It has been estimated that 70%-80% of patients with schizophrenia will fail to respond to antipsychotic treatment, but that half of the patients who do respond to treatment don't stick with it. Several novel therapies moving their way through development this year may soon expand treatment options for this population. New Treatments The most important FDA approval making headlines this year involved a first-of-its-kind transdermal patch containing the atypical antipsychotic asenapine (Secuado). The October approval was based on a randomized trial of 617 patients who showed significantly improved Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S) scores at 6 weeks versus placebo. The patch, designed to be replaced daily, provides an alternative to injectable treatments but comes with side effects: application site reactions as well as those related to the drug itself, including extrapyramidal symptoms and weight gain. Meanwhile, injectables forged forward. Shortly after the turn of the year, drugmaker Indivior's novel risperidone formulation (Perseris), a once-monthly extended-release injection, hit the market after demonstrating efficacy in a pivotal phase III trial and scoring FDA approval in July 2018. In the Pipeline Close behind Indivior is the Chinese drugmaker Luye Pharma, which submitted an application to the FDA in late March for another extended-release risperidone treatment going by the trade name of Rykindo, which the agency says will not need pediatric clinical studies to qualify for approval. Early studies submitted to the FDA found this microsphere formulation had similar pharmacokinetic and safety profiles to competitor injectables and Luye said the product could be approved next year. Drugmaker Alkermes expanded its New Drug Application (NDA) for a combination samidorphan and olanzapine treatment (ALKS 3831) to include the treatment of bipolar I disorder and schizophrenia. The move came after positive results in the ENLIGHTEN trial and its 52-week open-label extension. The addition of 10-mg samidorphan to the atypical antipsychotic olanzapine is intended to counteract the weight gain seen with the latter. Alkermes plans to formulate the product with olanzapine doses of 5, 10, 15, and 20 mg for once-daily administration. From the same drugmaker comes aripiprazole lauroxil (Aristada), a bimonthly, injectable adjunct therapy to monthly paliperidone palmitate (Invega Sustenna) that showed positive results in a phase IIIb study involving 200 patients with acute schizophrenia exacerbations. Both drugs "may be clinically useful in helping to bridge the critical transition between inpatient and outpatient settings of care," an Alkermes executive said. Therapeutic Flops, Delays Pimavanserin (Nuplazid), an atypical antipsychotic approved to treat hallucinations and delusions associated with Parkinson's disease psychosis, missed key endpoints as an adjunct therapy in the ENHANCE trial, which involved 396 patients not responding adequately to existing therapies. Some improvement in PANSS scores were seen but it failed to achieve statistical significance; a trial by drugmaker Acadia Pharmaceuticals investigating pimavanserin plus other agents in schizophrenia patients with predominant negative symptoms is underway. The FDA pushed back decisions regarding two other drugs in the pipeline -- Newron Pharmaceutical's evenamide and Intra-Cellular Therapies' lumateperone -- requesting further data regarding submitted animal studies. Evenamide, an oral selective glutamate inhibitor, did not set off any safety alarms in a 2017 phase II trial, but the agency cited concerns regarding central nervous events in dog and rodent studies that need further exploration before it could approve more phase II and III trials. Lumateperone, a once-daily oral, has a triple mechanism of action targeting serotonin, dopamine, and glutamate neurotransmitter pathways. After the manufacturer submitted additional animal data the FDA requested in July, the agency announced it would decide on drugmaker Intra-Cellular Therapies' NDA by year-end. In addition to improved schizophrenia symptoms, lumateperone was shown in a one-year open-label study to improve LDL cholesterol, total cholesterol, serum prolactin levels, and body weight, all of which may set the drug apart. Investigational Therapies Deuterated D-serine (CTP-692), intended to supplement deficiencies in schizophrenia patients, was safe and tolerated in a phase I trial sponsored by Concert Pharma. Designed to be taken alongside antipsychotics, CTP-692 was not associated with blood and urine markers indicative of renal impairment, a concern often cited with D-serine. It is currently being evaluated in a phase II trial. Another agent, SEP-363856, was granted "breakthrough" status by the FDA based on phase II data and an open-label study that showed improvements in symptom severity and overall illness. What sets this agent apart from other schizophrenia drugs is that is does not bind to dopamine 2 (D2) or serotonin 2A (f-HT2A) receptors, as existing antipsychotics do. Instead, it is thought to function by activating trace amine-associated receptors (TAAR1) in addition to serotonin 1A (5-HT1A); the exact mechanism of action is unknown, however. Also in the pipeline is an oral formulation of the muscarinic receptor agonists xanomeline and trospium, called KarXT, which showed promising results in a phase II trial, improving PANSS scores to a similar degree as current schizophrenia drugs. The proposed advantage of KarXT is to avoid weight gain, extrapyramidal disorder, and some of the other side effects associated with current therapies, and indeed, in this trial, these adverse events were similar between intervention and placebo arms. Most recently, BioXcel Therapeutics announced its sublingual dexmedetomidine therapy successfully improved agitation among patients with schizophrenia and bipolar disorder, and will be tested in the phase III SERENITY study soon to be initiated. Source
