Innovations In Clinical Neuroscience

ISCTM Supplement 2015

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

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[ 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 21S like effects. The second example is for a cannabinoid antagonist, where pharmacologically guided dose estimation was only implemented after r imonabant, the first compound in this class, showed unexpected psychiatric adverse effects following launch. A focus on pharmacology. Potential causes of highly selective, innovative drugs not progressing favorably during the drug development process may relate to not getting the pharmacology right. Arrowsmith 1 7 essentially details that failure of compounds in Phase II trials was largely attributed to a lack of efficacy. It would be expected that failures in Phase II trials would reduce the risk of efficacy failure in Phase III, but, unexpectedly, two-thirds of failed trials in late-stage development are still caused by lack of efficacy. 18 The lack of efficacy is not due to lack of understanding of the disease, per se, but of more specific factors, such as insufficient brain penetration or target engagement or increased variability of these factors in a clinical Phase III population due to interactions with disease or co-medication. In a sense, "failed efficacy" reflects the inability to understand Phase II trial results and to cultivate effective clinical trial initiatives from these results for later phase studies. Limitations, such as a lack of understanding of how drug targets impact the pathophysiology of the disease, the variability of the disease in the population, and dose efficacy trials only being defined in select populations, could also lead to drug development failures. 19 It seems that after performing Phase I trials, target engagement is almost completely forgotten and it is unknown if the drug still has the effect in the clinical population or in later phase trials. Take, for instance, the 25 drugs that were withdrawn after launch out of 275 drugs that were registered within the same period between the years 2006 and 2011—a third of these was later attributed to adverse events that were predictable and largely reflective of dose-related issues and lack of target engagement. From 1980 to 2000, dose reductions occurred in 27 percent of all new FDA registrations of CNS-active drugs, and 79 percent were due specifically to safety-related effects. This pattern o ccurred three times more often between the 1995 and 1999 than between the years 1980 and 1985. 20 Most dose reductions were pharmacologically based and highlights how getting the pharmacology right in early stages of development before a drug goes into patients can save more money and lead to improvements in clinical trial outcomes. Safety windows and therapeutic efficacy. Increasing the dose until the maximum tolerated dose is reached is difficult with drugs that have a small therapeutic window. Mainstay agents in psychiatry have small margins of safety and efficacy (such as older agents), and investigators are increasingly trying to develop drugs that have a wide margin of safety. To this end, selective or allosteric modulators, rather than direct or indirect agonists/antagonists, may be able to exhibit more favorable safety profiles. Drugs with larger therapeutic safety margins in healthy volunteers are used to measure efficacy, and often the aim is for the choosing the highest dose range with greatest chance of a therapeutic effect being reached. This approach can kill many drugs that have U-shaped dose curves and likely leads to dose reductions after launch or side-effects in patients that were unnecessary. So what needs to be done to get the dose right? First, it is important to consider that highly selective drug pharmacology that can cause efficacy is the same pharmacology that can also cause other events, and second, both of these can be measured in healthy volunteers to provide the therapeutic range measured effects. There is a range of different pharmacological endpoints with good PK/PD relationships that can exist, and these different effects will be in the therapeutic range. Screening new drugs with a series of different biomarkers that are sensitive to various agents will be able to produce a profile of drug effects that may be more encompassing than just single measures. These types of investigations can inform about the active concentration range that will d rive therapeutic effect. Furthermore, pharmacology and efficacy thereof can vary quite a bit for different classes of antipsychotics. We know that D 2 receptor occupancy needs to be in the range of 60 to 80 percent for antipsychotics, and for benzodiazepines it is between 5 to 30 percent. Larger dose ranges for compounds of similar modes of action can occur, and knowing how much target engagement is needed for a therapeutic effect is difficult to determine. Optimizing drug action. Pharmacology-guided dose selection for first in class CNS active drugs: Example 1—the dual orexin antagonist almorexant. Orexin is deficient in patients with narcolepsy, and patients with narcolepsy have sleep attacks. It is the latter that may be beneficial to induce in some individuals with sleep problems (e.g., insomnia) with almorexant, an oxerin antagonist, but not the associated sleep paralysis, hypnogogic hallucinations, or cataplexy that is found associated in patients with narcolepsy. No one knows how large of a therapeutic window for almorexant would be needed given that it is a first in class agent. A pharmacologic approach was taken that started at the low end of the concentration window to determine the safety window and was progressive in dose escalation until a detrimental effect was observed. Dosages before this safety concern result would ensure that a desired effect was not missed and provide confidence in the positive results if demonstrated with the agent on sleep. A positive control was also used to benchmark the effect by inclusion of zolpidem 10mg. Effects of 400mg of almorexant and 10mg of zolpidem induced a strong reduction in visual analog scales (VAS) of alertness, but at this almorexant dose the effects were much lower on body sway and potentially indicated that this drug may have a reduced propensity for

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