TopCoin,

As you probably already know, Resverlogix and the Clinical Steering Committee used the EXAMINE trial to help design BETonMACE. Like BETonMACE, EXAMINE enrolled patients with type 2 diabetes with a recent ACS event within 90 days of enrollment. As you pointed out, BETonMACE has an additional low-HDL requirement. In EXAMINE, patients had an average HDL-C at baseline of approximately 43 mg/dL. In BETonMACE, males must have HDL-C<40 mg/dL at baseline and females must have HDL-C<45 mg/dL at baseline. So the average baseline HDL-C for BETonMACE patients should be well below the 43 mg/dL average in EXAMINE. When the full BETonMACE basline data is presented at AHA in about a week, we will know these baseline values for sure. 

EXAMINE had a median follow up period of 1.46 years and at that point they observed 11.8% (placebo) vs. 11.3% (alogliptin) event rates for 3-point MACE. However, if this were expressed as events per 100 patient years, it would be approximately 8.08 vs. 7.74, respectively, for the placebo and alogliptin groups for 3-point MACE. So the average annual event rate for EXAMINE patients is about 8%. Importantly, EXAMINE trial ran from 2009 to 2013, whereas BETonMACE will run from 2015 to 2018 (or early 2019). One can't assume that BETonMACE placebo patients will have this exact same event rate as EXAMINE placebo patients. In addition to the low-HDL variable, standard of care changes over time and no two trials are going to have exactly the same event rate even if they are in similar patient populations run at about the same time. 

Earlier this year (~February I think), Resverlogix stated for BETonMACE update: "Projected primary MACE rate still 8.0 per 100 patient years." Resverlogix IR clarified: "To answer your questions, yes the actual events we are observing in the blinded analysis from BETonMACE is close to 8 per 100 patient years as we had planned. As you know this trial remains blinded and therefore, we do not have any access to who is on placebo or who is on drug, so these numbers are derived from all patients." Based on that clarification, the 8 per 100 patient years is an average of all patients in the trial. In a post from June this year, Tundup relayed from his conversation with management that the event rate had dropped down to ~7.2 per 100 patient years. 

A while back, I posted some info on how different combinations of the low-HDL requirement and apabetalone treatment may or may not affect the event rate. For example:

• No effect of low HDL, no effect of apabetalone
• No effect of low HDL, 30% relative risk reduction of apabetalone
• Low-HDL increases event rate, no effect of apabetalone
• Low-HDL increases event rate, 30% relative risk reduction of apabetalone

These are just a subset of possible scenarios. But as I hope you can appreciate, different scenarios would be expected to yield a range of event rates and more than one scenario may yield the same or similar average event rate. Therefore, one can't tell if apabetalone is working just based upon the company reported average event rate. 

BearDownAZ