Twelve Drugs in Pipeline Hope to Address Psychosis-Related Cognitive Function
Abstract
Drug manufacturers look to phosphodiesterase inhibitors (PDEs), serotonin receptor antagonists, and nicotinic receptor agonists to improve the cognitive function of people with schizophrenia.
While dopamine receptor antagonism remains the mechanism of most Food and Drug Administration-approved antipsychotics, researchers have been investigating other pathways that may offer targets capable of improving cognitive function with a better safety profile.
Bolstering cognitive function is a particularly attractive goal for the pharmaceutical industry, as it could be beneficial in a host of other neurological disorders with larger markets, including dementia and autistic spectrum disorder. One area of bustling activity is cyclic nucleotide phosphodiesterase (PDE) inhibitors.
PDEs are a superfamily of enzymes that catalyze the hydrolysis of cyclic AMP and GMP (cAMP and cGMP), which are key molecules in cellular signaling and protein regulation, making them central to many physiological functions throughout the body. Based on genetics, PDEs are divided into 11 structurally related but functionally different types (that is, PDE1 to PDE11), with variants within each type.
Certain PDE inhibitors are already used to treat conditions such as cardiovascular diseases and erectile dysfunction. In recent years, basic research has indicated that PDE1, PDE2, PDE4, PDE7, PDE8, PDE9, and PDE10 enzymes can be potential therapeutic targets for cognitive enhancement and other neurological problems.
OMS824 is a PDE10 inhibitor that is being tested by the Seattle-based pharmaceutical company Omeros. A phase 2 study involving patients with schizophrenia in 2014 revealed optimal doses of OMS824 that would allow inhibition of the PDE10 enzyme in the brain and tolerability by patients with schizophrenia who were also taking other antipsychotics, according to the company. However, a study investigating the effect of the medications on Huntington’s disease was suspended last October because of concerns related to blood toxicity in animals.
FRM-6308 is a PDE10 inhibitor owned by Forum Pharmaceuticals in Waltham, Mass. The company is conducting phase 1b studies, including a dose-escalating study in patients with schizophrenia.
TAK-063 is a selective PDE10A inhibitor being evaluated in phase 2 clinical studies for efficacy and safety in schizophrenia and Huntington’s disease by Takeda Pharmaceutical Co. Ltd.
ITI-214 is a PDE1 inhibitor in phase 1 development by the New York based Intra-Cellular Therapies Inc. The company has a platform to design and synthesize molecules to target several PDE subtypes that it hopes will identify additional drug candidates for treating various neurological disorders.
BI 409306 is a PDE9 inhibitor in phase 2 development for schizophrenia and Alzheimer’s dementia by Boehringer Ingelheim.
Targets other than PDEs are also being pursued as candidates for new antipsychotics and cognitive enhancement drugs.
ITI-007 is a potent 5-HT2A serotonin receptor antagonist with additional activities on dopamine receptors and serotonin transporters owned by Intra-Cellular Therapies. ITI-007 is being tested in phase 3 clinical trials for the treatment of schizophrenia and may be expanded to bipolar disorder, major depression, and other neuropsychiatric diseases, according to the company’s website.
Pimavanserin, developed by the San Diego-based Acadia Pharmaceuticals Inc., is another promising 5-HT2A receptor inverse agonist. The company announced in March that it plans to submit a New Drug Application to the FDA by the end of 2015 for pimavanserin with an indication for psychosis associated with Parkinson’s disease. The drug is in phase 2 development for psychosis associated with Alzheimer’s disease and schizophrenia.
MIN-101 is also a 5HT2A serotonin receptor antagonist in development for schizophrenia. MIN-101, which was developed by Minerva Neurosciences Inc., also blocks the sigma-2 receptor, which is involved in movement control, psychotic symptoms, and learning and memory. The company is conducting phase 2b trials on MIN-101 in Europe.
Encenicline, an alpha 7 nicotinic receptor modulator, is in phase 3 development by Forum Pharmaceuticals to treat cognitive impairment in patients with schizophrenia and Alzheimer’s disease.
DSP 3748, developed by Dainippon Sumitomo Pharma Co., also interacts with the alpha 7 nicotinic receptor to potentially enhance cognitive function in patients with schizophrenia and Alzheimer’s disease. It is in phase 1 studies.
LY500307 is a selective estrogen receptor beta agonist currently being evaluated in a phase 1b/2a study by Eli Lilly and Co. and Indiana University. Previous studies at Indiana University suggest that selective estrogen receptor beta agonists may improve cognitive function and normalize social behavior with minimal side effects associated with estrogen.
ALKS3831is a combination of samidorphan and olanzapine that has shown promising results in phase 2 studies, according to Alkermes Plc. Researchers suspect the addition of samidorphan, a mu-opioid receptor antagonist, may help to reduce the metabolic adverse effects of olanzapine and potentially benefit patients with schizophrenia and concomitant alcohol use. ■
