Evolocumab Results Unveiled at Packed Session: Phase 3 Studies Show Significant Lowering of LDL Cholesterol

Results from 3 phase 3 studies unveiled Saturday showed that investigational treatment for hyperlipidemia, evolocumab, significantly lowered low-density lipoprotein (LDL) cholesterol, that the results were sustained over time, and that the drug was well-tolerated without neurological side effects that are of concern to US Food and Drug Administration (FDA).¹

Attendees at the 63rd Scientific Sessions of the American College of Cardiology, being held in Washington, DC, packed the session room to hear the results. Amgen, the developer of evolocumab, fueled the buzz with a March 26 announcement that it would hold an investor’s webcast Sunday at 7 pm, following the presentation of 3 studies Saturday and 2 late-breaking studies on Sunday.² “There’s quite a bit of excitement,” Michael Koren, MD, said in presenting the first study.

Amgen took the same approach November 19, 2013, when it held an investors’ webcast after presented phase 2 results on evolocumab at the American Heart Association meeting in Dallas.³ A month later, Amgen announced, without offering full details, that evolocumab had outperformed both ezetimibe (Zetia) and placebo in lowering LDL cholesterol in phase 3 studies.¹ Amgen said at the time that the results were in line with reductions in the phase 2 studies.^4,5

Evolocumab is a human monoclonal antibody that targets PCSK9, a protein that limits the ability of LDL receptors to clear LDL or “bad” cholesterol from the blood. By inhibiting PCSK9, evolocumab allows a higher number of these receptors to eliminate the LDL cholesterol. As Saturday’s presenters explained, statins can “upregulate” PCSK9, which can make the same dose less effective over time; evolocumab’s promise is that it could be used as monotherapy, including for statin-intolerant patients, or in combination with statins.¹

Phase 3 studies presented Saturday were:

MENDEL-2. Presented by Dr Koren, chief executive officer of the Jacksonville Center for Clinical Research, this was a follow-up to the original MENDEL study with a smaller group of patients, which stood for Monoclonal Antibody Against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lip Levels.

Results of MENDEL-2 were simultaneously published online in the Journal of the American College of Cardiology.⁶ The study involved 614 patients with high cholesterol (LDL-C ≥100 and <190 mg/dL) who were not receiving lipid-lowering therapy. The patients were randomized with 306 receiving evolocumab as monotherapy, 155 receiving placebo, and 154 receiving ezetimibe.

Coprimary end points were the percent change from baseline in LDL cholesterol averaged at weeks 10 and 12, and at week 12. Levels were reduced 55% and 57% from baseline compared with placebo and 38% and 40% compared with ezetimibe.

DESCARTES. Presented by Dirk J. Blom MD, PhD, of the University of Cape Town, and simultaneously published in The New England Journal of Medicine, this is the longest and largest study to date involving evolocumab. This 52-week, multistep study started with a 2120 patients who were screened for lipid levels and put through a lipid stabilization phase with combinations of diet only, diet plus atorvastatin, and diet, atorvastatin and ezetimibe.

From this group, 901 with high LDL cholesterol levels and a range of cardiovascular risks were randomized into 4 groups: 2 groups receiving evolocumab, either 140 mg biweekly or 420 mg every 28 days, or placebo biweekly or every 28 days.

In this study, whose acronym stands for Durable Effect of PCSK9 Antibody Compared With Placebo Study, researchers found that the reduction of LDL cholesterol levels at 12 weeks was consistent with levels at 52 weeks, showing long-term efficacy. Compared to placebo, the mean LDL cholesterol reductions from baseline with evolocumab at week 52 were 56% for the group with only diet modifications, 62% for the group with diet changes and atorvastatin at 10 mg, 57% for the group with diet and atorvastatin at 80 mg, and 49% for diet and atorvastatin at 80 mg plus ezetimibe at 10 mg.

In his discussion and in the NEJM article, Dr Blom noted that the results take into account the run-in period of lipid-lowering therapy that was based on each patient’s LDL cholesterol goals.⁷ In NEJM, Dr Blom noted that the results were similar with the relative reduction in LDL cholesterol reported in the first year of the Open-Label Study of Long-term Evaluation against LDL-C (OSLER) study.⁷

RUTHERFORD-2. Frederick J. Raal, PhD, of the University of the Witwatersrand, Johannesburg, South Africa, presented results from the study that stands for Reduction of LDL Cholesterol with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder Study-2.⁸ This study evaluated how evolocumab aided patients with the condition HeFH, or heterozygous familial hypercholesterolemia.

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HeFH is a disorder most often caused by mutations in the LDLR gene encoding the LDL receptor; it is characterized by cholesterol deposits on the corneas, eyelids, and extensor tendons, and elevated plasma concentrations of LDL cholesterol. HeFH is more common among certain ethnic groups, including Qubcois and the Dutch South Afrikaners in Dr Raal’s country.⁹

The study involved 329 HeFH patients who had been treated with statins and other lipid-lowering drugs. Randomized groups were treated biweekly with 140 mg, or monthly with 420 mg of evolocumab, or biweekly or monthly with placebo. At week 12, the percent reduction in LDL cholesterol was 59% for those receiving 140 mg every 2 weeks and 61% for those receiving the larger dose at 4 weeks, compared with placebo.

Across all 3 studies, adverse events were limited and were typically nasolaryngitis, headaches, or nausea. The DESCARTES study reported 2 cardiovascular deaths among the patients receiving evolocumab (1 of myocardial infarction and 1 of cardiac failure). Dr Koren said that patients in the study did not object to receiving an injectable drug; in MENDEL-2, self-injected versions were used. Presenters did not report neurological side effects, save a patient in the DESCARTES trial who also reported taking a medicinal herb and had temporary memory loss. In an interview prior to the start of the sessions, ACC Program Co-Chair Prediman K. Shah, MD, said these results would be key because the FDA has been asking for drug makers to report any neurological effects.¹

References

1. Wood S. What’s going to be hot at ACC. Medscape Multispecialty. http://www.medscape.com/viewarticle/822354#2. Published March 26, 2014. Accessed March 29, 2014.
2. Amgen to webcast investor meeting at upcoming American College of Cardiology's 63rd Annual Scientific Session [press release]. Thousand Oaks, CA: PRNewswire; March 26, 2014. http://www.prnewswire.com/news-releases/amgen-to-webcast-investor-meeting-at-upcoming-american-college-of-cardiologys-63rd-annual-scientific-session-252508401.html. Accessed March 29, 2014.
3. Amgen to highlight new evolocumab (AMG 145) data at upcoming American Heart Association Scientific Sessions 2013 [press release]. Thousand Oaks, CA: PRNewswire; November 12, 2013. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2013&releaseID=1875344. Accessed March 29, 2014.
4. Amgen announces positive top-line results from phase III MENDEL-2 trial of evolocumab (AMG 145) in patients with high cholesterol [press release]. Thousand Oaks, CA: PRNewswire; December 17, 2013. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2013&releaseID=1885328. Accessed March 29, 2014.
5. Neale T. Evolocumab beats Zetia for LDL cholesterol. Medpage Today. http://www.medpagetoday.com/Cardiology/Dyslipidemia/43500. Published December 18, 2013. Accessed March 29, 2014.
6. Koren M, Lundqvist P, Bolognese M, et al. Efficacy and safety of evolocumab (AMG 145) monotherapy compared with ezetimibe and placebo in hypercholesterolemic subjects: a phase III randomized clinical trial. JACC 2014;63(12) DOI: 10.1016/j.jacc.2014.03.018.
7. Blom D, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. DOI: 10.1056/NEJMoa1316222.
8. Raal F, Dufour R, Turner T, et al. The addition of evolocumab (AMG 145) allows the majority of heterozygous familiar hypercholesterolemic patients to achieve low-density lipoprotein cholesterol goals — results from the phase III randomized, double-blind placebo-controlled study. JACC 2014;64(12)suppl A:abstract 400-405.
9. Yuan G, Wang J, Hegele RA, Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease. CMAJ. 2006;174(8):1124-1129.