Neurosearch Amends the ACR-16 Results

Statistical significance not achieved on primary endpoint.

In February, Neurosearch announced that there was a statistically significant difference between the treatment and control groups in the primary endpoint, the Modified Motor Score of the United Huntington's Disease Rating Scale. Probability was reported as .02 meaning that the likelihood of these results being a chance variation rather than a meaningful treatment difference is less than 1 in 50.

On April 28, they announced that they had adjusted for CAG counts in their original analysis (but had not disclosed this). They found faster progression as the CAG count increased. Including the CAG count as a variable in the analysis resulted in the probability of .02. Once that adjustment was removed from the analysis, however, p = .0425. A probability of .05 or less would normally be acceptable; however, since this study involved two treatment groups, p needed to be .025 or less for the results to be considered statistically significant.

The problem is that the results of a clinical trial must be assessed based on the way that it was originally set up. An adjustment for CAG counts was not originally specified as part of the assessment. Neurosearch should have been clear that they had made such an adjustment in reporting the results for the primary endpoint of the study. In addition, they still do not have all of the CAG counts of participants so the adjustment was a preliminary one.

This means that the results look promising but are not conclusive and it is likely that an additional Phase III study is likely to be necessary before Neurosearch can apply for approval. The difference between the treatment group and the experimental group on the Total Motor Score is statistically significant and that is encouraging. However, it was the Modified Motor Score that was the primary endpoint so again, the trial cannot be classified as successful.

Given the promising data obtained in this trial, I believe it is worthwhile for HD patients to participate in HART and any future trial of this drug.
 

Marsha Miller, Ph.D.
NeuroSearch A/S announces the results of additional assessment and analysis of data from the Phase III MermaiHD study with Huntexil® in Huntington's disease

Neurosearch

  • Further assessment of data from the study shows that the significance value for the primary study endpoint, the modified Motor Score (mMS) of p= 0.042 did not meet the pre-specified level of p< 0.025. With inclusion of the clinically relevant CAGn adjustment, the p-value is < 0.02 as previously communicated
  • This revised statistical conclusion is isolated to the primary endpoint, and there are no changes to the previously communicated results for other endpoints
  • Overall, the data confirm that Huntexil® has a unique and clinically meaningful effect on global motor function in Huntington's patients with a good safety profile
  • The regulatory strategy for Huntexil® is unchanged, and NeuroSearch will initiate dialogue with regulatory authorities based on the MermaiHD study results

Copenhagen, 28 April 2010 – NeuroSearch (NEUR) has completed additional data assessment and analyses of the MermaiHD study, a European Phase III study with Huntexil® in Huntington's disease.

Overall, the additional assessments and analyses confirm the clinical top-line results as previously communicated in Announcement no. 01-10 on 3 February 2010, namely that

  • Huntexil® significantly improves motor function in Huntington patients
  • Huntexil® demonstrates positive effects on both voluntary and involuntary motor symptoms
  • Huntexil® was very well tolerated with an adverse event profile similar to placebo

The conclusion regarding the primary endpoint, the mMS with a significance level of p< 0.02, which was communicated as part of the top-line results, was based on a clinically relevant baseline covariate adjustment for differences in patients' genetic disposition, i.e. the length of CAG repeats (CAGn) in the diseased gene sequence. This adjustment is judged to be clinically important and appropriate in ensuring a more meaningful representation of the data set. Based on this assessment, the primary endpoint for the MermaiHD study was concluded to be met (p< 0.025). The adjustment for individual differences in patients' CAGn x treatment was pre-specified in the study protocol as a sensitivity analysis but not as part of the main effects model for the primary analysis. In view of this, the statistical results have been re-assessed, demonstrating a formal p-value of 0.042 for the primary endpoint, the mMS, and consequently indicating that the study did not rearch the p< 0.025 significance level (Bonferroni adjustment) as pre-defined in the study protocol. As adjustments for CAGn are recommended for the analysis of clinical studies in Huntington's disease, NeuroSearch will include the CAGn covariate adjusted analysis in the presentation of the MermaiHD study results to regulatory authorities. Overall, in the MermaiHD study, 26 weeks treatment with Huntexil® (45 mg twice daily) led to significant improvements of patients motor function measured on both mMS and TMS (the Total Motor Score) as compared to placebo. The statistical significance outcomes are summarised below for both endpoints as measured in the ITT (Intention to Treat) population and the PP (Per Protocol) population (the 82% of the patients who completed the study in compliance with the study protocol):
 

ITT (Intention to Treat) population

Huntexil®(45 mg twice daily) vs placebo Main effects model1) +CAGn x trt2)* +CAGn x age3)*
mMS p = 0.042 p< 0.02 p< 0.01
TMS p = 0.004 p< 0.001 p<0.001

PP (Per Protocol) population:

Huntexil®(45 mg twice daily) vs placebo Main effects model1) +CAGn x trt2)* +CAGn x age3)*
mMS p = 0.014 p< 0.005 p< 0.005
TMS p< 0.01 p< 0.0025 p< 0.001

 

  1. Main effects model: ANCOVA including baseline mMS/TMS score, neuroleptic cotreatment and gender as covariates
  2. Main model plus CAGn x treatment as baseline covariate
  3. Main model plus CAGn x age as baseline covariates

 

 

  • CAG values not yet available for 44 patients (of which13 in the placebo group, 18 in the 45 mg once daily group and 13 in the 45 mg twice daily dose group)

 

The additional data assessment generally confirms the consistency and robustness of the results and supports the overall positive clinical outcome of the MermaiHD study, including the following positive findings:

 

  • Huntexil® demonstrates a superior treatment effect in patients with an elevated CAGn score (considered a surrogate marker for rate of progression and disease prognosis)
  • The significant improvements observed in mMS are driven primarily by positive effects on fine motor skills, gait and balance
  • Positive effects were also observed in certain cognitive and functional domains
  • Significant benefit was observed on the independence scale in patients with higher CAGn scores

In the study, Huntexil® also demonstrated a very good safety profile and was shown to have no significant disadvantages in terms of worsening of other disease signs or symptoms. The further data analysis also showed that there were no significant changes in vital signs between the treatment groups.

Conclusions and next steps
The revised statistics do not change the overall clinical evidence from the MermaiHD study demonstrating that Huntexil® offers clinically meaningful improvements to Huntington patients across a broad range of motor symptoms without worsening any other disease signs and symptoms and thus shows promise in being a uniquely efficacious and well tolerated therapeutic option. NeuroSearch continues to plan for initial interactions with regulatory authorities based on the results from the MermaiHD study.

Press Release