New drugs in development target several receptors, rather than just dopamine and serotonin, as with current antipsychotics. In the case of formulations, the newer versions have advantages such as a more convenient dosing schedule, which can improve patient adherence.
Long-Acting Injectable Formulations
A new, long-acting injectable formulation of aripiprazole (Abilify, Alkermes) is being developed for the treatment of schizophrenia.1,2 Called aripiprazole lauroxil, the drug differs from the long-acting preparation currently marketed by Otsuka and Lundbeck in that it will be available in a ready-to-use, prefilled syringe. Both one-month and two-month formulations are being studied.
Findings from a randomized, double-blind, placebo-controlled phase 3 clinical trial involving 623 patients with acute schizophrenia, indicate that those treated with the once-monthly injection of either 441 mg or 882 mg of aripiprazole lauroxil experienced statistically significant reductions in Positive and Negative Syndrome Scale total scores from baseline to week 12 compared with placebo (-10.9 points, P<0.001 for aripiprazole lauroxil 441 mg; and -11.9 points, P<0.001 for aripiprazole lauroxil 882 mg).2
Another long-acting injectable for schizophrenia, a three-month formulation of paliperidone palmitate (Invega, Janssen), is also in development.
Researchers enrolled 509 patients, who were first treated and stabilized with the FDA-approved one-month formulation of the drug (Invega Sustenna), and randomly assigned them to treatment with the investigational three-month formulation or placebo.
Results from an interim analysis indicated the three-month formulation was superior to placebo in delaying time to first relapse of schizophrenic symptoms. Drug maker Janssen is planning to file a New Drug Application with the U.S. FDA for the paliperidone palmitate three-month formulation by the end of 2014.3
Dopamine receptor partial agonists
Cariprazine (Forest) and brexpiprazole (Otsuka and Lundbeck), two new dopamine receptor partial agonists are currently in phase 3 clinical trials for schizophrenia and several mood disorders.4
They offer incremental improvements on already established therapies within the class of second-generation antipsychotics, and could serve as alternatives to aripiprazole, which is currently the only FDA-approved dopamine receptor partial agonist available.
Completed phase 3 studies for cariprazine include double-blind, randomized, controlled trials in schizophrenia (NCT01104779, NCT01104766, and NCT01412060)* and acute bipolar mania (NCT01058668, NCT01058096). An additional phase 3 study (NCT01715805) is ongoing for cariprazine as an adjunctive therapy in acute major depressive disorder (MDD).
A NDA for the drug’s schizophrenia and manic or mixed episodes associated with bipolar I disorder indications was submitted to the FDA in November 20125, but was not initially approved.6 However, the application is expected to be re-reviewed.
Completed phase 3 studies for brexpiprazole include double-blind, randomized, controlled trials for the drug’s adjunctive use in MDD (NCT01360632, NCT01360645) and for the treatment of acute schizophrenia (NCT01393613, NCT01396421).
Ongoing phase 3 studies are examining brexpiprazole’s use as a treatment for schizophrenia (NCT01668797, NCT01810380, NCT01451164), agitation associated with dementia of the Alzheimer’s type (NCT01862640, NCT01922258), adjunctive use in treating MDD (NCT01727726, NCT01837797, NCT01838681) and adjunctive use in treating posttraumatic stress disorder (NCT01987960).
A NDA for the drug’s schizophrenia and adjunctive treatment of MDD indications was just submitted on July 14, 2014.7
Differentiating features among the dopamine partial agonists are their varied pharmacodynamic profiles at the various dopamine (e.g. preferential binding to D3 vs. D2 receptors) and serotonin receptors.4,8 Pharmacokinetic differences may also be clinically relevant, such as the extended half-life of the didesmethyl-cariprazine metabolite of cariprazine.8
Of special interest are the more novel compounds that target various receptor sites rather than solely dopamine and serotonin.
There were two promising candidates in phase 3 trials that homed in on glutamate receptors for the treatment of schizophrenia — pomaglumetad methionil (Eli Lilly)9 and bitopertin (Roche).10 Unfortunately, both candidates failed in late stage trials and development has been stopped.
Still in the running, though, is encenicline (Forum Pharmaceuticals, formerly EnVivo Pharmaceuticals), an alpha-7 nicotinic receptor co-agonist that is being studied as an adjunctive procognitive treatment for patients with schizophrenia, who are receiving chronic stable atypical antipsychotic therapy.
Leslie Citrome, MD, MPH, is Clinical Professor of Psychiatry and Behavioral Sciences at New York Medical College in Valhalla, New York and a member of the Board of Directors of the American Society of Clinical Psychopharmacology.
Disclosures: In the past 36 months, Citrome has engaged in collaborative research with, or received consulting or speaking fees, from: Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Forest, Forum, Genentech, Janssen, Jazz, Lundbeck, Merck, Medivation, Mylan, Novartis, Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva and Valeant.
Alkermes announces positive topline results from pivotal phase 3 study of aripiprazole lauroxil for treatment of schizophrenia [press release]. Dublin, Ireland: Alkermes; April 8, 2014. Available at: http://phx.corporate-ir.net/phoenix.zhtml?c=92211&p=irol-newsArticle&ID=1916604
SR, Risinger R, Du Y et al. Poster #II-75. Safety and efficacy of aripiprazole lauroxil: results from a phase 3, multicenter, randomized, double-blind, placebo-controlled study in subjects with acute exacerbation of schizophrenia. Presented at: 54th Annual American Society of Clinical Psychopharmacology Meeting. June 16-19, 2014: Hollywood, Fla.
Janssen investigational treatment for schizophrenia shows positive efficacy, delays relapse [press release]. Titusville, NJ: Janssen; March 20, 2014. Available at: http://www.investor.jnj.com/releasedetail.cfm?ReleaseID=834181.
Citrome L. A review of the pharmacology, efficacy and tolerability of recently approved and upcoming oral antipsychotics: an evidence-based medicine approach. CNS Drugs. 2013; 27(11): 879-911.
Forest Laboratories submits New Drug Application for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder [press release]. New York, NY: Forest Laboratories; November 28, 2012.
Forest Laboratories and Gedeon Richter receive complete response letter for cariprazine [press release]. New York, NY: Forest Laboratories; November 21, 2013.
Otsuka and Lundbeck submit New Drug Application in the US for brexpiprazole for the treatment of schizophrenia and as adjunctive therapy for the treatment of major depressive disorder [press release]. Tokyo, Japan: Otsuka; July 14, 2014. Available at: http://www.otsuka.com/en/hd_release/release/pdf.php?news=966
Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol. 2013;9(2):193-206.
Lilly stops phase III development of pomaglumetad methionil for the treatment of schizophrenia based on efficacy results [press release]. New York, NY: Eli Lilly; August 29, 2012. Available at: http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=703018.
Roche provides update on the first two of six phase III studies of bitopertin in schizophrenia [press release]. Basel, Switzerland: Roche; January 21, 2014. Available at: http://www.roche.com/media/media_releases/med-cor-2014-01-21.htm.