Lurasidon (1) – Latuda®

a) Acute treatment of patients with schizophrenia

• For the acute treatment of schizophrenia, additional benefit is not proven compared with the appropriate comparator therapy.
• Neither the comparator therapy nor the active treatment arms in the three studies exhausted the full range of possible dose adjustments.
• Given the high variability in symptoms and in individual patient response to neuroleptic treatment known to occur as a therapeutic indication for schizophrenia, restricting the treatment regimen for the acute treatment of schizophrenia is not appropriate.
• The use of antipsychotics at fixed doses deviates from the dose adjustment required in the treatment of schizophrenia.
• As it is known that the therapeutic effect may be over- or underestimated depending on the choice of dosage, dose escalation or the lack of titration options for the antipsychotics used, the studies submitted by the pharmaceutical manufacturer are not suitable for demonstrating additional benefit.

b) Relapse prevention in patients with schizophrenia

• No additional benefit is proven for the prevention of relapse in schizophrenia compared with the appropriate comparator therapy.
• On balance, it is not possible to weigh up the additional benefit against the harm.
• Consequently, the additional benefit of lurasidone in relapse prevention compared with the appropriate comparator therapy, risperidone, is not proven.
• mortality
  • Two patients died during the course of the study. Both were being treated with lurasidone.
  • There is no statistically significant difference between the treatment groups.
  • No additional benefit or greater harm from lurasidone compared with the appropriate comparator therapy is not proven for this endpoint.
• Morbidity – relapse rate
  • The pharmaceutical manufacturer has defined the relapse rate as a composite endpoint; however, the dossier only contains results for one of the three components of the endpoint, namely rehospitalisation due to a worsening of psychosis.
  • Separate results for the other two components included in the ‘relapse rate’ endpoint, worsening of the symptom score (measured using the Positive and Negative Syndrome Scale, PANSS) and indications of the risk of self-harm or harm to others, are not adequately presented; the results for the composite endpoint are therefore of limited interpretability.
  • There are no statistically significant differences for either the rehospitalisation rate or the composite endpoint ‘relapse rate’.
• Morbidity – Schizophrenia symptoms
  • The severity of schizophrenia symptoms was measured using the PANSS. Results are available only for the difference in mean scores.
  • The results were not statistically significant for either the total score or the three subscales.
  • For the total score, the PANSS Positive Scale and the ‘psychopathological symptoms’ subscales of lurasidone, the upper limit of the confidence interval for the standardised mean difference (Hedges’ G) of the study results lies above the irrelevance threshold of 0.2; consequently, it cannot be ruled out with sufficient certainty that there is a relevant effect to the detriment of lurasidone for the endpoints mentioned.
  • In summary, no valid conclusions regarding the additional benefit of lurasidone compared with the appropriate comparator therapy can be drawn from the morbidity data.
• quality of life
  • Health-related quality of life was not assessed in Study 237.
  • An additional benefit for this endpoint is therefore not proven.
  • In summary, additional benefit or greater harm from lurasidone compared with the appropriate comparator therapy is not proven in terms of quality of life.
• Side effects
  • For the endpoint of serious adverse events (SAEs), there is no statistically significant difference between the treatment groups.
  • For the overall rate of therapy discontinuations due to AEs, a statistically significant difference was observed to the detriment of lurasidone compared with risperidone.
  • This was primarily due to discontinuations caused by AEs that were not attributable to symptoms of the underlying condition.
  • In an analysis excluding discontinuations due to symptoms of the underlying condition (i.e. excluding the SOC ‘Psychiatric disorders’), the result remained statistically significant.
  • For the endpoint of vomiting, consistent with the higher rate of nausea, a significant difference was observed to the detriment of lurasidone; in contrast, for the endpoints of constipation and disorders of the genital organs/breasts, significant differences were observed in favour of lurasidone.
  • Lurasidone was associated with a significantly lower rate of weight gain of >7% compared with risperidone.
  • Furthermore, changes in body weight at month 12 were significant; a decrease was observed with lurasidone, whilst an increase was observed with risperidone.
  • The endpoint of akathisia (so-called restlessness, a side effect associated with extrapyramidal movement disorders) according to MedDRA PT, which is relevant in the long-term treatment of schizophrenia, showed a significant difference to the detriment of lurasidone.
  • Akathisia was also measured using the Barnes Akathisia Scale (BAS). A statistically significant difference was found for the total BAS score, to the detriment of lurasidone.
  • However, the 95% confidence interval (CI) for the standardised mean difference (SMD) did not lie entirely above the irrelevance threshold of 0.2. An irrelevanteffect cannot therefore be ruled out.
  • In terms of side effects, the advantages and disadvantages of lurasidone are balanced; it is not proven that there is an additional benefit or greater harm from lurasidone compared with the appropriate comparator therapy.
• Conclusion
  • On balance, it is not possible to weigh up the additional benefit against the harm.
  • Consequently, the additional benefit of lurasidone in relapse prevention compared with the appropriate comparator therapy, risperidone, is not proven.

Courtesy translation only, please refer to the German original.