Toniv,

Thanks for the comments on the 20.31% vs. 4.71% cumulative MACE events in the diabetic population treated without or with RVX-208, respectively. Perhaps the data that Jan Johansson had in his 2014 ESC presentation was preliminary and better refined in later presentations, in which the MACE events were 13.8% and 3.9%. It could also be that one is cumulative (i.e. more than one MACE event per person allowed) and the other is percentage of patients with 1 or more individual MACE events in the 6 month time frame. Regardless, we have a 77% relative risk reduction elicited by RVX-208. In either case, the RVX-208 population had 3.5X to 4.3X less MACE events.

In regards to Dr. Stephen Nicholls, I agree that having him on the committee is a good thing. One may criticize the ASSURE clinical steering committee for trial design (i.e. number of patients, statistical power, etc) and the actual clinics for proper screening of low-HDL patients and patient adherence to drug intake. However, the main point is that ASSURE was based upon SUSTAIN results and the known mechanism of action of RVX-208 at the time (apoAI/HDL elevation). At this time, we didn't know about the true far reaching effects of RVX-208 and were only focusing on the apoAI/HDL angle. Now, we know about "Our lead drug compound, RVX-208 (“apabetalone”), targets BET proteins to impact several important biological processes that drive risk in vascular disease patients, namely: (i) therapeutic increases in apolipoprotein A-I (“ApoA-I”), a key protein in reverse cholesterol transport (“RCT”), (ii) reduced C-Reactive Protein (“CRP”) and IL-6, key vascular inflammation markers, (iii) reduction of glucose and alkaline phosphatase (“ALP”), two key markers of metabolic risk, (iv) modulation of complement, coagulation and acute phase response cascades, known drivers in cardiovascular disease (“CVD”) and acute cardiac events." The point is, ASSURE failed because no one could have predicted with the information available at the time, that RVX-208 worked through all of these mechanisms to reduce MACE. AND, keep in mind that MACE was not an endpoint of ASSURE. Now, our clinical steering committee, including Dr. Nicholls, has a lot more info to work with to design the best trial possible.

One last comment on the Annual Information document regarding publications. Regarding the diabetes research, "On July 23, 2014, we announced the preliminary results of the exploratory trial. The investigators postulated that the RVX-208 induced rise in ApoA-I/HDL-C may impact pancreatic insulin secretion and thereby lower blood glucose (detected using an oral glucose tolerance test). Patients (n=23) with pre-diabetes mellitus (also called metabolic syndrome) were given 200 mg/day RVX-208 for a short duration of only 4 weeks. The preliminary results were not consistent with their hypothesis. However, this finding was useful in understanding the ASSURE data because for RVX-208 to reduce blood glucose in patients with diabetes mellitus required at least 12 weeks of treatment. Analysis of data from the trial beyond preliminary results reported here will include; HDL abundance, lipidomics, platelet aggregation, monocyte activation and neutrophil adhesion. We are planning to submit the above important findings and other new data to scientific journals for peer review prior to publication and presentation at leading medical conferences."

Regarding SUSTAIN, "In August 2012, we announced that SUSTAIN met its primary endpoint. RVX-208 significantly increased HDL-C (statistical significance of p=0.001), the primary endpoint of SUSTAIN. SUSTAIN also successfully met secondary endpoints, showing increases in levels of ApoA-I (statistical significance of p=0.002) and large HDL particles (statistical significance of p=0.002). ApoA-I and HDL are both believed to be important factors in enhancing RCT, the process whereby cholesterol is packaged and transported by special particles in the plasma called lipoproteins for movement from peripheral tissues through the blood and back to the liver for excretion from the body. The SUSTAIN trial also showed that increases in alanine aminotransferase (“ALT”) liver signals similar to those which were reported in previous trials were infrequent and, when allowed according to the trial’s protocol, returned to normal either as a result of continued dosing or short-term interruption, with no new increases observed beyond week 12 of the 24-week trial. Management and the Clinical Steering Committee have chosen to submit the remaining data for a peer reviewed publication."