Nature Reviews | Drug Discovery

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Asenapine(3aRS,12bRS)-5-Chloro-2-methyl-2,3,3a,12b-tetrahydro-1Hdibenzo[2,3:6,7]oxepino[4,5-c]pyrrole (2Z)-2-butenedioateC17H16ClNO•C4H4O4 Mr = 401.84

fresh from the pipeline

AsenapineHerbert Y. Meltzer, Argyris Dritselis, Uma Yasothan and Peter Kirkpatrick Asenapine

Figure 1 | Asenapine.

In August 2009, asenapine (Saphris; Schering–Plough) was approved by the US FDA for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults.

Schizophrenia is a heterogeneous lifelong psychiatric disorder that is characterized by abnormal mental functions and disturbed behaviour, and has a prevalence of ~1%1. Symptoms include ‘positive’ symptoms, such as hallucinations, ‘negative’ symptoms, such as social withdrawal, and cognitive deficits1.

Bipolar disorder (also known as manic depressive disorder) is another chronic psychiatric disorder that also has a lifetime prevalence of ~1%2. It is characterized by mania and more frequent and persistent depressive episodes2. As in schizophrenia, cognitive function is considerably impaired, even when the mood of the patient is normal. The current view is that these conditions are part of a spectrum of psychotic disorders, rather than discrete entities.

Basis of discoveryAntipsychotic drugs (APDs) are the main treatment for schizophrenia, and are also commonly used in the treatment of bipolar disorder with psychotic symptoms, referred to as bipolar I disorder1–3. All currently approved APDs, with the exception of aripiprazole (Abilify; Bristol–Myers Squibb) block dopamine D2 receptors, but this is not the exclusive basis for the efficacy of all APDs1,3. Aripiprazole is a partial dopamine agonist, which provides reduced dopaminergic function by weakly stimulating the dopamine D2 receptor.

First-generation antipsychotics — usually referred to as typical APDs, because they typically produce extrapyramidal side effects (EPS) — were discovered in the 1950s. The exemplars are chlorpromazine and haloperidol. They are effective in treating positive symptoms of schizophrenia but generally have limited efficacy for other aspects of the disorder1,3. Clozapine, the first ‘atypical’ APD — so classified owing to its low tendency to cause EPS — was introduced in the 1960s but withdrawn in 1975 because of its association with agranulocytosis. However, it was reintroduced in 1989 after a landmark

study showed it was effective for treating positive symptoms in patients who had failed to respond to typical APDs. Other atypical APDs are risperidone (Risperdal; Janssen), olanzapine (Zyprexa; Lilly), quetiapine (Seroquel; AstraZeneca) and ziprasidone (Geodon; Pfizer). These drugs are not more effective than the typical APDs for treating positive symptoms but are better tolerated because of their low tendency to cause EPS. However, some of these APDs are associated with significant weight gain and insulin resistance3.

All atypical APDs are more potent 5-hydroxytryptamine receptor 2A (5-HT2A) antagonists than they are dopamine D2 receptor antagonists or partial dopamine receptor agonists3,4. They differ in their affinity for other types of 5-HT, adrenergic, histaminergic and cholinergic receptors, which influences their side-effect profiles and possibly efficacy3.

Drug propertiesAsenapine, which was first reported in 1990, has antagonistic activity at dopamine and serotonin receptors, as well as various other receptors (FIG. 1)5–9. It has the characteristic high affinity for dopamine D2 receptors and 5-HT2A receptors (inhibition constant (Ki) ratio for 5-HT2A/D2 ~20)8,9, and showed potent antipsychotic activity and a low tendency to cause EPS in preclinical tests7.

Clinical dataThe safety and efficacy of asenapine in the treatment of schizophrenia in adults was evaluated in three short-term, fixed-dose, randomized, double-blind, placebo-controlled and active-controlled trials of adult patients who met the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for schizophrenia and were experiencing an acute exacerbation of their schizophrenic illness8. The Positive and Negative Syndrome Scale (PANSS), which assesses the symptoms of schizophrenia, was used as the primary efficacy rating scale. The primary end point was the change from baseline on the PANSS total score8.

In one 6-week trial involving 174 patients that compared asenapine (5 mg orally twice daily) with placebo and risperidone (3 mg orally twice daily), asenapine was statistically superior to placebo on the PANSS total

score8,10. In a second 6-week trial involving 448 patients that compared two fixed doses of asenapine (5 mg and 10 mg twice daily) with placebo, asenapine 5 mg twice daily was statistically superior to placebo on the PANSS total score8. Asenapine 10 mg twice daily showed no additional benefit to 5 mg twice daily and was not significantly different from placebo8. In the third trial, asenapine could not be distinguished from placebo, although an active control (olanzapine) in that trial was superior to placebo8.

The safety and efficacy of asenapine in the treatment of acute mania was assessed in two similarly designed 3-week, randomized, double-blind, placebo-controlled and active-controlled (compared with olanzapine) trials of adult patients who met DSM-IV criteria for bipolar I disorder with an acute manic or mixed episode, with or without psychotic features8. The primary rating scale used for assessing manic symptoms in these trials was the Young Mania Rating Scale (YMRS)8.

In both trials, all patients who were randomized to asenapine were initially administered 10 mg twice daily, and the dose could be adjusted in the dose range of 5–10 mg twice daily from the second day onwards on the basis of efficacy and tolerability (90% of patients remained on the 10 mg twice daily dose)8. Asenapine was statistically superior to placebo on the YMRS total score and also the Clinical Global Impression — Bipolar severity of illness score (for mania) in both studies8.

IndicationsAsenapine is approved by the FDA for the acute treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder, with or without psychotic features, in adults8. ▶

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Analysing issues in the use of APDs is Herbert Y. Meltzer, M.D., Professor and Director of the Psychopharmacology Division, Vanderbilt university School of Medicine, Tennessee, uSA.

Asenapine joins a long line of serotonin– dopamine antagonists, which are now almost the only APDs in widespread use. The line began with clozapine, which provided a breakthrough because it was more effective than any typical APD in treating the positive symptoms specifically of those patients with schizophrenia whose positive symptoms had failed to respond to typical APDs, as well as some patients with treatment-resistant bipolar disorder11. Its lack of association with EPS was also revolutionary at the time. However, the need for blood monitoring owing to the increased risk of agranulocytosis has marginalized clozapine; not even the unequivocal evidence that it uniquely reduces the risk of suicide has led to widespread use12,13. This has stimulated the search for drugs that have the efficacy of clozapine without the risks of agranulocytosis.

The atypical APDs that followed — risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, iloperidone (Fanapt; Vanda) and now asenapine — have achieved only two-thirds of the objectives for a safer clozapine: limited EPS and the absence of an increased risk of agranulocytosis. Numerous clinical trials have failed to clearly show whether the atypical APDs are superior to the typical APDs in improving cognition and negative symptoms14. Indeed, clinicians continue to use both types of APDs and often switch patients from one drug to another in the hope of achieving greater improvement

in these two symptom domains as well as positive symptoms. This provides a context in which the introduction of another drug of this class, asenapine, could be valuable. The studies so far on its metabolic profile suggest it will cause fewer problems in this regard than olanzapine and quetiapine, but its efficacy in treatment-resistant patients and its ability to improve cognition are largely unknown. Pharmacogenetic studies on APDs are in progress and might provide a rational basis for choosing among APDs for specific patients15.

It is beyond the scope of this article to discuss the current controversy over whether the greater tolerability of the atypical APDs, because of a lower tendency than typical APDs to cause EPS, and their possible benefit to cognition, makes patients more willing to take them on a prolonged basis, leading to fewer relapses and an improved quality of life16. A Finnish epidemiological study of commonly used APDs reported that clozapine, olanzapine and a long-acting injectable formulation of the typical APD, perphenazine, were associated with the lowest rate of discontinuation and rehospitalization and were significantly better than oral perphenazine or haloperidol17. In a second study, the atypical APDs, including even clozapine and olanzapine, did not increase the risk of cardiovascular mortality13. Currently, the only atypical APDs that are available in a long-acting formulation, which is the best way to minimize non-compliance for non-institutionalized patients, are risperidone and its metabolite, paliperidone.

Overall, it seems that the most important unmet needs for schizophrenia and bipolar disorder are unlikely to be solved by asenapine; to meet such needs, more novel agents will be required. until they are found,

asenapine is likely to be widely tested in the hope that, even in some patients who are not treatment resistant, it will indeed be clozapine-like in its effectiveness.

Herbert Y. Meltzer is at Vanderbilt University School of Medicine, Nashville, Tennessee 32712, USA.

Argyris Dritselis and Uma Yasothan are at IMS Health, 7 Harewood Avenue, London, NW1 6JB, UK.

Peter Kirkpatrick is at Nature Reviews Drug Discovery.

e-mails: herbert.meltzer@vanderbilt.edu; ADritselis@be.imshealth.com; p.kirkpatrick@nature.com

doi:10.1038/nrd3027

1. van Os, J. & Kapur, S. Schizophrenia. Lancet 374, 635–645 (2009).

2. Belmaker, R. H. Bipolar disorder. N. Engl. J. Med. 351, 476–486 (2004).

3. Miyamoto, S. et al. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol. Psychiatry 10, 79–104 (2005).

4. Meltzer, H. Y., Matsubara, S. & Lee, J. C. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 25, 238–246 (1989).

5. Broekkamp, C. L. et al. Behavioural pharmacology of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrolidine maleate, a compound interacting with dopaminergic and serotonergic receptors. Arzneimittelforschung 40, 544–549 (1990).

6. De Boer, T. et al. Neurochemical studies with the potential antipsychotic compound trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrolidine maleate. Arzneimittelforschung 40, 550–554 (1990).

7. Franberg, O. et al. Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia. Psychopharmacology 196, 417–429 (2008).

8. Food and Drug Administration. FDA labelling information. FDA website [online]<http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022117s000lbl.pdf> (2009).

9. Shahid, M. et al. Asenapine: a novel psycho-pharmacologic agent with a unique human receptor signature. J. Psychopharmacol. 23, 65–73 (2009).

10. Potkin, S. G., Cohen, M. & Panagides, J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J. Clin. Psychiatry 68,1492–1500 (2007).

11. Meltzer, H. Y. Treatment-resistant schizophrenia — the role of clozapine. Curr. Med. Res. Opin. 14, 1–20 (1997).

12. Meltzer, H. Y. et al. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch. Gen. Psychiatry 60, 82–91 (2003)

13. Tiihonen, J. et al. Mortality in schizophrenia: an 11-year follow-up study of the total Finnish population (FIN11 Study). Lancet 374, 620–627 (2009).

14. Leucht, S. et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol. Psychiatry 14, 429–447 (2009).

15. Volpi, S. et al. Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia. J. Clin. Psychiatry 70, 801–809 (2009).

16. Lieberman, J. A. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353,1209–1223 (2005).

17. Tiihonen, J. et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 333, 224–227 (2006).

18. IMS MIDAS (IMS Health, 2009).19. Arnold, C. et al. Credit Suisse Equity Research Report

(Credit Suisse Security, 3 Feb 2009).20. Schott, C. et al. JP Morgan North America Equity

Research Report (JP Morgan & Chase, 3 Feb 2009).

Competing interest statementH.Y.M. declares competing financial interests: see web version for details.

AnAlysis | antIpsyChotIC Drugs

▶

Box 1 | the market for antipsychotic drugs (apDs)

Analysing the market for ApDs are Argyris Dritselis and Uma yasothan, ims health, london, UK.

Across the key pharmaceutical markets — the United states, the top five european countries and Japan — the market for ApDs was worth Us$18.1 billion in the 12 months from July 2008, representing 78% of the total psycholeptics market and showing 28% growth in the past 3 years18. the United states constituted 75% of the overall ApD market, with sales of $13.6 billion; the market in europe and Japan was worth $3.3 billion and $1.2 billion, respectively18. Within the ApD market, atypical ApDs dominate, with a 97% share18. Quetiapine (seroquel; AstraZeneca) is the market leader, with reported sales of $4.8 billion (27% of the overall market), followed by olanzapine (Zyprexa; lilly), with sales of $4 billion18. in third position is aripiprazole (Abilify; Bristol–myers squibb), sales of which have increased by ~115% over the past 3 years to $3.8 billion18.

Asenapine (saphris; schering–plough) , a new atypical ApD, is the most recent entrant to this competitive market, following its fDA approval for the acute treatment of adults with schizophrenia, as well as manic or mixed episodes associated with bipolar i disorder; it is under regulatory review in europe for similar indications. Analysts predict that initial annual sales will be in the range of $15–20 million, reaching ~$300 million by 2013 (REFS 19,20).

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