Yet another Failed HDL Therapy Trial

In spite of robust epidemiological evidence suggesting that HDL has a sturdy protective result towards cardiovascular disease, there has been no excellent proof showing that HDL-primarily based therapies are helpful. Huge trials of medicines that increase HDL levels, including niacin and CETP-inhibitors, have failed to show enhancements in final result. Some observers gleaned hope from numerous small scientific studies of drugs that mimic HDL activity but these research have been as well modest to supply convincing evidence. Now a new study– the biggest to ever examine an HDL mimetic– has failed to locate even a glimmer of benefit.

Final results of the CHI-SQUARE (Can HDL Infusions Substantially QUicken Atherosclerosis Regression) examine were published on the internet in the European Heart Journal. Within two weeks of having an acute coronary syndrome, 507 patients had been randomized to obtain 6 weekly infusions of either placebo or one of 3 doses of CER-001, an HDL-mimetic from Cerenis Therapeutics.

Benefits of the trial were extensively unfavorable. CER-001 had no substantial impact on atherosclerosis, as assessed by both intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). There were also no significant distinctions in the number of individuals who had at least a single significant cardiovascular occasion.

Cerenis was apparently so shocked by the unfavorable finding that it asked for a publish-hoc re-analysis of the IVUS recordings from a separate group. The outcomes, unluckily for them, were no diverse.

I asked several cardiologists who have performed HDL research to comment on the research. They remain remarkably optimistic about the prospects of HDL.

PK Shah sent the following response:

This is a really disappointing study displaying no quick phrase results of rHDL (containing wild kind Apo A-I linked to two phospholipid carriers) infusion at doses of 3, 6, 12 mg /kg on non-culprit coronary lesion size as assessed by IVUS and QCA.

If you are a pessimist and disregard all the biological plausibility information on vascular protective effects of Apo A-I or its mutants such as Apo A-I milano proven in preclinical models and modest clinical research , you could conclude that APo A-I infusions treatment may possibly not understand its guarantee on the other hand if you are an optimist , you could make the arguments that a damaging examine could have been due to:

1. Not measuring plaque composition which is more very likely to adjust just before plaque dimension modifications i.e not measuring lipid core dimension and irritation that goes with it. IVUS could not be the ideal methodology.


2. Not deciding on the sort of patient most likely to show a change in plaque, i.e., a patient with a lipid wealthy plaque rather than any plaque without regard to its composition.


3. Not employing a large ample dose ( Apo Milano review in 2003 utilized 15 and 45 mg/kg /per dose even though as the dose utilised in this study were 3, 6, 12 mg/kg/dose)???


4. Not using enough infusions to remodel the plaque ???


5. The compositional attributes of the HDL mimetic utilised in this examine may possibly not be optimum HDL containing APo A-I milano, probably a obtain of perform mutant, may possibly make different final results as suggested by preclinical scientific studies carried out in our laboratory.

As a believer in HDL’s vascular protective results, I stay optimistic that, even though HDL has been a difficult nut to crack, one particular of these days we will get it right making use of the correct formulation, appropriate patient and correct dose investigation in this area need to continue till we get it correct, the simple biology is very compelling.

I asked William Boden, PI of the NIH’s AIM-Substantial trial, if it was time to write the obituary for HDL:

You have to be kidding me! The finish of what? HDL RIP? How about: RIP suboptimal examine style and trial hypotheses? I proceed to be astonished that we see nothing but pejorative commentary and noise about the death knell for the HDL hypothesis and HDL-raising therapy when, time right after time and trial after trial, we see the very same unenlightened examine style perpetuated.

What do ILLUMINATE, Dal-OUTCOMES, HPS-two THRIVE, and this CHI-SQUARE trial all have in frequent? The answer is: an unreasonable review population in which to test HDL-raising treatment. The two CETP inhibitor trials and this 1 incorporated ACS individuals who have been not pre-chosen for a profile of minimal HDL-C cholesterol. In reality, I did not see any baseline lipid worth for CHI-SQUARE. The baseline apo-B values were &lt80 mg/dL in two groups and had been 81 and 86 in the other 2 groups–values that would be considered “optimal” or perfect. The Apo-A1 values of &gt130 mg/dL are likewise typical. Consequently, we can presume that the baseline LDL-C and HDL-C had been regular, or possibly optimum. Why on earth would one assume that a patient with an HDL-C of, say, 50 mg/dL to demonstrate a reduction in coronary atherosclerosis or clinical events when you are producing a regular baseline worth super-typical with an HDL-raising intervention? Since the epidemiology of HDL-C tells us that the danger of incident CV events is both inverse and curvilinear, if the starting up HDL-C is on the flat (typical) component of the event connection, then why would a single count on that raising the HDL-C to 70 or 80 would decrease CV events?

Our latest data (from four separate sources of observational and submit hoc RCTs) recommend that baseline HDL-C &lt30 mg/dL could be the threshold under which one particular requirements to target HDL-Raising therapy. This is the place the event curve steepens inversely and the place one might anticipate to see an HDL-raising therapeutic advantage.

So this trial tells me practically nothing new that I haven’t witnessed in the other above trials. In our submit hoc evaluation of AIM-Substantial (admittedly only “hypothesis-generating”) an HDL-C &lt31 mg/dL was associated with a niacin treatment method result for the primary endpoint. This would really be the 5th information set to present that it is the extremely lower HDL-C subset that we need to target, not these “all-comers” styles where patients have typical or high HDL-C to start.

We have nevertheless to see the right trial design and style. And, of course, since the wonderful bulk of AIM-Substantial and HPS-two individuals have been getting statins for one-5 years, how can you assume, as in HPS-two, to see an incremental HDL-C raising effect when the baseline LDL-C was 63 mg/dL and the baseline HDL-C was ~47 mg/dL? Perhaps we require trials of individuals who are statin naïve, not such well-taken care of patients exactly where danger mitigation possibly cannot be attained.

Yet another Failed HDL Therapy Trial