Thomas Blaettler

Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: A randomised, double-blind, placebo-controlled phase 2 trial

BACKGROUND Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. METHODS This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. FINDINGS The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. INTERPRETATION Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. FUNDING AFM Téléthon and Trophos SA.

Bitopertin in Negative Symptoms of Schizophrenia—Results From the Phase III FlashLyte and DayLyte Studies

BACKGROUND There is currently no standard of care for treatment of negative symptoms of schizophrenia, although some previous results with glutamatergic agonists have been promising. METHODS Three (SunLyte [WN25308], DayLyte [WN25309], and FlashLyte [NN25310]) phase III, multicenter, randomized, 24-week, double-blind, parallel-group, placebo-controlled studies evaluated the efficacy and safety of adjunctive bitopertin in stable patients with persistent predominant negative symptoms of schizophrenia treated with antipsychotics. SunLyte met the prespecified criteria for lack of efficacy and was declared futile. Key inclusion criteria were age ≥18 years, DSM-IV-TR diagnosis of schizophrenia, score ≥40 on the sum of the 14 Positive and Negative Syndrome Scale negative symptoms and disorganized thought factors, unaltered antipsychotic treatment, and clinical stability. Following a 4-week prospective stabilization period, patients were randomly assigned 1:1:1 to bitopertin (5 mg and 10 mg [DayLyte] and 10 mg and 20 mg [FlashLyte]) or placebo once daily for 24 weeks. The primary efficacy end point was mean change from baseline in Positive and Negative Syndrome Scale negative symptom factor score at week 24. RESULTS The intent-to-treat population in DayLyte and FlashLyte included 605 and 594 patients, respectively. At week 24, mean change from baseline showed improvement in all treatment arms but no statistically significant separation from placebo in Positive and Negative Syndrome Scale negative symptom factor score and all other end points. Bitopertin was well tolerated. CONCLUSIONS These studies provide no evidence for superior efficacy of adjunctive bitopertin in any of the doses tested over placebo in patients with persistent predominant negative symptoms of schizophrenia.

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

AQW051, a novel, potent and selective α7 nicotinic ACh receptor partial agonist: pharmacological characterization and phase I evaluation

Activation of the α7 nicotinic ACh receptor (nACh receptor) is considered an attractive target for the treatment of cognitive impairment associated with neurological disorders. Here we describe the novel α7‐nACh receptor agonist AQW051 as a promising drug candidate for this indication.

Reliability, validity and ability to detect change of the PANSS negative symptom factor score in outpatients with schizophrenia on select antipsychotics and with prominent negative or disorganized thought symptoms

The PANSS is a valid instrument assessing schizophrenia symptom severity. Analyses have identified a five-factor solution. The negative symptom factor (NSFS) is robust, having been replicated in multiple analyses. The score has superior content validity versus the negative subscale. Aspects of validity in patients with predominant negative symptoms have yet to be established. The present data are from a Phase IIb study of add-on bitopertin therapy in schizophrenia outpatients with prominent negative or disorganized thought symptoms treated with antipsychotics. Analyses were conducted to evaluate reliability, validity and sensitivity to change. Test-retest screening to baseline was high (ICC=0.93). This was maintained in-study, for patients with no change in CGI negative symptom severity (CGI-S-N). Internal consistency at baseline was adequate (α=0.71) and increased at later assessments. Pearson correlation at baseline showed a good association between NSFS and CGI-S-N (0.63), but not overall CGI-S (0.31). Association with PSP at baseline was moderate (-0.39) and for change at Week eight good (-0.65). NSFS responders (≥20% improvement) at Week eight showed a significant improvement in function. The analyses demonstrated reliability, validity and ability to detect change of the NSFS, in schizophrenia patients with prominent negative or disorganized thought symptoms.

EFFICACY AND SAFETY OF ADJUNCTIVE BITOPERTIN VERSUS PLACEBO IN SUBJECTS WITH PERSISTENT PREDOMINANT NEGATIVE SYMPTOMS OF SCHIZOPHRENIA TREATED WITH ANTIPSYCHOTICS – UPDATE FROM THE SEARCHLYTE PROGRAMME

Results: Young people living with psychosis had high rates of most WHOdefined risk factors for death and disability. Their rates of tobacco use were more than double the general population, and virtually all were sedentary or had very low rates of physical activity. Most did not eat daily recommended amounts of fruit and vegetables. Obesity was common, and comparison with the AusDiab sample showed that the psychosis population had higher rates of obesity even from the age of 25 years. In addition, from age 25 years, people with psychosis had significantly higher diastolic blood pressure, triglycerides and glucose (in women), and lower HDL-cholesterol. There were gender differences, for example tobacco use was more common in young men whilst young women were more likely to meet criteria for at-risk waist circumference. Conclusions: Many of the risk factors for premature death are present from a young age in people with psychosis. It is therefore likely that people with these disorders will continue to experience poor physical health and premature mortality, unless measures are put in place to address these risk factors. Such measures need to be an integral component of early intervention services for young people with psychotic disorders, and to continue to be provided as an essential part of comprehensive mental health care across the lifespan.

CLINICAL TRIAL DESIGN OF CREAD: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP PHASE 3 STUDY TO EVALUATE CRENEZUMAB TREATMENT IN PATIENTS WITH PRODROMAL-TO-MILD ALZHEIMER’S DISEASE

with sustained suppression at all doses. After multiple doses, change from baseline in mean CSF Ab42 was 63.2 and 79.3% in the 15 and 50 mg AZD3293 groups, respectively, with similar reductions in Ab40 (Table 2). Baseline CSFAb42 levels were similar in the healthy Japanese and non-Japanese subjects. Conclusions: AZD3293 was generally well tolerated and potently reduced plasma and CSFAb peptides in Japanese adult subjects. Reductions in CSF Ab peptides were similar to those previously reported in non-Japanese subjects with AD.

FREE AND CUED SELECTIVE REMINDING TEST AS AN INCLUSION CRITERION FOR EARLY ALZHEIMER'S DISEASE CLINICAL TRIAL POPULATIONS

ter the intervention with dual tracer F-FDG and C-acetoacetate PET. Cerebrospinal fluid (CSF) was collected at baseline and after each intervention and assayed for AD biomarkers (Ab42 and total tau) with INNO-BIA-Alzbio3. Results: Global C-acetoacetate uptake decreased after the lowfat diet intervention (Fig 1 A Baseline and Fig 1 B Post-Lowfat Diet) and increased after the ketogenic diet intervention (Fig 1C Baseline and Fig 1D Post-Ketogenic Diet), whereas no changes were observed for F-FDG after either diet. Interestingly, CSF total tau increased with the ketogenic diet (p<0.05), with a similar trend noted for Ab42 (p1⁄40.08). Furthermore, the increase in Ab42and tau biomarkers was correlated (r1⁄4, p1⁄40.002). No biomarker changes were observed after low fat diet intervention. Conclusions: Ketogenic diet intervention enhanced brain ketone utilization in MCI and prediabetes, and produced correlated increases in CSF total tau and Ab42. Future investigation is needed to examine the relationship of these effects to changes in cognition.

Validity and utility of the PANSS negative symptoms factor score as a clinical trial outcome

Validity and utility of the PANSS negative symptoms factor score as a clinical trial outcome☆ Chris J. Edgar , Thomas Blaettler , Dragana Bugarski-Kirola , Stephanie Le Scouiller , George M. Garibaldi , Stephen R. Marder d a Roche Products Ltd., United Kingdom b Department of Neuroscience, F. Hoffmann-La Roche, Switzerland c F. Hoffmann-La Roche, Switzerland d Desert Pacific Mental Illness Research, Education, and Clinical Center, Semel Institute for Neuroscience at UCLA, United States