Hartland stated "I may be wrong but almost all outr trials have actually failed."

I don't agree with that statement. Early trials were extremely informative for refining the dose, patient population, potential statin synergy, optimal endpoints, and other indications for which RVX-208 may be beneficial. 

The early Phase 1/2a trial of RVX-208 was more or less exploratory and provided information comprising safety, toxicity, pharmacokinetics and pharmacology in patients treated with 3 different doses of RVX-208 for 28 days. Notably, this trial met its primary endpoint of increasing plasma ApoA-I significantly.

They then proceeded with three Phase 2 trials: ASSERT, SUSTAIN, and ASSURE.

ASSERT, Phase 2: Failed primary endpoint, achieved secondary endpoint

For the primary objective, RVX-208 was associated with a dose-dependent increase in apoA-1 levels of up to 5.6% (p=0.035 for the trend), but none of the individual pairwise comparisons of apoA-I change (the primary end point) achieved statistical significance.

For the secondary objective, very strong results on HDL-C and HDL subclass were obtained. Compared with placebo, the 50-mg, 100-mg, and 150-mg doses of RVX-208 significantly increased the levels of HDL-C 3.2%, 6.3%, and 8.3%, respectively (p=0.02), and the number of large HDL particles increased by 11.1%, 20.2%, and 21.1%, respectively (p=0.003).

One key finding from this trial was determining that the 100 mg, twice a day dose was the optimal dose to be chosen in subsequent Phase 2 and 3 trials. 

SUSTAIN, Phase 2: Achieved primary and secondary endpoints

RVX-208 significantly increased HDL-C (p=0.001), the primary endpoint of the SUSTAIN trial, a phase 2b clinical study. SUSTAIN also successfully met secondary endpoints, showed increases in levels of Apo-AI (p=0.002) and large HDL particles (p=0.02).

Additionally, post-hoc analysis of SUSTAIN and ASSURE were very informative in understanding the optimal patient population (i.e. low-HDL, diabetic, high baseline CRP), identifying a synergistic interaction with Crestor/rosuvastatin, and refining the best endpoint (MACE).

ASSURE, Phase 2: 

ASSURE was a mixed bag of results, mostly negative, partially due to the unexpected favorable response observed in the placebo group. From the published abstract of ASSURE: 

"During treatment, apolipoprotein (apo)A-I increased by 10.6% with placebo (P < 0.001 compared with baseline) and 12.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.18. HDL-C increased by 9.1% with placebo (P < 0.001 compared with baseline) and 11.1% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.24. Low-density lipoprotein cholesterol (LDL-C) decreased by 17.9% with placebo (P < 0.001 compared with baseline) and 15.8% with RVX-208 (P < 0.001 compared with baseline), between groups P = 0.55. The primary endpoint, the change in percent atheroma volume, decreased 0.30% in placebo-treated patients (P = 0.23 compared with baseline) and 0.40% in the RVX-208 group (P = 0.08 compared with baseline), between groups P = 0.81. Total atheroma volume decreased 3.8 mm(3) in the placebo group (P = 0.01 compared with baseline) and 4.2 mm(3) in the RVX-208 group (P < 0.001 compared with baseline), P = 0.86 between groups."

However, one of the pre-stated secondary outcome measures was "Incidence of adverse events by treatment group, including major adverse cardiac events (MACE) (death, MI, stroke, coronary revascularization, hospitalization for ACS or heart failure)."

As stated above, post-hoc analysis of SUSTAIN and ASSURE were very informative in understanding the optimal patient population (i.e. low-HDL, diabetic, high baseline CRP), identifying a synergistic interaction with Crestor/rosuvastatin, and refining the best endpoint (MACE).

In addition to the trials above, RVX-208 has been used in an informative, successful safety and pharmacokinetic Phase 1 trial in New Zealand in patients with chronic-kidney disease treated with a single dose of RVX-208, as well as in an Austrailian Phase 2 trial in patients with pre-diabetes, which showed beneficial effects on glucose metabolism.

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