The Makalu Fund Managment research report on Resverlogix was great, but not without its flaws. As you pointed out, the report omitted the important fact that the post-hoc analysis of the Phase 2 MACE data from ASSERT, SUSTAIN and ASSURE is based on 5-point MACE, not 3-point MACE. There were very few strict 3-point MACE events in the post-hoc of the 24-26 week long ASSURE/SUSTAIN trials as I wrote about here. The 2018 Nichols paper also included the 12-week long ASSERT trial, but I don't have access to this paper.

Therefore, this passage from the Makalu report is very misleading "However, upon further analysis from its entire Phase 2 program of three clinical trials — ASSERT, SUSTAIN and ASSURE — consistent and statistically significantly relative risk reduction of MACE events were observed. MACE is described as a composite endpoint of nonfatal stroke, nonfatal myocardial infarction (a heart attack that did not kill), and cardiovascular death. This is the most important endpoint in cardio vascular disease risk."

I have a related criticism with this Makalu statement "The trials will be considered a success if the endpoint improves on MACE incidence by 25%. Earlier Phase 2 trials showed far higher efficacy at over 40% relative risk reduction." First, the %RRR isn't as important as the statistics. A 25% RRR in 3-point MACE would be unprecedented in modern cardiovascular medicine (Amarin's recent 25% RRR was in 5-point MACE and full data isn't out until Nov 10th). If BETonMACE achieves a 25% RRR in 3-point MACE that meets that statistical threshhold, then this is a blockbuster. Second, keep in mind that the 3-point MACE composite doesn't tell the whole story. If the 3-point MACE metric achieves statistical significance, one needs to then look at what is driving it: CVD death, non-fatal MI, non-fatal stroke, or a combination. Lastly, Makalu is comparing the >40% RRR from 5-point MACE with a 25% RRR in 3-point MACE. Not a fair comparison.

Makalu too quickly brushes off the potential for adverse events in this statement "Regarding toxicity: in one Phase 2 clinical trial, some patients had elevated serum enzymes (markers for liver injury); however other clinical tests indicated that there was no impairment in liver function and patients were asymptomatic for liver injury. Resverlogix has gone through seven data safety monitoring board reviews so far without any noted concerns for an ALT issue." ASSERT and ASSURE (see ASSURE study link in this post) showed increased liver transaminases. SUSTAIN probably did too but I don't think full results of SUSTAIN were ever published.  I've covered the liver transaminase issue before here. Apabetalone may get the approval of the DSMB for BETonMACE; however, it is not year in the clear safety wise from the FDA/EMA and fickle investors.

Despite these omissions and/or misrepresentations, it was a great research report. I agree with Golfyeti that this research did a great job with the comparisons to Amarin as a contemporary example of market reaction to a successful CVOT, and to Humira as a single product that can grow into a HUGE blockbuster based upon use in several indications.

BearDownAZ