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Message: Re: CVOTs on the Horizon
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Oct 01, 2018 04:04PM
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Oct 01, 2018 04:22PM
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Oct 01, 2018 04:58PM

"Does that mean we might have to do better than 30% RRR with BetonMace,... depending on the the results of these other upcoming trials you mention here."

A 30% RRR for 3-point MACE in BETonMACE would be outstanding! No therapies have achieved a 30% or greater reduction in 3-point MACE on top of statin standard of care in diabetics. The SGLT2 inhibs empagliflozin and canagliflozin and the GLP1-R agonist liraglutide only achieved 13-14% RRR in 3-point MACE. What made these results really pop was the effect to reduce cardiovascular death (one of the 3 components of the 3-point MACE). Another GLP1-R agonist, semaglutide, achieved 26% RRR in 3-point MACE is SUSTAIN, but was mainly due to effects on non-fatal stroke and non-fatal MI (the other two components of the 3-point MACE). Similarly, recall in the PSCK9 LDL-C lowering trials FOURIER and ODYSSEY, they acheived results in the range of 14-20% RRR for 3-point MACE, but effect was mainly on non-fatal MI and non-fatal stroke. The big win for BETonMACE would be a 25-30% (or more) RRR in 3-point MACE combined with a big effect on cardiovascular death reduction. Even better would be reductions in not just cardio death, but also in non-fatal MI and non-fatal stroke. I remember watching the webcast of the EMPA-REG OUTCOME trial for the SLGT2 empagliflozin and the announcement of the 14% RRR in 3-point MACE got a "good" reaction but the announcment of the 38% reduction in cardiovascular death got a standing room applause. Remember, lots of pre-specified sub-group analyses in BETonMACE, so we could see a sub-group like the rosuvastatin/apabetalone group have even a greater effect than in the combined atorvastatin+rosuvastatin group.

"From what i understand the phase 2 used a 4 point MACE and now we are using a 3 point,... so we should expect 10% less than what was seen in the phase 2 ... ?"

The Phase 2 trials did after the fact post-hoc analyses to look at 5-point MACE. But these Phase 2 trials were only 6 months long (BETonMACE patients dosed much longer), not enriched in diabetics (all BETonMACE patients are diabetics), did not have as strict of a low-HDL requirement like BETonMACE, and did not require patients to have a recent cardio event (BETonMACE patients must have CAD event of either unstable angina or myocardial infarction 7-90 days prior Visit 1). It is not correct to assume that one will observe 10% less, as you state, since the patient population and trial design are so much different in BETonMACE than in the Phase 2 ASSURE/SUSTAIN. The patients in BETonMACE have a huge absolute risk for cardio events; perhaps moreso from any other recent cardio outcomes trial. Huge potential for apabetalone to bring that absolute risk down and achieve an amazing RRR.

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Oct 02, 2018 02:53AM
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Oct 04, 2018 11:42AM
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