Cholesterol-Fighting Drug Evolocumab Also Reduces Cardiovascular Events, Study Finds

Coverage from the 64th Scientific Sessions of the American College of Cardiology.
Published Online: May 20, 2015
Mary K. Caffrey

The much-anticipated PCSK9 inhibitor evolocumab, already shown to have dramatic effects on lowering low-density lipoprotein (LDL), or “bad” cholesterol, has now been shown to reduce the like-lihood that patients using the drug will suffer a heart attack or stroke, or need a procedure to open blocked arteries, and thus may reduce mortality.

The study on cardiovascular (CV) effects was presented March 15, 2015, at a late-breaking session and press conference of the 64th Annual Scientific Sessions of the American College of Cardi-ology (ACC). Attendees came early to the packed session in San Diego, California, much as they did the year before when the drug’s cholesterol-fighting powers were revealed at ACC in Washington, DC.1 Results were simultaneously published in the New England Journal of Medicine.2

Evolocumab, an injectable drug that can be given either once or twice a month, is Amgen’s entrant in the race to see who will be first to win FDA approval for this new class of therapy, the PCSK9 inhibitors. (Amgen funded the study presented in San Diego.) The wait for evolocumab and Sanofi-Regeneron’s counterpart, alirocumab, has been called the most-anticipated pharmacy event of 2015. Both companies were highly vis-ible in San Diego, with educational presentations about the monoclonal antibody that inhibits PCSK9, or proprotein convertase subtilisinkexin type 9.

Pharmacy industry experts who spoke with The American Journal of Managed Care earlier this year predicted that this new class of cholesterol fighters will be a blockbuster, but could signifi-cantly raise costs in a therapeutic area where most patients have long relied on low cost statins. In the press conference after the late-breaking session, Marc Sabatine, MD, MPH, senior physician in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, Boston, deflected questions about cost.

“I don’t view these as potential competitors to statins,” Sabatine said. “Statins are the foundation.” However, he said, patients who can benefit from evolocumab include those who cannot tolerate statins, those who cannot achieve a sufficiently low LDL-choles-terol count on current therapies, and patients with a rare condition called familial hypercholesterolemia. (This condition has played a role in the race between Amgen and Sanofi-Regeneron.)

Clinical Findings. In 2 open-label, randomized trials, researchers enrolled 4465 patients who had previously taken part in phase 2 or 3 studies of evolocumab. Patients were randomized 2:1 to receive the study drug in either a 140mg dose every 2 weeks or a 420 mg dose once a month, plus standard therapy, or standard therapy alone. Patients were followed for a median of 11.1 months. Lipid levels, safety, and adjudicated CV events were recorded and data from the 2 trials combined.

Compared with standard therapy alone, evolocumab reduced LDL cholesterol 61%, from a median of 120 mg/ dL to 48 mg/dL (P <.001). The rate of CV events at 1 year was reduced from 2.18% in the standard therapy group to 0.95% in the evolocumab group.

Adverse events (AEs) were similar in both groups, although neurocognitive events were more frequently reported in the evolocumab group; the issue of neurocognitive events has already caught the attention of the FDA. Authors reported that the risk of AEs did not vary significantly with decline in LDL cholesterol. A trial of 27,500 patients to determine long-term cardiovascular outcomes and side effects is under way, with results expected in 2017.

Adverse events (AEs) were similar in both groups, although neurocognitive events were more frequently reported in the evolocumab group; the issue of neurocognitive events has already caught the attention of the FDA. Authors reported that the risk of AEs did not vary significantly with decline in LDL cholesterol. A trial of 27,500 patients to determine long-term cardiovascular outcomes and side effects is under way, with results expected in 2017.


 

On January 26, 2015, Sanofi and Regeneron announced that they had filed alirocumab for priority review, following the purchase of a $67.5 million voucher from BioMarin, which the company received for its development of a pediatric drug for Morquio A syndrome. Vouchers can be sold or transferred, and the Sanofi-Regeneron purchase is linked to alirocumab’s potential to aid patients with familial hypercholesterolemia. The purchase gives the FDA until July 24, 2015, to approve or reject the drug.3 Amgen, meanwhile, sued Sanofi and Regeneron in a US District Court on October 17, 2014, charging patent infringement.4 The FDA deadline for Amgen’s evolocumab application is August 27, 2015.

Sabatine faced tough questions from the press about which patients will take evolocumab and for how long, given the speculation about its possible cost. He said pricing issues were up to the manufacturer. “Typically, the indication for LDL cholesterol populations is determined by guidelines and by payers,” he said, adding that it was important to consider those patients “who have unmet medical need.”

He went on to discuss the possibility that medicine has not fully considered the potential to dramatically lower LDL cholesterol in patients for whom only modest reductions are currently pos-sible. “When we think about how much we should lower LDL, we haven’t found a floor beyond which we haven’t found a benefit,” he said. However, he acknowledged that the use of PCSK9 inhibitors would come down to a balance, based on each patient’s medical need and what cost payers were willing to bear.

An accompanying editorial in NEJM acknowledged the excitement over the results for patients who do not tolerate statins or have hard-to-lower cholesterol. However, the writers urged caution about using intense therapy to lower LDL cholesterol for most patients, when there are options available with well-established safety records.


“The evidence-driven cholesterol guidelines did not endorse the concept that lower LDL cholesterol levels are better at all costs,” wrote Neil Stone, MD, and Donald Lloyd-Jones, MD. The guidelines emphasized that, “while lower is better, it matters how you get there and whether the benefits outweigh the risks for that patient.”5 

References

1. Evolocumab results unveiled at packed ses-sion; phase 3 studies show significant lowering of LDL cholesterol. American Journal of Managed Care website. http://www.ajmc.com/confer-ences/ACC14/Evolocumab-Results-Unveiled-at-Packed-Session-Phase-3-Studies-Show-Sig-nificant-Lowering-of-LDL-Cholesterol. Published March 30, 2014. Accessed March 15, 2015.

2. Sabatine MS, Giugliano MD, Wiviott MD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events [published online March 15, 2015]. N Engl J Med. doi:10.1056/ NEJMoa1500858.

3. Weinstein D. Sanofi, Regeneron official in PCSK9 race. Medical Marketing & Media website. http://www.mmm-online.com/sanofi-regeneron-officially-in-pcsk9-race/article/394356/. Published January 26, 2015. Accessed March 12, 2015.

4. Amgen files lawsuit against Sanofi and Re-generon for patent infringement [press release]. Thousand Oaks, CA: PRNewswire; October 17, 2014. http://www.amgen.com/media/media_ pr_detail.jsp?releaseID=1978931 5. Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in who? [pub-lished online March 15, 2015]. N Engl J Med. doi:10.1056/NEJMe1502192.

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