From what I've seen, top-line results may or may not include details such as secondary outcomes. We'll just have to wait and see what we get. For certain, BETonMACE top-line data will indicate whether the primary outcome was met with statistical significance. However, we may or may not get an actual relative risk reduction (RRR) value in the top-line. For most cardiovascular outcomes trial top-line data readouts that I've seen, the RRR is not included in top-line.

Primary Outcome: Time to first occurrence of adjudication-confirmed narrowly defined MACE (single composite endpoint of CV death or non-fatal MI or stroke).

Beyond just the primary outcome are pre-specified subgroup analyses for the primary endpoint in BETonMACE that include:

– Rosuvastatin/Atorvastatin

– < 30 days/> 30 days post-acute coronary syndrome

– LDL/HDL/TG’s above and below median

– HbA1c above and below median

– eGFR >60 mL/min and < 60 mL/min

• Also change in eGFR for all patients with eGFR <60 mL/min

There are quite a number of secondary outcomes that get into the individual MACE components, clinical chemistry, kidney function and adverse events. My guess is that we won't hear about most of these in detail during top line reveal and will have to wait until full data set is presented for detailed data. As I stated above, some trials do read out secondary outcomes in top-line data. What we might see is a general comment that certain secondary outcomes were successfully met, but the company won't provide details in the top-line news release. If and when we hear about these secondary outcomes, this will be very exciting. They could reveal effects related to kidney function, glucose/insulin control, and reveal which individual MACE categories are showing the strongest apabetalone-mediated change. Recall that for the SGLT2 inhibitor empagliflozin, it wasn't its modest 14% RRR in 3-point MACE that caught the most headlines but its 38% RRR in cardiovascular death.

Secondary Outcomes:

- Time to first occurrence of adjudication-confirmed broadly defined MACE (CV death, non-fatal MI, hospitalization for CVD events, or stroke)

- Group difference in all-cause mortality

- Percent change in apoA-I, apoB, LDL-C, HDL-C and TG concentration 

- Change in HbA1C, fasting glucose, fasting insulin over time

- Change in alkaline phosphatase (ALP) and estimated glomerular filtration rate (eGFR) 

- Incidence of AEs and Serious AEs within and between treatment groups 

Other outcomes not classified as primary or secondary are more in the exploratory category. I don't think there is any obligation for the company to comment on exploratory outcomes during top-line release. But perhaps if the data is intriguing enough, they may indicate whether certain exploratory outcomes were acheived during top-line data release. As with secondary outcomes above, I doubt if detailed data would be revealed in top-line.

Other/Exploratory Outcome Measures:

- Percent change in hsCRP within and between treatment groups

- Percent change in fibrinogen within and between treatment groups

- Transcription (messenger RNA [mRNA]) change in whole blood 

- Health Related Quality of Life (HRQOL) as measured using the EQ-5D-5L 

- Montreal Cognitive Assessment (MoCA) test on all patients 70 and over (~18% of patients). Cognition subgroup is those with MoCA < 25 (~275 patients).

As for the BETonMACE cognition subgroup and the MoCA test and how this relates to Biogen/Eisai and their BAN2401 Alzheimer's trial results.......first, there is a lot of skepticism about the amyloid beta hypothesis. Many, many similar anti-amyloid antibody therapies have failed. BAN2401 is an anti-amyloid beta antibody. Sure, not all anti-amyloid beta antibodies are the same. But the field is very skeptical of trusting Biogen/Eisai's claim of Phase 2 success with BAN2401 before seeing the full data set. Second, keep in mind that only the highest of 5 BAN2401 doses (10mg/kg antibody infusion given every two weeks, given as a 60 minute intravenous infusion) showed significant slowing of the ADCOMS score. Presumably, the other 4 doses showed no effect. The ADCOMS score combines items from the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), the Clinical Dementia Rating Sum of Boxes (CDR-SB) scale and the Mini-Mental State Examination (MMSE) to enable sensitive detection of changes in early AD symptoms. Third, they are presenting on this BAN2401 Phase 2 trial in a couple of weeks at AAIC 2018. Hopefully this will shed some light on the therapeutic potential of BAN2401.

Keep in mind for the MoCA that is being used in BETonMACE that a MoCA score of 26 or over is considered to be normal. In one study that first established the MoCA scale, normal people scored an average of 27.4, people with mild cognitive impairment (MCI) scored an average of 22.1 and people with Alzheimer's disease scored an average of 16.2. So the BETonMACE cognitive subgroup will likely be enriched primarily with patients with mild cognitive impairment, whereas those patients in the Biogen/Eisai Alzheimer's trial likely had more severe cognitive impairment AND confirmed amyloid pathology in the brain. It is important to point out that the Biogen/Eisai BAN2401 trial used the ADCOMS score, not MoCA. Differences between these two scores likely preclude their direct comparison. Nonetheless, a positive outcome for MoCA in BETonMACE cognition subgroup will be a great proof of principle for a follow up, focused Alzheimer's/Cognition clinical trial.

BearDownAZ