New clinical data were presented at APA 2012 that showed that Latuda is effective as an adjunctive treatment for bipolar depression and may possess a procognitive effect in schizophrenia patients. These findings set Latuda apart from the competition and may allow the drug to shine in a fiercely competitive antipsychotics market.
Pilot study suggests that Latuda may have procognitive effects in schizophrenia patients
It is well established that antipsychotics are effective in treating the positive symptoms of schizophrenia, although they are considerably less effective on negative symptoms and cognitive deficits. Sunovion, the US subsidiary of Dainippon Sumitomo, presented a poster on the cognitive performance of schizophrenia patients treated with Latuda (lurasidone) or Seroquel XR (quetiapine; AstraZeneca) that hinted that Latuda may have a procognitive effect.
The study included a six-week double-blind stage, in which clinically unstable schizophrenia patients were randomized to receive Latuda 80mg or 160mg, Seroquel XR 600mg, or placebo. Patients that completed this period were eligible to enroll in a double-blind extension study involving continued treatment with flexible once-daily doses of Latuda (40-160mg) or Seroquel XR (200-800mg),with those in the placebo group allowed to enter the Latuda arm. Cognitive impairment was assessed by the primary CogState composite Z-score.
After the six-week, double-blind, placebo-controlled phase, Latuda 160mg produced a significant cognitive improvement over both placebo and Seroquel XR in secondary analyses of cases meeting prespecified criteria for data evaluability. Furthermore, at three months and six months following the start of the extension phase, cognition in patients remaining on Latuda was again superior to Seroquel XR. At six months, the superiority in cognition was independent of Positive and Negative Syndrome Scale (PANSS) positive, negative, or overall symptom reductions. The publication of this trial is timely as it coincides with the expansion of Latuda's label to include daily doses up to 160mg; the FDA had previously approved the 40mg and 80mg doses of Latuda for schizophrenia.
This represents the first trial in which an active drug was superior to placebo on cognition and a functional co-primary measure, as well as superior to an active comparator in cognition. This is an extremely exciting result, although these data must be tempered with the fact that the study was relatively small (n=488 for the initial six-week period, n=292 for the six-month period). Nevertheless, if Sunovion can substantiate and build upon these findings in larger studies, Latuda will have a large advantage over its competitors in the schizophrenia market.
Latuda is effective in relapse prevention and maintains efficacy over two years, although long-term use must be cautioned by increased EPS risk
Another trial investigated the effectiveness of Latuda and Seroquel XR for relapse prevention in schizophrenia. This study - an extension of a Seroquel XR- and placebo-controlled six-week trial - measured relapse and rehospitalization over the course of 52 weeks. The primary endpoint was met, as Latuda demonstrated non-inferiority to Seroquel XR in time-to-relapse, while 12 months of Latuda treatment was associated with a 27.2% reduction in absolute risk of relapse compared to Seroquel XR.
Additionally, the risk of rehospitalization was significantly lower over 12 months of Latuda treatment, with greater improvement in the PANSS total and Montgomery-Asberg Depression Rating Scale (MADRS) scores. While the metabolic risk of Latuda was low in this trial, incidences of akathisia and Parkinsonism were far higher in Latuda-treated patients (12.6% and 6.0%, respectively) compared to patients receiving Seroquel XR (2.4% and 0.0%). Overall, this trial presents a compelling argument for maintenance treatment with Latuda, with signs of superiority over Seroquel XR, although this comes at an increased risk of extrapyramidal side effects (EPS).
A 22-month open-label extension study verified the long-term efficacy and safety of Latuda in schizophrenia patients. The analysis showed that improvements in mean PANSS total and subscale scores achieved after the initial six-week double-blind stage were maintained during the entire 22-month extension period. There were minimal effects on weight, glucose, lipids, or prolactin, which are complications associated with some of the other atypical antipsychotics.
However, as with the 52-week comparison with Seroquel XR, Latuda was again associated with EPS. A fifth (19.2%) of patients experienced at least one EPS-related event, with a 10.8% incidence of akathisia and a 6.4% incidence of Parkinsonism. Other common side effects included somnolence (10.8%), vomiting (10.8%), nausea (8.4%), insomnia (8.0%), anxiety (7.6%), headache (6.0%), and weight decrease (6.0%). This study tells us that Latuda maintains its positive treatment effect on schizophrenia symptoms as measured by the PANSS over two years, although these benefits must be balanced with an increased risk of EPS-related events.
Latuda's efficacy in adjunctive treatment of bipolar depression holds promise in addressing unmet need
In addition to its availability for schizophrenia, Latuda is currently in Phase III development for the potential treatment of bipolar depression and bipolar maintenance. Dainippon Sumitomo plans to submit a supplemental New Drug Application for lurasidone in bipolar I depression to the FDA by the end of 2012. At APA 2012, Sunovion presented the results from a six-week, double-blind, placebo-controlled study of lurasidone as an adjunct to lithium or valproate for the treatment of bipolar I depression. A total of 340 individuals who met DSM-IV criteria for bipolar I depression with a MADRS score of 20 or more were randomized to six weeks of double-blind treatment with either lurasidone 20-120mg/day or placebo, both adjunctive to either lithium or valproate.
Results of the study demonstrated that use of lurasidone compared to placebo significantly reduced depressive symptoms (as measured by the MADRS) in patients with bipolar I depression who had inadequate response to either lithium or valproate alone. At the week 6 study endpoint, lurasidone was associated with a significantly greater MADRS reduction versus placebo (-17.1 versus -13.5). In addition, treatment with lurasidone significantly improved measures of social and occupational function as well as quality of life. The tolerability and safety profile of lurasidone observed in the study was consistent with that reported in previous studies in schizophrenia. Importantly, lurasidone induced minimal changes in weight, lipids, and measures of glycemic control.
Datamonitor regards this Phase III trial data as particularly encouraging and, should lurasidone be successful in obtaining regulatory approval, the drug will serve to address one of the most pressing unmet needs in the management of bipolar disorders: improved therapies for the treatment of the depressive phase of the disorder. Moreover, since most patients with bipolar disorder spend more time in the depressed rather than the manic phase of the illness, approval of lurasidone in bipolar depression offers considerable revenue potential to Dainippon Sumitomo and Takeda.