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Spotlight is on promising investigational antipsychotics.


COPENHAGEN -- A wave of novel investigational antipsychotic agents advancing through the regulatory approval process was spotlighted at the annual congress of the European College of Neuropsychopharmacology.

Two of the highlighted agents pimavanserin and SEP-363856--were designed to eschew the traditional antipsychotic target, the dopamine D2 receptor, in favor of other mechanisms of action aimed at the negative symptoms of schizophrenia, for which there is a long-recognized major unmet need for better therapies.

A third agent, known for now as ALKS 3831, is composed of a combination of olanzapine and samidorphan, an opioid receptor antagonist. This once-daily oral combination of olanzapine/samidorphan (OLA/ SAM) is designed to retain the clinical efficacy of olanzapine while mitigating the drug's limiting side effect of substantial weight gain.

OLA/SAM New Drug Application submitted

Christine Graham, PhD, presented highlights of the pivotal phase 3 ENLIGHTEN-2 study, a double-blind clinical trial in which 661 U.S. outpatients with schizophrenia were randomized to OLA/ SAM or olanzapine alone at 10 or 20 mg/day for 24 weeks, at which point everyone was switched to open-label OLA/SAM at 10 or 20 mg/10 mg for an additional 52-week extension safety study.

At 24 weeks, the OLA/SAM group had a mean 4.21% weight gain from baseline, significantly less than the 6.59% gain with olanzapine alone. A clinically meaningful and unwelcome weight gain of 7% or greater occurred in 27.5% of OLA/SAM patients, compared with 42.7% of controls, for an adjusted 50% reduction in risk in the group on the investigational medication. Similarly, a 10% or greater weight gain occurred in 17.8% of OLA/SAM patients and 29.8% of controls; once again, that represented a 50% relative risk reduction. The two therapies were equally effective, achieving roughly 10-point reductions in the Positive and Negative Syndrome Scale (PANSS) for schizophrenia total score.

Both treatments showed similar weight gain trajectories for the first 4 weeks. However, by week 6 the trajectories diverged, with body weight plateauing in the OLA/SAM group and remaining stable throughout the remainder of the 76-week, two-part study. Meanwhile, body weight continued to climb in the olanzapine-only group throughout the 24 weeks, reported Dr. Graham, senior clinical research scientist at Alkermes, in Waltham, Mass.

"The waist circumference results were surprising: We saw that waist circumference separated between the two groups as early as week 1, considerably earlier than the week 6 separation in weight. This suggests to us that even when weight gain is similar between the two treatments, OLA/SAM is showing an early effect at limiting central fat accumulation --and this has important health implications, as central fat has been shown to be potentially pathogenic for developing diabetes, cardiovascular disease, and even some forms of cancer," she said.

The safety profile of OLA/SAM was essentially the same as for olanzapine-only, with the exception of the weight gain.

Alkermes reported in late November that it had submitted its New Drug Application for OLA/SAM to the Food and Drug Administration. The company broadened its application to include bipolar I, based on advice from FDA officials. Dr. Graham and coinvestigators have demonstrated that OLA/SAM has no clinically significant effect on the pharmacokinetics of lithium or valproate (Clin Drug Investig. 2019 Oct 4. doi: 10.1007/S40261-019-00860-y).

Pimavanserin in midst of phase 3 trial

Pimavanserin is an oral selective serotonin inverse agonist, or SSIA, with a high affinity for 5-HT2A receptors, very low affinity for 5-HT2C receptors, and "absolutely no affinity" for dopaminergic, histaminergic, adrenergic, or muscarinic receptors, explained Dragana Bugarski-Kirola, MD, a psychiatrist and vice president of clinical development at Acadia Pharmaceuticals in San Diego.

"Those sites are thought to contribute to sedation, cognitive impairment, and orthostatic hypotension," she said.

Pimavanserin is at present FDA approved for a narrow indication: Treatment of hallucinations and delusions associated with Parkinson's disease psychosis. But the drug's unique mechanism of action suggests broad efficacy across a range of psychiatric disorders.

Indeed, after a successful phase 2 clinical trial of pimavanserin for treatment of Alzheimer's-related psychosis, a phase 3 randomized, double-blind, placebo-controlled clinical trial of the drug for relapse prevention in dementia-related psychosis is now enrolling a planned 360 outpatients at 95 centers in 13 countries. This 26-week study, known as HARMONY, is preceded by open-label psychotherapy to ensure that study participants truly need pharmacotherapy. Patients are eligible regardless of their type of dementia, because psychosis in patients with various forms of dementia is clinically pretty much the same, whether the underlying disorder is Alzheimer's disease, vascular dementia, Parkinson's disease, or Lewy body dementia, according to Dr. Bugarski-Kirola.

Pimavanserin also is the subject of an ongoing phase 3 randomized trial in patients with major depressive disorder inadequately responsive to an selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor. A 380-patient phase 2 study of the drug as adjunctive treatment for negative symptoms of schizophrenia also is underway based upon earlier promising results.

Across the board for these potential indications, the drug has been well tolerated, with a side effect profile similar to that of placebo. Importantly, pimavanserin has not been associated with cognitive impairment when used for dementia-related psychosis, unlike the antipsychotics now being used off label in clinical practice, the psychiatrist said.

SEP-363856 part of 'novel class'

SEP-363856 is a nondopaminergic D2, trace amine-associated receptor agonist (TAAR1) under development for treatment of schizophrenia. Phase 3 trials in adults and adolescents with schizophrenia will begin before the end of the year on the strength of positive phase 2 results, according to Kenneth S. Koblan, PhD, head of global translational medicine and early development, as well as head of discovery sciences, at Sunovion Pharmaceuticals, Marlborough, Mass.

"We believe that SEP-363856 actually represents the first candidate in a novel class of antipsychotics. It's a monoamine receptor activator, unlike the atypical antipsychotics, which work through blockade of the monoamine receptor via dopamine and serotonin. We believe that it's the monoamine receptor activation that leads to the safety and efficacy of the class," he explained.

In the four-country, double-blind, 4-week phase 2 trial conducted in 245 hospitalized acutely psychotic patients, oral SEP-363856 flexibly dosed at 50 or 75 mg/day had a side-effect profile like that of placebo. Negative symptoms as assessed via the Brief Negative Symptom Scale improved by an average of 7.1 points at 4 weeks with SEP-363856, significantly more than the 2.7-point improvement with placebo. The PANSS total score improved by 17.2 points in the SEP-363856 group and 9.7 points in controls at 4 weeks, with a further 10-point drop in PANSS during a 6-month open-label extension phase of the study. Moreover, the SEP-363856 cohort showed significant functional improvement at 4 weeks in the UCSD Performance-Based Skills Assessment, with continued improvement during the open-label extension study.

Dr. Koblan said the pharmaceutical industry has overemphasized the development of dopaminergic D2-based drugs for schizophrenia. In the past 2 decades, about 30,000 patients have been enrolled in industry-sponsored, placebo-controlled, phase 2 or 3 randomized trials of drugs with that mechanism. Many of those drugs have reached the marketplace.

In contrast, far fewer randomized clinical trials--and no product launches - have taken place of antipsychotics with non-D2 mechanisms of action. "When you consider that the cost is about $50,000 per research subject and 50,000 subjects have been studied since 2000, the pharmaceutical industry has invested on the order of billions of dollars to try to come up with the next breakthrough medication," he said.


Caption: Dr. Graham

Caption: Dr. Bugarski-Kirola

Caption: Dr. Koblan

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Author:Jancin, Bruce
Publication:Clinical Psychiatry News
Article Type:Drug overview
Date:Dec 1, 2019
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