Replies to post #41643 on Biotech Values

[drbio45]

In the primary pre-pivotal trial in CABG (PRIMO-CABG):

a) It was about a 24% reduction in MI/Death

b) The 30 day p value was 0.01


send the link

[drbio45]

primo cabg data

http://www.medscape.com/viewarticle/464397

I will take Medicure's data anyday


Return to Medscape coverage of: American Heart Association Scientific Sessions 2003


PRIMO-CABG: Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery
Disclosures

Luis Gruberg, MD, FACC
Presenter: Edward Verrier, University of Washington (Seattle)

Since 1981, complement activation has been known to occur in patients who undergo coronary artery bypass graft (CABG) surgery. We also know that inflammation is a critical component of experimental ischemia, reperfusion injury, and clinical myocardial infarction (MI), and that it has been strongly implicated in the pathogenesis of atherosclerotic cardiovascular disease. Complement activation occurs in 2 phases in patients undergoing CABG surgery. Ischemia and biocompatibility of the bypass circuits activate C3 (which protects from bacterial infections by opsonization) and induce cleavage of C5 into C5a and C5b-9, which directly contribute to inflammation, vasoconstriction, vascular leakage, and leukocyte activation, with consequent cardiac damage and apoptosis.

Pexelizumab is a high-affinity, humanized anti-C-5 antibody fragment that blocks C-5 cleavage, thereby preventing inflammation.

Hypotheses
The phase 3, randomized, double-blind, placebo-controlled Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft Surgery (PRIMO-CABG) study was undertaken to test 3 hypotheses:

Perioperative MI is highly predictive of long-term mortality.
Pexelizumab reduces perioperative MI.
The reduction in perioperative MI with pexelizumab results in a reduction in morbidity and mortality in patients undergoing CABG.
Endpoints
The primary endpoint of the study was the composite of all-cause mortality and MI at 30 days in patients undergoing CABG with cardiopulmonary bypass, with or without valve surgery.

Secondary endpoints included:

Composite of death and MI by intention-to-treat analysis at 4 and 30 days
Composite of death and MI in CABG-only patients at 4 days
Death at 180 days.
Study Design
The study enrolled a total of 3099 patients at 205 centers in Europe and North America. Patients undergoing CABG only (n = 2746) or CABG with valve surgery (n = 353) who had > 1 preoperative risk factor (ie, diabetes mellitus, prior CABG, prior MI) were randomized in a double-blind fashion to either pexelizumab (bolus + infusion) (n = 1378) or placebo (bolus + infusion) (n = 1368).

Results
Baseline clinical characteristics and risk factors were similar for both the pexelizumab and the placebo arms. Pexelizumab administration was associated with rapid and complete inhibition of serum complement activity for 24 hours, which normalized at 72 hours. The results from this study showed that perioperative myocardial damage clearly predicts mortality, as patients with a peak CK-MB > 100 ng/mL had a 15.9% mortality rate at 180 days compared with only 2.3% in patients with a peak CK-MB of < 20 ng/mL. Furthermore, MI (defined as a CK-MB > 100 ng/mL) at day 4 predicted mortality in these patients, irrespective of the type of surgery performed.

According to the results from this study, patients treated with pexelizumab had significantly lower rates of peak CK-MB, and thus, there was a significant reduction in the combined endpoint of death or MI in pexelizumab-treated patients who underwent CABG only (Figure 1) and in all pexelizumab-treated patients at 4-day follow-up (Figure 2).


Figure 1. PRIMO-CABG: death, MI, and death/MI in CABG-only patients at day 4.

Figure 2. PRIMO-CABG: death, MI, and death/MI in all patients at day 4.
At 30-day follow-up, there was a strong trend toward a reduction in the combined endpoint of death/MI in CABG-only treated patients (primary endpoint) (Figure 3). However, when evaluating the overall population, there was a significant 18% reduction in the primary endpoint (Figure 4). In addition, at 90 days, there was a trend toward a reduction in death in all pexelizumab-treated patients compared with the placebo group (3.6% vs 4.8%, respectively; P = .096). There was also no reported difference between the 2 groups with respect to the incidence of side effects or complications, including the rate of infections.


Figure 3. PRIMO-CABG: death, MI, and death/MI in CABG-only patients at 30 days.

Figure 4. PRIMO-CABG: death, MI, and death/MI in all patients at 30 days.
Conclusions
Investigators drew the following conclusions from their reported results:

Pexelizumab appears to be safe and well tolerated in patients undergoing CABG.


Perioperative MI predicts long-term morbidity and mortality.


Pexelizumab significantly reduces perioperative MI at day 4 and day 30.


Pexelizumab reduces death or MI in CABG-only patients at day 30 (primary endpoint).


Pexelizumab significantly reduces death or MI in CABG-only patients at day 4 and in the overall population at day 4 and day 30 (secondary endpoint).


Mortality benefit is sustained at 6-month follow-up.


Pexelizumab may have an even greater benefit in high-risk patients.
Discussant: Robert C. Robbins, Stanford University School of Medicine (Stanford, California)
More than 20 million patients have benefitted from cardiopulmonary bypass, which was first performed about 50 years ago. However, it has been well documented that there is a systemic inflammatory response from the contact of the heparinized blood with the foreign surfaces of the cardiopulmonary machine. The activation of the complement is one of the most important factors in this process.

Although the results from this study are positive, they also show us that there is a redundancy of the complement activation with probable activation of the system via complement C-3. Further trials are currently under way to determine whether systemic inhibition of both systems will have a more profound effect in patients undergoing heart surgery with cardiopulmonary bypass.





Copyright © 2003 Medscape.

[donotknowityet]

Iwfal,

Thanks for the answer.
My question was why was the huge difference between previous pahse III and the pivotal phase III? and your answer is that it would be nice to understand.
Does anybody understand?
And in general, why does this happen often?
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The pivotal alexion trial failed.
In the primary endpoint they had 0.069. I would not characterize that as bombed.
Had they had a larger n (e.g. 3000 like MCU's current trial) with similar outcome, or primary endpoint (like MCU's again)
their drug would be on market already.
Instead they scrapped it altogether. My bet is that they did not feel they were competitive against MC-1 at that point. Any other guess?

Incidentally for MCU according to the claim inclusion exclusion criteria is the same. Principal investigators are the same.
Most old sites repeat, and virtually all that contributed many subjects. I assume that these sites will provide a very substantial subset of patients. Of course there will be lot more new sites, as the site number is much larger in this trial.

Of course we do not know everything.

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