By Denise Myshko MALARIA Research Update

Global efforts to address malaria treatment and prevention are starting to see some success. PharmaVOICE of

espite the successful deployment of say a is needed because current preven- worldwide. More than 70% of these deaths multiple interventions against ma- tion methods are only partially effective. were among children under 5 years of age. D laria, there were an estimated 212 “The most efficient way to prevent any in- Sub-Saharan Africa accounts for the high- million cases of malaria and an estimated fectious disease is with a vaccine,” says Stephen est share of global malaria burden, with 429,000 malaria deaths worldwide in 2015, Hoffman, M.D., CEO, Sanaria. “The human around 89% of malaria cases and 91% of according to the most recent figures from the infectious diseases that have been eliminated malarial deaths in 2015. The high impact World Health Organization. or dramatically reduced — smallpox, polio, of this life-threatening disease is influencing Malaria is a mosquito-borne disease caused and measles — were controlled with a vaccine. governments across various countries, compa- by a parasite. People with malaria often ex- “The magnitude of the problem is so nies, investors, and nonprofit organizations to perience fever, chills, and flu-like illness. Left huge that it’s very difficult to get to the end contribute toward curbing the spread of this untreated, they may develop severe complica- of the game with the current measures,” Dr. disease. tions. Hoffman continues. “It doesn’t mean it can’t In the past 15 years, there have been Malaria is caused by parasites (Plasmodium be done, but malaria is most intense in areas enormous efforts to reduce worldwide malaria falciparum and ComplimentsPlasmodium vivax) transmit- that are relatively poor and don’t have health prevalence, says Slava Elagin, executive VP, re- ted to people through the bites of infected delivery systems as good as we might have here search and development, Meridian Bioscience. mosquitos. Artemisinin-based combination in United States.” He points to the Bill & Melinda Gates therapies (ACTs) are currently the standard of More than 40% of the global population Foundation’s efforts for a malaria-free world, care against falciparum infections. Yet, rising is at risk of malaria, according to a World which has contributed $2 billion in grants resistance to artemisinin is seen. Health Organization (WHO) malaria fact to combat malaria, as well $1.6 billion to the

(c) PharmaLinx LLC. Rights do not include promotional use. For distribution or printing rights, contact [email protected] The development of effective malaria vac- sheet and World Bank estimates. The WHO Global Fund to Fight AIDS, Tuberculosis and cines has been a major goal of the malaria says around 214 million malaria cases were Malaria, which provides about 50% of interna- research community for many decades. Experts reported in 2015, leading to 438,000 deaths tional funding for malaria control worldwide.

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We have good medicines for malaria but there are still significant gaps in access that we need to look at and understand from a systems view to determine where the barriers are and how we overcome them.

DR. DAVID HUGHES Novartis

Addressing malaria requires a poverty, increase global healthcare costs by children from malaria caused by Plasmodium different approach because of the $1.2 trillion, and cost low-income countries falciparum. high risk and low financial reward to more than 5% of GDP by 2050. RTS,S, which was developed in partnership Treatments are available for malaria, but with PATH MVI, is the first candidate vaccine pharma and biotech companies. The many patients still don’t have access to the for the prevention of malaria to have success- public sector has to carry much more medications. In fact, a study done by research- fully completed a Phase III clinical trial. The of the burden for funding, through ers at the University of California, San Fran- trial was conducted between 2009 and 2014 all stages of development and cisco, and published in April in The Lancet through a partnership involving GSK, PATH introduction. found that that just 20% of children younger MVI, and a network of 11 research sites across than 5 received artemisinin-based therapies, seven African countries. DR. ASHLEY BIRKETT which are effective for uncomplicated Plasmo- Data from this trial demonstrate that over PATH Inititative dium falciparum malaria infection. the first 18 months following three doses of RTS,S, malaria cases were reduced by almost Vaccine Research EffortsPharmaVOICEhalf in children 5 to 17 months old at the time “Controlling the mosquito population is of first vaccination and by 27% in infants 6 to one obvious approach,” he says. “Developing Developing against parasites such 12 weeks old. better informatics tools to understand where as those that lead to malaria has its challenges. At study end, four doses of RTS,S reduced malaria epicenters are is a second approach In fact, no vaccines areof available against any malaria cases by 39% over four years of follow that could help. The third approach is to create human parasites. up in children, and by 27% over three tools that can detect people who have malaria “Parasites are much more complex than years of follow-up in infants. but no symptoms to help prevent transmission viruses and bacteria, where we have been In areas with the high- of the disease from one patient to another.” relatively successful in developing effective est malaria burden, more than Another global effort to control malaria vaccines; parasites have very complicated life- 6,000 clinical malaria cases was launched in April. Leaders from govern- cyles,” says Ashley Birkett, Ph.D., director were prevented over the study ments, pharmaceutical companies, and char- of PATH’s Malaria Vaccine Initiative (MVI). period for every 1,000 children itable organizations convened at a five-day “We don’t know precisely what type of im- vaccinated. summit in Geneva to pledge new commit- mune response a vaccine needs to induce high The efficacy of RTS,S was ments to the collective efforts to control and efficacy and durable protection but significant evaluated in addition to exist- eliminate neglected tropical diseases (NTDs). progress is being made. In recent years, two ing malaria control measures, such as The summit coincided with the launch of independent vaccine approaches have been insecticide treated bed nets, which were used the WHO’s Fourth Report on NTDs, show- associated with high levels of efficacy (approx- by about 80% of the children and infants in ing transformational progress against these imately 90%) in controlled human infection the trial. debilitating diseases, and a commitment by models conducted in the United States.” In April of this year, the World Health Or- the United Kingdom to more than double its Therefore, researchers are optimistic that ganization announced that Ghana, Kenya, and funding for NTDs. a vaccine can be developed to induce effective Malawi will take part in a WHO-coordinated Additionally, an April coalition of global immune responses against the parasites that pilot implementation program that will make health organizationsCompliments has called on the G20 to cause malaria. the malaria vaccine available in selected areas provide leadership in combating pandemics, This optimism is also fueled by progress of beginning in mid-2018. drug resistance, and major poverty-related the most advanced vaccine: GlaxoSmithKline’s The WHO pilot program will assess and neglected diseases, which include drug Mosquirix (RTS,S,). In July 2015, this vaccine whether the vaccine’s protective effect in chil- resistant strains of HIV/AIDS, TB, malaria, received a positive opinion from the Commit- dren 5 to 17 months old during Phase III test- diarrheal disease, and pneumonia. tee for Medicinal Products for Human Use ing can be replicated in real life. Specifically,

(c) PharmaLinx LLC. Rights do not include promotional use. For distribution or printing rights, contact [email protected] The World Bank has estimated that, with- (CHMP) of the European Medicines Agency the pilot program will assess the feasibility of out additional resources, these diseases will for children 6 weeks to 17 months of age. delivering the required four doses of RTS,S, push an additional 28.3 million people into Mosquirix was developed to protect young the vaccine’s potential role in reducing child-

PharmaVOICE  June 2017 44 Malaria

hood deaths, and its safety in the context of FAST FACT routine use. One goal of the pilot program is to gather more information on the ability of the vaccine THE MALARIA VACCINES to prevent severe malaria and mortality, Dr. Birkett says. MARKET IS EXPECTED TO “In the Phase III trial, relatively few chil- dren experienced severe malaria,” he says. “The REACH $591.8 MILLION BY 2024. healthcare infrastructure associated with the Phase III trial was exceptional, which is not Source: Coherent Market Insights what you typically see in areas of Africa most impacted by malaria. The trial doesn’t give us an accurate sense of how the vaccine would actually work in terms of preventing severe Furthermore, protection was achieved with malaria and death in a real-world setting. just three doses of the vaccine and against a With a pilot implementation, as opposed to a strain of parasite similar to one in the vac- controlled study, the idea is to generate a more cine for at least 24 weeks. This Phase II trial accurate assessment of the potential impact of included 69 volunteers, 19 to 45 years old. the vaccine in a real-world setting.” Forty-five volunteers received at least one dose Dr. Birkett says the pilot will also aim to of the vaccine, 24 volunteers were control generate more safety data. subjects. “As is typical with vaccines evaluated in About 2 billion sporozoites (PfSPZ) pro- clinical trials, there are safety signals from the Over the past 15 years, there has been duced by Sanaria have been injected in clinical Phase III study that need to be followed up as an enormous effort to reduce malaria trials. Dr. Hoffman says the company’s manu- the vaccine is administered to more children,” prevalence worldwide. These efforts facturing of the vaccine is unique. he says. “Parasites are much more complex than vi- have decreased malaria cases by 50%. PATH MVI has partnered with GSK for ruses or bacteria,” he says. “Our manufacturing more than a decade on the development of this SLAVA ELAGIN process is unique in that we are manufacturing vaccine, which required building infrastruc- a whole parasite and using mosquitoes as the Meridian Bioscience tures at the sites where the clinical trials were bioreactor.” conducted, Dr. Birkett says. PharmaVOICEDr. Hoffman says the company is cur- “The data generated from this pilot could rently developing the protocol for a Phase III set the stage for a broader policy recommenda- The GSK spokesperson says once a WHO study, which will be conducted in the United tion for this vaccine going forward,” he says. pre-qualification is granted, GSK will apply States, Europe, and Africa. In September 2016, “Current data suggests this vaccine will most for marketing authorizationof in countries in Sanaria received FDA Fast Track designation likely have the greatest public health impact sub-Saharan Africa on a country-by-country for its preventive PfSPZ-Vaccine for malaria. in medium-to-high transmission settings. For basis. about 10 years, we’ve worked closely with Sanaria is another company working to Malaria Treatment and Research malaria endemic countries on a tool we call the developing a vaccine against malaria. Sanaria Malaria Vaccine Decision-Making Framework PfSPZ-Vaccine is being developed against Effective malaria drugs are available, but to help ensure countries considering the intro- . It is composed of live, they may be losing their effectiveness in some duction of a malaria vaccine take into radiation-attenuated purified, cryopreserved places as malaria-causing parasites have devel- account all the information necessary malaria parasites, which are administered in oped resistance. Industry experts say changes to make the most informed decision an injection. in mosquito behavior and insecticide resistance possible.” In February, Sanaria announced results of are increasing concerns about drug resistance. Two of the WHO’s inde- a study done in Mali that found protection “The plasticity of the mosquito and the pendent advisory groups — was sustained for the 24 weeks of the study. Plasmodium parasite has led to increasing re- the Strategic Advisory Group In the Mali study, five doses of PfSPZ vaccine sistance to antimalarial medicines and in- of Experts (SAGE) on Immu- were administered to 44 subjects and saltwater secticides,” says Andrzej Piotrowski, M.D., nization and the Malaria Policy placebo was given to 44 subjects. Volunteers Ph.D., medical monitor, KCR. “Resistance Advisory Committee (MPAC) — were followed for six months through the sub- to artemisinin-based combination therapies are jointly reviewing the evidence sequent rainy season to determine the presence has been detected in Southeast Asia – Greater base for RTS,S and they will make a of malaria parasites in the blood. The vaccine Mekong subregion. The spread of these strains joint policy recommendationCompliments for how it might was 52% protective. to Africa or the Indian subcontinent could be be used, says a spokesperson for GSK. Another study of Sanaria PfSPZ-Vaccine catastrophic.” Following the WHO policy recommenda- was conducted by a team of clinical investiga- Artemisinin-based combination therapies tion, GSK will also submit an application to tors at the Naval Medical Research Center and are the treatment of choice for uncomplicated the WHO for pre-qualification of RTS,S. Walter Reed Army Institute of Research. This malaria in sub-Saharan Africa. A pre-qualification decision is used by the study found that that the vaccine protected “However, their administration over a

(c) PharmaLinx LLC. Rights do not include promotional use. For distribution or printing rights, contact [email protected] United Nations’ agencies and other large scale against Plasmodium falciparum malaria when three-day period is associated with treatment public procurement agencies to help inform clinical trial participants were exposed to two adherence problems resulting in reduced effec- vaccine purchasing decisions. strains of parasites. tiveness of currently recommended antimalar-

45 June 2017  PharmaVOICE Malaria

ials,” Dr. Piotrowski says. “The development of a single-dose combination therapy would constitute a breakthrough in the control of Malaria at a Glance malaria. This innovative treatment approach would simultaneously close the effectiveness MALARIA IN THE UNITED STATES MALARIA WORLDWIDE gap of the current three-day regimens. It Malaria was eliminated from the United 3.2 billion people live in areas would also revolutionize population based interventions in the context of malaria elimi- States in the early 1950s. at risk of malaria nation campaigns.” Between 1,500 and 2,000 cases of malaria transmission in 106 Dr. Piotrowski says new lines of drugs are reported every year in the United States, countries and territories. must be explored before existing drugs lose almost all in recent travelers. Reported The World Health Organization their efficacy. malaria cases reached a 40-year high of estimates that in 2015 malaria The development pipeline for malaria has 1,925 in 2011. caused 214 million clinical episodes, never been stronger, with promising new tools to detect, treat, and prevent the disease, such First- and second-generation immigrants and 438,000 deaths. as innovative diagnostics, medicines, vaccines, from malaria-endemic countries returning vector control products, and improved mecha- to their “home” countries to visit friends and BIOLOGY, PATHOLOGY, EPIDEMIOLOGY nisms for surveillance and response. relatives tend not to use appropriate Among the malaria species that infect There are at least 25 projects in the global malaria prevention measures and thus are humans, P. vivax and P. ovale can develop malaria vaccine pipeline as well as 47 medi- cines and 13 vector control products. There are more likely to become infected with dormant liver stages that can reactivate also several next-generation diagnostic tools malaria. after symptomless intervals of up to 2 (P. and reference methods currently in develop- Between 1957 and 2015, in the United vivax) to 4 years (P. ovale). ment, with many expected to be introduced in States, 63 outbreaks of locally transmitted Pregnant women have increased the next decade. mosquito-borne malaria have occurred; in susceptibility to P. falciparum malaria; in “The development and deployment of such outbreaks, local mosquitoes become malaria-endemic countries, P. falciparum these tools, supported by strategies that ensure rapid uptake in target populations, enhanced infected by biting persons carrying malaria contributes to 8% to 14% of low birth mechanisms for information management, parasites (acquired in endemic areas) and weight, which in turn decreases the chance surveillance, as well as continued financial then transmit malaria to local residents. of a baby’s survival. and political commitment are all essential to PharmaVOICE achieving global eradication of malaria,” Dr. Source: Centers for Disease Control Piotrowski says. He says in Africa, resistance has been detected against two or more insecticides in erazines. Nonclinical ofand clinical data suggest Development of KAF156 and KAE609, two-thirds of those countries where malaria is KAF156 has the potential to be effective the company’s second program, is a joint endemic. Up to 80% of infections are asymp- against infections resistant to all currently research program with the Novartis Institute tomatic, and parasites remain available antimalarial drugs. for Tropical Diseases (NITD), the Genomics dormant for months or even years after initial The company is developing KAF156 with Institute of the Novartis Research Foundation, infection. support from Medicines for Malaria Venture, and the Swiss Tropical and Public Health In- “The causes of drug resistance are generally in collaboration with the Bill & Melinda Gates stitute, supported by the Wellcome Trust, the mutations or changes in the copy number of Foundation. Singapore Economic Development Board, and genes relating to the drug’s parasite target,” In September 2016, Novartis published Medicines for Malaria Venture. he says. proof-of-concept study results in the New Dr. Hughes stresses the partnerships No- Leaders from Novartis — whose Coartem England Journal of Medicine showing that vartis has are not only to develop new medi- is recommended by the Centers for Disease KAF156 demonstrated activity against both cines for malaria, but also to make sure they Control and Prevention (CDC) as first-line Plasmodium falciparum and Plasmodium vivax are distributed to those who need them. For treatment for acute, uncomplicated malaria malaria, including artemisinin-resistant par- example, the NITD, part of the Novartis In- infections — say they are monitoring the use asites. Dr. Hughes says both compounds are stitutes for BioMedical Research (NIBR), was of the drug to assess resistance. beginning Phase IIb programs, primarily in set up as a public-private partnership between “These data are helpful when we do our Africa. Novartis and the Singapore Economic Devel- clinical trials of new compounds; we are able The trial for KAF156 is an adaptive trial opment Board. to put the information into context and under- in several cohorts of patients to assess dosing In December the company launched SMS stand the target profileCompliments that we are looking for in adults and children. This trial will also for Life 2.0, which builds on the SMS for Life because we understand what works and where evaluate KAF156 in five sites in Asia to assess program launched by Novartis in 2009, which there might be gaps,” says David Hughes, treatment of resistant infections. used cell phones to manage stock-outs of ma- M.D., global program head of anti-infectives “Both of these drugs involve novel classes laria medicines in more than 10,000 health- development, Novartis. of medicines and novel mechanisms of action,” care facilities in sub-Saharan countries. The Novartis currently has two malaria pro- Dr. Hughes says. “These medicines came out new program will now add smartphones and

(c) PharmaLinx LLC. Rights do not include promotional use. For distribution or printing rights, contact [email protected] grams in development. KAF156, currently in of our high throughput screening efforts in tablet computers to address key operational Phase II, is the first compound from a novel partnership with academic and other partners challenges at peripheral healthcare facilities in class of antimalarials known as imidazolopip- to see what works against malaria parasites.” Kaduna State, Nigeria.

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