BOSTON—Schizophrenia remains a challenging disorder not just for those who suffer from it (and their friends and family), but also for researchers and companies trying to develop effective treatments for it. But Karuna Therapeutics Inc., a clinical-stage biopharmaceutical company committed to developing novel therapies for people with disabling and potentially fatal neuropsychiatric disorders and pain, announced results in November from a Phase 2 clinical trial that might be a major sign of progress.
The experimental therapeutic in question is KarXT, and the trial is aimed at the treatment of acute psychosis in patients with schizophrenia. KarXT is an oral coformulation of xanomeline (a novel muscarinic receptor agonist) and trospium (a muscarinic receptor antagonist) designed to treat psychosis and related symptoms through preferential stimulation of muscarinic receptors in the central nervous system (CNS).
This combination has the potential to be a new option for treating the difficult symptoms of debilitating CNS disorders, such as schizophrenia, without subjecting patients to the problematic side effects associated with current antipsychotic standard-of-care therapies, according to Karuna.
In the clinical trial, KarXT demonstrated a statistically significant and clinically meaningful 11.6 point mean reduction in total Positive and Negative Syndrome Scale (PANSS) score compared to placebo and also demonstrated good overall tolerability. A statistically significant reduction in the secondary endpoints of PANSS-Positive and PANSS-Negative scores were also observed.
KarXT was well tolerated in the Phase 2 trial, with similar discontinuation rates between KarXT (20 percent) and placebo (21 percent). Data thus far shows no evidence of somnolence, extrapyramidal side effects or weight gain relative to placebo.
“The results of the Phase 2 trial are impressive and encouraging because they indicate that KarXT, if approved, could represent a game-changing therapeutic advance in the treatment of patients with schizophrenia,” said Dr. Jeffrey Lieberman, chairman of the Department of Psychiatry at Columbia University and a member of Karuna’s scientific advisory board. “The effectiveness of antipsychotics has been limited by the frequent and serious side effects of first- and second-generation drugs, which are difficult for many patients to tolerate, are potentially harmful, and lead to high rates of discontinuation and relapse. In addition to its novel mechanism of action, KarXT could be a new therapeutic option that has the potential to offer robust efficacy devoid of weight gain, metabolic effects and extrapyramidal side effects.”
Added Dr. Steve Paul, CEO, president and chairman of Karuna: “The schizophrenia treatment landscape has remained rather stagnant for decades with therapeutic options relying on discoveries dating back to the 1950s. KarXT and its novel muscarinic receptor mechanism of action represent the potential to become a true advancement in how schizophrenia is treated, allowing patients relief from their debilitating psychotic symptoms without experiencing some of the very troubling side effects associated with current treatments.”
As noted by Karuna, muscarinic acetylcholine receptors emerged in the 1990s as a promising alternative target to dopamine-receptor based treatments for treating psychosis, but adverse side effects limited their development as a therapeutic option.
Because the prevailing wisdom was that these side effects were the result of the stimulation of muscarinic receptors in peripheral tissues, researchers at Karuna decided to tackle the issue by combining xanomeline, a novel muscarinic receptor agonist that preferentially stimulates M1 and M4 muscarinic receptors, with trospium, an approved muscarinic receptor antagonist that does not measurably cross the blood-brain barrier. The resulting therapeutic, known as KarXT, was designed to activate muscarinic receptors in the CNS while avoiding the side effects associated with activating muscarinic receptors in peripheral tissues.
“We are extremely pleased with these results, as the 11.6-point PANSS score separation from placebo far exceeded the five-point minimum improvement that has historically supported approval of current antipsychotics,” said Dr. Stephen Brannan, chief medical officer of Karuna. “With this information, and following our anticipated end-of-Phase 2 meeting with the FDA in the second quarter of 2020, we will work to initiate a Phase 3 clinical trial of KarXT in patients with schizophrenia by the end of 2020. We also plan to further analyze these results to better understand the potential of KarXT in patients with schizophrenia experiencing negative and cognitive symptoms, and to explore other CNS disorders that could benefit from this approach, such as psychosis in Alzheimer’s disease as well as the management of pain.”
Data and analytics company GlobalData believes that KarXT is set to be a promising treatment option for acute psychosis in schizophrenia, noting that the potential recipients of the drug, were it to be approved, represent “a large and underserved patient population characterized by psychosis and cognitive impairment.”
“The drug's clinical trial results showed that it was well tolerated and could provide a new treatment option for people affected by the disease, as in many patients, approved antipsychotics offer modest efficacy and significant side effects,” noted Alessio Brunello, a senior pharma analyst at GlobalData.
“According to GlobalData, there are 15 candidates in the late-stage schizophrenia pipeline that are expected to launch in the next 10 years in the seven major markets,” Brunello continued. “Three of these late-stage drug candidates are in pre-registration, namely ITI-007 (lumateperone tosylate), Latuda (lurasidone HCL), and Rykindo (risperidone ER) with the last two being a reformulation of marketed drugs to increase compliance and provide a better safety profile and way of administration. Additionally, there are also 18 candidates in Phase 2 and 24 in Phase 1.
“However, these products can face competition from atypical antipsychotic products, as these drugs have dominated the market in terms of sales revenue for over a decade, which is why there is a need for new players to develop novel therapeutic options. The current schizophrenia treatment landscape includes a high number of established, atypical anti-psychotic products that can effectively manage the positive symptoms of the disorder. However, there is a significant unmet need for novel, effective treatment options that address the negative symptoms and cognitive impairments seen in schizophrenia.”