Atozet/Zeteze is approved in Australia for the treatment of primary hypercholesterolaemia and HoFH. The proposed indication does not increase the patient population eligible to receive Atozet therapy but would extend the claims made by the sponsor to include reduction in CV events. The rejection of the proposed indication would not restrict access to this combination therapy, therefore rejection would not disadvantage patients and would have no impact on public health. First round recommendation regarding authorisation It is recommended that the submission to register Atozet/Zeteze for the proposed indication relating to the prevention of cardiovascular disease be rejected. The main reasons for rejection are the lack of direct evidence for Atozet for the proposed indication, the insufficient justification to support the use of indirect evidence, the extrapolation of the justification to all doses of Atozet, the inclusion of only one pivotal study that was insufficiently compelling and the questionable clinical significance of the IMPROVE-IT study results. Clinical questions General Provide an update on the international regulatory status of the submission. The application cover letter lists only the combination product and does not include the composite pack ARTG numbers. Does the sponsor intend to extend the indications for both the combination product and composite pack product? What evidence is there to support the statement that the CV risk reduction associated with presence of both NPC1L1 and HMGCoA reductase genetic variants is additive? Indicate which of the GCP breaches listed were considered serious breaches in the CSR. Efficacy Clarify the age range of the IMPROVE-IT study patient population and state how many patients were aged less than 50 years of age in each treatment arm. Specify the NNT and the ARR for the primary composite endpoint in the IMPROVE-IT study. The sensitivity analysis for the primary composite endpoint censoring subjects at the time of dose titration does not appear to be consistent with the analysis of the composite primary endpoint. The sensitivity analysis shows higher event rates in the simvastatin/ezetimibe group for each of the composite endpoints except for non-fatal stroke and a higher overall event rate for this treatment group. Clarify the source of this discrepancy and discuss how the findings impact interpretation of the results for the composite primary endpoint analysis. Provide the analysis of between group change in the non-HDL-C/HDL-C ratio or identify the associated table in the submission. Safety Specify the time period covered by the post-market review of safety.
Atozet/Zeteze is approved in Australia for the treatment of primary hypercholesterolaemia and HoFH. The proposed indication does not increase the patient population eligible to receive Atozet therapy but would extend the claims made by the sponsor to include reduction in CV events. The rejection of the proposed indication would not restrict access to this combination therapy, therefore rejection would not disadvantage patients and would have no impact on public health. First round recommendation regarding authorisation It is recommended that the submission to register Atozet/Zeteze for the proposed indication relating to the prevention of cardiovascular disease be rejected. The main reasons for rejection are the lack of direct evidence for Atozet for the proposed indication, the insufficient justification to support the use of indirect evidence, the extrapolation of the justification to all doses of Atozet, the inclusion of only one pivotal study that was insufficiently compelling and the questionable clinical significance of the IMPROVE-IT study results. Clinical questions General Provide an update on the international regulatory status of the submission. The application cover letter lists only the combination product and does not include the composite pack ARTG numbers. Does the sponsor intend to extend the indications for both the combination product and composite pack product? What evidence is there to support the statement that the CV risk reduction associated with presence of both NPC1L1 and HMGCoA reductase genetic variants is additive? Indicate which of the GCP breaches listed were considered serious breaches in the CSR. Efficacy Clarify the age range of the IMPROVE-IT study patient population and state how many patients were aged less than 50 years of age in each treatment arm. Specify the NNT and the ARR for the primary composite endpoint in the IMPROVE-IT study. The sensitivity analysis for the primary composite endpoint censoring subjects at the time of dose titration does not appear to be consistent with the analysis of the composite primary endpoint. The sensitivity analysis shows higher event rates in the simvastatin/ezetimibe group for each of the composite endpoints except for non-fatal stroke and a higher overall event rate for this treatment group. Clarify the source of this discrepancy and discuss how the findings impact interpretation of the results for the composite primary endpoint analysis. Provide the analysis of between group change in the non-HDL-C/HDL-C ratio or identify the associated table in the submission. Safety Specify the time period covered by the post-market review of safety.