Breakthroughs Blog: Malaria

Photo: CDC/ Melissa Dankel A new study conducted by the Malaria Genomic Epidemiology Network (MalariaGEN)—a community of researchers across malaria-endemic regions—reveals a formerly unknown genetic variations that make people less susceptible to malaria. The team collected over 20,000 samples from across sub-Saharan Africa, and have identified a genetic variation that provides 33 percent protection against malaria (although the rate varies across populations) as well as dozens of additional genes that appear to have some connection to natural resistance to the disease. The location of these genetic mutations in the human genome is near a region unusually similar to the chimpanzee genome, which suggests that these mutations could have developed millions of years ago. According to the study’s lead author Dominic Kwiatkowski, a process known as balancing selection might have occurred: “[the mutations] would be maintained at a sort of intermediate frequency”—common but not ubiquitous—“implying that it had both beneficial and deleterious effects.” Furthermore, this phenomenon has been observed with sickle cell trait, a gene mutation well known for providing partial protection against malaria, but that can cause a serious blood disorder when two copies of the mutation are present.   A new report from the Access to Medicine Foundation evaluates the vaccine pipelines of 20 major pharmaceutical companies, calling on these leaders in vaccine development to address the gaps in vaccine research and development (R&D) and take steps to ensure that their products will ultimately be accessible and affordable in low- and middle-income countries. The report identifies 70 vaccine candidates against 13 high-burden diseases, noting that nearly half are being developed by just three companies: GlaxoSmithKline, Novartis, and Sanofi. Of the 70 candidates, 16 target diseases for which there are currently no approved vaccines, including dengue fever, HIV and AIDS, malaria, tuberculosis, leishmaniasis, and Chagas disease. Nearly half of the candidates are for lower-respiratory infections (19 candidates), including pneumonia and influenza, or diarrheal diseases (14 candidates). There are currently access provisions—plans to ensure access to the final product—for only 12 of the candidates. Starting October 15, the US Food and Drug Administration (FDA) will have the ability to destroy   drugs sent to the US by mail if they are denied admission into the country. The FDA blocks the importation of drugs that are incorrectly labeled, not approved for use in the United States, or that appear to be counterfeit, including those that do not have the active ingredient, that have inadequate or excessive amounts of the active ingredient, or that contain the wrong, or even harmful, ingredients. Currently, the FDA returns these refused packages to the sender, and not only does this allow the sender to make another attempt, but it’s not uncommon for the same exact parcel to be sent right back to the United States “with the sticker indicating prior refusal by FDA still attached and visible.”

In this post, Amie Batson, MBA—chief strategy officer at GHTC member PATH—discusses a new PATH-led initiative to identify and showcase lifesaving innovations with the promise to transform global health by 2030 and offers insights into what it will take to accelerate the impact of innovation. This post originally appeared in the Innovation Countdown 2030 Report: Reimagining Global Health. What if the solutions to the greatest health challenges of our time were within reach? Imagine if the world came together around those solutions and worked to accelerate the ones with the most potential to transform health. How might the world source, assess, finance, and coordinate investment in the highest-impact innovations and dismantle the barriers that keep them from reaching the very people who need them most? This is the intriguing premise behind the PATH-led Innovation Countdown 2030 (IC2030) initiative. With support from the Norwegian Agency for Development Cooperation, the Bill & Melinda Gates Foundation, and the US Agency for International Development, we set out to identify, evaluate, and showcase health technologies and interventions with great promise to accelerate progress toward solving the world’s most urgent health issues. We turned to experts and innovators all over the globe, crowdsourcing transformative ideas and innovations that could dramatically increase the affordability, accessibility, or effectiveness of health care compared to the current standard of care. Reimagining Global Health, the inaugural report of the IC2030 initiative, features 30 innovations that experts believe could quicken the pace of progress toward the health targets in the proposed UN Sustainable Development Goals (SDGs), along with commentaries from health, technology, and business leaders. These 30 innovations are presented in four categories mapped to the proposed health targets: maternal, newborn, and child health (MNCH); infectious diseases, including malaria, HIV and AIDS, and tuberculosis (TB); reproductive health; and noncommunicable diseases (NCDs), including diabetes, cancer, and chronic respiratory and cardiovascular disease. We cast a wide net in our search because innovation is truly diverse and global. Our call for nominations brought in more than 500 ideas submitted by people in nearly 50 countries across five platforms: devices; diagnostics; drugs and therapeutics; systems and services, including digital health; and vaccines. We then tapped more than 60 health experts to evaluate and rank those innovations, selecting the final set featured here. For a detailed look at our methodology, please see pages 37–41 of the Reimagining Global Health report. Four strategies to accelerate the impact of innovation Our list of 30 promising innovations and our dialogue with experts and innovators around the world offer important insights into what it will take to harness the power of innovation to save lives. 1. Tap and support innovation wherever it occurs. Innovators are everywhere, not just in well-funded labs and technology companies in wealthy nations. Today’s innovation ecosystem is diffuse, with smart ideas coming from every corner of the globe and across every sector and discipline. The world increasingly sees the importance of user-centric solutions that are demand-driven, relevant, and affordable. The opportunities for accelerating innovation—wherever it comes from—have never been greater, empowered by digital platforms where new ideas, data, and approaches can be shared, developed, and deployed. Our crowdsourcing approach for gathering innovations is one example of the new tools that are redefining health innovation. Nearly 30 percent of the 500-plus submissions received by IC2030 came from people in low- and middle-income countries, giving voice to their growing role in health innovation. There were many more promising ideas than we could feature in this report. Strengthening the capacity of low- and middle-income countries to identify, develop, adapt, produce, regulate, assess, and share innovations is critical for a robust innovation pipeline. Investments in countries’ innovation ecosystems will catalyze better overall global health while ensuring that innovations are appropriate for low-resource markets and local contexts and cultures. Innovators with direct experience working with limited resources may be the best source for frugal innovations—cost-effective solutions to address the needs of the poor, wherever they live. 2. Assess and advance innovations that deliver the most health for the money. Rigorous and transparent assessment of an innovation’s health impact, market size, and technological feasibility compared to alternatives in the pipeline is important for informing decisions about where to invest precious health resources. Low- and middle-income country governments are requesting assistance in evaluating the potential health and economic value of introducing one innovation versus another amid a burgeoning supply of new tools and interventions. Investors are also demanding more and better data on which to base investment decisions. However, comparing innovations across diseases and conditions is a challenge. Health experts frequently focus on specific conditions and make decisions with a single health outcome in mind. A key feature of IC2030 is the health and cost impact modeling process we developed to quantify lives saved, cases of disease averted, and costs for a subset of MNCH innovations. This model could provide a common framework to assess innovations with the greatest potential to address the SDG health targets. Our impact modeling results for select maternal, newborn, and child health innovations are featured on pages 13–19 of the Reimagining Global Health report. The data provide new insights into prioritizing global health investments for greatest impact. For example, we found that new tools for community-level water treatment to prevent diarrheal disease and the scale-up of a low-cost drug to prevent newborn infections could save more lives over the next 15 years compared to other innovations we modeled. Measuring the impact of crosscutting innovations is equally important. These health systems and platform innovations, including digital tools and broad diagnostics, have the potential to address multiple SDG health targets simultaneously. About one in five of the innovations submitted to IC2030 was crosscutting in nature. Yet assessing their impact is particularly challenging because of the complexity of linking multiple health outcomes to the foundational structure of the health system that supports them. In this first year of IC2030, we did not systematically evaluate crosscutting innovations, but they will be a focus going forward. New assessment tools and more comparable, comprehensive, and reliable financial and technical data are critical to help spotlight and advance innovations with particular promise that might otherwise be overlooked. A clear and rigorous framework to gauge the best value for money in a range of low- and middle-income settings is needed to inform national and subnational purchasing decisions and the decisions of those purchasing on behalf of countries. This will also help innovation investors more accurately assess potential impact, markets, and revenue flows. Zeroing in on health solutions that offer the greatest value for money is the essential next step in reaching the millions of people still waiting to share in the gains of our progress. 3. Develop new financing mechanisms for global health innovation. The pool of public and private funds to invest in health innovations is large and evolving. Funds from traditional R&D and development donors—typically dedicated public funds from wealthy countries—are being augmented by resources from philanthropies, social impact investors, private-sector mechanisms, and domestic sources. This new mix of innovation funding creates both opportunities and challenges. Domestic funding to introduce and scale up health innovations is becoming central to innovation funding. As low- and middle-income economies grow and countries graduate from aid, they are expected to finance their own health expenditures, creating new markets for affordable health tools and interventions. Sustainable financing of innovation will depend on the decisions of domestic stakeholders, including governments, insurance entities, corporations, and individuals. As more viable markets emerge, we will see a rebalancing of innovation from being primarily supply-side driven by donors and the R&D community to being more demand-side driven by countries and markets. Supporting country decision-makers to buy or, in the case of insurance mechanisms, cover or reimburse cost-effective health innovations must be at the heart of a new and improved financing model. Global funding mechanisms, including the Global Fund to Fight AIDS, Tuberculosis and Malaria and the new Global Financing Facility at the World Bank, may be well-positioned to act as intermediaries, as Gavi, the Vaccine Alliance, currently does for vaccines. These mechanisms can increase the certainty that funds will be readily available to purchase high-priority innovations if countries demand them. To play this role, they will need a window into the innovation pipeline and a means of engaging with eligible governments to identify high-impact innovations. The next generation of health financing mechanisms must also be responsive to the increasing requirements of social impact and private investors who base their investment decisions on not only the potential health impact of an innovation but also its probable market in low- and middle-income countries. While traditional funders have always understood the importance of having a clear “line-of-sight” to the market, it was often discounted. The assumption has been that if an innovation demonstrated significant public health value, a donor would eventually support it. New financing mechanisms must spotlight and bridge the critical links between R&D decisions, market uptake, and health impact. Innovators will respond to incentives that encourage them to maintain a focus on the market from the beginning of the development process to ensure the creation of sustainable and affordable innovations. New financing mechanisms must also provide more efficient and effective models for making and executing investment decisions. Over the past decade, the evolving spectrum of innovation funders has led to increasing fragmentation of investment decisions and growing transaction costs. Each investor—whether a public agency representative, a social impact investor, or a minister of health—brings a unique mix of risk tolerance, due diligence processes, data sources, expected returns, and interest in specific platforms, geographies, or health areas. For any investor, the difficulty and risk of investing alone is high, but today, the transaction cost of coordinating decisions and investment can be even higher. Global health investment funds try to address this challenge but require all investors to align on risk/reward preferences. The growing diversity of funders, while currently a challenge, has the potential to be a benefit if investors can leverage their different interests and risk tolerance. If actively coordinated, mixed sources of funding can be structured to finance different stages in the innovation cycle with a focus on the market. This means recognizing the growing role of purchasers in establishing a market, as well as finding new ways to align the decisions of investors and purchasers. All parties would make better decisions if they knew, and could count on, what others were doing. 4. Coordinate investments to ensure a strategic approach to health innovation. Coordinated investments in innovations across the continuum of care, including prevention, diagnosis, treatment, and disease management, have the potential to ensure a comprehensive suite of health tools and services designed for the greatest possible impact. The proposed SDGs provide the opportunity for investors to work toward shared health targets and better coordination in how they source, assess, and invest in innovations that achieve those targets. Yet we found potential inefficiencies in investment approaches that may underscore the current lack of coordination. In certain health areas, for example, we received nominations for multiple devices all taking a similar approach to address the same health condition. While competition might result in better tools at better prices, it also raises the question of whether donors are aware of what others are investing in and whether scarce resources could be more strategically targeted. In maternal health, we received many submissions for diagnostics to predict and detect preeclampsia/eclampsia—the second leading cause of maternal mortality—but few innovations for the treatment of these life-threatening conditions. In many low-resource settings, the existing treatment, magnesium sulfate, is underused, incorrectly administered, or unavailable. Diagnostics will have limited value unless innovations in new treatments and delivery systems are developed in parallel. A broader understanding of where investments in innovation are high—or very low—is also warranted. NCDs now account for about two-thirds of global deaths, yet we received very few innovation nominations. Donors may assume others are funding NCD innovations while they focus on infectious diseases. Will they be surprised when they pivot to NCDs and discover the lack of appropriate innovations for people in low-resource settings? Could investments in preventive innovations today allow countries to effectively leapfrog developed nations and avoid creating the huge treatment burdens associated with NCDs? Conclusion The robust and growing innovation pipeline presents an exciting opportunity to accelerate high-impact solutions that can create better health and opportunity for all. Ensuring the best ideas are surfaced—wherever they come from—is the first critical step we must take to deliver on the promise of the SDG health targets. This should include investing in the innovation ecosystem in low-resource countries to enable local entrepreneurs to develop, produce, and share their ideas. It also means using new crowdsourcing tools to gather ideas and data visualization to make the comprehensive pipeline more visible to national and global investors, policymakers, and innovators. Developing and adopting assessment methodologies that provide common, consistent, and comparable evaluations of innovations is the second step. Countries are in great need of health technology assessment tools that allow governments and insurance entities to decide which of the many innovations available today and in the future should be procured, covered, and reimbursed. These tools also will improve the quality of market estimates, one of the most critical and yet weakest components of innovation assessment for all investors. The third step is to develop innovative financing mechanisms that both recognize the growing importance of domestic finance in determining markets in low- and middle-income countries and benefit from the growing diversity of investors. Financiers have the potential to leverage their investments by aligning with other funders while maintaining a strategic focus on the market. Aligned investment across the different stages of the innovation cycle, from development to production, commercialization, purchase, and wide-scale use, has the potential to dramatically accelerate our progress. The fourth step may be the most essential—coordinating the resources and attention of investors, innovators, and policymakers on innovations with the greatest potential value for money. Our progress depends on decision-makers sharing information to ensure that collectively, the world is investing in the portfolio of innovations that will allow us to achieve our shared goals embodied in the SDGs. Innovation is the key to sustainable health impact. But innovation isn’t a random set of ideas and inventions. High-impact innovation is more likely to result from the kind of sourcing, assessment, financing, and coordination described above. It is our hope that one or more of the innovations highlighted in this report will become a game-changer for global health over the next 15 years. But beyond the success of any single innovation, we hope IC2030 will be a platform to catalyze discussion, collaboration, investment, and momentum toward the day when everyone has an equal chance for a healthy life. Photo: PATH/Gabe Bienczycki.

The Drugs for Neglected Disease initiative (DNDi) and the Medicines for Malaria Venture (MMV)—nonprofit product development partnerships (PDPs) and members of the Global Health Technologies Coalition—have teamed up to ensure two treatments for malaria continue to reach the patients who need them most. The treatments—two fixed-dose artemisinin combination therapies (ACTs) known as ASAQ and ASMQ—were developed by DNDi and partners and launched in 2007 and 2008, respectively; going forward, MMV will work with those partners to ensure these drugs remain available and accessible in countries where they are most needed. Dr. Bernard Pécoul, CEO of DNDi, passes the ball to Dr. David Reddy, CEO of MMV. (Photo credit: MMV) To commemorate the handover, DNDi CEO Dr. Bernard Pécoul passed the ball—a literal rugby ball—to MMV CEO Dr. David Reddy during a side event at the 68th World Health Assembly in Geneva, Switzerland. We’re joined by Jean-René Kiechel, PhD, Senior Pharma Advisor & Product Manager of DNDi and George Jagoe, Executive Vice President of Access & Product Management at MMV to learn more about this handover and the existing and potential impact of these medicines. Q: What impact could ASAQ and ASMQ have in the fight against malaria? The FACT (Fixed-Dose Artesunate Combination Therapy) consortium was formed in 2002 to develop combinations of artesunate (AS) with amodiaquine (AQ) or mefloquine (MQ). These treatments were recommended by the World Health Organization (WHO) in response to increasing chloroquine resistance, but were not available in easy-to-use fixed-dose combinations (FDCs). The FACT consortium was transferred to DNDi when the organization was created in 2003. It led to the creation of two FDCs: ASAQ: In 2007, ASAQ Winthrop® became the first treatment to be launched by DNDi. It was developed by a number of partners across almost the full development range, from formulation work to post-registration studies. There were significant challenges to overcome, including developing a stable bilayer formulation of the two drugs, together with the aluminum blister packaging designed to withstand the rigors of a tropical environment. Manufacturing and distribution of this stable formulation were undertaken by Sanofi, who were already providing co-blistered Coarsucam™ to Africa at the time, and who committed to making the generic ASAQ Winthrop® available at less than US$1 per adult treatment for the public market. ASAQ’s low price and prequalified status, which allows purchase by procurement agencies, led to price decreases not only of ASAQ but also for other ACTs. Lower drug costs led to increased patient access to high quality treatments. To date, more than 400 million treatments of ASAQ have been distributed worldwide, including products developed by generic companies. ASMQ: Launched in 2008, ASMQ was developed in collaboration with Farmanguinhos/Fiocruz, a Brazilian public pharmaceutical company. A South-South technology transfer agreement to Cipla Ltd in India ensured a second supplier of the treatment, principally for the Asian market but also for Africa. Recent results from a multi-center trial carried out in Africa showed ASMQ is as efficacious as artemether-lumefantrine—Africa’s most widely adopted treatment—in children under 5 years of age, and is well tolerated. ASMQ also demonstrated high cure rates and good efficacy in a number of studies in Asia and Latin America, including a large intervention study in Brazil with more than 23,000 patients. In a study comparing five ACTs in Myanmar, ASMQ FDC showed the highest cure rates, the lowest rates of gametocyte carriage (which are believed to affect the transmissibility of malaria), and provided the best post-treatment suppression of malaria. By the end of 2014, 832,000 ASMQ treatments had been distributed. Q: DNDi and MMV are both product development partnerships. What value do you see in collaborating with one another and what inspired this handover? In May 2015, in order to ensure the best future implementation of these two treatments, DNDi handed over its malaria program to MMV. MMV is a long-term partner of DNDi, and is managing the largest portfolio to date of antimalarial drugs—from all phases of drug discovery, development, and delivery. Collaboration is at the heart of the PDP model. The PDP is a form of public-private partnership whereby a varied collection of partners collaborate in a flexible, 'virtual' model. This includes biotech, pharma (large and start-up), nongovernmental organizations (NGOs), academia, and private and public sponsors who operate in the disease-endemic countries or globally. A key requirement for these participants from very different backgrounds is agreement on a specific common goal and specific objectives that address the disease in question while at the same time being guided by WHO priorities, the needs of country control programs, and ad hoc experts. The direct, open dialogue between partners who normally do not work together (and may even compete) promotes creativity and out of the box thinking. It fosters the innovation and creativity required to overcome the many challenges that arise in product development. PDPs such as MMV and DNDi have helped to address major market failings in malaria drug development. By enhancing the focus of drug research partners and by mobilizing donor funding for this critical work, both organizations have shown that this model of research and development can make a huge impact on the lives of patients suffering from diseases that have historically been neglected by most pharma companies. Thanks to the collaborative approach that MMV and DNDi have taken in orchestrating the hand-off of ASMQ and ASAQ, both organizations have been able to refine their focus areas for the future. Q: What role have diverse geographic and cross-sector partnerships had in the development and introduction of ASAQ and ASMQ? Both ASAQ and ASMQ demonstrate the ability of innovative private-public partnerships, with a strong commitment from endemic countries, to develop, deliver, and disseminate new high-quality, affordable treatments within a short time frame. ASAQ Winthrop® is a case in point: the partnership that led to the development and registration of ASAQ Winthrop® had to ensure the new drug's successful launch and adoption by endemic countries. First among the many partners needed at this crucial stage are endemic countries' national malaria control programs. Sanofi and DNDi engaged in collaborations with a number of other partners to facilitate the implementation and availability of ASAQ Winthrop®, including experts, WHO, research institutes, funding agencies, and other NGOs. For example, DNDi coordinated a clinical study with the Indian Council of Medical Research to facilitate the adoption of a new anti-malarial policy in India. This study allowed for the registration of ASAQ Winthrop® in India. DNDi also convened an independent panel of experts, the FACT Implementation Advisory Group, to provide independent advice and critical guidance about issues related to implementation and rational use of ASAQ Winthrop®, ensuring equitable access. Another example of the power of partnerships is the DNDi partnership with Sanofi, MMV, and national malaria control programs in Africa. The aim is to collect high-quality data on ASAQ effectiveness and safety, as part of a Risk Management Plan. This is the first of its kind to be submitted to the WHO, and the first to be set up entirely in Africa. It involved some 15,000 patients in one of the studies carried out in Côte d’Ivoire, collecting data on the drug’s safety and effectiveness in real-life conditions. Results are expected to be published by the end of 2015. Q: What are the next steps in ensuring these products are available to the people who need them most? To support uptake of new medicines like ASMQ and ASAQ, several hurdles must be overcome. These include: Inclusion of the medicines by WHO in standard treatment guidelines. Adoption by national disease control programs. National registration by drug regulatory authorities. Education and training on the use of the medicines. Dissemination of new safety and efficacy evidence post-launch. Mobilization of requisite funding for procurement and introduction. As a widely used ACT, ASAQ has met many of these challenges and will continue to play an important role in malaria treatment for many years to come. With new evidence emerging about ASMQ’s efficacy and tolerability, MMV and partners will target broader registration and use of this drug in Latin America, Southeast Asia (where its role in containing drug-resistant strains of malaria is critical), and in Africa, where it has had little use to-date.

Photo: Medicines for Malaria Venture The Medicines for Malaria Venture (MMV)—a member of the GHTC—and the University of Dundee’s Drug Discovery Unit have developed an antimalarial compound that could treat drug-resistant cases of malaria with a single dose. The compound has been tested in both human blood and mice and the researchers involved believe it could ultimately be administered for only US$1 per dose. MMV has entered an agreement with pharmaceutical company Merck KGaA to advance the compound through the research and development (R&D) pipeline, transferring the rights to develop and commercialize any resulting product. Researchers at the US National Institutes of Health (NIH) have developed a vaccine that has protected against leishmaniasis in monkeys. Leishmaniasis infects one million people per year and is caused by the Leishmania parasite, transmitted through the bite of phlebotomine sand flies. Scientists noted that monkeys bitten by uninfected phlebotomine sand flies were less susceptible to future infections, and subsequently determined that a protein in the flies’ saliva—known as PdSP15—triggers an immune response. Seven of ten monkeys receiving an injection of PdSP15 developed immune cells against the Leishmania parasite and were significantly less likely to get the disease than members of the control group. Human cells also reacted to PdSP15 in a laboratory setting, indicating the potential of the protein in protecting humans from leishmaniasis. The fastest and most accurate tuberculosis (TB) test is expensive—$17,000 per machine and an additional $10 per test—and not conducive for use in rural settings because it requires electricity, refrigeration, and access to a computer. The test, known as GeneXpert is significantly more sensitive than traditional TB diagnostics, and its use increases successful diagnosis by 39 percent. Its popularity among health officials and donors has demonstrated that there is a major market for TB diagnostics, and has galvanized private-sector investments in TB R&D. There are now 191 TB diagnostics in the pipeline, and the manufacturers of GeneXpert are working to make the technology cheaper and to develop a remote, cloud-based version of the test. Since 2010, the Pediatric Trials Network has been conducting research to determine the safety and appropriate dosage of different medicines for young children, including premature infants. Children are often excluded from clinical trials, due to issues of consent and communication, and consequently, many drugs are not tested on children before entering the market. The NIH-funded Pediatric Trials Network has gathered research from nearly 90 sites and 3,500 children across the United States, and the results have often been counterintuitive. Medical professionals often determine the appropriate dosage of a drug based on a child’s weight, however the Network’s research has indicated that underdeveloped organs, particularly in premature infants, may struggle to fully process the drugs, ultimately requiring a higher dose per pound.