Amgen's cholesterol-fighting PCSK9 inhibitor was shown to reduce the likelihood that patients would suffer cardiovascular events. The question now is whether FDA will grant approval soon and how widely the drug will be used, given speculation about its cost.
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 likelihood that patients would die, suffer a heart attack or stroke, or need a procedure to open blocked arteries.
The study on cardiovascular (CV) effects was presented Sunday at a late-breaking session and press conference of the 64th Annual Scientific Sessions of the American College of Cardiology (ACC), a year after its cholesterol-fighting powers were shared at ACC in Washington, DC.1 The meeting took place March 14-16, 2015, in San Diego, California. 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 chief competitor being Sanofi-Regeneron’s alirocumab. Both companies have been highly visible in San Diego with educational presentations about the monoclonal antibody that inhibits PCSK9, or proprotein convertase subtilisin-kexin type 9. Amgen provided funding for the study presented Sunday.
Pharmacy industry experts who spoke with The American Journal of Managed Care last month predicted that this new class of cholesterol fighters will be a blockbuster, but could significantly 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, chair of the TIMI Study Group and 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 low enough LDL-cholesterol on current therapies, and a 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 140 mg 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, adjudicated cardiovascular (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<0.001). 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 gained notice with the FDA. Authors reported that the risk of AEs did not vary significantly with declines in LDL cholesterol.
A trial of 27,500 patients to dfetermine long-term cardiovascular outcomes and side effects is under way, with results expected in 2017.
Vying for first-in-class. Multiple published reports have chronicled the heated race between Amgen and Sanofi-Regeneron to be the first to win FDA approval for a PCSK9 inhibitor.2,3 Since 3 studies on evolocumab were presented to packed sessions at ACC a year ago, both Amgen and Sanofi-Regeneron have taken aggressive steps to be the first of this new class to reach consumers.1-3
Sanofi and Regeneron announced January 26, 2015, 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 FDA until July 24 to approve or reject the drug.3Â Amgen, meanwhile, sued Sanofi and Regeneron in 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 at Sunday’s press conference about who will take evolocumab and for how long, given the speculation about its possible cost. He declined to discuss the drug’s price, saying that was a matter for manufacturers. “Typically the indication for LDL cholesterol populations are 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 possible. “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, it urged caution about using intense therapy for most patients when options with well-established safety records are available.
“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. “They emphasized that, while lower is better, it matters how you get there and whether the benefits outweigh the risks for that patient.”5
1.Â Â Â Â Â Evolocumab results unveiled at packed session; phase 3 studies show significant lowering of LDL cholesterol. American Journal of Managed Care website. http://www.ajmc.com/conferences/ACC14/Evolocumab-Results-Unveiled-at-Packed-Session-Phase-3-Studies-Show-Significant-Lowering-of-LDL-Cholesterol. Published March 30, 2014. Accessed March 15, 2015.
2.Â Â Â Â Â 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.Â Â Â Â Â Weinstein D. Sanofi, Regeneron official in PCSK9 race. Medical Marketing & Media. http://www.mmm-online.com/sanofi-regeneron-officially-in-pcsk9-race/article/394356/. Published January 26, 2015. Accessed March 12, 2015.
4.Â Â Â Â Â Amgen files lawsuit against Sanofi and Regeneron for patent infringement [press release]. Thousand Oaks, CA: PRNewswire; October 17, 2014. http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1978931
5.Â Â Â Â Â Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in who? [published online March 15, 2015]. N Engl J Med. DOI: 10.1056/NEJMe1502192.