Behind The Scenes Of The MMV Story – From Coartem Dispersible’s ‘Opening Act’ To A New Drug For Relapsing Malaria Supported Series 23/11/2019 • Editorial team Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to print (Opens in new window) Over the last 20 years, MMV has worked with over 400 partner organizations in 55 countries; involving tens of thousands of individuals. At a recent anniversary event held in Geneva, some of those key players told their stories – bringing to life the contributions made by so many more people over the past 20 years. As Mauro Poggia, Swiss State Advisor who accompanied the ceremonies said, “MMV has played a key role in developing the new medicines that are being used for malaria and thanks to those treatments, it’s 2 million human lives that have been saved. Public health is a public good… and health can only be assured when it is undertaken when all of the parties converge, be they the manufacturers, the researchers, the individuals, the pharma industries. It is only together that we will see this deadly infectious disease eliminated.” But each life saved is also more than a number. It is a story, said David Reddy, chief executive officer at MMV, “When I first started at MMV back in 2011 one of my first duties was to attend a meeting of the African Leaders Malaria Alliance, in Ethiopia where I went to a rural health clinic and met a little girl called Zakhiya. She was suffering from malnutrition and malaria, but was being cured with one of the MMV-partnership drugs. This made me realize how successful my predecessors had been, how grateful I was for what they had achieved and determined to carry this forward.” Health Policy-Watch presents key excerpts of several successful partnerships, as told by some of the people who helped make the history. David Reddy Opening Act – Coartem for Children MMV’s first story begins back in 2003 – At that time, a medicine called Coartem®, developed by the Swiss pharmaceutical company Novartis, had become the artemisinin-based combination therapy (or ACT) of choice for treating uncomplicated malaria in adults. However, there were no high-quality ACTs formulated specifically for use in children. Equipped with insights into the realities of treating malaria in the field, MMV worked with Novartis to develop a new dispersible formulation of Coartem that would be safe for use in those most at risk – small children. Since the launch of Coartem Dispersible 10 years ago, 385 million treatments have been distributed to malaria-endemic countries. It’s estimated to have saved the lives of around 825,000 children to date. Lessons learned, from paediatric clinical trials to packaging, have paved the way for the development of other child-friendly formulations. (left – right) Jaya Banerji, Rebecca Stevens, Hans Rietveld Rebecca Stevens, head of Global Health Partnerships at Novartis For me, the story of Coartem is a very personal one. As a young child growing up in Sierra Leone, I often had to take bitter tablets whenever I had malaria. More than the illness itself, taking the bitter tablets was just horrible. So, with Coartem Dispersible, MMV and Novartis have significantly contributed to making taking medicine much less traumatic, while providing children with a life-saving treatment for uncomplicated malaria. As a Sierra Leonean, and an African – I am proud to have played a role in helping to develop a medicine that will have a positive impact on the lives of African children. Hans Rietveld, director of the Access & Product Management Team at MMV Finding the right formulation was not straightforward, and I remember the persistence of the MMV team pushing for a dispersible tablet – rather than granules in a capsule, or sachet packaging. When the formulation was agreed upon, we realized that bioequivalence between the crushed tablets and the dispersible tablets could not be established, hence the need for a pivotal Phase III clinical trial involving 900 patients. With efficacy and safety established, the collaboration naturally extended to jointly developing and testing patient-centric packaging to aid with treatment adherence. We developed and tested a comprehensive training toolkit for health workers for the roll-out of the new formulation. Jaya Banerji, senior director of Communications in Corporate Affairs at MMV Administering the drug to children was a complex process, and because of this, we committed to supporting local healthcare workers and communities to ensure safe use of the medicine and thus maximize the benefit to young patients. To make it easier for caregivers with lower literacy and to transcend language barriers, we used iconography and infographics in our communications, an approach that was very well received and effective. Around the time that MMV and Novartis began to work on Coartem Dispersible, another major problem needed to be addressed – the empty antimalarial drug pipeline. MMV partnered with global pharmaceutical companies to explore their chemical libraries for novel compounds to replenish the pipeline, and supported the establishment of high-throughput technology to enable a better and faster screening process. Since the early 2000s, MMV’s platforms have catalysed the discovery of 30 novel drug candidates, and continue to evolve in response to market need. Act II – Honing the Science of Molecule Screening, Drug Assays & Chemical Fingerprints Elizabeth Winzeler, professor, School of Medicine, University of California, San Diego In 2004, I ran an academic lab at the Scripps Research Institute that had been developing high-throughput ways of studying malaria parasites. Given my lab’s expertise in parasite biology, and the institute’s high-throughput phenotypic screening capabilities, which in early 2000’s were unparalleled, we set about developing inexpensive, simple and precise assays that might predict if a compound could be developed into an effective antimalarial medicine. (left-right) Elizabeth WInzeler, Javier-Gamo Benito, Didier Leroy Javier Gamo-Benito, researcher, GlaxoSmithKline At the same time, we were developing a methodology at GSK to allow us to accurately measure the killing rate of a given drug and shed light on its possible mechanisms of action… We found notable differences between widely- used standard antimalarials in terms of killing rate. We realized that this could help with the prioritization and clinical development of future antimalarials. Most recent antimalarial candidates have been analysed through our assay in collaboration with MMV and GSK. In fact, the parasite reduction ratio has become an important part of the data package for new compounds and plays an important role in portfolio prioritization decisions. Didier Leroy, senior director in Drug Discovery at MMV High-throughput screening technology made the cost of screening projects competitive, it made collaboration with Pharmaceutical companies viable. To date, MMV and partners have developed and validated more than 15 different assays throughout the entire life cycle of the parasite. Seven years ago, we published a fingerprinting exercise whereby around 50 molecules representing the chemical diversity of the various classes of antimalarials were used to validate these assays. Being able to reconstitute in vitro the complexity of the life cycle of the parasite was the basis of our current process for the profiling of our portfolio compounds… Today, we continue to explore ways to harness new technology to improve our discovery and translational platforms whose fundamental bases were established 10 years ago by our deeply missed visionary colleague Ian Bathurst. Act III – Pyramax It can take 10 to 15 years to bring a new drug to market. In 2001, MMV and Shin Poong, a Korean pharmaceutical company, joined forces to develop and deliver Pyramax®, a powerful and convenient alternative ACT. This project brought about a valuable therapy that may never have come to market without a partnership approach. Isabelle Borghini–Fuhrer, senior director of Product Development and Lead on the Pyramax Project We designed and conducted five Phase III trials, in Asia, in Africa, in adults, in children, in Plasmodium falciparum and in Plasmodium vivax. Some of the trials were so successful that the children were climbing out of the windows to play with their friends before the end of the three-day protocol for administration of the drug. Following up with them sometimes involved interrupting a game of football! Members of the Pyramax team (From left to right): Adam Aspinall, Isabelle Borghini, Bernards Ogutu. So why Pyramax? Well, in 1999, the WHO approached Shin Poong to explore whether it would be possible to develop a new ACT (combining pyronaridine and artesunate) to diversify front-line treatment options for malaria, in anticipation of the possible emergence of resistance. Despite being mainly focused on manufacturing and distributing generics, then Chairman of Shin Poong, Mr Yong Taek Chang, accepted wholeheartedly. In 2001, MMV was invited to contribute its antimalarial drug development expertise to the project… We are delighted that Mr Chang’s son is also passionate about Pyramax and will continue our partnership, developing and today facilitating access to the product in malaria endemic countries. Professor Bernhards Ogutu, chief research officer at the Kenya Medical Research Institute (KEMRI) The real-world evidence generated by MMV and partners looking at Pyramax has been really important for us as frontline care givers and policy makers – it informs policy change by letting us know whether new treatments or ways of deploying them will be effective. It allows us to teach evidence-based medicine to our health workers and help them make effective treatment decision, and it is needed for consensus building among stakeholders, so we can all understand what options (both medicines and deployment strategies) are available and decide which one will work best for us. Adding Pyramax, with its huge data package, to the antimalarial options we have in our country gives us healthcare professionals more choice. ACT IV – Injectable & Rectal Artesunate – Getting Effective Products Into the Field Today, injectable artesunate has become the recommended frontline therapy for severe malaria with the first such WHO Pre-Qualified treatment, Artesun®, approved in 33 countries worldwide. Since 2010, 144 million vials of Artesun®, Fosun Pharma’s injectable artesunate product, have been delivered, saving an estimated 950,000 additional lives, in comparison to what would have been the outcomes with quinine, the former standard of care. In 2018, as demand continued to grow, MMV supported a second manufacturer (Ipca) in achieving WHO prequalification as well, ensuring supply security. But ensuring formal approval and widespread use of rectal and injectable artesunate was not a foregone conclusion. (left-right) Pierre Hugo, Christian Lengeler, Elizabeth Chizema Kawesha Pierre Hugo, senior director of Access & Product Management at MMV I worked with partners to support the introduction and use of injectable artesunate in the DRC – a country with the highest rate of severe malaria, and consequently the highest death rate from malaria in the world. Already in 2011 Médecins Sans Frontières had released a policy paper advocating for countries to switch from quinine to injectable artesunate for severe malaria. So, with Artesun already WHO-prequalifed, in 2012, we set out to successfully bring injectable artesunate to one of the hardest-hit countries in the world. We knew it would be an uphill struggle to get severe malaria treatment to patients, but – with the help of our partners (STPH, PMI and PNLP) – we succeeded. Christian Lengeler, professor of Epidemiology at the Swiss Tropical and Public Health Institute (Swiss TPH) In 2012, with MMV’s support, we embarked on a feasibility study called MATIAS in the Democratic Republic of Congo, to support implementation of the policy of using injectable artesunate to treat severe malaria at health facilities. The results confirmed that injectable artesunate was safe, easier to use than quinine, and led to better treatment outcomes, and this was the evidence base for large-scale implementation in the DRC. Elizabeth Chizema, coordinator of Zambia’s End Malaria Council and former director of the National Malaria Elimination Centre in the Zambian Ministry of Health Giving rectal artesunate to children with suspected severe malaria allows us to buy time while the child is transported to a district health facility. Almost 100% of the children treated with rectal artesunate for suspected severe malaria in a pilot study in two districts reached a health facility in good time. Zambia recently revised its national policy to align with WHO recommendations, replacing quinine with injectable artesunate for treatment of severe malaria, and rectal artesunate for the pre-referral management. To make this successful, we worked with partners to train almost 14,000 community health volunteers to proactively diagnose and manage cases of severe malaria at the community level, rather than waiting for cases to present at district health facilities. This in turn reduces the pool of individuals who can contribute to malaria transmission. Ultimately, for maximum coverage, we hope that initiatives like this will, one day, be present in all 114 districts of Zambia. I also hope that our experience will inspire other African countries to consider similar projects and forge new collaborations. ACT V –Human Volunteer Infection Studies – Accelerating Clinical Development Since 2012, human volunteer infection studies have helped to transform the antimalarial drug development pathway, accelerating the development and prioritization of new medicines. This ground-breaking platform, offered an ethical means of bridging the gap between safety studies in volunteers, which only tested a drug’s adverse effects but not its efficacy, and clinical trials in difficult field conditions among people who were actually ill, many of them children. Since there are efficacious medicines for malaria available, healthy volunteers infected with the parasite in carefully controlled conditions could always be cleared of the disease with an approved drug once the experimental drug was tested: (left-right) James McCarthy, Jörg Möhrle Jörg Möhrle, vice president and head of Translational Medicine at MMV By the end of 2010, our pipeline was starting to fill up with new chemical entities, and we needed a way to characterize their activity – alone and in combination – without placing a huge burden on patients. Following the completion of first-in-human Phase I trials, there was still a significant gap in our understanding between the tolerability of a drug in volunteer patients and the ability of that drug to kill parasites in real-life patients at a well-tolerated dose. Interestingly, infecting humans with the malaria parasite was a concept that had originally been used to treat patients with syphilis, as malaria caused episodes of high fever that killed Treponema pallidum. In malaria research, human infection studies had previously been used during the development of primaquine, mefloquine and atovaquone/proguanil. So, when MMV was looking for ways to properly characterize the antimalarial activity of new and repurpose-able drugs (i.e. those with the good safety data), this was an obvious way to go. James McCarthy, professor of Tropical Medicine and Infectious Diseases at The University of Queensland, School of Medicine I worked with MMV to develop a way to experimentally infect healthy volunteers with malaria and let their parasitemia grow to a level where we could test how well antimalarial drugs work in killing parasites… At a time when a major focus of everyone doing medical research and anti-infective product development is on minimising risk, the idea of deliberately infecting people with a potentially lethal infection takes some getting used to, but by the end of this year, we will have characterised over 16 drugs, and 2 combinations in over 300 volunteers. In addition to studying the activity of drugs on asexual blood-stage parasites, we can now observe the effect of new drugs on female and male gametocytes, and assess the ability of new compounds to block onward transmission of the disease. We have K13-mutant, artesunate-resistant parasites suitable for use in the volunteer studies, which enables us to test drugs that can hopefully combat the spread of drug resistance. On top of all this, the work we have done together has opened up new possibilities to investigate how pathogenic organisms make us sick, as well as discovering new ways to diagnose them, and prevent them killing us with drugs or vaccines. ACT VI –Building Research Networks in Endemic Countries A key thrust of MMV’s work in the past 20 years, as well as the future, has been partnerships with clinicians, researchers and institutions in endemic countries of Africa, Latin America and South East Asia to build institutional capacity for more local research and development. In particular, MMV has focused on empowering African institutions, scientists and industry to join the fight against malaria and be part of the solution to one of the continent’s greatest health threats. One of the first anchors of this collaboration was a partnership created between MMV and the University of Cape Town (UCT), later to include the Universities of Gondar and Jimma in Ethiopia to continue research on the first antimalarial compound to be discovered by an African-led team, MMV048. (left-right) Kelly Chibale, Cristina Donini, Rezika Mohammed, Daniel Yilma Kelly Chibale, director, Drug Development and Discovery Centre, University of Cape Town in South Africa I met Tim Wells at London’s Heathrow airport in 2008…The collaboration we started that day was based on a shared passion to energize and advance drug discovery in Africa, empowering a new generation of scientists to participate in the fight against malaria. We started by taking forward small-molecule starting points, or ‘hits’, identified from high-throughput screening of a commercial compound library from BioFocus. The screening was conducted at the Eskitis Institute of Griffiths University, in Brisbane, Australia, by Prof. Vicky Avery. The in vitro and in vivo biology was carried out by Dr Sergio Wittlin at the Swiss Tropical and Public Health Institute (Swiss TPH), and Prof. Susan Charman conducted the in vitro and in vivo pharmacokinetics at the Centre for Drug Candidate Optimisation at Monash University, in Melbourne, Australia. MMV also appointed an experienced project mentor, Dr Michael J Witty, who had 30 years of pharmaceutical industry experience with Pfizer. Thanks to the success of this project, the MMV–UCT partnership has facilitated the formation of a research hub at UCT, with the infrastructure, experience and knowledge of regulatory requirements needed to pursue the clinical development of novel therapies. Rezika Mohammed, researcher at the University of Gondar and Daniel Yilma, researcher at Jimma University in Ethiopia In 2017, following successful completion of the first-in-human trials at UCT, we started a Phase IIa clinical trial of MMV048 at two sites in Ethiopia…It was a stressful project in the beginning, but ultimately very exciting to see the patients successfully treated with MMV048, without any safety concerns. In terms of local capacity-building, the trial has brought huge benefits. We now have new infrastructure in place, new equipment in our health centres that meets good clinical practice guidelines, and better-trained staff than we had previously… Empowering African researchers to come up with solutions to the health challenges in their communities is so important for the future, and we hope our experience will inspire new collaborations and capacity-building efforts. ACT VII –Tafenoquine for Relapsing Malaria The Plasmodium falciparum parasite is the big killer worldwide, but the burden of relapsing malaria caused by Plasmodium vivax is often neglected. Relapsing malaria affects 7.5 million people and threatens 2.5 billion – a third of the world’s population – every year. For over a decade, MMV and GSK worked to co-develop a new drug for relapsing malaria. In 2018, they shepherded tafenoquine, the first new therapy for relapsing malaria in more than 60 years, to regulatory approval. But deployment of tafenoquine remains complex. It requires two suitable point-of-care diagnostics before it can be launched: one for confirmation of the P. vivax infection, and another to make sure patients have adequate G6PD enzyme to ensure the medicine can be administered safely. Here are members of the tafenoquine team to tell us about this new treatment and its deployment: (left-right) Elodie Jambert, Alison Webster Elodie Jambert, director of Access & Product Management at MMV For 60 years, the only approved treatment for P. vivax malaria was primaquine, a treatment administered once a day for 14 days. As you can imagine, this long regimen led to issues with patient compliance, so the global community desperately sought a cure requiring fewer doses – ideally a single-dose cure In 2008, MMV and GSK embarked on a programme to find the right dose of tafenoquine and then the right Phase III population to get the drug approved and to market – as a radical cure for the prevention of relapse caused by P. vivax. After 9 years in clinical development, tafenoquine was approved by the US FDA and the Australian TGA in 2018. And I’m pleased to announce that the Brazilian Health Regulatory Agency has just this month granted Marketing Authorization Application for single-dose tafenoquine – and the regulatory submission process is ongoing in other vivax-endemic countries. Alison Webster, head physician of the Diseases of the Developing World Unit at GSK Specific diagnostic tools were needed to accompany the launch of tafenoquine because both primaquine and tafenoquine, which belong to the same class of compounds (the 8-aminoquinolines), can cause haemolysis in individuals deficient in the enzyme G6PD. We were very clear at the outset that launching a drug for relapsing malaria would need an as-yet-unavailable, affordable, point-of-care diagnostic for G6PD deficiency, and we would need experts in diagnostic development to take the lead on this. To help identify patients eligible for treatment, MMV’s partner PATH supported the development of a quantitative, point-of-care G6PD diagnostic tool that has been approved by the Expert Review Panel for Diagnostics, and by many P. vivax-endemic countries. Now that tafenoquine and the G6PD diagnostic tool are available, we are busy generating the evidence to support their use in both rural and urban settings before tafenoquine is made more widely available. We hope that tafenoquine will deliver both individual and public health benefit in terms of reduced relapses and onward transmission of P. vivax, and will help us take another step towards the eventual elimination of relapsing malaria in P. vivax-endemic countries. Editor’s Note: This series was supported by MMV Image Credits: E Fletcher/HP-Watch, MMV. 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