Pomp,

Just a bit more info for your modeling. Two-thirds of the ~2400 patients enrolled in BETonMACE were enrolled by the end of June 2017. Assuming dosing goes to end of 2018, this means that  ~1600 patients in BETonMACE will have been dosed for 18 months or more (first dosing was Nov 11, 2015 so max dosing duration close to 38 months). The other 1/3 (~800 patients) will have been dosed for between 9 to 18 months at the end of Dec 2018 with the exception of the last China patients that didn't finish enrolling until end of June 2018 (see AGM transcript). The estimated mean dosing period for BETonMACE according to the AHA BETonMACE baseline/design poster is 26 months. The median BETonMACE dosing period will likely be somewhere around 21 months, since patient #1200 was enrolled around March 2017. If I recall, the original mean/median dosing period was planned to be 18 months with the first patient enrolled dosed for 24 months and last patient enrolled dosed for 12 months. But due to BETonMACE protocol change, dosing period was extended. According to the AGM transcript and the AHA baseline poster, the minimum dosing period required is 6 months. We could reasonably expect this final China cohort to meet with 6 month requirement by end of December. 

The only two recent CVOTs with similar patient populations as BETonMACE that I know of are EXAMINE and ELIXA. Both were type 2 diabetes patients with recent ACS event (within 90 days for EXAMINE and within 180 days for ELIXA). BETonMACE patients are closer to EXAMINE patients in terms of both having requirement for ACS w/i 90 days, but BETonMACE also is unique in having the low-HDL requirement. So placebo event rate in BETonMACE may be higher than that observed in EXAMINE and ELIXA due to low-HDL. Neither drug in either EXAMINE or ELIXA elicited benefit. Median dosing period for EXAMINE was about 18 months and about 24 months in ELIXA. At this median dosing period, the event rate was ~11.5% at 18 months for EXAMINE and ~13.3% at 24 months in ELIXA. Note, ELIXA was 4-point MACE but there were negligible unstable angina events that only comprised about 2.5% of total 4-point MACE events. Converting this to events per 100 patient years gives about 7.9 and 6.4 for EXAMINE and ELIXA, respectively.

The last "official" report from management for events per 100 patient years in BETonMACE was March 2018 BIO-Europe that stated projected rate still 8.0 events per 100 patient years. About 3 months later in June 2018, Tundup reported that in a convo with management the rate had dropped to 7.2 events per 100 patient years. Looking at the Kaplan-Meier curves for EXAMINE and ELIXA, it appears that most events occur in the first 9 months of dosing. Since BETonMACE now allows patient to remain on dosing until end of trial, almost all patients in BETonMACE have now been dosed for at least 9 months, it is reasonable to expect this 7.2 events per 100 patient years number to have continued to drop over time between June 2018 and current. Therefore, it may be wise to use number lower than 7.2 for projecting # of events by year end. The event projection uncertainty is further compounded by not knowing 1) the low-HDL effect on event rate; 2) the apabetalone %RRR, and 3) # of patient years.

Not accounting for patient drop outs or patients negated for already having events, I project ~3800 patient years by years end. However, Tundup's June post indicated at the time that BETonMACE was about 2400 patient years and adding about 210 per month. This would give closer to 3600 patient years by year end. At the AGM, we were at about 200 events but we don't know the events per 100 patient years rate. If we assume 7.2 then there were about 2800 patient years at time of AGM Sept 12, 2018. But if we assume the event rate has dropped since June to let's say 6.7%, then the patient years were closer to 3000. 

All the stars are aligning. The duration of dosing requirement, the patient year requirement, the minimum number of event requirement. Tick tock.

BearDownAZ