The Pandemic Response Box─Accelerating Drug Discovery Efforts after Disease Outbreaks.

The current Covid-19 pandemic has underlined the need for a more coordinated and forward-looking investment in the search for new medicines targeting emerging health care threats. Repositioning currently approved drugs is a popular approach to any new emerging disease, but it represents a first wave of response. Behind this would be a second wave of more specifically designed therapies based on activities against specific molecular targets or in phenotypic assays. Following the successful deployment and uptake of previous open access compound collections, we assembled the Pandemic Response Box, a collection of 400 compounds to facilitate drug discovery in emerging infectious disease. These are based on public domain information on chemotypes currently in discovery and early development which have been shown to have useful activities and were prioritized by medicinal chemistry experts. They are freely available to the community as a pharmacological test set with the understanding that data will be shared rapidly in the public domain.

Reassessing therapeutic antibodies for neglected and tropical diseases.

In the past two decades there has been a significant expansion in the number of new therapeutic monoclonal antibodies (mAbs) that are approved by regulators. The discovery of these new medicines has been driven primarily by new approaches in inflammatory diseases and oncology, especially in immuno-oncology. Other recent successes have included new antibodies for use in viral diseases, including HIV. The perception of very high costs associated with mAbs has led to the assumption that they play no role in prophylaxis for diseases of poverty. However, improvements in antibody-expression yields and manufacturing processes indicate this is a cost-effective option for providing protection from many types of infection that should be revisited. Recent technology developments also indicate that several months of protection could be achieved with a single dose. Moreover, new methods in B cell sorting now enable the systematic identification of high-quality antibodies from humanized mice, or patients. This Review discusses the potential for passive immunization against schistosomiasis, fungal infections, dengue, and other neglected diseases.

Partnering to fight malaria in India: Past, present and future.

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.

Two successful decades of Swiss collaborations to develop new anti-malarials.

Over the last two decades there has been a renaissance in the pipeline of new drugs targeting malaria, with the launch of new products that help save the lives of children throughout the world. In addition, there is a wealth of new molecules both entering and progressing through clinical development. These bring hope for a new generation of simpler and more effective cures that could overcome the emerging threat of drug resistance. In addition, there is hope that some of these medicines will have prophylactic activity and can be used to protect vulnerable populations, given the absence of a highly effective vaccine. Switzerland has played a key role in the development of these medicines. First, the country has a long history of understanding the biology of parasites and the pharmacology of drug responses through the leadership of the Swiss Tropical and Public Health Institute in Basel. Second, the highly successful Swiss pharmaceutical industry brings, beyond excellence, a strong interest in neglected diseases, building on work at Hoffmann-La Roche in the last century and with more recent products from Novartis and other Swiss companies. Third, the emergence of product-development-partnerships, in this case led by the Medicines for Malaria Venture, based in Geneva, has helped to catalyze the development of new medicines and bring the community together within Switzerland and beyond. Finally, this progress would not have been possible without the engagement of the Swiss people and the support of the federal government through the Swiss Agency for Development and Cooperation (SDC), the State Secretariat of Education, Research and Innovation (SERI) and the Swiss Republic and Canton of Geneva.

A discovery and development roadmap for new endectocidal transmission-blocking agents in malaria.

Reaching the overall goal of eliminating malaria requires halting disease transmission. One approach to blocking transmission is to prevent passage of the parasite to a mosquito, by preventing formation or transmission of gametocytes. An alternative approach, pioneered in the veterinary field, is to use endectocides, which are molecules that render vertebrate blood meals toxic for the mosquito vector, also killing the parasite. Field studies and modelling suggest that reducing the lifespan of the mosquito may significantly reduce transmission, given the lengthy maturation process of the parasite. To guide the development of new endectocides, or the reformulation of existing molecules, it is important to construct a framework of the required attributes, commonly called the target candidate profile. Here, using a combination of insights from current endectocides, mathematical models of the malaria transmission dynamics, and known impacts of vector control, a target candidate profile (TCP-6) and a regulatory strategy are proposed for a transmission reducing agent. The parameters chosen can be used to assess the potential of a new medicine, independent of whether it has classical endectocide activity, reduces the insect and parasite lifespan or any combination of all three, thereby constituting an 'endectocidal transmission blocking' paradigm.

Injectable anti-malarials revisited: discovery and development of new agents to protect against malaria.

Over the last 15 years, the majority of malaria drug discovery and development efforts have focused on new molecules and regimens to treat patients with uncomplicated or severe disease. In addition, a number of new molecular scaffolds have been discovered which block the replication of the parasite in the liver, offering the possibility of new tools for oral prophylaxis or chemoprotection, potentially with once-weekly dosing. However, an intervention which requires less frequent administration than this would be a key tool for the control and elimination of malaria. Recent progress in HIV drug discovery has shown that small molecules can be formulated for injections as native molecules or pro-drugs which provide protection for at least 2 months. Advances in antibody engineering offer an alternative approach whereby a single injection could potentially provide protection for several months. Building on earlier profiles for uncomplicated and severe malaria, a target product profile is proposed here for an injectable medicine providing long-term protection from this disease. As with all of such profiles, factors such as efficacy, cost, safety and tolerability are key, but with the changing disease landscape in Africa, new clinical and regulatory approaches are required to develop prophylactic/chemoprotective medicines. An overall framework for these approaches is suggested here.

The antimalarial pipeline.

Over the past decade, new high-throughput phenotypic assays with malaria parasites have been developed, and these were used to screen millions of compounds. This effort, as well as improving older chemical scaffolds and optimising compounds against both known and new drug targets has resulted in the discovery of exciting new pipeline drug candidates that are now being evaluated in a number of clinical trials. In addition, the pitfalls and opportunities from this experience has led to a better definition of the optimal target compound and product profiles for new antimalarials, including medicines that treat uncomplicated or severe malaria, provide chemoprevention, or stop disease transmission, covering all stages of the parasite. An important decision element is how to combine these new molecules with existing ones in today's dynamic resistance landscape.

Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study.

BACKGROUND: DSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection. METHODS: This proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18-70 years, weighing 45-90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290). FINDINGS: Between Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common symptoms of malaria, and no patients had any treatment-related serious adverse events or adverse events leading to study discontinuation. INTERPRETATION: After a single dose of DSM265, P falciparum parasitaemia was rapidly cleared, whereas against P vivax, DSM265 showed less effective clearance kinetics. Its long duration of action provides the potential to prevent recurrence of P falciparum after treatment with a single dose, which should be further assessed in future combination studies. FUNDING: The Global Health Innovative Technology Fund, the Bill & Melinda Gates Foundation, the National Institutes of Health (R01 AI103058), the Wellcome Trust, and the UK Department of International Development.

Multidrug-resistant gonorrhea: A research and development roadmap to discover new medicines.

Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.

Both Intrinsic Substrate Preference and Network Context Contribute to Substrate Selection of Classical Tyrosine Phosphatases.

Reversible tyrosine phosphorylation is a widespread post-translational modification mechanism underlying cell physiology. Thus, understanding the mechanisms responsible for substrate selection by kinases and phosphatases is central to our ability to model signal transduction at a system level. Classical protein-tyrosine phosphatases can exhibit substrate specificity in vivo by combining intrinsic enzymatic specificity with the network of protein-protein interactions, which positions the enzymes in close proximity to their substrates. Here we use a high throughput approach, based on high density phosphopeptide chips, to determine the in vitro substrate preference of 16 members of the protein-tyrosine phosphatase family. This approach helped identify one residue in the substrate binding pocket of the phosphatase domain that confers specificity for phosphopeptides in a specific sequence context. We also present a Bayesian model that combines intrinsic enzymatic specificity and interaction information in the context of the human protein interaction network to infer new phosphatase substrates at the proteome level.

New developments in anti-malarial target candidate and product profiles.

A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma.

The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases. Overall PTP family expression levels appeared independent of characteristic genetic aberrations associated with lower grade or high grade gliomas. Notably, seven PTP genes (DUSP26, MTMR4, PTEN, PTPRM, PTPRN2, PTPRT and PTPRZ1) were differentially expressed between grade II-III gliomas and (grade IV) glioblastomas. For DUSP26, PTEN, PTPRM and PTPRT, lower expression levels correlated with poor prognosis, and overexpression of DUSP26 or PTPRT in E98 glioblastoma cells reduced tumorigenicity. Our study represents the first in-depth analysis of PTP family expression in diffuse glioma subtypes and warrants further investigations into PTP-dependent signaling events as new entry points for improved therapy.

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study.

BACKGROUND: Ferroquine (SSR97193) is a candidate anti-malarial currently undergoing clinical trials for malaria. To better understand its pharmacokinetic (PK) and pharmacodynamic (PD) parameters the compound was tested in the experimentally induced blood stage malaria infection model in volunteers. METHODS: Male and non-pregnant female aged 18-50 years were screened for this phase II, controlled, single-centre clinical trial. Subjects were inoculated with ~1800 viable Plasmodium falciparum 3D7A-infected human erythrocytes, and treated with a single-dose of 800 mg ferroquine. Blood samples were taken at defined time-points to measure PK and PD parameters. The blood concentration of ferroquine and its active metabolite, SSR97213, were measured on dry blood spot samples by ultra-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Parasitaemia and emergence of gametocytes were monitored by quantitative PCR. Safety was determined by recording adverse events and monitoring clinical laboratory assessments during the course of the study. RESULTS: Eight subjects were enrolled into the study, inoculated with infected erythrocytes and treated with 800 mg ferroquine. Ferroquine was rapidly absorbed with maximal exposure after 4-8 and 4-12 h exposure for SSR97213. Non-compartmental PK analysis resulted in estimates for half-lives of 10.9 and 23.8 days for ferroquine and SSR97213, respectively. Parasite clearance as reported by parasite reduction ratio was 162.9 (95 % CI 141-188) corresponding to a parasite clearance half-life of 6.5 h (95 % CI: 6.4-6.7 h). PK/PD modelling resulted in a predicted minimal parasiticidal concentration of 20 ng/mL, and the single dosing tested in this study was predicted to maintain an exposure above this threshold for 454 h (37.8 days). Although ferroquine was overall well tolerated, transient elevated transaminase levels were observed in three subjects. Paracetamol was the only concomitant treatment among the two out of these three subjects that may have played a role in the elevated transaminases levels. No clinically significant ECG abnormalities were observed. CONCLUSIONS: The parameters and PK/PD model derived from this study pave the way to the further rational development of ferroquine as an anti-malarial partner drug. The safety of ferroquine has to be further explored in controlled human trials. Trial registration anzctr.org.au (registration number: ACTRN12613001040752), registered 18/09/2013.

Open data in drug discovery and development: lessons from malaria.

There is a growing consensus that drug discovery thrives in an open environment. Here, we describe how the malaria community has embraced four levels of open data - open science, open innovation, open access and open source - to catalyse the development of new medicines, and consider principles that could enable open data approaches to be applied to other disease areas.

Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers.

OBJECTIVES: OZ439, or artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins. We wished to measure key pharmacokinetic and pharmacodynamic parameters and the pharmacokinetic/pharmacodynamic relationship of artefenomel in humans to guide the drug's further development as combination therapy in patients. PATIENTS AND METHODS: We tested artefenomel in the human induced blood-stage malaria (IBSM) model. Plasmodium infection was monitored by quantitative PCR (qPCR) and upon reaching 1000 parasites/mL single doses of 100, 200 and 500 mg of artefenomel were administered orally with evaluation of drug exposure and parasitaemia until rescue treatment after 16 days or earlier, if required. RESULTS: A single 100 mg dose had only a transient effect, while the 200 mg dose resulted in a significant reduction in parasitaemia before early recrudescence. At the highest (500 mg) dose, initial clearance of parasites below the limit of detection of qPCR was observed, with a 48 h parasite reduction ratio (PRR48) >10 000 and a parasite clearance half-life of 3.6 h (95% CI 3.4-3.8 h). However, at this dose, recrudescence was seen in four of eight subjects 6-10 days after treatment. Pharmacokinetic/pharmacodynamic modelling predicted an MIC of 4.1 ng/mL. CONCLUSIONS: These results confirm the antimalarial potential of artefenomel for use in a single-exposure combination therapy. The observations from this study support and will assist further clinical development of artefenomel.

Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development.

Effective progression of candidate antimalarials is dependent on optimal dosing in clinical studies, which is determined by a sound understanding of pharmacokinetics and pharmacodynamics (PK/PD). Recently, two important translational models for antimalarials have been developed: the NOD/SCID/IL2Rγ(-/-) (NSG) model, whereby mice are engrafted with noninfected and Plasmodium falciparum-infected human erythrocytes, and the induced blood-stage malaria (IBSM) model in human volunteers. The antimalarial mefloquine was used to directly measure the PK/PD in both models, which were compared to previously published trial data for malaria patients. The clinical part was a single-center, controlled study using a blood-stage Plasmodium falciparum challenge inoculum in volunteers to characterize the effectiveness of mefloquine against early malaria. The study was conducted in three cohorts (n = 8 each) using different doses of mefloquine. The characteristic delay in onset of action of about 24 h was seen in both NSG and IBSM systems. In vivo 50% inhibitory concentrations (IC50s) were estimated at 2.0 µg/ml and 1.8 µg/ml in the NSG and IBSM models, respectively, aligning with 1.8 µg/ml reported previously for patients. In the IBSM model, the parasite reduction ratios were 157 and 195 for the 10- and 15-mg/kg doses, within the range of previously reported clinical data for patients but significantly lower than observed in the mouse model. Linking mouse and human challenge models to clinical trial data can accelerate the accrual of critical data on antimalarial drug activity. Such data can guide large clinical trials required for development of urgently needed novel antimalarial combinations. (This trial was registered at the Australian New Zealand Clinical Trials Registry [http://anzctr.org.au] under registration number ACTRN12612000323820.).

Hit and lead criteria in drug discovery for infectious diseases of the developing world.

Reducing the burden of infectious diseases that affect people in the developing world requires sustained collaborative drug discovery efforts. The quality of the chemical starting points for such projects is a key factor in improving the likelihood of clinical success, and so it is important to set clear go/no-go criteria for the progression of hit and lead compounds. With this in mind, the Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease. Here, we present the agreed criteria and discuss the underlying rationale.

Malaria medicines: a glass half full?

Despite substantial scientific progress over the past two decades, malaria remains a worldwide burden that causes hundreds of thousands of deaths every year. New, affordable and safe drugs are required to overcome increasing resistance against artemisinin-based treatments, treat vulnerable populations, interrupt the parasite life cycle by blocking transmission to the vectors, prevent infection and target malaria species that transiently remain dormant in the liver. In this Review, we discuss how the antimalarial drug discovery pipeline has changed over the past 10 years, grouped by the various target compound or product profiles, to assess progress and gaps, and to recommend priorities.