ACC is done for another year, with a multitude of exciting trials presented, including FOURIER, EBBINGHAUS, SPIRE-1 and -2, ORION-1, and CARAT. There were negative as well as positive results, making for a very interesting meeting and some important scientific breakthroughs.
Let’s start with the positive. The results from FOURIER, the cardiovascular outcomes trial for Amgen’s PCSK9 inhibitor Repatha (evolocumab), were keenly awaited being the first from this novel class. There was widespread hope that the promising LDL-cholesterol reductions would translate into clinically meaningful CV benefits and they did, albeit only in terms of morbidity and not mortality: significant 27% and 21% reductions in myocardial infarctions and strokes, respectively, but no significant reduction in CV death. And what’s good for the heart does not have an adverse effect on the brain, at least according to the results of the EBBINGHAUS trial, which showed that there was no difference in cognitive impairment between Repatha and placebo. The general consensus amongst the delegates at ACC seemed to be that the results for Repatha were important and reassuring, although some were disappointed that CV death rates were not reduced and others raised the question of whether the results were good enough to justify the $14,000/year price tag. However, another positive trial result may eventually have a negative impact on Repatha. In the ORION-1 trial, The Medicine Company and Alnylam Pharmaceuticals’ inclisiran, which targets PCSK9 via interference of RNA, achieved impressive LDL-cholesterol reductions of up to 81% using a twice-yearly dosing regimen. Not only could this dosing regimen be more convenient for patients, it could improve compliance and potentially be less expensive.
On the down side, the details from the CV outcomes trial for Pfizer’s discontinued PCSK9 inhibitor bococizumab were eagerly awaited to see how and why things went wrong. And it appears to have gone wrong right at the very beginning, with bococizumab being a humanized antibody, whereas Repatha and Praluent are both fully human antibodies. This small difference in formulation was apparently enough for anti-drug antibodies to develop in enough bococizumab recipients to significantly attenuate the mean treatment effect of bococizumab over time and increase the rate of injection-site reactions. Notably, there was also a wide range of response to bococizumab reported. As might be expected, SPIRE-2 failed to demonstrated a benefit in terms of reduced CV events for bococizumab in patients with LDL-cholesterol of ≥ 70 mg/dL on statin therapy (or partially statin intolerant). However, in the higher risk group with LDL-cholesterol of ≥ 100 mg/dL on stain therapy (or statin intolerant), bococizumab did reduce CV events. This silver lining from the SPIRE cloud is further evidence supporting the LDL-cholesterol hypothesis and PCSK9 inhibition. However, while the LDL-c hypotheses was reinforced, the negative Phase II CARAT study results have dealt another blow to the HDL hypothesis. In this trial, serial infusions of Cerenis Therapeutics’ CER-001, an HDL mimetic, failed to show any significant effect on coronary disease progression as measured by intravascular ultrasound.
All in all, ACC provided a bit of a rollercoaster of results and whets the appetite for the results of ODYSSEY OUTCOMES, the CV outcomes trial for Sanofi and Regeneron’s Praluent (alirocumab). So what can we take from all these results? 1) further evidence of the LDL-cholesterol hypothesis, and that lower for longer is better, 2) PCSK9 inhibition appears to be a safe and effective means of reducing CV events, 3) Repatha and Praluent might not be the last word in PCSK9-targeting drugs, 4) the HDL-cholesterol hypothesis has taken another hit, and, of course, 5) money still matters: PCSK9 prices could still provide a stumbling block to wider use despite their effectiveness.
For DRG’s analysis of the Dyslipidemia market, please click here.