Center for Human Drug Research

Leiden, Netherlands

Center for Human Drug Research

Leiden, Netherlands
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News Article | September 20, 2017
Site: www.prnewswire.co.uk

Colorectal cancer is the third most common cancer worldwide with approx. 41,000 people diagnosed every year in the UK and over 1.4 million people worldwide. Imaging with white light colonoscopy is the established method for the diagnosis and prevention of CRC. However, up to a quarter of cancerous and precancerous bowel cancer tumours can be missed using this method. EMI has developed a novel fluorescent Optical Imaging Agent - EMI-137 - which targets and "lights-up" the cancer cells, helping surgeons to more easily identify and remove suspicious tumours. EMI-137 targets the cancer marker C-Met, which is overexpressed in CRC cells and cancer precursor cells. The phase IIb study will be conducted by the Centre for Human Drug Research (CHDR), a world renowned clinical research organization based in Leiden, in close collaboration with the Leiden University Medical Centre and the University Medical Center of Gröningen, The Netherlands. The Clinical Investigators at these sites are Professor James Hardwick and Dr Wouter Nagengest, who are among Europe's leading clinicians advancing the diagnosis and treatment of colorectal cancer. "The identification of flat, small non-polypoid lesions is a major problem as they cannot be detected by conventional imaging. EMI-137 has the potential to address this major unmet medical need by combining targeted molecular imaging probes and advanced imaging technology to improve polyp detection. Our team is extremely motivated to complete this product's development and get it into the hands of physicians in order to benefit patients." "More than 9 out of 10 people will survive bowel cancer if it is detected at an early stage when treatments are more likely to be effective. Optical imaging techniques, using agents like EMI-137, could potentially reduce the number of polyps missed during colonoscopy, therefore significantly improving outcomes for patients. This next phase of the research will help us understand whether this method could be introduced routinely in practice and offer real benefits to patients. It is vital that that the UK and Europe continue to invest in studies and clinical trials to keep finding quicker and more effective ways to identify and diagnose patients early when the disease is curable." The objective of the clinical study is to assess the efficacy of EMI-137 in aiding clinicians to detect pathological lesions during colonoscopy. The study will involve up to 200 patients with a high suspicion of CRC. Interim results from the trial are expected in Q1 2018. EM Imaging and CHDR collaborated on the Phase I study of EMI-137 which showed a 25% increase in bowel cancer lesion detection compared to standard colonoscopy. Improved polyp detection in this study might lead to further studies in extended target populations and, possibly, in the end to a wider adoption of fluorescence-guided endoscopy. EM Imaging is also working with doctors and clinical centres in the UK, Europe, US and Asia to use EMI-137 to detect tumours during surgery. Studies are planned to look at improving cancer detection in a range of cancers including Breast Cancer, Gastric Cancer, Thyroid Cancer, Head & Neck Cancer, Prostate Cancer and Brain Cancer. Edinburgh Molecular Imaging (EM Imaging) is a clinical phase biotechnology company focused on enabling image-guided therapy. The Company's molecular imaging technology, based on Fluorescent Imaging, has the potential to detect disease in real-time during interventional procedures including surgery, providing more accurate treatment while sparing healthy tissue. EM Imaging discovers and develops small molecules and peptides that, when conjugated with fluorescent dyes, targets diseased tissue - specifically cancerous cells. This will provide the clinician with a clearer view and decision-making tool to benefit the patient. For more information go to: www.edinimage.com The Centre for Human Drug Research (CHDR) is a world renown Clinical Research Organisation in Leiden, The Netherlands with strong academic links which focuses on early drug development. Its mission is to develop compounds, therapeutic or diagnostic in an innovative and highly informative manner to allow early introduction of novel treatment paradigms into the clinic. www.chdr.nl Epidarex invests in early-stage, high growth life science and health technology companies in under-ventured markets in the US and Europe. With offices in Bethesda, Maryland and in Edinburgh, Scotland, Epidarex works closely with the management of its portfolio companies to more effectively translate their world-class research to commercial, patient-driven success. Epidarex's international management team has a track record of successfully partnering with scientists and entrepreneurs to develop highly innovative products for the global healthcare market. Its global network includes investment professionals, scientists, industry executives, health practitioners, policy experts, regulatory advisors and business development leaders. More information is available at www.epidarex.com For Further information: Edinburgh Molecular Imaging Ian Wilson Tel: +131-(0)-650-5307 Email: media@edinimage.com @edinimage #CRCcure Centre for Human Drug Research Josine Vrouwe, MD Email: jvrouwe@chdr.nl Tel: +31-71-751-7163 For patients: www.proefpersoon.nl


News Article | September 20, 2017
Site: www.prnewswire.com

Colorectal cancer is the third most common cancer worldwide with approx. 41,000 people diagnosed every year in the UK and over 1.4 million people worldwide. Imaging with white light colonoscopy is the established method for the diagnosis and prevention of CRC. However, up to a quarter of cancerous and precancerous bowel cancer tumours can be missed using this method. EMI has developed a novel fluorescent Optical Imaging Agent - EMI-137 - which targets and "lights-up" the cancer cells, helping surgeons to more easily identify and remove suspicious tumours. EMI-137 targets the cancer marker C-Met, which is overexpressed in CRC cells and cancer precursor cells. The phase IIb study will be conducted by the Centre for Human Drug Research (CHDR), a world renowned clinical research organization based in Leiden, in close collaboration with the Leiden University Medical Centre and the University Medical Center of Gröningen, The Netherlands. The Clinical Investigators at these sites are Professor James Hardwick and Dr Wouter Nagengest, who are among Europe's leading clinicians advancing the diagnosis and treatment of colorectal cancer. "The identification of flat, small non-polypoid lesions is a major problem as they cannot be detected by conventional imaging. EMI-137 has the potential to address this major unmet medical need by combining targeted molecular imaging probes and advanced imaging technology to improve polyp detection. Our team is extremely motivated to complete this product's development and get it into the hands of physicians in order to benefit patients." "More than 9 out of 10 people will survive bowel cancer if it is detected at an early stage when treatments are more likely to be effective. Optical imaging techniques, using agents like EMI-137, could potentially reduce the number of polyps missed during colonoscopy, therefore significantly improving outcomes for patients. This next phase of the research will help us understand whether this method could be introduced routinely in practice and offer real benefits to patients. It is vital that that the UK and Europe continue to invest in studies and clinical trials to keep finding quicker and more effective ways to identify and diagnose patients early when the disease is curable." The objective of the clinical study is to assess the efficacy of EMI-137 in aiding clinicians to detect pathological lesions during colonoscopy. The study will involve up to 200 patients with a high suspicion of CRC. Interim results from the trial are expected in Q1 2018. EM Imaging and CHDR collaborated on the Phase I study of EMI-137 which showed a 25% increase in bowel cancer lesion detection compared to standard colonoscopy. Improved polyp detection in this study might lead to further studies in extended target populations and, possibly, in the end to a wider adoption of fluorescence-guided endoscopy. EM Imaging is also working with doctors and clinical centres in the UK, Europe, US and Asia to use EMI-137 to detect tumours during surgery. Studies are planned to look at improving cancer detection in a range of cancers including Breast Cancer, Gastric Cancer, Thyroid Cancer, Head & Neck Cancer, Prostate Cancer and Brain Cancer. Edinburgh Molecular Imaging (EM Imaging) is a clinical phase biotechnology company focused on enabling image-guided therapy. The Company's molecular imaging technology, based on Fluorescent Imaging, has the potential to detect disease in real-time during interventional procedures including surgery, providing more accurate treatment while sparing healthy tissue. EM Imaging discovers and develops small molecules and peptides that, when conjugated with fluorescent dyes, targets diseased tissue - specifically cancerous cells. This will provide the clinician with a clearer view and decision-making tool to benefit the patient. For more information go to: www.edinimage.com The Centre for Human Drug Research (CHDR) is a world renown Clinical Research Organisation in Leiden, The Netherlands with strong academic links which focuses on early drug development. Its mission is to develop compounds, therapeutic or diagnostic in an innovative and highly informative manner to allow early introduction of novel treatment paradigms into the clinic. www.chdr.nl Epidarex invests in early-stage, high growth life science and health technology companies in under-ventured markets in the US and Europe. With offices in Bethesda, Maryland and in Edinburgh, Scotland, Epidarex works closely with the management of its portfolio companies to more effectively translate their world-class research to commercial, patient-driven success. Epidarex's international management team has a track record of successfully partnering with scientists and entrepreneurs to develop highly innovative products for the global healthcare market. Its global network includes investment professionals, scientists, industry executives, health practitioners, policy experts, regulatory advisors and business development leaders. More information is available at www.epidarex.com For Further information: Edinburgh Molecular Imaging Ian Wilson Tel: +131-(0)-650-5307 Email: media@edinimage.com @edinimage #CRCcure Centre for Human Drug Research Josine Vrouwe, MD Email: jvrouwe@chdr.nl Tel: +31-71-751-7163 For patients: www.proefpersoon.nl


Klaassens B.L.,Leiden University | Klaassens B.L.,Center for Human Drug Research | van Gorsel H.C.,Center for Human Drug Research | Khalili-Mahani N.,Montreal Neurological Institute | And 5 more authors.
NeuroImage | Year: 2015

The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9. h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p < 0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate. © 2015 Elsevier Inc.


Cohen A.,Center for Human Drug Research | Bye A.,Alan Bye and Company Ltd
Current Opinion in Pharmacology | Year: 2014

Clinical Pharmacology in Neuroscience Drug Discovery in recent years has concentrated on First Time in Human safety and pharmacokinetics. The more traditional pharmacological research in humans has been reduced mainly as a response to the difficulty of developing human pharmacology models in neuroscience diseases. As a consequence, opportunities are being missed to aid in target selection and in target validation. The decision of big Pharma to reduce investment from the Neurosciences has had implications for clinical pharmacologists in this area. It remains to be seen whether academia, government laboratories and contract houses will respond to the challenge of carrying out increased Clinical Pharmacology in the Neurosciences.© 2013 Elsevier Ltd. All rights reserved.


Klumpers L.E.,Center for Human Drug Research | Cole D.M.,Leiden University | Cole D.M.,Imperial College London | Khalili-Mahani N.,Leiden University | And 4 more authors.
NeuroImage | Year: 2012

Resting state-functional magnetic resonance imaging (RS-FMRI) is a neuroimaging technique that allows repeated assessments of functional connectivity in resting state. While task-related FMRI is limited to indirectly measured drug effects in areas affected by the task, resting state can show direct CNS effects across all brain networks. Hence, RS-FMRI could be an objective measure for compounds affecting the CNS. Several studies on the effects of cannabinoid receptor type 1 (CB1)-receptor agonist δ9-tetrahydrocannabinol (THC) on task-dependent FMRI have been performed. However, no studies on the effects of cannabinoids on resting state networks using RS-FMRI have been published. Therefore, we investigated the effects of THC on functional brain connectivity using RS-FMRI. Twelve healthy volunteers (9 male, 3 female) inhaled 2, 6 and 6. mg THC or placebo with 90-minute intervals in a randomized, double blind, cross-over trial. Eight RS-FMRI scans of 8. min were obtained per occasion. Subjects rated subjective psychedelic effects on a visual analog scale after each scan, as pharmacodynamic effect measures. Drug-induced effects on functional connectivity were examined using dual regression with FSL software (FMRIB Analysis Group, Oxford). Eight maps of voxel-wise connectivity throughout the entire brain were provided per RS-FMRI series with eight predefined resting-state networks of interest. These maps were used in a mixed effects model group analysis to determine brain regions with a statistically significant drug-by-time interaction. Statistical images were cluster-corrected, and results were Bonferroni-corrected across multiple contrasts. THC administration increased functional connectivity in the sensorimotor network, and was associated with dissociable lateralized connectivity changes in the right and left dorsal visual stream networks. The brain regions showing connectivity changes included the cerebellum and dorsal frontal cortical regions. Clear increases were found for feeling high, external perception, heart rate and cortisol, whereas prolactin decreased. This study shows that THC induces both increases and (to a lesser extent) decreases in functional brain connectivity, mainly in brain regions with high densities of CB1-receptors. Some of the involved regions could be functionally related to robust THC-induced CNS-effects that have been found in previous studies (Zuurman et al., 2008), such as postural stability, feeling high and altered time perception. © 2012 Elsevier Inc.


Oei N.Y.L.,Leiden University | Rombouts S.A.,Leiden University | Soeter R.P.,Leiden University | Van Gerven J.M.,Center for Human Drug Research | Both S.,Leiden University
Neuropsychopharmacology | Year: 2012

Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the reward system. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate wanting in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication. © 2012 American College of Neuropsychopharmacology.


Osanto S.,Leiden University | Van Poppel H.,Catholic University of Leuven | Burggraaf J.,Center for Human Drug Research
Future Oncology | Year: 2013

Tasquinimod, an oral quinolone-3-carboxamide with anti-tumor activity in preclinical models of prostate cancer, has been tested in patients with minimally symptomatic castration-resistant prostate cancer (CRPC), showing promising inhibitory effects on the occurrence of metastasis and delayed disease progression. Although its mode of action is not fully understood, tasquinimod presumably exerts its unique anti-tumor action through inhibition of angiogenesis and immunomodulation. In clinical studies, tasquinimod demonstrated anti-tumor activity in prostate cancer in combination with a mild-to-moderate side effect profile. With single-agent tasquinimod, dose-limiting toxicity was amylase elevation without signs of pancreatitis and sinus tachycardia. The maximum tolerated dose in Phase I studies in patients with CRPC was once daily administration of 0.5-1-mg tasquinimod orally. In a Phase II trial, significant clinical activity has been demonstrated in asymptomatic or minimally symptomatic, chemotherapy-naive, metastatic CRPC (mCRPC) patients. Men were randomized to tasquinimod or placebo in a 2:1 fashion; treatment with tasquinimod resulted in significant improvement of median progression-free survival (7.6 vs 3.3 months with placebo; p = 0.0042). Based on these encouraging effects, a randomized, double-blind, placebo-controlled trial in men with minimally symptomatic mCRPC has been designed. This large Phase III trial, powered for a primary end point of progression-free survival, has now enrolled the target number of 1200 men. If the Phase II data are validated in the Phase III trial a new compound with a unique mode of action might become approved as a future therapy for minimally symptomatic mCRPC patients. © 2013 Future Medicine Ltd.


Cohen A.F.,Leiden University | Cohen A.F.,Center for Human Drug Research
Nature Reviews Drug Discovery | Year: 2010

New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I- Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management. © 2010 Macmillan Publishers Limited. All rights reserved.


Moors E.H.M.,University Utrecht | Cohen A.F.,Center for Human Drug Research | Schellekens H.,University Utrecht
Drug Discovery Today | Year: 2014

Drug development has become the exclusive activity of large pharmaceutical companies. However, the output of new drugs has been decreasing for the past decade and the prices of new drugs have risen steadily, leading to access problems for many patients. By analyzing the history of drug development and the pharmaceutical industry, we identified the main factors causing this system failure. Although many solutions have been suggested to fix the drug development system, we believe that a combination of reforms of the regulatory and patent systems is necessary to make drug development sustainable. These reforms must be combined with a larger, open-access role for public research institutes in the discovery, clinical evaluation and safety evaluation of new drugs. © 2014 Elsevier Ltd.


Sidharta P.N.,Actelion Pharmaceuticals | Diamant Z.,Center for Human Drug Research | Dingemanse J.,Actelion Pharmaceuticals
Fundamental and Clinical Pharmacology | Year: 2014

Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders. © 2014 Société Française de Pharmacologie et de Thérapeutique.

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