Biotech Values

[dangerM]

DVAX reuters summary / highlights from FDA's document

reuters summary here www.reuters.com/article/us-dynavax-techs-fda-vaccine-idUSKBN1AB1Q0


to get started with the original document, what I highlighted in it:

- p. 17/18 describes the autoimmune events - IMHO the most interesting is the one titled

c-ANCA positive vasculitis (granulomatosis with polyangiitis, formerly Wegener’s granulomatosis) (Heplisav Group)

- p. 30 onwards will probably be the focus of the VRBPAC, the fatal SAE some pages before are relatively few cases, but the non-fatal ones also show an imbalance

As noted above, rates of cardiac SAEs were more frequent in the Heplisav group compared to the Engerix-B group (Heplisav 0.9%, Engerix-B 0.5%). This difference in frequency was most notable in the preferred term of acute myocardial infarction (AMI), which was reported in 14 subjects in the Heplisav group (0.25%) and one subject in the Engerix-B group (0.04%). Rates of non-serious MAEs in the organ system of cardiac disorders were similar between treatment groups (Heplisav 1.22%, Engerix-B 1.19%). Because of the differences noted, further evaluation was performed by the Applicant and the FDA, which is summarized here.

- p. 32 introduces the confounding factors (age, hypertension etc.)

- p. 36 contains the summary which I had condensed to a "about the imbalance of cardiac events, we cannot exclude Heplisav as cause"

Overall, the rate of all MAEs and SAEs reported in the 56-week study period were similar between the Heplisav and Engerix-B groups. Imbalances between trial arms in the frequency of deaths, myocardial infarctions, and herpes zoster were observed. After excluding deaths that were due to overdose or injury, 0.29% of Heplisav and 0.14% of Engerix-B recipients experienced fatal SAEs. Based on the standard Medical Dictionary for Regulatory Activities (MedDRA) query for MI (including the preferred terms acute myocardial infarction, myocardial infarction, coronary artery occlusion, acute coronary syndrome, and angina unstable), 19 Heplisav subjects (0.3%) and three Engerix-B subjects (0.1%) reported events of MI. All subjects who reported SAEs of MI had cardiovascular risk factors. A discrete risk window was not identified, but proportionally more subjects in the Heplisav group reported events of MI within three months after the last active injection. While the number of cardiovascular events is small, the relative risk in the Heplisav group is approximately three times that of the Engerix-B group. A comparison of cardiovascular AEs between groups was not prospectively specified, potentially leading to under ascertainment of events. Additionally, there are issues of multiplicity and alpha error inflation in post hoc safety analyses, further complicating interpretation of the results. However, one is more concerned with false negatives in safety analyses, at least initially.

- btw, the Bell's palsy (which was intensively discussed in the past by many people) is written about quite parenthetically (if I recall correctly from another part of the document all but one case eventually resolved)

Nine subjects in the Heplisav group (0.2%) reported new onset AESIs without an alternative plausible cause (VIIth cranial nerve palsy in five subjects, alopecia areata, ulcerative colitis, polymyalgia rheumatica, and granulomatous dermatitis).

- p. 39 - back to the cardiac events, there is a passage I'd summarize with a "ok, there are confounding factors, but I don't accept a simple logistic regression with a test of significance for a study group dummy"

The Applicant also conducted a multivariate logistic regression analysis for the pivotal trials with MI events (by preferred terms in the SMQ narrow for MI) as the dependent variable, and age, sex, race, hypertension, BMI, diabetes mellitus, smoking, history of MI or stroke, and treatment group as the independent variables. This analysis indicated that hypertension (Odds Ratio [OR] = 3.78; 95% CI: 1.44, 9.91) and age (OR = 1.07 per one year increase; 95% CI: 1.02, 1.13) were statistically significant independent predictors of MI. Treatment group was not a significant independent predictor of events identified by the MI SMQ (OR = 2.21; 95% CI: 0.76, 6.45). Other known risk factors for cardiovascular disease were not significant independent predictors in this model as well. Limitations to this analysis include a small number of events leading to limited power to draw robust conclusions, post-hoc assessment of MI may contribute to incomplete ascertainment of events, issues with pooling data across trials with different lengths of follow-up and baseline population characteristics, no distinction between first and recurrent events, omission of some covariates (dyslipidemia), and use of binary variables instead of continuous variables.

- p. 40-43 contains DVAX analysis and line of argument of a ~ "compared to expectations on population level Engerix had lower than usual cardiac events, which explains the imbalance to Heplisav", however, this is where the FDA will present an additional analysis only as late as at the VRBPAC (it did not make it into the document except for the following)

The FDA statisticians performed additional analyses of cardiovascular events, using Bayesian analysis methods. These results will be presented during the VRBPAC meeting.

- p. 44/45 another uncertainty which we will only know at the meeting or even later is if DVAX and the FDA will have agreed about a satisfactory post marketing study (see "7.0 Pharmacovigilance Plan")

dM