Hello all,
I am new to this forum and this is my first post.
Recently, I read an old article (sorry, I am behind on my reading) by Nick Paul Taylor dated 16
th November 2016 titled, “CSL heart attack drug hits on safety, misses efficacy in PhIIb”
https://www.fiercebiotech.com/biotech/csl-heart-attack-drug-hits-safety-misses-efficacy-phiib
The article summarizes CSL112 phase IIb trial result as, ”…met its co-primary safety endpoints. The result, when paired to data supporting the mechanism of action, prompted CSL to start looking toward a Phase III trial, despite the drug failing to best placebo in a secondary efficacy endpoint.”
Dishearten by the article (CSL112 failing to beat a placebo) I read the research paper, “Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I)”
Yeah, it’s a mouthful.
The pdf document is attached and can be downloaded from Circulation:
http://circ.ahajournals.org/content/early/2016/11/11/CIRCULATIONAHA.116.025687
Admittedly, the research paper goes way over my head but I am inviting everyone to confirm my understanding:
The phase 2b trial was a multicentre, randomised, double blind placebo-controlled dosage. In layman’s terms, neither the patient nor the doctor / researcher were aware who was administered CSL112 therapy or placebo (sugar water?) and, the test locations randomised such that no one location administered just CSL112 therapy or placebo alone.
The primary objective of the trial was to test the safety of the study drug CSL112 in 2g and 6g doses in four weekly infusions versus placebo; the secondary objective was to observe the occurrence of the first MACE (Major Adverse Cardiovascular Event e.g. Heart attack, stroke or cardio event causing death) versus placebo.
The trial confirmed the ability of CSL112 to boost cholesterol efflux, in other words, enhanced the body’s ability to rid cholesterol via bowel motions; and, proved the safety of the therapy through no adverse affects to kidney and liver function with statistics showing, “… no clustering of death in proximity to the CSL112 infusion” (so clinically detached….. but good to hear). The paper mentioned that whilst the trial was not large enough to form a meaningful conclusion for the secondary MACE objective, the results showed that CSL112 therapy was similar to placebo.
Still with me?
The Phase IIb trial had a total of 1,258 patients enrolled with 1,244 patients (99.6%) receiving 1 dose of the study drug CSL112 and 1,147 patients (91.2%) receiving all 4 dosages (either 2g or 6g of CSL112).
The CSL112 2g group had a patient population of 419, the CSL112 6g group had 421 patients and the placebo group had 418.
Now, what’s confusing me is, 99.6% of the patient enrollment population was given 1 dose of CSL 112, that would mean nearly everyone in the placebo (control) group got 1 dose of CSL112.
Huh???
If I recall correctly from high school science class, you don’t include the test in the control group. It is supposed to be treatment versus no treatment for comparison. But in this case they’ve included one dose of CSL112 in the control group.
By having one dose of CSL112 in the control group I think its reasonable to expect that CSL112 therapy would have a similar result to placebo for the secondary MACE end point.
Thoughts anyone???
So, what I am getting at here is that Nick Taylor’s article may not be correct (“…failed to best placebo in a secondary efficacy endpoint”) because the phase IIb trial wasn’t designed for it, it was mainly a test for human safety, (one dose of CSL112 was included in the control group).
Phase IIb was a dosage / safety test and Phase III a test of the MACE endpoint with ideally a treatment v no treatment (control group).
If my understanding is correct then I am more hopeful of CSL112’s probable success even though things are still a flip of the coin with phase III trials notorious for its high failure rate. If CSL112 proves to be a disappointment I am confident CSL’s main profit engine would overcome any short term hits to its share price.
Disclosure: I am long CSL
(20min delay)