Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

Issue link: https://innovationscns.epubxp.com/i/499434

Contents of this Issue

Navigation

Page 6 of 41

[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 7S testing can dictate the decision to move forward with or reject a target compound (go/no-go decisions). One example of a go/no-go d ecision focuses on an early phase study in healthy subjects with a norepinephrine transport inhibitor that was to be developed as a new pain drug. The compound (A) was developed from a snake venom and was a small (1400 Da) stable 13- amino acid peptide that could not pass the blood brain barrier (BBB) and therefore had to be administered intrathecally. Because of its very high potency, it was being developed for severe chronic pain and potentially for postoperative pain. In initial Phase I studies, 20 healthy individuals were administered a single dose of compound A intravenously. The efficacy of compound A was examined in response to an earlobe electric stimulation test. Unfortunately, no pain-reducing efficacy of the compound was observed. In another early phase study examining its effects on patients with cancer, doses up to 40mg were given, which appeared to be beneficial. However the study was an uncontrolled, open- label design so definitive conclusions about the analgesic effects could not be made. More importantly, at the highest dose, there were two serious adverse events: an aseptic meningitis and a generalized epileptic seizure. Particularly, the potential epileptogenicity of the compound led to the FDA putting the development of the compound on halt when the company tried to get a study approved in 200 bunionectomy patients, which by then had already begun in Eastern Europe. Subsequently, the company decided to perform a safety study, aimed solely at the potential epileptogenicity by examining electro-encephalographic effects of the compound when administered to healthy subjects. By then, four studies in humans had been performed and still very little was known about the potential analgesic effects of the compound or about the pharmacokinetics in CSF. The final study investigated the effects of compound A at 0.5, 1, and 2.5mg (n=8 per dose) or placebo (n=8) a dministered intrathecally to healthy subjects . In this study, pharmacokinetics in the CSF were measured using a spinal catheter and CSF sampling over a period of 32 hours. Concurrently, the analgesic potential of the compound was determined, using a nociceptive test battery, which was administered multiple times after drug administration. The nociceptive test battery comprises two different paradigms of electrical pain, 3 pneumatic pain, 4 the cold pressor, 5 and thermal stimulation. Improved response to pain lasting up to 96 hours was observed at the highest dose (2.5mg) in two of the four nociceptive tests, providing evidence for the analgesic potential of the compound. However, at that dose level (2.5mg), CSF exposure as measured using 32-hour sampling turned out to be higher than expected and to exceed the safety limit that was defined in advance, based on the potential of the drug to cause epilepsy in dogs. Because of the findings in the study, it was decided to stop the development of this compound. This study is an example of a situation where failing earlier in the development may have saved time and cost. In a second example, a partial GABA-A agonist was being developed for anxiety. Agonists at the alpha 1 receptor are linked to sedation of benzodiazepines, alpha 2 and alpha 3 subtype selective agonists are associated with muscle relaxation and anxiolytic effects, while the alpha 5 subunit is linked to cognitive impairments induced by GABA-A receptor agonists. In this study, an alpha 2/3 subtype selective GABA-A receptor agonist was tested in a central nervous system test battery lasting 20 to 25 minutes, including adaptive tracking, finger tapping, and 30-word learning. A dosage of 1.5mg of the new compound was found to be equipotent to 2.0mg lorazepam according to their influence on saccadic eye movements, a biomarker for the effects of b enzodiazepines. At the equipotent dose of 1.5mg, however, the new compound had fewer sedative effects than 2.0mg of lorazepam. This could not have been predicted using PET, as the new compound had a 10-fold higher receptor occupancy compared with lorazepam. This is, therefore, a good example of the added value of pharmacodynamic testing when trying to benchmark a new compound compared to existing comparable drugs. Because of its apparent advantages in terms of lower sedation compared to lorazepam, this novel subtype selective GABA-A receptor agonist was taken forward in clinical development. In conclusion, these examples demonstrate that measuring pharmacodynamic effects and trying to rationally assess the properties of a drug early in clinical drug development can greatly inform decisions for later stage development, which has implications on cost. Answering the questions with the highest uncertainty first in drug development may lead to lower overall development costs. 6 EXPOSURE RESPONSE MODELING IN EARLY DEVELOPMENT Phase I testing can be conducted to be more informative during early development of compounds. Such an approach can facilitate quantitative bridging of nonclinical and clinical data. Experiments, therefore, need to be designed to be informative for this purpose. Such an approach can improve early and data-driven decision-making of the go/no-go status of a compound as well as aid in the interpretation of effects recorded in studies. One example is to design Phase I experiments to better predict dose response and time course of a novel biomarker to a compound with an unprecedented mechanism of action. A road-map of the components used

Articles in this issue

Archives of this issue

view archives of Innovations In Clinical Neuroscience - ISCTM Supplement 2015