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noretreat   Monday, 11/18/19 04:49:23 PM
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Total BETonMACE population (~2400 patients): Narrow miss on hitting the primary 3-point MACE endpoint: 18% Hazard Reduction (95% CI; 0.65-1.04) p=0.11. When excluding undetermined cause of death, there is a 21% Hazard Reduction (95% CI; 0.62-1.01) p=0.06. There was an early and sustained separation of the Kaplan-Meier survival curves. Breaking down the 3-point MACE composite, there was a 20% reduction in non-fatal MI (p=0.15) and 19% reduction in cardiovascular death (p=0.29). Forest plots show a trending improvements in hazard ratios for 11 out of 12 of pre-specified endpoints (no effect on stroke). Anticipated 7.5% 3-point MACE events per year in placebo, observed placebo rate was 5.8% per year (5.8 events per 100 patient years).

Congestive Heart Failure (CHF) in Total Population: In the total population, there was a 41% reduction for first hospitalization for CHF (95% CI; 0.38-0.94) p=0.03. Also 53% reduction for first and recurrent hospitalization for CHF. If stroke was replaced with first hospitalization for CHF in the 3-point MACE composite, there would have been a 24% reduction with p=0.02. DM mentioned that this is twice the effect of heart failure medication Entresto and that CHF market is twice that of the stroke market. An exploratory outcome composite of first hospitalization for CHF or cardiovascular death showed a 27% reduction (p=0.04). CHF partnering discussions ASAP, already initiated.

CKD population with baseline eGFR<60: In those patients with impaired renal function at baseline (eGFR<60; 124 patients apabetalone, 164 patients placebo), there was an incredible 50% Hazard Reduction in narrow 3-point MACE (95% CI; 0.26-0.96) p=0.03.

eGFR < 60 : 13/124 (10.4%) apabetalone vs. 35/164 (21.3%) placebo; HR 0.50 [95% CI (0.28 - 0.96)]

eGFR > 60: 112/1084 (10.3%) apabetalone vs. 114/1041 (11.0%) placebo; HR 0.94 (95% CI (0.73 – 1.22)]

This data is out of this world. You must view slides 21 to 29 for yourself to appreciate the robust and consistent effect on various cardiovascular outcomes in those patients with eGFR<60 compared to those with eGFR>60. It appears that the benefit is almost exclusively in those with eGFR <60 with little benefit in those with eGFR>60. All cardio data has an amplified benefit in this CKD sub-group! Renal partnering discussions planned ASAP.

Unfortunately, there was no mention of other CKD-substudy data (i.e. change in eGFR) other than the incredible MACE reduction. The only renal data shown is eGFR for the total population of ~2400 patients. At baseline, the apabetalone group had mean eGFR of 104.9 compared to 101.7 in the placebo group. At 100 weeks, the apbetalone group had mean eGFR of 104.3 compared to 105.2 in the placebo group. The data table indicates a -0.4 change in apabetalone group and a +2.1 change in placebo group, with p=0.03 for the group difference. These small changes in the total population seem clinically insignificant and in my opinion are nothing to worry about even though they are going in the wrong direction. The jury is still out on the CKD sub-study patients, who only represent ~10% of the total BETonMACE patients.

Below median LDL-C subgroup: Unexpected and yet to be understood and explained is the 40% Hazard Reduction for narrow 3-point MACE (95% CI; 0.42-0.86) p=0.02 in those with below median LDL-C at baseline. Similar to the data stratification for eGFR, it appears that most if not all of the benefit across various cardio endpoints is observed in those with below median LDL-C at baseline and little to no benefit in those with above median LDL-C at baseline. To be continued.....

Synergy with SGLT2 inhibitors: A critically important finding of apabetalone in BETonMACE is the synergy with the SGLT2 inhibitor class of diabetes drugs. ~12.3% of total patients (298 total patients; 150 apabetalone, 148 placebo) were on SGLT2 inhibitors. In this subgroup, there was a 60% Hazard Reduction in narrow 3-point MACE (95% CI; 0.16-1.00) p=0.05. Specifically in those patients taking Jardiance (Empagliflozin), there was a 66% Hazard Reduction (95% CI; 0.12-1.01) p=0.05. To put in perspective, SGLT2i by themselves in CANVAS and EMPA-REG elicited a 14% reduction in 3-point MACE. Importantly, this apabetalone effect is on top of the SGLT2i. Intellectual property has been filed, they now own IP on this moving forward. Additional patents in progress. SGLT2i partnering discussions have been initiated.

Safety: Safety is amazing. As expected, there were more patients with elevated liver enzymes in the apabetalone group; however, nothing else stands out. Amazing safety! 78/1212 apabetalone patients (6.4%) had ALT elevation of more than 3X above the upper limit of normal (ULN) compared to 18/1207 placebo patients (1.5%). Those with elevations 3X to 5X above ULN for ALT are sort of like a yellow caution flag. When specifically looking at those with greater elevations (>5X ULN), there were 40/1212 (3.3%) apabetalone patients compared to 9/1207 (0.9%) placebo patients. This rate is low and only 2.6% greater than placebo. Importanty, there was no Hy’s law cases reported indicated no liver damage. Lastly, only 35/1212 (2.9%) apabetalone patients had to discontinue due to liver enzyme elevations compared to 11/1207 (0.9%) of placebo patients. Overall, very good safety profile consistent with previous Phase 2 observations.

Cognition sub-study data: Under embargo and coming at CTAD Dec 5th. Will do webcast and update after this conference.

Near term commercialization steps: Breakthrough therapy status filings, both FDA and EMA, over the next 90-120 days. SGLT2i partnering discussions, one has already been initiated, key patent already filed. Renal partnering discussions ASAP. Congestive Heart Failure partnering discussions ASAP, already initiated. Orphan partnering discussions initially focused on PAH and HIV only at this time. PAH enrollment has already commenced. HIV funding being derived from a yet to be named US based organization.

hsCRP, apo-AI, triglyerides and other secondary endpoints: BETonMACE hsCRP data shown was only on a subset of patients at baseline and at 52 weeks. In this subset, there was no difference between placebo and apabetalone values at baseline or at 52 weeks. There was also no apo-AI data shown for baseline or on treatment. The lack of complete hsCRP data or any apo-AI data is very surprising to me. Baseline triglyceride values are shown (no difference between placebo and apabetalone); however, no on treatment triglyceride values are shown. I elaborated on these observations here. Additionally, there are some other secondary and exploratory endpoints mentioned in past trial design posters or publications that haven't been presented yet including fibrinogen, neutrophil to leukocyte ratio (NLR), platelet numbers, inflammatory cytokines, RNA profile in leukocytes. To be continued.....

Alkaline Phosphatase: In BETonMACE, AP went from 83.3 at baseline to 77.6 at 100 weeks in the apabetalone group (-4.8) compared to 81.9 at baseline to 84.2 at 100 weeks (+2.2) in the placebo group (p=0.003 apabetalone vs. placebo). Very interesting alkaline phosphatase (AP) story. They also presented a poster on AP today at AHA (see here) that is very similar to the poster at ASN earlier this month (see here). There were two other AP ASN posters too (see here and here). There is an interesting inter-relationship amongst AP, renal function, cognition, and cardiovascular disease. AP may end up being an incredibly useful biomarker. More on apabetalone and alkaline phosphatase here. Also, a new article recently came out Current Opinion in Nephrology and Hypertension from Resverlogix and members of the renal clinical advisory board: Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease. AP is a hot topic!

That's all from me. Exciting stuff!

BDAZ

No Retreat ... No Surrender
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