Can Schering-Plough’s asenapine improve prospects for schizophrenia and bipolar patients

More than half of schizophrenia patients are expected to relapse within two years if untreated and 4 out of 5 within five years, according to experts. Antipsychotics can reduce the relapse rate so long as patients continue on treatment. However, adherence is notoriously poor. A new antippsychotic – asenapine – shows promise of being effective and better tolerated.

The prospect of an antipsychotic drug that keeps schizophrenia patients well without paying the price of intolerable side effects came a little closer this week with publication of new data on a recently FDA-approved atypical antipsychotic, asenapine. 

Phase III data from a schizophrenia relapse prevention study of asenapine versus placebo were presented at the 22nd annual meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul by scientists from Schering-Plough.  

Results from the multinational, year-long, study (6 months open-label followed by a six-months randomized double blind placebo-controlled phase involving 386 patients) show the relapse rate was highly significantly reduced for asenapine-treated patients (12 per cent compared to 47 per cent for placebo p<0.0001). Moreover the benefit was not achieved at a cost of high side effects. In the double-blind placebo-controlled phase, treatment-related adverse events were actually higher among placebo group patients than in the asenapine-treated group. 

A secondary endpoint – time to treatment discontinuation – was also significantly longer for asenapine (p<0.001). Patients who discontinued asenapine for any reason stayed on treatment significantly longer than patients who discontinued placebo, suggesting patients tolerate the drug relatively well. Only 3.7% of asenapine patients had clinically significant weight gain (more than 7 per cent increase from baseline). The most frequently reported adverse events were anxiety (8.2 per cent with asenapine vs 10.9 per cent with placebo), increased weight (6.7 per cent for study drug vs 3.6 per cent for placebo) and insomnia (6.2 per cent for asenapine vs 13.5 per cent for placebo).  

Safety data were also presented in Istanbul this week from a year-long extension phase of a six-week study in which asenapine was compared against haloperidol, the gold standard antipsychotic. John Panagides, a senior research scientist of Schering-Plough said the trial showed asenapine was associated with only modest side effects regarding weight gain, metabolic syndrome, sedation and extrapyramidal symptoms (involuntary movements) and that raised prolactin, a common side effect of antipsychotic use, ‘was not an issue’. “It has a very good risk benefit profile,” he commented.  

FDA and guideline committee approval Schering-Plough announced FDA approval in August this year to market asenapine sublingual tablets as Saphris in adults for acute treatment of schizophrenia and for acute treatment of manic or mixed episodes associated with bipolar 1 disorder with or without psychotic features. The license, which allows asenapine to be used first line, is the first to grant initial approval to an antipsychotic for both indications simultaneously. In Europe, the drug is currently under review by the European Medicines Evaluation Agency (EMEA) as a treatment for schizophrenia and bipolar 1 mania. The new relapse prevention data form part of the license application. Schering-Plough hopes to market the drug in Europe under the brand name Sycrest.  

Despite not yet having European approval and not yet being available (it is expected to launch October 2009 in the US), guideline committees for bipolar disorder are already recommending asenapine for bipolar manic episodes in their updated guidelines. The joint CANMAT (Canadian Network for Mood and Anxiety Treatments) and ISBD (International Society for Bipolar Disorders) guidelines recommend asenapine, as does the WFSBP (World Federation of Societies for Biological Psychiatry) guideline. With data from 11 phase III trials expert committee representatives said at ECNP this week that it has level 1evidence to support its use.  

Rich pharmacology
Data from other Schering-Plough studies suggest that asenapine may offer both efficacy and tolerability advantages. “It may be the most potent of all the drugs in the market place right now,” noted Dr Panagides. “It has a rich pharmacology and targets many receptors - serotonergic, alpha adrenergic and histamine receptors besides the dopaminergic receptors, which may add to its effectiveness.”  

A company press release in July this year reported a study on asenapine’s efficacy in the difficult-to-treat negative symptoms of schizophrenia which include apathy, loss of drive, lack of emotion and poor social functioning, among others. In the study, asenapine was significantly more effective than olanzapine in the reduction of negative symptoms as assessed using the 16-item Negative Symptom Assessment scale (NSA-16).”Full results of the trial, including efficacy, safety and tolerability data, will be submitted for presentation at a medical meeting at a later date,” says the company.  

A poster at ECNP led by University of California and Yale University scientists using a primate model suggests asenapine may have potential to treat cognitive impairment in schizophrenia. The researchers concluded from asenapine’s effects on serotonergic receptors in monkeys that the drug might also improve cognitive impairment in schizophrenia although they stress large scale clinical studies would be needed for confirmation of these effects in patients.  

Regarding its other indication, bipolar 1 mania, or mixed symptoms, a poster at ECNP showed asenapine rapidly reduced symptoms within 2 days and improved scores on all 11 items of the YMRS (Young Mania Rating Scale) - the standard measure for mania assessment within two weeks.  

Asenapine was originally synthesised in The Netherlands by Organon Biosciences which Schering-Plough acquired two years ago. It is one of five products that Schering Plough identified as rising stars in its late stage development pipeline at its R&D update last November.