Few thoughts and speculations on PIII PRIMO results:
In PIIb key data are:
a) CABG (without ckmb>100ng/ml): 41% reduction in the incidence of the composite endpoint of death or non-fatal MI (p<0.047), placebo=13.2% versus PEXE=7.8%.
b) CABG (with ckmb>100ng/ml): death and non-fatal MI (nonQW and QW, BOTH WITH >100 ng/ml criteria) ~9.7% for placebo and 3.4% (~65% reduction) for drug, (p=0.003).
c) CABG + valve: data unknown (to me)?
PRIMO:
1. PRIMO trials was powered (even for CABG alone) to detect 33% reduction at +99% confidence (p<0.01).
2. While company implied (CC) that there was not big difference (for CABG alone) in event rate relative to PIIb trials, I do think that event rate did went down, and I will assume that event rate for death-MI combination was <8% in placebo. So, for 30% reduction it should be 5.6% for PEXE.
3. Due to fast enrollment I will further assume that protocol and Pts selection was more liberal, so Pts at lower risk for MI-death.
4. Because PEXE in two MI PII trials did not show reduction in MI (reperfusion, ckmb level), and protective functions are more due to anti-inflammatory property, I will speculate that MI rate (>100ng) were low in CABG group and other factors mortality is key factor to separate PEXE from placebo.
5. Further, due to several positive secondary endpoints at 30 days (death, stroke, renal function, pulmonary function, cognition,…???), again imply that PEXE benefit was on mortality, not MI and death due to MI.
6. Because ckmb level (>50 ng/ml) is mortality prognostic factor in CABG ( >100 ng/ml even with higher probability, 2-3X normal rate), luck of primary end-point success again imply that PEXE benefit is more likely from anti-inflammatory property.
7. Also, I will speculate that event rate in valve surgery group was +12%. Valve surgery group (10% of total, 150 Pts in each group) have higher rate of the MI (>100 ng/ml) and combination non-fatal MI-death.
Now, fur pure speculation lets assume that in CABG population they have:
1. 20% reduction, or for placebo 8% and for PEXE 6.4% (108 versus 96). And, for CABG + valve they have 50% reduction (12 versus 6%, 18 versus 9), which for ALL ITT give 8.4% for placebo and 6.3% for drug. Which is only 25% reduction, and short of requirement. I think that 50% reduction for CABG + valve is reasonable assumption.
2. 25% reduction, 8% versus 6% (108 versus 81), and 12% versus 6% (18 versus 9) give for ALL ITT 8.4% for placebo and 6.0% for PEXE which is 29% reduction, or positive primary end-point.
Normally, there are many other ways to look at possible outcome.
My take from this (over the head numbers) are that Pexe does not reduce CABG post operative MI significantly (concomitant drugs and surgery technique improved), while it does generate benefit for at risk population (general health, more complicated surgery, co-morbidity factors,..). I do not think that 150 Pts valve sub-group will be sufficient for NDA, unless they can generate long term (90 and 180 days) benefit, in CABG alone group as well. Market for PEXE (CABG procedure) shrunk after this trial, imo. Drug will be reserved for high-risk procedure. If stroke and death (30 days) are convincing and more positive than MI alone, than ALXN may argue that drug have significant benefit for ALL CABG. But, this can only be evaluated with full data set.
Miljenko |
