Publications by authors named "Rob Hooft van Huijsduijnen"

54 Publications

Reassessing therapeutic antibodies for neglected and tropical diseases.

PLoS Negl Trop Dis 2020 01 30;14(1):e0007860. Epub 2020 Jan 30.

Global Health Innovative Technology Fund, Tokyo, Japan.

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.
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http://dx.doi.org/10.1371/journal.pntd.0007860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991954PMC
January 2020

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

J Vector Borne Dis 2019 Jan-Mar;56(1):15-24

Medicines for Malaria Venture, Geneva, Switzerland.

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.
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http://dx.doi.org/10.4103/0972-9062.257769DOI Listing
August 2019

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

Malar J 2019 Mar 22;18(1):94. Epub 2019 Mar 22.

Swiss Tropical & Public Health Institute, Socinstrasse 57, 4002, Basel, Switzerland.

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.
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http://dx.doi.org/10.1186/s12936-019-2728-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431002PMC
March 2019

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

Malar J 2018 Dec 10;17(1):462. Epub 2018 Dec 10.

Medicines for Malaria Venture, Route de Pré Bois 20, 1215, Geneva 15, Switzerland.

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.
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http://dx.doi.org/10.1186/s12936-018-2598-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287360PMC
December 2018

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

Malar J 2018 Nov 1;17(1):402. Epub 2018 Nov 1.

Medicines for Malaria Venture, Route de Pré Bois 20, 1215, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1186/s12936-018-2549-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211409PMC
November 2018

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.

Lancet Infect Dis 2018 08 13;18(8):874-883. Epub 2018 Jun 13.

Medicines for Malaria Venture, Geneva, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/S1473-3099(18)30309-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060173PMC
August 2018

The antimalarial pipeline.

Curr Opin Pharmacol 2018 10 31;42:1-6. Epub 2018 May 31.

Medicines for Malaria Venture, 20 route de Pre-Bois, 1215 Geneva, Switzerland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.coph.2018.05.006DOI Listing
October 2018

Malaria.

Nat Rev Dis Primers 2017 Aug 3;3:17050. Epub 2017 Aug 3.

Medicines for Malaria Venture, Geneva, Switzerland.

Malaria is caused in humans by five species of single-celled eukaryotic Plasmodium parasites (mainly Plasmodium falciparum and Plasmodium vivax) that are transmitted by the bite of Anopheles spp. mosquitoes. Malaria remains one of the most serious infectious diseases; it threatens nearly half of the world's population and led to hundreds of thousands of deaths in 2015, predominantly among children in Africa. Malaria is managed through a combination of vector control approaches (such as insecticide spraying and the use of insecticide-treated bed nets) and drugs for both treatment and prevention. The widespread use of artemisinin-based combination therapies has contributed to substantial declines in the number of malaria-related deaths; however, the emergence of drug resistance threatens to reverse this progress. Advances in our understanding of the underlying molecular basis of pathogenesis have fuelled the development of new diagnostics, drugs and insecticides. Several new combination therapies are in clinical development that have efficacy against drug-resistant parasites and the potential to be used in single-dose regimens to improve compliance. This ambitious programme to eliminate malaria also includes new approaches that could yield malaria vaccines or novel vector control strategies. However, despite these achievements, a well-coordinated global effort on multiple fronts is needed if malaria elimination is to be achieved.
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http://dx.doi.org/10.1038/nrdp.2017.50DOI Listing
August 2017

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

PLoS Med 2017 Jul 26;14(7):e1002366. Epub 2017 Jul 26.

Global Antibiotics Research and Development Partnership (GARDP), Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland.

Emilie Alirol and colleagues discuss the development of new treatments for gonorrhea.
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http://dx.doi.org/10.1371/journal.pmed.1002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528252PMC
July 2017

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

J Biol Chem 2017 03 3;292(12):4942-4952. Epub 2017 Feb 3.

From the Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy,

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 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 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.
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http://dx.doi.org/10.1074/jbc.M116.757518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377807PMC
March 2017

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

Malar J 2017 01 13;16(1):26. Epub 2017 Jan 13.

Medicines for Malaria Venture, Route de Pré Bois 20, 1215, Geneva 15, Switzerland.

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.
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http://dx.doi.org/10.1186/s12936-016-1675-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237200PMC
January 2017

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

Malar J 2016 Sep 13;15:469. Epub 2016 Sep 13.

Medicines for Malaria Venture, Route de Pré-Bois 20, 1215, Meyrin, Geneva, Switzerland.

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.
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http://dx.doi.org/10.1186/s12936-016-1511-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5022189PMC
September 2016

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

Acta Neuropathol Commun 2016 09 1;4(1):96. Epub 2016 Sep 1.

Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 26, 6525, GA, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1186/s40478-016-0372-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009684PMC
September 2016

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

Nat Rev Drug Discov 2016 10 12;15(10):661-2. Epub 2016 Aug 12.

Medicines for Malaria Venture, 20 Route de Pré-Bois, Geneva 1215, Switzerland.

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.
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http://dx.doi.org/10.1038/nrd.2016.154DOI Listing
October 2016

Open Source Drug Discovery with the Malaria Box Compound Collection for Neglected Diseases and Beyond.

PLoS Pathog 2016 07 28;12(7):e1005763. Epub 2016 Jul 28.

Department of Biochemistry and Molecular Biology and Huck Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania, United States of America.

A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.
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http://dx.doi.org/10.1371/journal.ppat.1005763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965013PMC
July 2016

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

J Antimicrob Chemother 2016 09 5;71(9):2620-7. Epub 2016 Jun 5.

Department of Translational Medicine, Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Meyrin, Geneva, Switzerland

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.
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http://dx.doi.org/10.1093/jac/dkw174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992851PMC
September 2016

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

Antimicrob Agents Chemother 2016 06 23;60(6):3669-75. Epub 2016 May 23.

Medicines for Malaria Venture, Geneva, Switzerland

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.).
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http://dx.doi.org/10.1128/AAC.02883-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879391PMC
June 2016

Profile of William C. Campbell, Satoshi Ōmura, and Youyou Tu, 2015 Nobel Laureates in Physiology or Medicine.

Proc Natl Acad Sci U S A 2015 Dec 22;112(52):15773-6. Epub 2015 Dec 22.

Medicines for Malaria Venture, 1215 Geneva, Switzerland.

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http://dx.doi.org/10.1073/pnas.1520952112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702971PMC
December 2015

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

Nat Rev Drug Discov 2015 Nov 5;14(11):751-8. Epub 2015 Oct 5.

Global Health Innovative Technology (GHIT) Fund, Ark Hills, Sengokuyama Mori Tower (25F), 1-9-10 Roppongi, Minato-ku, Tokyo 106-0032, Japan.

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.
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http://dx.doi.org/10.1038/nrd4683DOI Listing
November 2015

Ferroquine: welcome to the next generation of antimalarials.

Lancet Infect Dis 2015 Dec 3;15(12):1365-6. Epub 2015 Sep 3.

Medicines for Malaria Venture, 1215 Geneva 15, Switzerland.

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http://dx.doi.org/10.1016/S1473-3099(15)00148-6DOI Listing
December 2015

Malaria medicines: a glass half full?

Nat Rev Drug Discov 2015 Jun 22;14(6):424-42. Epub 2015 May 22.

1] Medicines for Malaria Venture, 20 Route de Pré-Bois, 1215 Geneva 15, Switzerland. [2] Division of Allergy and Infectious Diseases, Department of Medicine and Departments of Global Health and Microbiology, University of Washington, 750 Republican Street, Seattle, Washington 98195, USA.

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.
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http://dx.doi.org/10.1038/nrd4573DOI Listing
June 2015

Inhibition of protein tyrosine phosphatases enhances cerebral collateral growth in rats.

J Mol Med (Berl) 2014 Sep 27;92(9):983-94. Epub 2014 May 27.

Center for Cardiovascular Research (CCR), Department of Internal Medicine/Cardiology, Richard-Thoma-Laboratories for Arteriogenesis, Charité-University Medicine Berlin, Hessische Str. 3-4, 10115, Berlin, Germany.

Unlabelled: Arteriogenesis involves the rapid proliferation of preexisting arterioles to fully functional arteries as a compensatory mechanism to overcome circulatory deficits. Stimulation of arteriogenesis has therefore been considered a treatment concept in arterial occlusive disease. Here, we investigated the impact of inhibition of protein tyrosine phosphatases (PTPs) on cerebral arteriogenesis in rats. Arteriogenesis was induced by occlusion of one carotid and both vertebral arteries (three-vessel occlusion (3-VO)). Collateral growth and functional vessel perfusion was assessed 3-35 days following 3-VO. Furthermore, animals underwent 3-VO surgery and were treated with the pan-PTP inhibitor BMOV, the SHP-1 inhibitor sodium stibogluconate (SSG), or the PTP1B inhibitor AS279. Cerebral vessel diameters and cerebrovascular reserve capacity (CVRC) were determined, together with immunohistochemistry analyses and proximity ligation assays (PLA) for determination of tissue proliferation and phosphorylation patterns after 7 days. The most significant changes in vessel diameter increase were present in the ipsilateral posterior cerebral artery (PCA), with proliferative markers (PCNA) being time-dependently increased. The CVRC was lost in the early phase after 3-VO and partially recovered after 21 days. PTP inhibition resulted in a significant increase in the ipsilateral PCA diameter in BMOV-treated animals and rats subjected to PTP1B inhibition. Furthermore, CVRC was significantly elevated in AS279-treated rats compared to control animals, along with hyperphosphorylation of the platelet-derived growth factor-β receptor in the vascular wall in vivo. In summary, our data indicate PTPs as hitherto unrecognized negative regulators in cerebral arteriogenesis. Further, PTP inhibition leading to enhanced collateral growth and blood perfusion suggests PTPs as novel targets in anti-ischemic treatment.

Key Messages: PTPs exhibit negative regulatory function in cerebral collateral growth in rats. Inhibition of pan-PTP/PTP1B increases vessel PDGF-β receptor phosphorylation. PTP1B inhibition enhances arteriogenesis and cerebrovascular reserve capacity.
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http://dx.doi.org/10.1007/s00109-014-1164-zDOI Listing
September 2014

Anticancer properties of distinct antimalarial drug classes.

PLoS One 2013 31;8(12):e82962. Epub 2013 Dec 31.

Medicines for Malaria Venture (MMV), Geneva, Switzerland.

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC50s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC50s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082962PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877007PMC
August 2014

Designing the next generation of medicines for malaria control and eradication.

Malar J 2013 Jun 6;12:187. Epub 2013 Jun 6.

Medicines for Malaria Venture-MMV, PO Box 1826, Route de Pré-Bois 20, Geneva 151215, Switzerland.

In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For those parts of the world where the existing combinations show less than optimal activity, the priority is to have activity against emerging resistant strains, and other criteria take a secondary role. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. In this paper, an outline definition of the ideal and minimally acceptable characteristics of the types of clinical candidate molecule which are needed (target candidate profiles) is suggested. In addition, the optimal and minimally acceptable characteristics of combination medicines are outlined (target product profiles). MMV presents now a suggested framework for combining the new candidates to produce the new medicines. Sustained investment over the next decade in discovery and development of new molecules is essential to enable the long-term delivery of the medicines needed to combat malaria.
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http://dx.doi.org/10.1186/1475-2875-12-187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685552PMC
June 2013

Identification of VHY/Dusp15 as a regulator of oligodendrocyte differentiation through a systematic genomics approach.

PLoS One 2012 11;7(7):e40457. Epub 2012 Jul 11.

Merck Serono S.A., Geneva, Switzerland.

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by a progressive loss of myelin and a failure of oligodendrocyte (OL)-mediated remyelination, particularly in the progressive phases of the disease. An improved understanding of the signaling mechanisms that control differentiation of OL precursors may lead to the identification of new therapeutic targets for remyelination in MS. About 100 mammalian Protein Tyrosine Phosphatases (PTPs) are known, many of which are involved in signaling both in health and disease. We have undertaken a systematic genomic approach to evaluate PTP gene activity in multiple sclerosis autopsies and in related in vivo and in vitro models of the disease. This effort led to the identification of Dusp15/VHY, a PTP previously believed to be expressed only in testis, as being transcriptionally regulated during OL differentiation and in MS lesions. Subsequent RNA interference studies revealed that Dusp15/VHY is a key regulator of OL differentiation. Finally, we identified PDGFR-beta and SNX6 as novel and specific Dusp15 substrates, providing an indication as to how this PTP might exert control over OL differentiation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040457PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3394735PMC
April 2013

Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells: FLT3 ITD sustains high levels of DUSP6 expression.

Cell Commun Signal 2012 Jul 11;10(1):19. Epub 2012 Jul 11.

Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.

Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation.
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http://dx.doi.org/10.1186/1478-811X-10-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464674PMC
July 2012

Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

J Mol Cell Cardiol 2012 Jun 15;52(6):1257-64. Epub 2012 Mar 15.

INSERM U1096, Rouen, France.

Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
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http://dx.doi.org/10.1016/j.yjmcc.2012.03.003DOI Listing
June 2012

12/15-lipoxygenase-derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases.

Proc Natl Acad Sci U S A 2010 Sep 23;107(36):15774-9. Epub 2010 Aug 23.

Helmholtz Center Munich, Institute of Clinical Molecular Biology and Tumor Genetics, Germany.

Protein tyrosine phosphatases (PTPs) are regulated through reversible oxidation of the active-site cysteine. Previous studies have implied soluble reactive oxygen species (ROS), like H(2)O(2), as the mediators of PTP oxidation. The potential role(s) of peroxidized lipids in PTP oxidation have not been described. This study demonstrates that increases in cellular lipid peroxides, induced by disruption of glutathione peroxidase 4, induce cellular PTP oxidation and reduce the activity of PDGF receptor targeting PTPs. These effects were accompanied by site-selective increased PDGF beta-receptor phosphorylation, sensitive to 12/15-lipoxygenase (12/15-LOX) inhibitors, and increased PDGF-induced cytoskeletal rearrangements. Importantly, the 12/15-LOX-derived 15-OOH-eicosatetraenoic acid lipid peroxide was much more effective than H(2)O(2) in induction of in vitro PTP oxidation. Our study thus establishes that lipid peroxides are previously unrecognized inducers of oxidation of PTPs. This identifies a pathway for control of receptor tyrosine kinase signaling, which might also be involved in the etiology of diseases associated with increased lipid peroxidation.
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http://dx.doi.org/10.1073/pnas.1007909107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936618PMC
September 2010

Chemical inducers and transcriptional markers of oligodendrocyte differentiation.

J Neurosci Res 2010 Sep;88(12):2546-57

Merck Serono, Geneva 1202, Switzerland.

Oligodendrocytes generate and maintain myelin, which is essential for axonal function and protection of the mammalian central nervous system. To advance our molecular understanding of differentiation by these cells, we screened libraries of pharmacologically active compounds and identified inducers of differentiation of Oli-neu, a stable cell line of mouse oligodendrocyte precursors (OPCs). We identified four broad classes of inducers, namely, forskolin/cAMP (protein kinase A activators), steroids (glucocorticoids and retinoic acid), ErbB2 inhibitors, and nucleoside analogs, and confirmed the activity of these compounds on rat primary oligodendrocyte precursors and mixed cortical cultures. We also analyzed transcriptional responses in the chemically induced mouse and rat OPC differentiation processes and compared these with earlier studies. We confirm the view that ErbB2 is a natural signaling component that is required for OPC proliferation, whereas ErbB2 inhibition or genetic knockdown results in OPC differentiation.
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http://dx.doi.org/10.1002/jnr.22434DOI Listing
September 2010
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