RE:RE:RE:RE:REPATHAAs you pointed out, BETonMACE patient population is different (diabetic, low-HLD, ACS event in past 90 days) than FOURIER, whose main inclusion criteria were history of clinically evident cardiovascular disease at high risk for a recurrent event, fasting LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) or non-HDL-C ≥ 100 mg/dL (> 2.6 mmol/L).
So yes, different patient populations, different drugs, different targets, different modulated pathways. But the primary endpoint is the same.......how does this or that therapy lower risk of MACE on top of standard of care statin treatment.
In this case, the primary question was: Does aggressive LDL-lowering with anti-PCSK9 antibodies, to a level not achievable with statins alone, result in a profound reduction in MACE. As described in the first paragraph below, Repatha dramatically lowers LDL. However, as described in the later text below, they "only" achieved ~20-25% reduction in MACE. Although this is great news, apparently investors/clinicians were expecting much more.
What this study suggests, in my opinion, is that there is a limit to which LDL lowering can elicit MACE reducing effects. Maybe there would have been a more profound RRR if Repatha was used in a patient population similar to BETonMACE. However, to me FOURIER, along with other recent cardiovascular outcomes studies like EMPA-REG OUTCOME and LEADER, help to set the bar for what we hope and expect RVX-208/apabetalone to do. Out of FOURIER, EMPA-REG OUTCOME, and LEADER, none of them have exceeded 20% RRR for 3-point MACE (time to first heart attack, stroke or cardiovascular death).
From the Amgen
press release:
"
When added to statin therapy, Repatha reduced LDL-C from a median of 92 to 30 mg/dL, a reduction of 59 percent at week 48, which was sustained throughout the trial. At 48 weeks, the LDL-C was reduced to at least 25 mg/dL in 42 percent of patients treated with Repatha, as compared with <0.1 percent in the placebo group (p<0.001). Additionally, treatment with Repatha had favorable effects on other lipid parameters."
"The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding Repatha to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The robust benefit in this objective measure started as early as six months and continued to accrue through the median 2.2 years of the study. In fact, the magnitude of the risk reduction in the hard MACE composite endpoint grew over time, from 16 percent in the first year to 25 percent beyond the first year.
The study also found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularization, heart attack, stroke or cardiovascular death.
Patients on Repatha experienced a reduction in the risk of heart attack (27 percent, nominal p<0.001), stroke (21 percent, nominal p=0.01) and coronary revascularization (22 percent, nominal p<0.001). Consistent with recent trials of more intensive LDL lowering, there was no observed effect on cardiovascular mortality.1-5 Similarly, there was no observed effect on hospitalization for unstable angina. In an exploratory analysis, the relative risk reduction for fatal and non-fatal heart attack or stroke was 19 percent in the first year (p=0.003) and 33 percent beyond the first year (p<0.00001)."