Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 36th Annual Congress of the European Society of Cardiology (ESC)

Barcelona, Spain / August 30-September 3, 2014

Barcelona - A new therapeutic drug class can reduce low-density lipoprotein cholesterol (LDL-C) levels by more than 60% in patients on maximally tolerated statins, according to a series of phase 3 trials conducted in high-risk patient groups. This novel class of therapy, called proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK 9), lowers LDL-C by inhibiting the enzyme responsible for LDL receptor degradation. At the 2014 ESC, extensive efficacy and safety data from four phase 3 trials were presented on the PCSK 9 inhibitor, alirocumab, which has become the most extensively studied. In these trials, the PCSK 9 inhibitor was associated with a placebo-like tolerability profile and sustained LDL-C control in trials with extended follow-up, which exceeds more than one year. In the study with the longest follow-up, an early signal of protection against cardiovascular (CV) events was observed. This has intensified interest in trials now underway that are evaluating CV risk reduction as the primary endpoint.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Clinical data with proprotein convertase subtilisin/kexin type 9 (PCSK 9) inhibitors, a new class of lipid-lowering therapy, was greatly expanded by four phase 3 studies presented at the 2014 ESC Congress in Barcelona. The findings from these trials, all conducted with the agent alirocumab, confirm that inhibition of PCSK 9 produces unprecedented reductions in LDL-C when employed on maximally tolerated LDL-C-lowering therapy and is well tolerated. If CV risk reductions are commensurate with LDL-C reductions achieved on statins, these agents will represent a major clinical advance.

“Based on the data we have, alirocumab will permit LDL-C control in the majority of patients, including those at high CV risk, who are not reaching targets on maximally tolerated statins,” reported Dr. Jennifer Robinson, Director, Prevention Intervention Center, University of Iowa, Iowa City.

Five Phase 3 Trials

Five phase 3 trials have been presented with alirocumab as part of a 14-trial program called ODYSSEY. The first of these trials, presented at the 2014 Scientific Sessions of the American College of Cardiology (ACC), has been joined by four additional trials presented at the 2014 ESC. Other PCSK 9 inhibitors in phase 3 testing include evolocumab and bococizumab. These drugs, all of which are monoclonal antibodies (mAbs) differ in several ways that may be clinically relevant. For example, both alirocumab and evolocumab are fully human mAbs, whereas bococizumab is a humanized mAb. Each is delivered by subcutaneous (SC) injection to target PCSK 9, an important mediator of circulating LDL-C levels that was first isolated just 11 years ago.

In the largest of the studies at ESC, called ODYSSEY Long-Term, 2,341 patients at high or very high CV risk were enrolled. Participants were randomized in a 2:1 ratio to 150 mg of alirocumab administered SC every two weeks or a matching placebo. All patients were on maximally tolerated doses of statins. The efficacy endpoint of the ongoing study, which now has a mean follow-up of 65 weeks, was LDL-C reduction at 24 weeks.

At the 24-week efficacy endpoint, LDL-C was reduced by an average of 61% in the group receiving alirocumab versus an average increase of 1% in the group receiving placebo. At 52 weeks, the mean achieved LDL-C level was 1.4 mmol/L with alirocumab. From a clinical standpoint, the more important result may be that 79% of patients on alirocumab versus 8% of those in the placebo arm reached the predefined target, which in most cases was <1.8 mmol/L. Rates of adverse events were generally comparable to placebo.

Based on these data, the effect of PCSK 9 inhibitors is so great they have the potential “to almost eliminate LDL-C as a risk factor,” reported Dr. Robinson. Presenting the ODYSSEY Long-Term data on behalf of the multinational team, Dr. Robinson characterized the large reductions achieved with alirocumab “as another potential important evolution” in a progression of CV risk reductions initiated with statins.

Post-Hoc Analysis of CV Events

Trials confirming that the large LDL-C reductions achieved with alirocumab translate into CV risk reductions comparable to those achieved with lipid lowering on statins are ongoing, but a post-hoc analysis of ODYSSEY Long-Term provided initial support. The post-hoc analysis evaluated CV risk reduction by comparing arms for the time to first adjudicated CV event (death due to coronary heart disease, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, and unstable angina requiring hospitalization). It is the same endpoint being used in the ongoing ODYSSEY Outcomes Trial. In the post-hoc analysis, alirocumab was associated with a 54% CV risk reduction (95% CI 0.18- 0.74; P<0.01) relative to placebo after a mean follow-up of only 65 weeks.

“These data are only suggestive, but they provide us with some encouragement that the LDL-C reductions we are seeing with the PCSK 9 inhibitors will produce the desired clinical benefits,” Dr. Robinson reported.

Large and durable LDL-C reductions were observed in all three of the remaining ODYSSEY phase 3 trials, which had different designs and study populations. In the ODYSSEY Combo II trial, 720 high-risk patients on a maximally tolerated statin were randomized in a 2:1 ratio to 75 mg alirocumab administered subcutaneously every two weeks, or 10 mg per day of ezetimibe. Both groups received a placebo substitute for the agent employed in the other arm of the study. If LDL-C remained >1.8 mmol/L at eight weeks, the dose of alirocumab was increased to 150 mg. Data was presented on the pre-specified 52-week analysis of the ongoing 104-week trial.

77% Reach Rigorous LDL-C Target

“In high-risk patients on standard-of-care therapy with maximally tolerated statins, alirocumab brought 77% to the treatment goal of <1.8 mmol/L,” reported Dr. Christopher P. Cannon, Harvard Clinical Research Institute, Boston. The mean reduction in LDL-C was 50.6% for alirocumab versus 20.7% for the comparative arm. These differences were reached even though only 18.4% of the alirocumab patients were uptitrated to the higher dose at 12 weeks.

In the ODYSSEY FH I and FH II phase 3 trials, which were presented together, the goal was to test the lipid-lowering efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia (HeFH). The FH I and FH II studies randomized 486 and 249 patients, respectively, in a 2:1 ratio to alirocumab or placebo with the same uptitration scheme used in ODYSSEY Combo II.

The average LDL-C reductions relative to placebo were similar in the two studies (57.9% in one and 51.4% in the other) at week 24. On placebo, LDL-C increased over the same time period in both studies. On alirocumab, 72% of patients in one study and 81% of those in the other reached guideline LDL-C goals.

“We already knew that 80% of patients with familial hypercholesterolemia do not reach treatment goals on statins, so these results are very encouraging,” reported Dr. Michel Farnier, Point Medical, Dijon, France.

Key Questions Remain Unanswered

Although no new data were presented on evolocumab at ESC, the only other PCSK 9 inhibitor with phase 3 data available, the existing data have been encouraging. In a 901-patient, 52-week phase 3 trial published earlier this year (Blom et al. N Engl J Med 2014;370:1809-19), patients were stratified according to risk categories and then assigned to background lipid-lowering therapy with diet alone, with diet plus 10 mg atorvastatin, with 80 mg atorvastatin, or with 80 mg atorvastatin plus 10 mg ezetemibe. After a run-in period of up to 12 weeks, those with LDL-C of 1.9 mmol/L or higher were randomized to receive evolocumab or placebo. At 52 weeks, the mean reduction in LDL-C from baseline taking into account change in the placebo group was 57%.

“Drugs in this class are potentially the most effective approach to reducing LDL-C that we have ever had,” reported Dr. Evan A. Stein, Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio. In a presentation that summarized data with each of the PCSK 9 inhibitors that have reached various stages of clinical testing, Dr. Stein reported that consistent LDL-C reductions have been achieved in healthy volunteers, in individuals already on a statin, in individuals intolerant to statins, and in individuals with FH.

However, several key questions need to be more fully answered before these can emerge as viable therapies, according to Dr. Shaun Goodman, Associate Head, Division of Cardiology, St Michael’s Hospital, Toronto. In addition to demonstrating that the large LDL-C reductions achieved with PCSK 9 inhibitors translate into CV protection, Dr. Goodman suggested long-term compliance must be demonstrated. Although PCSK 9 inhibitors are delivered with a disposable delivery device comparable to those effectively used by patients with diabetes to self-inject with insulin—and compliance at one year was 85% in ODYSSEY Long-Term—motivations for lipid and glucose control may differ.

Yet, more effective alternatives to statins are an important unmet need. More than 40% of high-risk patients have a LDL-C above the target, according to Dr. Goodman, who cited a recently published meta-analysis (Boekholdt et al. J Am Coll Cardiol 2014;64:485-94). It is this population for which PCSK 9 inhibitors could represent a major advance.

Conclusion

PCSK 9 inhibitors will allow the vast majority of high-risk patients to reach treatment goals, according to four multicenter phase 3 studies presented with alirocumab at the ESC. If the reduction in LDL-C achieved with this class of therapy provides the same proportional reductions in CV risk as those achieved with statins and other lipid-lowering therapies, these agents are expected to represent a major clinical advance and potentially impact clinical practice.  

Note: At press time, PCSK 9 inhibitors are not available in Canada.