Invicro Case Studies
Electronic CigarettesElectronic cigarettes are a relatively novel technology, and research on their effects is still quite lacking. Invicro UK (formerly Imanova) scientists recently began to use e-cigarettes as substitutes for real cigarettes in a study of brain activity in smoker’s, using functional MRI (fMRI). Practical and safety issues mean that it is impossible to visualize brain activity during active smoking with traditional cigarettes, however e-cigarettes are usable in the confined space of an MRI scanner. For the first time, the brain activity related to the sensory and behavioral aspects of smoking have been recorded, showing a network of brain regions including the motor cortex and insula, and the putamen; an area previously implicated in reward functions and addiction. This work was presented at the British Neuroscience Association conference in April 2015, and a journal publication is forthcoming.
Researchers at Invicro UK (formerly Imanova) Limited have produced and tested a promising new imaging biomarker which may help to accelerate drug development for CNS disorders whilst further elucidating the function of the phosphodiesterase 10A (PDE10A) enzyme – a key target in CNS disorders which holds the interest of the pharmaceutical industry and academics alike.
The positron emission tomography (PET) imaging biomarker, 11C-IMA-107, will assist in research to distinguish the differences in how PDE10A is expressed in CNS disorders and also boost understanding of pharmacological endpoints to. It is a carbon-11 labelled molecule which binds the PDE10A enzyme, allowing visualisation and quantification of the levels of the protein in the brain. This can provide valuable insight into PDE10A levels in disease and in response to drugs.
Invicro UK researchers demonstrated that [11C]IMA107 could provide information to further elucidate the PDE10A function, characterise PDE10A expression in disease populations, and also help understanding pharmacological endpoints and therefore accelerate drug development.
Invicro UK (formerly Imanova) is undertaking studies with beta amyloid radioligands such as Amivid, Neuroseq and Vizamyl, designed to stratify subjects into Phase II studies, looking at the treatment of Alzheimer’s disease.
Invicro UK has also implemented Tau PET-radioligand 18F-T807. Ongoing studies are evaluating the utility of 18F-T807 to quantify Tau protein density in conditions such as Alzheimer’s disease, Cortico-basal degeneration, frontico tempral dementia and traumatic brain injury.
Use of MRI to visualize weight-loss under the skin
MRI structural scanning of the body has been used in a study of the weight-loss treatment Orlistat (sold as ‘Alli’ in the UK). The MRI images in this case were used to quantify the amount of fat lost over a 3-month period, while the subjects were following a calorie-controlled diet and also using Alli. Overall weight loss is clearly very simple to measure with an ordinary bathroom scale, but what the MRI images showed was that a substantial proportion of visceral fat (fat that accumulates internally around the body organs, highlighted orange on the image) was lost, as well as subcutaneous fat. This is important because visceral fat deposits are thought to be more dangerous to health and is associated with health problems such as type 2 diabetes. These results were published in the following paper:
Thomas, E. L., Makwana, a, Newbould, R., Rao, a W., Gambarota, G., Frost, G., … Beaver, J. D. (2011). Pragmatic study of orlistat 60?mg on abdominal obesity. European Journal of Clinical Nutrition, 65(11), 1256–62. doi:10.1038/ejcn.2011.108.
Invicro UK (formerly Imanova) benefits from its location in West London on the Imperial Hammersmith Campus. Located within 50 miles of six Russell Group Medical schools with access to a diverse pool of population of over 15 million, makes working with Invicro UK an added advantage. Additionally with UCL, King’s and Imperial as shareholders, Invicro UK is in a unique position to easily collaborate with academics at these institutions.
Recent studies at Invicro UK included examination of patients with conditions such as:
Psychiatric Conditions – Schizophrenia, Substance abuse, Alcoholism, Down Syndrome, Autism
Neurological Conditions – Multiple Sclerosis, Parkinson’s Disease, Huntington’s Disease, Alzheimer’s Disease and MCI, other traumatic brain injury
Infectious Diseases – HIV Infection, HTLV-1 Infection
Respiratory Diseases – Chronic Obstructive Pulmonary Disease, Idiopathic Pulmonary Fibrosis
Connective Tissue Diseases – Rheumatoid Arthritis, Systematic Amyloidosis, Inflammatory Bowel Disease
Drug Distribution –Evaluation of GSK 103 4702
The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. In this study, led by Invicro UK (formerly Imanova), a suitable PET ligand was not available for the evaluation of a potent muscarinic acetylcholine receptor type-1 (M1) allosteric agonist (GSK1034702) in the primate and human brain. Hence, direct radiolabelling of the novel molecule was performed and positron emission tomography (PET) measurements were obtained and combined with in-vitro equilibrium dialysis assays to enable assessment of BBB transport and estimation of the free brain concentration of GSK1034702 in-vivo.
In primate and human PET studies designed to evaluate the transport of a novel M1 allosteric agonist (GSK1034702) across the BBB, Invicro UK demonstrated good brain uptake, and BBB passage consistent with passive diffusion or active influx. These studies discharged some of the perceived development risks for GSK1034702 and provided information to progress the molecule into the next stage of clinical development.
Dose Selection (early stage) – Vernalis
Invicro UK (formerly Imanova) worked with Vernalis, a biotech company, on a drug candidate targeting the Adenosine A2A receptor for treatment of neurological disorders, which demonstrated how imaging can be used to provide early information in man and reduce both the cost and time of entering proof-of-concept studies. In this instance, a suitable PET ligand, [11C]SCH4424, had already been reported in the literature but needed to be implemented at Invicro UK to a GMP standard.
Using an adaptive study design, the PET study was carried out in parallel with the single ascending dose (SAD) study to relate occupancy at the A2A receptor in the brain with drug dose and plasma concentration. For each drug dose, A2A receptor occupancy was calculated for 2 plasma drug levels.
The data generated clearly demonstrated the relationship between plasma concentration and receptor occupancy in the CNS showing that the drug crosses the blood brain barrier and interacts with the target receptor. Using this data, Vernalis was able to take the drug into further development. Importantly, the quantitative data generated from imaging was used to determine the dose to be used in patient studies for efficacy, thus reducing the number of doses to be tested, saving considerable time and money.
This study clearly demonstrates the value imaging can add to aid decisions about drug development. In this way, imaging holds the key to reducing time and costs of drug development overall.