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Message: CANTOS and CIRT

Tada wrote: "The only thing I would add to your comments about the 30% RRR, CV death reduction and 3 Point MACE reduction would be increased kidney function and better cognitive function for the trial participants affected that these secondary end points may provide. We can only hope that they talk ALL of this up a lot if our results are as good as what they are hoping for."

Yes indeed! Lots of pre-specified secondary/other outcome measures beyong the 3-point MACE primary outcome (see list below summarized from ClinicalTrials.gov).

Furthermore, sub-group analyses coud be huge! As shown for the CANTOS/canakinumab trial (see yesterday's EndPoints News article), once a drug proves itself to meet its primary endpoint, especially in a Phase 3, sub-group analyses (aka post-hoc analyses) can prove extremely useful to identify high-responder populations. BETonMACE is already focusing on diabetic patients with low-HDL. But it could be that sub-groups (many of which are already pre-specified) may respond to apabetalone even better. For example, those with CKD, high ALP, high hsCRP, those on rosuvastatin vs. atorvastatin, etc. The key is BETonMACE meeting its primary endpoint with statistical significance first! Or I should say, second...since we still await the futility analysis!

From the EndPoints article, one can see that the high baseline hsCRP population was a high-responding subgroup in CANTOS:

"Using a simple biomarker test, Novartis’ $NVS development chief, and soon CEO, Vas Narasimhan says that the drug proved more clearly impactful for heart attack patients whose hsCRP level — a measure of inflammation using high-sensitivity C-reactive protein — fell below 2mg/L after three months of treatment. By that score, they tracked a 31% reduction in cardiovascular death and a 31% reduction in all-cause mortality."

Here is the list of other non-primary outcome measures that I referred to above from BETonMACE ClinicalTrials.gov

 

  • Broadly defined MACE (CV death, non-fatal MI, hospitalization for CVD events, or stroke), All-cause mortality, Incidence of adverse events (AEs) and Serious AEs within and between treatment groups
  • Transcription (messenger RNA [mRNA]) change in whole blood. My note: This is very broad and could be very useful for identifying high-responder groups and other useful surrogate endpoints.
  • Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L. My note: I think, but I am not entirely sure, that this is the cognitive test that is also being done. If not, they are including cognititive testing as part of the pre-specified protocol.
 
Inflammation/Acute Phase Response/Thrombosis:
  • Percent change in hsCRP, fibrinogen
 
Lipids:
  • Percent change in apoA-I, apoB, LDL-C, HDL-C, TG
 
Glucose/Insulin:
  • Change in HbA1c, fasting glucose, fasting insulin
 
Kidney Function/ALP:
  • Change in alkaline phosphatase (ALP) concentration
  • Change in kidney function based on estimated glomerular filtration rate (eGFR).

 

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