kARUNA IS thinking differently about treatments for disabling neuropsychiatric conditions.
Our lead product candidate, KarXT, has broad therapeutic potential for treatment of schizophrenia, psychosis in Alzheimer’s Disease (AD), as well as pain.
Psychosis is a prominent and debilitating symptom that occurs in many neuropsychiatric disorders. Current antipsychotic therapies rely on the same fundamental mechanism of action as those first discovered serendipitously in the 1950s. With little innovation, these dopamine receptor reliant drugs treatment options only partly address symptoms, often with undesirable side effects. We think there’s a better way.
Karuna’s mission is to deliver a more effective and better-tolerated treatment for these large and under-served patient populations. Our product pipeline is built on a completely different mechanism of action (MOA). Muscarinic cholinergic receptors are promising targets for many CNS disorders with promising clinical data generated in previous Phase 2 studies, but previous development efforts have been stymied by poor tolerability due to side effects caused by muscarinic receptors peripheral tissues. We are realizing the potential of muscarinic receptor targets by leveraging a novel therapeutic approach designed to selectively activate muscarinic receptors in the brain. Our lead product candidate, KarXT, combines xanomeline, a muscarinic agonist, with trospium, an approved muscarinic antagonist that. We believe the result, KarXT, offers promising antipsychotic and cognitive benefits for patients in need.
tHE nEED - sCHIZOPHRENIA
Schizophrenia is a chronic, severe and disabling brain disorder. In 2017, an estimated 2.7 million Americans, or approximately 0.5% to 1.0% of the U.S. population, had schizophrenia. Worldwide, it is estimated that schizophrenia affects over 21 million people. People with schizophrenia have a 10 to 15 year reduction in life expectancy compared to the general population, struggle to maintain employment or live independently and are often unable to maintain meaningful interpersonal relationships.
Psychosis is a prominent and debilitating symptom that occurs in schizophrenia. Psychotic symptoms, also known as positive symptoms, include hallucinations and delusions. Patients with schizophrenia also experience negative symptoms, such as apathy, reduced social drive, loss of motivation and lack of social interest. Schizophrenia is also often associated with significant cognitive impairment, which further limits a patient’s ability to be gainfully employed and maintain relationships.
Antipsychotics medicines have undergone only modest innovation relative to first generation drugs developed in the 1950s. Current antipsychotics have modest efficacy in many patients and significant side effects. At least half of patients fail to adequately respond to current antipsychotic drugs. Additionally, current treatments are often associated with severe side effects, including sedation, extrapyramidal side effects such as motor rigidity, tremors and slurred speech, and significant weight gain resulting in the complications of diabetes, hyperlipidemia, hypertension and cardiovascular disease. The clinical benefit of current antipsychotics is further limited by poor adherence. In a 1,493-patient clinical trial funded by the National Institutes of Health, approximately 75% of patients reported discontinuing their antipsychotic medication within 18 months of starting treatment.
Current antipsychotic treatments work primarily by inhibiting D2 dopamine receptors and are often used by physicians to address a wide range of disorders in addition to schizophrenia, including bipolar disorder and psychotic depression, as well as psychosis and agitation in elderly patients with dementia. These treatments are approved for the treatment of positive symptoms of schizophrenia, such as hallucinations and delusions, but there are no approved therapies for the treatment of negative and cognitive symptoms of schizophrenia.
We believe there is a substantial need for a new antipsychotic drug that has an improved efficacy and side effect profile, and for a drug that can treat the negative and cognitive symptoms of the disease.
Karuna is conducting a Phase 2 trial of our lead product candidate, KarXT, in schizophrenia patients experiencing acute psychosis. Top line data is expected by the end of 2019.
A phase 1b study of KarXT for the treatment of the cognitive symptoms of schizophrenia is expected to begin in 2020.
A phase 1b study of KarXT for the treatment of the negative symptoms of schizophrenia is also expected to begin in 2020.
THE NEED - ALZHEIMER’S DISEASE
There are currently no approved medicines for treatment of psychosis in Alzheimer’s patients. While diagnostic criteria for AD mostly focus on the associated cognitive deficits, it is often the psychotic and behavioral symptoms that are most troublesome for caregivers and lead to poor quality of life for patients. Despite black box warnings for increased morbidity and mortality and lack or regulatory approval for use in Alzheimer’s, current antipsychotics are often prescribed to address Alzheimer’s disease psychosis.
According to the Alzheimer’s Association, 5.7 million people in the United States are living with AD and it is currently the fifth leading cause of death in people 65 years of age or older. Alzheimer’s disease is the most common cause of dementia among older adults and it has been estimated that 50 million people worldwide are living with AD and other forms of dementia. This number is expected to increase to 82 million by 2030 and to 152 million by 2050. Published studies have suggested that approximately 50% of patients with AD develop psychosis at some point during the course of their disease, commonly consisting of hallucinations, delusions and troublesome behavioral symptoms such as agitation. The diagnosis of AD psychosis is also associated with more rapid cognitive and functional decline and often requires institutionalization.
Karuna will commence a Phase 1b clinical trial to assess the safety and tolerability of KarXT in elderly volunteers in the second half of 2019.
THE NEED - PAIN
Reducing or eliminating the use of opioids for the treatment of pain is a major public health need. There is significant preclinical animal model data to support the use of muscarinic agonists, including xanomeline, for the treatment of pain. Confirmatory experiments demonstrated that the action of xanomeline in these pain models is attributable to its stimulation of M1 and M4 muscarinic receptors in the CNS and importantly, these studies also showed that opiate receptors do not mediate the analgesic actions of xanomeline.