The FDA has to balance the "public health" aspect of any drug. That, simply put is risk-benefit. The drug is superior, no question about it. The question is: is it riskier than the current SOC ?. The data gathered did not, and cannot, answer that question as was not designed to qualify MACEs.
In the FDA own worlds the number was small and , in DVAX words "Framingham Risk Score model for coronary heart disease event prediction. Accounting for risk factors in the population-based risk estimation models increased the expected number of events over the age-, sex-, and race-adjusted estimates. The number of observed events was similar to or lower than predicted in each trial and in HBV-16 and HBV-23 combined". The issue is that in the Engerix-B arm the incidence was much lower.
The AdComm has two venues: request further tests focusing in the Cardio safety (CRL with no approval) or, approve with Post-Marketing Surveillance Plan (which DVAX suggested on their proposal).
I firmly believe that the latter rather than the former will be the outcome as, in reading in NARRATIVES OF POTENTIAL MYOCARDIAL INFARCTIONS most of the events occurred to people that were already sick. "A 62-year-old white man with a relevant medical history of coronary artery disease with an old lateral myocardial infarction (MI), dyslipidemia, multiple prior coronary stents, and obesity experienced an ST elevation myocardial infarction 319 days after the second HEPLISAV-B injection. " or "A 69-year-old white woman with a relevant medical history of obesity and dyslipidemia experienced a non-ST elevation myocardial infarction 208 days after the second HEPLISAVB injection. " or "A 46-year-old white man with a relevant medical history of sleep apnea, hyperlipidemia, hypertension, and obesity experienced an acute MI 175 days after the second HEPLISAV-B injection. " or "A 64-year-old white woman with a relevant medical history of type 2 diabetes mellitus, dyslipidemia, hypertension, heart palpitations, and sleep apnea experienced an event of coronary artery occlusion 14 days after the first HEPLISAV-B injection" just copying the FIRST 4 narratives (not cherry picking here :-)"
One cannot blame DVAX for recruiting subjects with prior medical history, and, bedsides, one cannot forget that there was a difficult to explain, unbalance with the other arm.
I am optimistic of the outcome and, obviously putting my money where my mouth is. Hopefully the AdComm and FDA will give DVAX the opportunity toprove that
Dynavax originally made the mistake of running its first trial with a 4 to 1 ratio against the control. The second trial was 3 to 1 which is also a mistake. They have since run the trial 2 to 1 and have shown that there is no statistical evidence that this is less safe than Engerix. At the past vote they got efficacy vote of 13-1. We all agree that it is a good effective vaccine. Last vote was 8-5 for more data on safety. They have since done everything the FDA has asked for and it is all in the briefing document.
Thanks to all for actually having decent conversations on this board instead of just bs. Can I ask, is there a link to FDA where I can see other items that are up for vote and a schedule so that I can do research on other upcoming votes? Thank you everyone!
Heplisav's safety profile is outstanding and it brings significantly better seroprotectivity, in only two doses, no less! The AdComm members are looking for efficacy and safety. All of Heplisav's studies support both. They will recommend approval and require Phase VI AE review, which will prove the long-term safety even more as time passes.
Look at the Cardiology consults' appendix on page 51-52...
"7. What is your assessment of the cardiovascular risk associated with Heplisav? What, if any, problems have you identified with the Applicant’s conclusions with regard to the analyses they have presented? • There are a number of factors that make us think that this is not likely to be a reliable safety signal. i. An imbalance of MI that was not statistically significant was observed in study HBV-23. This imbalance was not observed in previous smaller studies; however, HBV-23 study population included a higher percentage of subjects with higher cardiovascular risk. ii. Analyses of adjudicated, confirmed stroke, cardiovascular death and MACE events in HBV-23 showed similar directionality (e.g., RR> 1.0), but none of the analyses showed a statistically significant difference between the two treatments. The cardiovascular death events were few and the RR was not robust. iii. The imbalance in cardiac events did not occur shortly after the first or second dose of vaccine; according to the Kaplan-Meier curve for MACE events, the two groups appear to separate only after 100 days. Thus, we agree with the applicant that there is not a close temporal relationship between vaccine administration and cardiovascular events. This timing is particularly incompatible with attribution to the adjuvant. iv. Non-clinical and clinical studies failed to reveal a plausible mechanism for MI. The risk of MI could result from accelerated atherosclerosis, sustained increase in blood pressure, or some prothrombotic state. None of these is in evidence. 52 v. The sponsor’s assessment that the event rate in the control arm is spuriously low is plausible. It is also plausible that the observed between-group difference is spurious. • Based upon the low likelihood that there is a real safety signal here, and the low absolute risk that these data suggest, we would label the finding in section 6 only and consider ways to monitor this risk post-marketing through some passive surveillance system."
I hate irresponsible, sensationalist reporting. What they didn't say is that the FDA-approved Hep B vaccine most widely used had a statistically equivalent number of deaths. With any study you can't control the wellness of the broad patient population. Anything that occurs in the test panel has to be documented, just all part of the process. Those that didn't do their own fact-check likely already bailed this morning.
How many here think it will be approved and how many think it will be denied?
I am hoping for approval as there is such a small difference in death rate between Heplisav (.21%) and Engerix (.18%). Good luck to everyone.
They think this is a $600M potential and if the shot cost $150, that means 200K patients. If the death rate is .21%, that equals about 420 people, not that low of a figure as some are making it out to seem. I picked up some shares and gambling here, but would not bet the farm on a thumbs up. Is my number wrong? 420 people who basically had maybe a 1% chance of getting hep-b, will have some complication from this vaccine. I also own VBIV who would benefit by this one tripping up.
looking good, a very serious effort to separate investors from there shares commenced yesterday with the first story reuters put on line (sad, Toni) then a half hour later a re-release of same story citing down pre market price (caused by first story) and one hour later story tweeked again. all in a effort by market maker and friends (reuters, motley fool) scare away investment and shake tree on shareholders.. i went thru same process with Sarepta (SRPT)
Looks like an over-reaction to me:
iii. The imbalance in cardiac events did not occur shortly after the first or second dose of vaccine; according to the Kaplan-Meier curve for MACE events, the two groups appear to separate only after 100 days. Thus, we agree with the applicant that there is not a close temporal relationship between vaccine administration and cardiovascular events. This timing is particularly incompatible with attribution to the adjuvant.
As others have said, I think this will come down to Packer. The ID/Immunology types will be skittish re: CV events. I expect they will not vote to approve a vaccine for healthy people in the face of CV signal. But if Janssen, and I think the DVAX CMO is the best person they could have leading this argument, can win over Packer, the CV expert, the vaccine people will fall in line. The votes are done electronically so no one knows who is voting for what, but if it appears Janssen has won Packer during the Q&A, I think DVAX will win. If Packer is negative/neutral, I think DVAX will lose. Watch the Janssen-Packer interaction during Q&A.
When do you guys think adcom will make their recommendation? before markets open or after?
VERY INTERESTING NEWS DAY -- PRE MARKET DVAX IS FLYING UP TO 13 THEN THERE IS A RUETERS NEWS POST ABOUT THE "SAFETY ISSUE" AND THE STOCK CRANKS BACK DOWN ALL THE WAY TO THE 8'S. THEN THE MARKET OPENS AND IT STARTS BACK UP 9 - 950 10 AND IT IS GETTING LEGS THEN ANOTHER RUERTERS STORY TITLED A LITTLE DIFFENTLY ABOUT THE "SAFETY ISSUE. BOTH STORIES ARE BY TONI CLARK - WHY TWO BY THE SAME WRITER -- WAAAIIIITTT YOU DON'T THINK IT WAS A SHORTIE HEDGIE FRONT TO MANIPULATE THE PRICE -- NAHHHH. MEANWHILE THE PRICE GOES BACK UP AND IS STILL GOING BACK TO 13 AND THE MF ARTICLE COMES OUT WITH THE SAME MANIPULATIVE BS. THIS WAS AN ORCHASTRATED HEDGIE SHORT NEWS BLITZ. THEY HAVE ONE MORE DAY TO PLAY AND MAYBE NOT EVEN THEN. THE SAFETY ISSUE HAS BEEN DEBUNKED BY SOME GOOD POSTINGS HERE ON THIS BOARD.
This is one of the FDA's cardiologist consultants' own words...
" Based upon the low likelihood that there is a real safety signal here, and the low absolute risk that these data suggest, we would label the finding in section 6 only and consider ways to monitor this risk post-marketing through some passive surveillance system."
And there it is. I think the adcom will give this opinion a lot of weight.
After digesting more of the FDA's briefing document, my gut tells me another CRL and request for additional safety study is coming Aug. 10. But, we'll see what the experts think on Friday.
Last call for alcohol
All bets in
Good luck to all of the old veterans
CUT TO THE CHASE: 1.8.2 Over all Summary of Safety "In Summary, the safety data demonstrates that HEPLISAV- B was well tollerated with an overall SAFETY PROFILE similar to that of Energix-B."
Mute estuardo. Longs will be happy tomorrow.
you will see this shoot up tomorrow and Friday....shenanigans aside.