|Year : 2019 | Volume
| Issue : 1 | Page : 15-24
Partnering to fight malaria in India: Past, present and future
Kirandeep Samby, Hanu Ramachandruni, Jaya Banerji, Jeremy N Burrows, Penny Grewal Daumerie, Rob A.M. Hooft van Huijsduijnen, Stephan Duparc, Timothy N.C. Wells
Medicines for Malaria Venture, Geneva, Switzerland
|Date of Submission||27-Mar-2019|
|Date of Web Publication||7-May-2019|
Timothy N.C. Wells
Medicines for Malaria Venture, route de Pré-Bois 20, 1215 Geneva 15
Source of Support: None, Conflict of Interest: None
The global fight against malaria requires continual development of new tools. Collaborations in India have played a key role in MMV’s partnerships to discover, develop and deliver new medicines. Over the last decade, India has become a focal point of global medicinal chemistry, and combined with investments in basic science, this has led to the discovery of new potential drugs. India also brings significant experience to drug development, in clinical trials, but also in formulation and manufacturing. Finally, innovative new approaches in case management have streamlined impact at the level of communities and the patients.
Keywords: Access; drug discovery; malaria; vaccines
|How to cite this article:|
Samby K, Ramachandruni H, Banerji J, Burrows JN, Daumerie PG, Hooft van Huijsduijnen RA, Duparc S, Wells TN. Partnering to fight malaria in India: Past, present and future. J Vector Borne Dis 2019;56:15-24
|How to cite this URL:|
Samby K, Ramachandruni H, Banerji J, Burrows JN, Daumerie PG, Hooft van Huijsduijnen RA, Duparc S, Wells TN. Partnering to fight malaria in India: Past, present and future. J Vector Borne Dis [serial online] 2019 [cited 2020 Sep 29];56:15-24. Available from: http://www.jvbd.org/text.asp?2019/56/1/15/257769
| Introduction|| |
Malaria remains one of the world’s deadliest infectious diseases, with an estimated 435,000 deaths in 2017. Although, there has been significant progress in reducing the incidence and mortality over the last decade, the recent reports show that this progress is stalling. The fight against malaria needs both new tools: medicines which can optimally treat and protect, and new insecticides. The fight also requires new methodologies for better deploying the available tools.
Malaria in India
India plays a key role in the overall picture of malaria control for several reasons. First, 70% of the global malaria burden occurs in nine African countries and India. Among these countries, only India recorded a substantial decline in cases in 2017, with three million fewer cases than in the previous year, a 24% drop. Most of these cases are from the more common parasite, Plasmodium falciparum, which is responsible for most of the 17,000 annual deaths. However, India is also the country with the highest estimated number of cases of P. vivax. World Health Organization (WHO) estimates that India is home to 48% of all P. vivax cases in the world. Vivax malaria can relapse: new cases arise by activation of dormant forms in the liver. Untreated, this can lead to repeated infections without an infectious insect bite. As such, this results in increase in mortality due to chronic anaemia and other associated pathology. Estimating the number of cases is a major challenge, given the association of malaria with poverty; concerns that the number of cases was severely underestimated have led to a renewed drive to improve the accuracy of surveillance.
Another urgency for malaria elimination efforts in India relates to the country’s geographic location. The mainstay of malaria drug therapy worldwide is artemisinin combination therapies (ACT). These are combinations of a derivative of the natural product artemisinin, with a partner drug. There are now four fixed-dose combinations that are recommended by the WHO malaria treatment guidelines and are registered by stringent regulatory authorities or prequalified for purchase by UN agencies. All the compounds partnering with artemisinin in ACT are effectively next generations of quinine and chloro-quine. The fifth option is a loose combination of artesunate and sulphadoxine-pyrimethamine, which remains the standard of care in India, except for the northeastern states. Unfortunately, the epicentre of resistance generation appears to be in the Greater Mekong Sub-region, where resistance to artemisinin was first described in 2008,,, and a molecular marker for this resistance identified as mutations in the Kelch13 gene. In addition, resistance to three of the potential partner drugs (mefloquine, piperaquine, amodiaquine) leading to lack of adequate clinical response has been described in the Greater Mekong. Though clinical failure due to inadequate response to artemisinin combination therapies has not been observed in India to date, in 2015, Kelch13 mutant P. falciparum parasites with resistance against artemisinin were found in Myanmar at just 25 km from the border with India. At that time, Kelch13 mutations were also found in India, but these were not yet associated with resistance,.
Taken together, this points to the two challenges of malaria control. First, it is important to have optimal deployment of the medicines available: for treating patients, and also for protecting vulnerable populations. (The efforts to produce a highly effective vaccine have been substantial, but to date the best provides only 30–50% protection). Second, it is important to develop new medicines which will be able to combat the multi-drug resistant strains of malaria. Such medicines need to be developed with the patient in mind: simplifying the regimen where possible, and child-friendly,,. Historically, India has played a key role in both of these processes. The historical investment in basic biology in India dovetails with the contribution from medicinal chemistry-based companies that have emerged in the last two decades. In drug development, India has played a key role in clinical evaluation, providing important insights into the response of both P. falciparum and P. vivax. India has been described as the pharmaceutical manufacturing engine room of the world; and Indian organisations have played key roles in optimising manufacturing, and also in formulation development. Finally, India has participated in multi-centre clinical trials to establish the safety and efficacy of new antimalaria treatments.
Medicines for Malaria Venture (MMV) is a non-profit organisation set up almost 20 years ago to catalyse the discovery, development and delivery of new medicines to control and eventually drive the elimination of malaria. In this review, we highlight a few of the areas where collaborations in India are helping the agenda to reduce the impact of malaria.
India as a Leader in Antimalarial Drug Discovery
Models for malaria developed at the CSIR-Central Drug Research Institute
India is a major player in malaria research. Over the last 10 years the country has produced over 4600 publications on malaria (Scopus, Elsevier B.V.). Among these players, the CSIR-Central Drug Research Institute in Lucknow, India stands out; a review in 2011 noted it was the largest publisher on antimalarial drug discovery for the past five years. The contributions by the CSIR-Central Drug Research Institute were recently reviewed (summarized in [Table 1]), along with the history of other malaria control measures in the country. Some of the molecules that India helped develop, like tafenoquine, pyronaridine and dihydroartemisinin are today part of standard treatments for malaria. Bulaquine (Elubaquine, CDRI-80/53) successfully completed clinical trials and is marketed in India since 2000.
|Table 1: Antimalarial drug discovery at CSIR-Central Drug Research Institute, Lucknow, India|
Click here to view
The commitment to find new cures for relapsing P. vivax malaria is a good example. Since the 1950s, the WHO-recommended regimen for preventing relapse has been a 14-day course of primaquine, in patients with adequate G6PD (glucose-6-phosphate dehydrogenase) activity. The issue is that since the disease is asymptomatic for this stage, patient compliance with the regimen was poor, and a new, simpler therapy was needed. Early work was supported by the use of P. cynomolgi infections of Rhesus monkey at the CSIR as a model for P. vivax infection of humans. This model was set up and used since the late 1970s in collaboration with the WRAIR (the U.S. Walter Reed Army Institute of Research), testing 80–100 compounds over the next decade. One of these compounds, WR238605, was of particular interest, as it had established a curative dose in the experimental model. Subsequent clinical studies showed that it had a long duration of effect, and could potentially replace 14 days of primaquine with a single dose. This early work formed the basis of further clinical development for the compound, now called tafenoquine, which was taken on by GlaxoSmithKline and MMV as collaboration in 2008. India participated in the tafenoquine Phase-2b dose finding studies. Subsequent clinical trials culminated in the submission and approval in 2018 by both the US and Australian regulators,. The next stage for this important medicine is the regulatory submission, approval and distribution of this medicine throughout countries with a significant P. vivax burden. Beyond the discovery and development role of India, it is important to note that India plays an additional role: tafenoquine is also manufactured by M/s. Piramal in India.
Another key role played by CSIR was in the development of the clinical data supporting the use of rectal formulations as a pre-referral emergency treatment for children suffering from severe malaria/cerebral malaria,. In many remote places, children with severe malaria need to be brought to a health care centre for intravenous artesunate treatment. However, since travel in the hours of darkness is problematic, WHO recommends the use of artemisinin suppositories as an easy to administer stop-gap: Improving the outcome of patients who live more than 6 h from treatment centres. The manufacturing of the suppositories was pioneered in India by M/s. Cipla and M/s. Strides, and products have now been prequalified by the WHO. In the last two years, almost 2 million suppositories have been distributed in Africa.
Pioneering new, synthetic drugs based on the artemisinin class
A major problem of the artemisinin drug class (a component in all ACTs) is that these compounds cannot be synthesized completely. Originally, one key issue with artesunate was the price fluctuation and availability. MMV helped to set up a partnership which led to the development of fully synthetic endoperoxides—One of which was the 1, 2, 4-trioxalane OZ277. This was taken into early clinical trials by M/s. Ranbaxy as RB–11160, with the studies being led by Dr Neena Valecha’s team under the aegis of the ICMR–National Institute of Malaria Research in New Delhi,,,,,,.
The compound (renamed arterolane) was developed as a fixed-dose combination with piperaquine. It is manufactured by M/s. Sun Pharmaceuticals and is presently being marketed in India and a number of African countries to treat malaria, with informal estimates of around one million treatments per year. CDRI also delivered the synthetic trioxolane CDRI97-98 which completed Phase-I in 2014.
New drug candidates from M/s. AstraZeneca Institute, Bengaluru, Karnataka
In 2010, MMV and M/s. AstraZeneca initiated a strategic collaboration to deliver candidate antimalarial drugs from the state-of-the art discovery site based in Bengaluru, Karnataka. Through this collaboration, a 500,000 compound library from M/s. AstraZeneca was screened in Queensland, Australia, by Professor Vicky Avery, delivering hits that led to new projects. The fruit of this important collaboration was three-fold. First, at the end of 2015 a pre-clinical candidate AZ412 (MMV253), a novel triaminopyrimidine was nominated by the team (led by Dr Sambandamurthy, Dr Hameed and the late Dr Solapure). This molecule has a novel mode of action and resistance (through the parasite vacuolar ATPase). In vitro and in the SCID mouse model it demonstrated rapid parasite killing, acting even faster than chloroquine. Importantly, this invention was solely the discovery of Indian scientists based in India, and represents arguably the first truly home-grown chemical series. After the decision by M/s. AstraZeneca to withdraw from infectious disease drug discovery and close the Bengaluru site, MMV took the initiative to find an Indian partner to continue the project. The compound was taken in by M/s. Zydus Cadilla, who have worked to optimise the synthesis and to make the medicine affordable, and also completed the preclinical safety studies required before testing in humans, now scheduled for early 2019. Second, from other two series being followed up: A benzimidazole series was transferred to University of Campinas in Brazil, a good example of a South-South transfer of an innovative project. Third, Dr Narayanan, former Head of M/s. AstraZeneca Discovery India, established the Foundation for Neglected Disease Research (FNDR) which has continued to progress some of these key chemical series.
India as an innovative partner for medicinal chemistry
One of the major trends over the last two decades has been the emergence of a world class contract chemistry culture in India, which has now blossomed into full-fledged drug discovery. Although the initial attraction of working in India was the much lower cost structure, it is now fair to say that much of the synthesis and some of the design expertise in the new generation of chemists are in India. Historically, many of the drug discovery collaborations set up by MMV have strongly relied on partners providing synthetic and medicinal chemistry as a key supporting component. The earliest collaborations were with M/s. Syngene (Bengaluru) who supported projects with the Universities of Cape Town (South Africa) and University of Texas South Western (U.S.) amongst others, as part of international projects that developed clinical candidates (MMV048 and DSM265, respectively). They also have supported projects with industrial partners such as M/s. Sanofi and M/s. Celgene, where Indian medicinal chemistry was able to provide critical mass. Other early collaboration involved M/s. Eurofins Advinus (Bengaluru, India). More recently, partnerships with M/ s. TCG Life Sciences (Kolkata) have supported projects with M/s. Novartis (Emeryville, USA), TropIQ (The Netherlands), Imperial College London (U.K.) and Drexel Med University (Philadelphia, U.S.). In 2015, MMV and Daiichi Sankyo Research Centre in India, supported by the Global Health Innovative Technology (GHIT) Fund started a collaboration to work on hits identified through phenotypic screening of Daiichi Sankyo’s library. The program went into lead optimisation stage, and subsequent to site closure in India, the program was shifted to the Shinagawa site in Japan. M/s. GVKBio (Hyderabad) and M/s Eurofins Advinus collaborated with MMV Open team to make useful compounds, and helped with series generation when MMV Open screens identified hits. To emphasise the importance of these collaborations to the overall drug discovery portfolio, at its peak, MMV has funded over 60 chemists in India across all projects and partners. A fact that is not obvious on the surface is that for every scientist working in discovery at MMV in Geneva, the organisation has 3–4 Indian scientists working with them. Indian scientists from these partner organisations have been recognized as co-authors on high impact papers, and as recipients of MMV Project of the Year awards.
Setting up a novel Plasmodium vivax malaria assay
India is the country with the highest burden of P. vivax, and so it is natural that this should be a priority for basic research. One issue is that unlike for P. falciparum, malaria blood-stage vivax malaria parasites cannot be cultured continuously in vitro. This means that the sporozoites (which develop in the mosquito, and can be used to infect liver cells) can only be obtained from the blood of vivax-infected patients. MMV’s strategy, therefore, has been to bring the assays to where the patients are: focusing the development of vivax liver-stage assays in collaboration with vivax malaria-endemic countries, including India. With the support of Dr Ghosh at the National Institute of Malaria Research (NIMR), Dr Sundaramurthy at the National Centre for Biological Sciences (NCBS) and Dr Narayanan at FNDR (all based in Bengaluru) the heroic logistical challenge of ferrying vivax-fed mosquitoes (from NIMR Mangaluru to Bengaluru), and the ultimate infection of hepatocytes with vivax sporozoites in NCBS and FNDR was overcome. The assay remains in development, but obtaining an Indian vivax liver-stage assay remains a priority, given the known geographical diversity of parasites. The NIH-funded International Center of Excellence for Malaria Research (ICEMR) led by Dr Pradip Rathod, based in Goa, has similarly established both field isolate testing and capabilities to potentially support vivax liver-stage assays, and these interactions will be further explored.
Target-based drug discovery
The International Centre for Genetic Engineering and Biotechnology has a Centre based in New Delhi with world class expertise in genetics, target validation, protein expression and structural biology, and five groups working in Malaria Biology and Drug Discovery. Prof Amit Sharma is the leading global expert on Plasmodium amino acyl-tRNA synthetases, and through collaboration with MMV and other partners is playing a key role in maximizing the potential of a target family with increasingly strong validation and demonstrated drug discovery tractability. MMV’s strategy with Professor Sharma has been to focus on protein expression and assay development of prioritized amino acyl-tRNA synthases, including prolyl, phenylalanyl, lysyl, threonyl and other synthases. This has been performed in collaboration with the Bill & Melinda Gates Foundation-funded Drug Accelerator; MalDA) and others. His group has focused on expression of P. falciparum and P. vivax enzymes (from an efficacy perspective) but also the mammalian counter parts in mouse, rat, dog and human (from an off-target, safety perspective). Finally, where possible, structural biology expertise has enabled the delivery of protein-ligand X-ray crystal structures to support drug discovery. His expertise has supported academic groups (for example at the Broad Institute, Cambridge, U.S.) and pharmaceutical partners (for example at Takeda, Japan), as well as providing support for projects considered for high-throughput screening with the Global Health Drug Discovery Institute in Beijing, China.
Open Drug Discovery in India
MMV is committed to open publication of data and open access to compounds and data where feasible. All these activities come under an internal framework which has been called MMV Open; details about the collections can be found at www.mmv.org/mmv-open. Initial work on phenotypic screening (testing compounds for their activity directly against the blood-stage parasites) defined over 25,000 compounds with activity in the low-to submicro molar range. Although the structures were available in online databases, there was a request to make these compounds physically available: a project launched in 2011, called Malaria Box allowed the free distribution of 400 representative compounds. Following the success of this, a second-generation collection including new screening hits from a wider variety of pathogens was funded by the Bill & Melinda Gates Foundation, resulting in a new set called Pathogen Box,, launched in 2015. Here, the collaboration between MMV and TCGLS (Kolkata) has been a critical success factor, since many of these compounds had to be synthesised. An important by-product of this work, therefore, is the availability of synthetic protocols, which can be shared with partners who find new activities for the Pathogen Box compounds. This work has been particularly important in the development of a third collection, called Pandemic Response Box in collaboration with DNDi (Drugs for Neglected Diseases Initiative). This Pandemic Response Box is supported financially by UK Department for International Development and other government partners. This is a collection of 400 antibacterial, antifungal and antiviral compounds which again is being distributed free of charge. Finally, MMV was a partner with the Open Source Drug Discovery India project, specifically interacting with the CDRI based in Lucknow. As more and more important discoveries are made using the MMV Open boxes, there has been an increasing call for more support and medicinal chemistry advice. In 2018, MMV moved the operational leadership for this project to India, under the management of Dr Kirandeep Samby (Chandigarh).
Developing an effective vaccine against malaria remains extremely challenging. Though GSK has been able to introduce a vaccine, RTS,S to young children in Africa,,, it has limited efficacy and use, and is mostly inactive in regions where P. vivax predominates. In the last decade, scientists at Indian institutes like ICGEB, CSIR-Centre for Cellular and Molecular Biology (CCMB), School of Biotechnology, Jawaharlal Nehru University (JNU) and Tata Institute of Fundamental Research (TIFR) have been working to develop vaccines targeting different stages of the parasite’s life cycle.
The malaria group at ICGEB has undertaken efforts to develop vaccines for both P. falciparum and P. vivax in the Multi Vaccines Development Program. With funding support from the Department of Biotechnology and multiple international agencies including PATH, Malaria Vaccine Initiative (MVI) and European Vaccine Initiative (EVI) a recombinant blood-stage experimental vaccine (JAIVAC1) was developed against P. falciparum, which has undergone Phase-I testing. Translational activities like GMP production, preclinical immunogenicity, and GLP toxicity were conducted with the help of Indian partners including M/s. Bharat Biotech, Hyderabad. Though the vaccine produced good antibody responses to PfF2 it was not taken further due to lack of efficacy. As a follow-up to this, the group developed a novel approach to improve the immunogenicity through its next vaccine candidate JAIVAC-2, and is also developing a recombinant vaccine (PvDBPII) against P. vivax malaria.
A team of scientists at ICGEB and SBT, JNU has shown that antibodies against Cysteine-rich protective antigen (CyRPA), which is involved in the protein-protein interaction with PfRH5/PfRipr on the merozoite surface displayed potent strain-transcending invasion inhibition, similar to one observed for PfRH5.
Another group, at TIFR, has identified a five-amino acid segment in Plasmodium enolase that can be used to develop antibodies when displayed on novel nanoparticles developed by collaborators at the University of Maryland. The group has identified monoclonal antibodies against this epitope which have shown that inhibition is species-and strain-transcending, and further efforts are ongoing to develop this into an effective vaccine.
India as a WorldWide Supplier of Antimalarial Medicines
Among malaria-endemic countries, India is unique in its capacity to produce pharmaceuticals, both for national and international use. As previously mentioned, in terms of new chemical entities, M/s. Sun Pharmaceuticals located in Gurugram, manufactures Synriam™, a product discovered as part of an MMV-sponsored collaboration, and developed by M/s. Ranbaxy with support from the Indian government. More importantly, seven Indian companies provide antimalarial medications to the Global Fund for further distribution [Table 2].
|Table 2: Antimalarials produced in India for the Global Fund (www.theglobalfund.org)|
Click here to view
The impact of Indian manufacturing on the price and therefore, availability of ACTs has been dramatic. Artemether-lumefantrine was originally developed as a co-formulation by M/s. Novartis, and in a paediatric form as Coartem-D in collaboration with MMV. After launch in the early 2000s, Novartis was able to increase the efficiency of production, and the price for an adult course of therapy dropped from around $4 to $1.50. However, with the entry of Indian manufacturers (initially Cipla, but now Ipca and others) the price has dropped again to below $0.70 per adult treatment. This is an important saving, bearing in mind that the Global Fund and other UN agencies are aiming to purchase 150–200 million courses of treatment. Careful supply chain management, and integration of local APIs were critical to this price decrease. Cipla has also played a key role in manufacturing mefloquine-artesunate, originally developed as a fixed-dose formulation with DNDi. The Indian-manufactured material was sufficiently high-quality to enable product to be prequalified by WHO for procurement by UN agencies. Although, the relatively high price of mefloquine makes this a niche product, it is still important: in the Greater Mekong sub-region, where it has been the mainstay of fighting piperaquine resistant malaria.
India has also played a key role in producing new options for the management of severe malaria: as mentioned above, Cipla and Strides have manufactured a suppository for pre-referral treatment of severe malaria, which is now being deployed widely in Africa. Finally, Ipca now produces WHO-prequalified artesunate for injection–for the intravenous and intramuscular treatment of severe malaria. Given the number of children requiring artesunate for severe malaria (between 2011 and 2017 over 100 million vials were produced by the Chinese company Guilin, a division of Fosun Pharmaceuticals), it is important that the global health community has multiple suppliers.
Medicines can be used for protecting vulnerable populations as well as for treating disease. WHO recommends Seasonal Malaria Chemoprevention with monthly amodi-aquine and sulphadoxine-pyrimethamine to each child under the age of 5 years in the sub-Sahel, throughout the rainy season. The initial medicines to supply this need were produced by the Guilin. However, the success of the program (16 million children were protected in 2017) and the potential to scale up (this number could become 50 million if children up to the age of 10 were included), highlights the need for a second manufacturer. In this case, the manufacturer is S-Kant Health Care Ltd. (Mumbai), who have added innovation by making the medicine taste-masked (sweetened) and dispersible. These additional qualities are important, given that the target population are small children. The Indian manufactured new life cycle management activities are summarised in [Table 3].
|Table 3: Indian pharmaceutical manufacturers who develop quality assured antimalarial drugs in collaboration with the Medicines for Malaria Venture|
Click here to view
In addition, several Indian companies also produce quality antimalarial drug substances. Their innovation in developing efficient and cheaper synthetic routes have contributed to driving down the costs of antimalarial medicines worldwide. Such medicines are produced by Anuh Pharmaceuticals, Calyx Pharmaceuticals, Ipca Laboratories, Managalam Drugs and Organics, Ltd, Micro Laboratories Ltd., Mylan Laboratories Ltd and Solara Active Pharma Sciences Ltd, all of which supply API (active pharmaceutical ingredients) that are prequalified by the WHO.
India a Critical Partner of Medicines for Malaria Venture
Indian organizations play an important role in the partnerships that are led by Medicines for Malaria Venture (MMV). MMV’s past and current Indian partners are shown in [Table 4]. These entities, as well as 10 individual consultants (not listed here), play various roles in moving drugs forward along the malaria pipeline or supporting efforts to improve access to malaria services.
|Table 4: Indian organizations that partner with Medicines for Malaria Venture|
Click here to view
Reaching malaria patients: The comprehensive case management programme
As discussed above, India has played a key role in the clinical studies supporting the registration of new artemisinin combination therapies, new antirelapse therapies, and new treatments for severe malaria. However, even after registration of a new product, there is still a need for ongoing clinical studies to optimise use on the ground.
As an additional approach to eliminate malaria, India is also pioneering improved processes to identify and treat malaria patients in settings that lack good infrastructure. The comprehensive case management programme (CCMP) was initiated in 2013 to assess the impact of improved coverage and quality of diagnosis and treatment services and surveillance on malaria transmission in different settings in the State of Odisha, against the backdrop of prevailing vector control measures. Pairs of intervention and control sub-districts (blocks), each with a population of about 100,000 inhabitants, were selected in four districts with different transmission intensities. CCMP is a collaborative programme between the NIMR, and the State NVBDCP, Odisha, with technical and financial support from MMV [Figure 1].
|Figure 1: Key elements of comprehensive case management programme (CCMP).|
Click here to view
The key difference between the CCMP intervention areas and the control areas is stringency of the service: ensuring no stock-outs of malaria tests and drugs occur. Well-trained and motivated community health workers (ASHAs) are important to verify surveillance data, stratify areas based on risk factors and appoint alternative providers to underserved areas. When appropriate they also initiate ‘Mass Screening and Treatment’ (MSAT) in malaria-prone areas to drive down the reservoir of infection. MSAT was incorporated in the Indian National Strategic Plan on Malaria Elimination, based results from this program. A full report on this activity is published in the same edition of this journal.
This program has led to significantly higher rates of testing for malaria, more cases being diagnosed and treated at the ASHA level (the village health workers), and to a better understanding of the epidemiological situation on a village or sub-centre level allowing for targeted interventions. CCMP provided insights into how to achieve universal coverage of malaria services and improve its quality through a routine, state-run programme.
The data highlight the value of improved surveillance and the need of additional malaria officers who are trained to analyse data and take action based on it. Odisha has already started scaling up the approaches developed in CCMP to other areas in the state, using their own resources. As India moves towards the elimination of malaria, CCMP is providing valuable lessons to accelerate this process.
| Summary|| |
Among malaria-endemic countries, India is uniquely positioned by its strong commitment to all stages of drug discovery, development, manufacturing and deployment of new medicines which can be part of the agenda to reduce the impact of malaria. This is critical for India, given the impact of the disease on the country’s population, but also the risk posed by multidrug resistance on the eastern borders. The last two decades have seen a substantial increase in the number of collaborations both between Indian groups and MMV, but also between Indian research groups, each tackling aspects of eliminating the disease. The drive to eliminate malaria elsewhere is critically dependent on the supply of medicines from India, and companies in India continue to innovate by providing new formulations and life cycle management. The many examples in this review illustrate how the country’s talents and other assets team up with international partners to develop new molecules, improve global access to medicines and pioneer best procedures that may also be applicable in other malaria-endemic regions.
| Acknowledgements|| |
The authors thank Paul Willis, Benoît Laleu and Brice Campo (all at the Medicines for Malaria Venture) for their contribution. This report was funded by the Medicines for Malaria Venture. MMV donors are listed on the MMV website (http://www.mmv.org/about-us/our-donors).
Conflict of interest
The authors declare no conflict of interest.
| References|| |
Rosenthal PJ, John CC, Rabinovich NR. Malaria: How are we doing and how can we do better? Am J Trop Med Hyg
Million Death Study Collaborators—Bassani DG, Kuma R, Awasthi S, Morris SK, Paul VK, et al
. Causes of neonatal and child mortality in India: A nationally representative mortality survey. Lancet
Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al
. Artemisinin resistance in Plasmodium falciparum
malaria. N Engl J Med
Htut ZW. Artemisinin resistance in Plasmodium falciparum
malaria. N Engl J Med
Taylor SM, Juliano JJ, Meshnick SR. Artemisinin resistance in Plasmodium falciparum
malaria. N Engl J Med
(18): 1807; Author reply 1808.
Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al
. A molecular marker of artemisinin-resistant Plasmodium falciparum
Mishra N, Prajapati SK, Kaitholia K, Bharti RS, Srivastava B, Phookan S, et al
. Surveillance of artemisinin resistance in Plasmodium falciparum
in India using the Kelch13 molecular marker. Antimicrob Agents Chemother
Mishra N, Bharti RS, Mallick P, Singh OP, Srivastava B, Rana R, et al
. Emerging polymorphisms in falciparum Kelch 13
gene in Northeastern region of India. Malar J
Muller IB, Hyde JE. Antimalarial drugs: Modes of action and mechanisms of parasite resistance. Future Microbiol
Burrows JN, Duparc S, Gutteridge WE, Hooft van Huijsduijnen R, Kaszubska W, Macintyre F, et al
. New developments in anti-malarial target candidate and product profiles. Malar J
Macintyre F, Ramachandruni H, Burrows JN, Holm R, Thomas A, Mohrle JJ, et al
. Injectable anti-malarials revisited: Discovery and development of new agents to protect against malaria. Malar J
Burrows J, Slater H, Macintyre F, Rees S, Thomas A, Okumu F, et al
. A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria. Malar J
Burrows JN, Waterson D. Discovering new medicines to control and eradicate malaria. Topics Med Chem
Dutta GP. New antimalarial drug discovery in India and future strategy for malaria control. Proc Nat Acad Sci
Krudsood S, Wilairatana P, Tangpukdee N, Chalermrut K, Srivilairit S, Thanachartwet V, et al
. Safety and tolerability of elubaquine (bulaquine, CDRI 80/53) for treatment of Plasmidium vivax
malaria in Thailand. Korean J Parasitol
Llanos-Cuentas A, Lacerda MV, Rueangweerayut R, Krudsood S, Gupta SK, Kochar SK, et al
. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax
malaria (DETECTIVE): A multicentre, double-blind, randomised, phase 2b dose-selection study. Lancet
Llanos-Cuentas A, Lacerda MVG, Hien TT, Velez ID, Namaik-Larp C, Chu CS, et al
. Tafenoquine versus primaquine to prevent relapse of Plasmodium vivax
malaria. N Engl J Med
Okebe J, Eisenhut M. Pre-referral rectal artesunate for severe malaria. Cochrane database of systematic reviews
von Seidlein L, Deen JL. Pre-referral rectal artesunate in severe malaria. Lancet
Valecha N, Looareesuwan S, Martensson A, Abdulla SM, Krudsood S, Tangpukdee N, et al
. Arterolane, a new synthetic trioxolane for treatment of uncomplicated Plasmodium falciparum
malaria: A phase II, multicenter, randomized, dose-finding clinical trial. Clin Infect Dis
Gautam A, Ahmed T, Sharma P, Varshney B, Kothari M, Saha N, et al
. Pharmacokinetics and pharmacodynamics of arterolane maleate following multiple oral doses in adult patients with P. falciparum
malaria. J Clin Pharmacol
Valecha N, Krudsood S, Tangpukdee N, Mohanty S, Sharma SK, Tyagi PK, et al
. Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated Plasmodium falciparum
malaria: A comparative, multicenter, randomized clinical trial. Clin Infect Dis
Patil C, Katare S, Baig M, Doifode S. Fixed dose combination of arterolane and piperaquine: A newer prospect in antimalarial therapy. Ann Med Health Sci Res
Toure OA, Rulisa S, Anvikar AR, Rao BS, Mishra P, Jalali RK, et al
. Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate dispersible tablets in paediatric patients with acute uncomplicated Plasmodium falciparum
malaria: A phase II, multicentric, open-label study. Malar J
Valecha N, Savargaonkar D, Srivastava B, Rao BH, Tripathi SK, Gogtay N, et al
. Comparison of the safety and efficacy of fixed-dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax
malaria: A phase III, multicentric, open-label study. Malar J
Lanteri CA, Chaorattanakawee S, Lon C, Saunders DL, Rutvisuttinunt W, Yingyuen K, et al. Ex-vivo
activity of endoperoxide antimalarials, including artemisone and arterolane, against multidrug-resistant Plasmodium falciparum
isolates from Cambodia. Antimicrob Agents Chemother
Shafiq N, Rajagopalan S, Kushwaha HN, Mittal N, Chandurkar N, Bhalla A, et al
. Single ascending dose safety and pharmacokinetics of CDRI-97/78: First-in-human study of a novel antimalarial drug. Malar Res Treat
Hameed PS, Solapure S, Patil V, Henrich PP, Magistrado PA, Bharath S, et al
. Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate. Nat Commun
Ramachandran S, Hameed PS, Srivastava A, Shanbhag G, Morayya S, Rautela N, et al
. N-aryl-2-aminobenzimidazoles: Novel, efficacious, antimalarial lead compounds. J Med Chem
Veale CGL. Unpacking the Pathogen Box: An open source tool for fighting neglected tropical disease. Chem Med Chem
Wells TNC, Willis P, Burrows JN, Hooft van Huijsduijnen R. Open data in drug discovery and development: Lessons from malaria. Nat Rev Drug Discov
Van Voorhis WC, Adams JH, Adelfio R, Ahyong V, Akabas MH, Alano P, et al
. Open source drug discovery with the Malaria Box compound collection for neglected diseases and beyond. PLoS Pathog
Duffy S, Sykes ML, Jones AJ, Shelper TB, Simpson M, Lang R, et al
. Screening the MMV Pathogen Box across multiple pathogens reclassifies starting points for open source drug discovery. Antimicrob Agents Chemother 2017;
61(9). pii: e00379–17
RTS,S Clinical trials partnership. Efficacy and safety of RTS,S/ AS01 malaria vaccine with or without a booster dose in infants and children in Africa: Final results of a phase 3, individually randomised, controlled trial. Lancet
Greenwood B, Doumbo OK. Implementation of the malaria candidate vaccine RTS,S/AS01. Lancet
Olotu A, Fegan G, Wambua J, Nyangweso G, Leach A, Lievens M, et al
. Seven-year efficacy of RTS,S/AS01 malaria vaccine among young African children. N Engl J Med
Chitnis CE, Mukherjee P, Mehta S, Yazdani SS, Dhawan S, Shakri AR, et al
. Phase-I clinical trial of a recombinant blood stage vaccine candidate for Plasmodium falciparum
malaria based on MSP1 and EBA175. PLoS One
Reddy KS, Amlabu E, Pandey AK, Mitra P, Chauhan VS, Gaur D. Multiprotein complex between the GPI-anchored CyRPA with PfRH5 and PfRipr is crucial for Plasmodium falciparum
eryth-rocyte invasion. Proc Natl Acad Sci USA
Dutta S, DasSarma P, DasSarma S, Jarori GK. Immunogenicity and protective potential of a Plasmodium
spp. enolase peptide displayed on archaeal gas vesicle nanoparticles. Malar J
Dutta S, Tewari A, Balaji C, Verma R, Moitra A, Yadav M, et al
. Strain-transcending neutralization of malaria parasite by antibodies against Plasmodium falciparum
enolase. Malar J
Pradhan S, Pradhan MM, Dutta A, Shah NK, Joshi PL, Pradhan K, et al
. Improved access to early diagnosis and complete treatment of malaria in Odisha, India. PLoS One
[Table 1], [Table 2], [Table 3], [Table 4]