Dynavax Technologies Corp (DVAX)

[MrGuru]

Questions for the consultant

Consult 1

1. In the “Evaluation of Acute Myocardial Infarction and Major Adverse Cardiovascular Events in the Phase 3 Heplisav Clinical Trials,” the Applicant uses the following tools to assess cardiovascular risk: 1) identification of reported events of AMI in the safety database and multivariate logistic regression analysis to assess risk factors associated with MI in Study DV2- HBV-23, 2) a three-point MACE analysis to identify serious cardiovascular events in the three Phase 3 studies, 3) comparison of observed to expected number and rate of cardiovascular events in studies DV2-HBV-16 and -23, and 4) discussion of the Bradford Hill criteria for assessment of causation applied to the three-point MACE analysis. Are these the appropriate tools to use to evaluate the cardiovascular risk following Heplisav? Are there any additional tools you would use to assess cardiovascular risk associated with Heplisav?
Consultant questions:
Response:

• The tools listed, as well as the applicant’s analysis of absolute risk and risk difference, seem reasonable in evaluating cardiac risk.

• In general, comparing rates of observed cardiovascular events in the study population to expected event rates in the overall population raises the issue of comparability. However, on its face, the sponsor’s argument that MI and cardiovascular death rates in the Engerix-B group appear lower than predicted seems plausible.

2. Please comment on whether the appropriate cardiovascular outcomes have been selected for inclusion in the analyses. Specifically, we have the following questions:

? In order to identify subjects with myocardial infarction, are SAEs with preferred terms in the MedDRA SMQ narrow for myocardial infarction the most appropriate criteria? ? What, if any, additional preferred terms, or other criteria, would you recommend using to identify subjects with probable myocardial ischemic events?