APA meeting 2009: new schizophrenia products and depot formulations

The annual meeting of the American Psychiatric Association is the year's largest psychiatry event. This year's conference in San Francisco indicated that long-acting depot versions of atypical antipsychotics continue to prove useful tools in the treatment of schizophrenia. In addition, new potential market entrants reported mixed data from new oral antipsychotics.

Although the majority of antipsychotics are now broadly used across most psychiatric conditions, the schizophrenia market continues to attract attention from developers of both novel antipsychotics and new formulations aimed at addressing the major unmet need of compliance.

The long-dosing regimen and intramuscular administration of long-acting injectable depot formulations of atypical antipsychotics results in a greater transparency of compliance. Eli Lilly presented new data for Zypadhera (olanzapine long-acting injection), as it continues to seek US approval and enter the market that Johnson & Johnson (J&J) has pioneered through Risperdal Consta (risperidone long-acting injection).

Data from new oral atypical antipsychotics were also presented. Vanda followed up the recent surprise approval of oral Fanapt (iloperidone) by presenting two posters detailing comparative data. Dainippon Sumitomo, meanwhile, provided delegates the first chance to see Phase III data for lurasidone.

Risperdal Consta long-term data shows functional improvement

J&J presented an analysis of two prospective, observational two-year studies, showing that Risperdal Consta consistently and significantly improved clinical and functional outcomes and reduced rates of rehospitalization among patients with schizophrenia.
Risperdal Consta remains the first and only long-acting intramuscular (depot) atypical antipsychotic to be approved for schizophrenia. By offering improved compliance of treated patients (a key unmet need in treating schizophrenia) and no direct competition, J&J has been able to generate blockbuster revenues for Risperdal Consta with global sales reaching around $1.1 billion ($483m in the US) in 2008. However, with the company developing its own improved follow-on depot (paliperidone palmitate), and Eli Lilly set to enter the market with Zypadhera, Risperdal Consta will lose significant market share to these second generation depots which possess longer durations of action and therefore less frequent dosing schedules. The link between paliperidone (Invega) and risperidone in the oral market has inhibited sales of the follow-on product as cheap generic versions of risperidone enter the market. J&J will hope that this link proves to be a positive association in the minds of psychiatrists in the case of Risperdal Consta and paliperidone palmitate in the long-acting depot market.

Three-year safety data for depot Zypadhera

Eli Lilly presented data on the short- and long-term efficacy and safety of olanzapine long-acting injection (LAI) in the treatment of adults with schizophrenia or schizoaffective disorder. Results from the 190-week interim analysis of a six-year, ongoing, open-label study showed that adults with schizophrenia or schizoaffective disorder treated with olanzapine LAI had a discontinuation rate of 46.3%. Although this may seem high, premature discontinuation of antipsychotic drug therapy is a common phenomenon. For example, in the Clinical Antipsychotic Trials of Intervention Effectiveness study, 74% of patients discontinued their drug within 18 months due to either poor tolerability or lack of efficacy.

Olanzapine LAI is an investigational formulation that combines the atypical antipsychotic Zyprexa with pamoic acid, allowing for the sustained delivery of olanzapine for up to four weeks. Olanzapine LAI is approved in the EU under the brand name Zypadhera for maintenance treatment of adults with schizophrenia who have been sufficiently stabilized during acute treatment with oral olanzapine. However, following the FDA's non-approvable letter for the formulation following concerns of post-injection delirium/sedation syndrome (PDSS) early in 2008, US regulatory review is ongoing.

In January 2009, Lilly stated that it was preparing a proposed Risk Evaluation and Mitigation Strategy (REMS) to be submitted in the near future in response to an FDA complete response letter. Assuming Eli Lilly can clarify the risk and underlying cause of PDSS and put in place a comprehensive REMS plan, Datamonitor forecasts Zypadhera to generate peak seven major market schizophrenia-specific sales revenues of $456m in 2013. However, this is not enough to maintain growth of Lilly's franchise upon the patent expiry of multi-blockbuster Zyprexa.

Comparative data for Fanapt presented following surprise approval

Vanda presented two posters which compared data of its newly approved atypical antipsychotic, Fanapt, to two well-established antipsychotic agents. The timeliness of these posters attracted particular attention from attending psychiatrists. The FDA surprised both the psychiatry and investment communities by approving Fanapt for the acute treatment of adult patients with schizophrenia a few weeks earlier, backtracking on its July 2008 approvable letter in which the regulator expressed concern about efficacy in patients relative to the active comparator, risperidone, used in prior studies, as well as stating that it would require additional safety data.

Mixed Phase III lurasidone data get their first showing

Meanwhile, Dainippon Sumitomo announced results from the first Phase III clinical trial of lurasidone for the treatment of patients with an acute exacerbation of schizophrenia. This six-week, double-blind, placebo-controlled trial (PEARL 1) assessed the safety and efficacy of three daily doses of lurasidone compared to placebo.

Lurasidone was associated with greater improvement at all visits between weeks two and six. However, while 80mg/day lurasidone proved significantly more effective than placebo at the two study endpoints at week six, neither the 40mg/day nor the 120mg/day doses demonstrated separation from placebo. Lurasidone's apparently favorable side-effect profile was further supported in the study, with a lower overall discontinuation rate compared to placebo.

Lurasidone is a novel compound with a unique receptor-binding profile. PEARL 1 is part of an extensive worldwide Phase III clinical development program, involving more than 2,000 patients, intended to evaluate the safety and efficacy of lurasidone for the treatment of schizophrenia. Although a previous head-to-head Phase II clinical trial showed lurasidone to be statistically superior to Geodon (ziprasidone, Pfizer), a positive outcome from the ongoing head-to-head long-term safety Phase III study against Risperdal will be essential to support the drug's approval process and future market positioning, especially in the light of the inconsistent Phase III trial result published at this meeting. Datamonitor maintains its cautious stance regarding the commercial potential of lurasidone. Following an anticipated 2010 filing, Datamonitor forecasts lurasidone to accrue disappointing seven major market annual schizophrenia-specific sales of around $150m by 2014 in this competitive and soon-to-be highly genericized atypical antipsychotic market.

Related research:
• Pipeline and Commercial Insight: Schizophrenia - Second generation depots protect market value priced $15,200 DMHC2441

• Commercial Insight: CNS Market Overview - Commercial dynamics and outlook of the neurology, pain and psychiatry market sectors priced $15,200 DMHC2379

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