much depends on P. vivax malaria and its treatment. the partner drug used with it and this is why we are running the current trial. Can P. vivax cause severe malaria and be fatal? How can you be sure that part- Recent work certainly suggests that it icipants in the trial are suffering can be fatal. More evidence is need- from a malaria relapse and not ed, but certainly I believe the long- just a new malaria infection? Although primaquine is the only approved medicine for radical cure of relapsing held consensus of the disease being benign is incorrect and probably quite dangerous to patients. The participants in the trial are all soldiers who have returned with malaria from their duties in Papua Province and malaria, very little is known about are treated back at the base in Luma- how well it works in combination How is P. vivax malaria jang, East Java. As there is very little The trial is almost complete. Our results offer compelling evidence affirming the safety and efficacy of primaquine when used with DHA-PQP for radical cure. with other medicines that treat the blood-stage infection. In order to maximize its effective use until a suitable alternative can be developed, Oxford University, Eijkman Institute and MMV have joined forces to run a series of trials. The first trial compared primaquine + dihydroartemisinin-piperaquine (Eurartesim ) with primaquine + quinine and with artesunate. The next trial will look at the efficacy of primaquine + pyronaridineartesunate (Pyramax ) compared to primaquine + Eurartesim and to artesunate alone. The efficacy of OZ439 against the relapse will likely also be investigated. managed in Indonesia in terms of diagnosis and treatment? Is there a difference compared to P. falciparum malaria? Most malaria in Indonesia is diagnosed based on symptoms initially and then confirmed with microscopy diagnosis. No distinction is usually made between P. falciparum and P. vivax. The treatment is DHA-PQP the government recommended first-line treatment for uncomplicated malaria. In the cases where P. vivax malaria can be confirmed, the recommendation is to also treat with 14 days of primaquine. What are the flaws in the way P. vivax malaria is currently managed in Indonesia? One of the main issues is the lack of malaria transmission in this region we can be sure that any further malarial episode is a relapse and not a completely new infection. How is the trial progressing and what have you learnt about primaquine? The trial is almost complete. Our results offer compelling evidence affirming the safety and efficacy of primaquine when used with DHA-PQP for radical cure of P. vivax malaria in eastern Indonesia. I am very pleased with these results and proud of my soldiers and commanders for their enthusiastic support. access to laboratory diagnosis and the lack of a rapid test to diagnose both P. vivax and P. falciparum malaria and G6PD deficiency. With improved diagnosis of G6PD deficiency we would be able to use primaquine safely and Even with further data on primaquine and the development of tafenoquine there Primate Research Centre in the Netherlands, we have identified liver forms of the monkey para- will remain a need for new anti- site P. cynomolgi, believed to be relapse medicines. Research to hypnozoites. This breakthrough discover new medicines has been enables us to identify a new che- hampered by the lack of a suitable mical series with activity against Fluorescent-stained P. cynomolgi liver forms model of the hypnozoite to test new compounds. In collaboration with scientists at the Biomedical the hypnozoite, bringing us a step closer to the next cure for relapsing malaria. 31

5 Fluorescent-stained late-stage gametocytes Green/blue: gametocyte Red: mitochondria 32

6 Blocking transmission In an infected patient a small proportion of parasites form gametocytes, the sexual form of the parasite. It is these gametocytes, taken up by the mosquito when she feeds, that ultimately allow the parasite to infect the next person. In collaboration with partners (Imperial College London, GSK, Radboud University, the Netherlands and Griffith University, Australia) MMV has developed a range of tools to screen and identify compounds with activity against gametocytes. These tools have enabled us to identify a number of interesting molecules that not only target the blood stage of the lifecycle but the sexual stages as well. To ensure the pipeline remains populated the hunt is on to discover further compounds with such dual activity. The screening technology we use is... incredibly information rich... It s the difference between having a tractor and a Ferrari! Pr Prof. Vicky Avery Chief Investigator & Head of Discovery Biology, Griffith University, Australia. Prof. Avery talks about her work to develop a new late-stage gametocyte assay to identify compounds that could block the transmission of malaria. Prof. Avery operating the Opera High Content Screening System How does the assay work? The assay is based on imaging technology. We use 384-well microtiter plates; each well contains cultured gametocytes which express fluorescent proteins. A green protein identifies the parasite, while red tells us whether it s alive. We can determine that the parasite is a late-stage gametocyte by its shape. We then add compounds to the wells and assess their effect on the cells by studying changes in the parasite florescence. What is different about your approach? The screening technology we use is based on state-of-the-art imaging technology and so is incredibly information-rich. We are looking at the whole parasite in one go rather than a simple target, as with other screening technology. It s the difference between having a tractor and a Ferrari! What has been achieved so far? We have a late-stage gametocyte assay up and running. Using the assay we have started to screen the 25,000 compounds known to be active against blood-stage malaria. The preliminary data generated is very exciting and there are already plans to screen many more compounds. We aim to screen 250,000 compounds this year. What value has MMV added to your work? Working with MMV has provided me with the opportunity to focus on an area of drug discovery I otherwise wouldn t be able to. It means I can bring the skills I have developed in pharma and academia to an issue that needs to be addressed. I enjoy coming to meetings at MMV as I interact with and learn from people who work across the whole pipeline. Working with MMV has also opened doors to people doing research that is similar or complementary to mine. 33

7 Top 10 MMV publications of 2011 Nambozi M et al. Safety and efficacy of dihydroartemisinin-piperaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Zambian children. Malar J. 10:50 (2011). Demonstrates the posttreatment prophylactic potential of dihydroartemisinin-piperaquine in Zambian children. Pivotal Phase III study demonstrating the efficacy of pyronaridine-artesunate in treating blood-stage P. vivax malaria. Poravuth Y et al. Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial. PLoS One. 6(1) (2011). Kern SE et al. Community screening and treatment of asymptomatic carriers of Plasmodium falciparum with artemether-lumefantrine to reduce malaria disease burden: a modelling and simulation analysis. Malar J. 10:210 (2011). Shows that the treatment of asymptomatic carriers with artemether-lumefantrine may reduce malaria transmission significantly. Kalilani-Phiri LV, Lungu D, Coghlan R. Knowledge and malaria treatment practices using artemisinin combination therapy (ACT) in Malawi: survey of health professionals. Malar J. 10:279 (2011). Highlights the need for further training of healthcare professionals to ensure correct and optimum use of ACT in Malawi. McCarthy JS et al. A pilot randomized trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. PLoS One. 6(8) (2011). Demonstrates a safe alternative to testing the efficacy of new antimalarials in humans, without exposing symptomatic patients to potentially ineffective treatment. Describes the identification of a potent and selective inhibitor (DSM265) of the malaria parasite s dihydroorotate dehydrogenase enzyme essential for its survival. Coteron JM et al. Structure-Guided Lead Optimization of Triazolopyrimidine-Ring Substituents Identifies Potent Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors with Clinical Candidate Potential. J Med Chem. 54(15): (2011). Burrows JN et al. Challenges in antimalarial drug discovery. Future Med Chem. 3(11): (2011). Details MMV s perspective on the challenges the malaria eradication agenda poses for drug discovery. An opinion piece extolling the need for a patient-data led approach to drug discovery drawing on natural products. Wells TN. Natural products as starting points for future anti-malarial therapies: going back to our roots? Malar J. 10 Suppl 1:S3 (2011). Kremsner PG et al. A simplified intravenous artesunate regimen for severe malaria. J Infect Dis. 15;205(2):312-9 (2012). Epub 2011 Dec 15. Shows that 3 doses of artesunate are not inferior to 5 doses for the treatment of severe malaria in children. Details the identification of the imidazolopiperazine compound series active against the liver and blood stage of malaria. Meister S et al. Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery. Science 334(6061) (2011). 34

Dr Ian Bathurst, MPhil, PhD (1949 2011) In June 2011, MMV lost a dear friend For example, he was constantly and colleague.

8 Dr Ian Bathurst, MPhil, PhD ( ) In June 2011, MMV lost a dear friend For example, he was constantly and colleague. seeking novel ways to facilitate the production of antimalarials and was Born and raised in Christchurch, New an active member of the Artemisinin Zealand, Dr Ian Bathurst completed Enterprise that sought to optimize his studies in the UK, obtaining a PhD the production and extraction of in Biochemistry from the University of artemisinin. London. He then pursued a successful career in academia at the University Ian was an invaluable member of the of Otago, New Zealand. MMV team and a much respected mentor to the discovery team. He In 1986 Ian changed tack and moved was planning an active retirement in to San Francisco to work at Chiron 2011, when he passed away. He is Corporation on the expression of sorely missed, but will be remembe- yeast red for his passion and commitment recombinant proteins, HIV genes and potential vaccine candi- to MMV s work. dates. Always a pioneer, he continued this work through start-up companies In his memory, MMV and the Bathurst LXR Biotechnology Inc. and Arriva family have collected donations and Pharmaceuticals Inc. set up a sponsorship programme to support 10 to 12 scientists from a r Ian brought this wealth of academic malaria-endemic countries to attend and industry experience to the MMV Keystone team when he joined as Director of Meeting in January 2013 in New Drug Discovery in As one of the Orleans. Ian would have been de- first members of the discovery team, lighted that young researchers in he was instrumental in helping to malaria establish MMV s networks and early- were receiving support to attend the stage projects. He ensured projects meeting in his name. Symposia s and neglected Malaria diseases ran smoothly, with good humour and openness to new ideas and inspiration. 35 MMVreport_ _PROD3b.indd :51

The long walk to a malaria-free world

1 The long walk to a malaria-free world Message from the Chairman and CEO Mr Ray Chambers Chairman of the Board Dr David Reddy MMV s CEO It always seems S impossible until it s done. Nelson Mandela (1918