Significance of the Futility Analysis

The original trial design was based on 2400 patients and was planned to be completed when 250 MACE events had occurred. I believe the design was powered statistically to detect 30% relative risk reduction at the 95% or higher confidence level (hopefully much higher like 99% (p=0.01) or higher). I’m assuming it was also designed to detect statistical significance in the various subgroups including the 2 SOC groups.

I’m fairly confused on what is happening in the BoM trial.

• It is my understanding that a sample size estimation estimate will be done at approximately 188 adjudicated events and we don’t know when this will occur.

Also, I’m confused regarding the futility analysis because Don did not address it properly but I am assuming a futility analysis will occur at some point. Doing a futility analysis would seem to be prudent because if it fails it could save RVX considerable amounts of time and money and they can then begin to explore the other indications if they can get funding.

We’ve also been told to expect top line results by the end of 2018. Therefore, it seems like the futility analysis and top lines will be fairly close together unless the sample size estimate recommends that the trial size be increased to 3600. This has interesting implications including cost.

The combined post hoc analysis of the ASSERT/SUSTAIN/ASSURE trials revealed significant RRRs based on 5 point MACE and very high RRR in the diabetes mellitus (DM) subgroup from what I recall. However, the combined data did not provide enough statistical data to determine if 3 point MACE had statistically significant differences between test and control groups. (Please correct me if I am wrong on this.).

Therefore, apabetalone moved from phase 2 trials to the phase 3 BoM trial with little or no information about apabetalone’s impact on 3 point MACE which is the primary end point of the BoM trial.

There are significant differences between the BOM trial design and previous trials;

1. Sample size & length – BoM is much larger and treatment length is basically double previous trials.
2. Sample structure – BoM is targeted at patients with coronary artery disease(CAD) and diabetes mellitus(DM) that have low HDL.
3. There are probably other important differences.

I assume this targeting will increase the likelihood of achieving the primary endpoint.

The BETonMACE trial was approved originally in the EU and the first patient was dosed on Nov 11, 2015.

On Jan 11, 2018 (2 years and 2 months after EU dosing start) the BOM trial for apabetalone was given FDA approval (congrats to the CSC and RVX teams). So there are many very bright minds looking at and overseeing this trial.

The post hoc findings about the MOA of apabetalone since ASSURE have been extensive and profound including the multimodal MOA of apabetalone impacting numerous systems positively including reductions in mediators that promote inflammation of the vasculature, increased ApoA-I (positive effects on lipid content of HDL), reduced oral glucose absorption & endogenous production, reductions in mediators that promote calcium deposition in the vasculature, reductions in components of the coagulation cascade, reductions in the components & function of the complement cascade (reference any recent RVX update). All of these positive findings make me wonder if the ASSURE trial had been extended from 26 weeks to a year or more if the primary end point of PAV regression might have been achieved?

There have been positive findings for other indications including renal, retinal, muscular dystrophy (FSHD) and HIV. Independent researchers are now experimenting with apabetalone. The momentum is building on the science side.

On Nov 1, 2017 the 5th positive safety report was issued by the DSMB.

So we have an incredible amount of positive findings and yet we don’t know tangible information about apabetalone’s impact on 3 point MACE.

The Van Leewenhoek Research (Marcel Wijma) of Jan 16th, 2018 pegs the LOA (likelihood of approval by the FDA) at 55% without the futility analysis data and they put a NPV on the share at $14.

The first sentence in the Nov 15th, 2017 independent coverage of Resverlogix by Beacon’s David Kideckel, PhD, MBA reads “The Canadian biotechnology sector is primed for a big turnaround”.  They put their RVX target at $8.55 based on the risk adjusted NPV of it’s 2 initial disease states of CVD and DM. This as well is pre futility analysis.

What, I wonder, do Wijma and Kideckel know about compounds like apabetalone and the RVX platforms that the markets don’t know. They both have reputations to protect and build and in the Beacon case they have institutional clients investing based on their recommendations.

The market feels RVX is worth $1.80 to $2.00.

In my opinion the situation on the science side has never been more positive for RVX nor have the timelines been closer to ultimate success and yet the share languishes.

Even though this is another one of my rambling posts the point I started out to make is that the huge gap between the market and expert’s analysis means that for me the futility analysis is critical at this stage. If I am an investor coming in to do a PP with no information regarding BoM and 3 point MACE and if I am going to pay a fair price then I want that positive FA before I cut a deal.

If an investor comes in prior to the FA I believe they will pay only a very discounted price and we have seen the trend OR investors that are insiders like Eastern or Hepalink (perhaps through a partner) could come in with more confidence. Of course there could be an investor who understands the implications of the multi-modal MOA of apabetalone that would be more willing to pay. But why when Don appears to be up against the wall.

So Don, please give us an update on the FA status.

GLTA

Toinv (the rambler …LOL). I do apologize for the rambling thinking out loud. I'm getting old and I need my apabetalone!