Deborah Brauser

March 15, 2015

SAN DIEGO, CA — Long-term efficacy results appear positive for two investigational inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9,), gaining a lot of buzz and on track for possible US Food and Drug Administration (FDA) approval later this year.

At a late-breaking clinical-trial session here at the American College of Cardiology (ACC) 2015 Scientific Sessions, investigators from the first and second Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER-1 and OSLER-2) reported that evolocumab (Repatha, Amgen) plus standard therapy reduced LDL cholesterol by 61% after 11 months of use vs standard therapy alone[1]. Exploratory analysis showed that it was also associated with reduced incidence of cardiovascular events, such as MI, heart failure requiring hospitalization, and death.

The findings were simultaneously published today in the New England Journal of Medicine. The same issue published results from the ODYSSEY Long Term trial[2], for which top-line results had been announced previously.

It showed that high-risk patients with hypercholesterolemia who received the PCKS9 monoclonal antibody alirocumab (Sanofi/Regeneron Pharmaceuticals) plus statins for up to 78 weeks had consistently lowered LDL-cholesterol levels compared with those receiving placebo plus statins. Post hoc analysis also showed significantly lower rates of adverse cardiac events.

Dr Marc Sabatine

"We now have many studies in a variety of different populations where we've seen the ability of these drugs to significantly reduce LDLcholesterol," OSLER lead author Dr Marc Sabatine (Brigham and Women's Hospital, Boston, MA), told heartwire from Medscape.

"And all the data we have point to the fact that the reduction in clinical events is tied to the reduction in LDL cholesterol," said Sabatine.

"We still need an outcomes study, but it seems like we're on the right track with these agents. It's good times," added ODYSSEY lead author Dr Jennifer G Robinson (University of Iowa, Iowa City), who is also an investigator for the OSLER trials.

OSLER Program

OSLER-1 included 1324 patients who participated in one of five phase 2 parent studies, whereas OSLER-2 included 3141 who completed one of seven phase 3 parent studies. The mean age for all was 58 years.

Sabatine noted that safety and efficacy results for both trials were combined for the presentation and journal article under the "OSLER Program" umbrella.

All participants were randomly assigned to receive for approximately 1 year either standard therapy alone (n=1489) or with an injection of evolocumab (n=2976) taken once every 2 weeks at a dose of 140 mg or once monthly at 420 mg.

The primary end point was incidence of treatment-related adverse events. Secondary end points included LDL-cholesterol changes from baseline. Cardiovascular clinical outcomes were considered prespecified and "exploratory."

A total of 69.2% of the evolocumab group and 64.8% of the standard-therapy group reported an adverse event, and 7.5% of each group reported a serious adverse event. Although low overall, the rate of neurocognitive adverse events was higher in the PCSK9 group than in the standard therapy group (0.9% vs 0.3%).

From baseline to 12 weeks on-treatment, the evolocumab group reduced LDL cholesterol from a median of 120 mg/dL to 48 mg/dL (P<0.001), which was sustained up to 48 weeks. Exploratory analysis showed that 0.95% of the intervention group had some type of adverse cardiovascular event vs 2.18% of the standard-therapy group (P=0.003).

"Ongoing are several dedicated cardiovascular-outcomes trials. But in the interim, we're starting to accumulate enough patients and enough follow-up that we can now get some sense of the effect of these drugs on cardiovascular outcomes," said Sabatine.

ODYSSEY and Alirocumab

Although previous studies have shown significantly lower levels of LDL cholesterol after 8 to 12 weeks of treatment with alirocumab plus statin therapy, the ODYSSEY investigators sought to assess the combination during a longer follow-up.

The current analysis examined 2341 patients (63.2% men; mean age 60 years) considered to be at high risk for cardiovascular events, with LDL-cholesterol levels of at least 70 mg.dL, and receiving a maximum tolerated dose of statins. All were randomized to also receive either 150-mg alirocumab (n=1553) or matching placebo (n=788) by injection every 2 weeks.

The primary efficacy end point was change from baseline to week 24 in LDL-cholesterol level. At that time, results showed that the calculated LDL-C level was lowered by 61% for the alirocumab group vs 0.8% for the placebo group (P<0.001). Mean absolute LDL-C level at 24 weeks was 48 mg/dL vs 119 mg/dL, respectively.

In addition, reduced levels remained consistent throughout the full 78 weeks observed.

Treatment-related adverse events that were more prevalent in the alirocumbab group vs the placebo group included injection-site reactions (5.9% vs 4.2%, respectively), myalgia (5.4% vs 2.9%), and neurocognitive events (1.2% vs 0.5%). The latter included amnesia and memory impairment

However, as in the evolocumab study, those receiving alirocumab had significantly lower major adverse cardiovascular events (1.7% vs 3.3% of those receiving placebo; hazard ratio 0.52; P=0.02).

"Important Arrows in the Quiver"

Both drugs have been grabbing a lot of attention. In fact, advertising here at the ACC meeting by their respective drug companies is hard to miss. Banners, bus signs, and even escalator wraps have been trumpeting excitement over the new drug class.

Still, Sabatine noted that a large, dedicated outcomes trial is still needed. "We won't have that data for about 2 years or so, but this give us some very encouraging data in the interim."

When asked about the possibility of eventually looking at mortality rates, he reported that the upcoming FOURIER study will have 27 500 patients with known cardiovascular disease, who will be followed for several years to examine such outcomes as deaths.

In an accompanying editorial[3], Drs Neil J Stone and Donald M Lloyd-Jones (Bluhm Cardiovascular Institute, Northwestern University, Chicago, IL) note that the "what's new" in both OSLER and ODYSSEY centers on adverse cardiovascular events—and the fact that both PCSK9 inhibitors showed 50% reductions at 1-year to 18-month end points. The editorialists point out that previous research examining statins have shown event rates greater after vs during the first year.

"With the potential for improved adherence and a greater reduction in LDL-cholesterol levels, the data from larger, longer studies of PCSK9 inhibitors could be compelling," they write.

The current studies "whet our appetites for further results that show cardiovascular benefit and documented safety, even at substantially lower LDL-cholesterol ranges than achieved before."

However, Stone and Lloyd-Jones note that endorsing these drugs for widespread use now, before more studies have been completed, would be "premature."

"Much work remains to be done, but PCSK9 inhibitors appear on track to become important arrows in our quiver for targeting reduction of cardiovascular events among higher-risk patients when statins are not enough," they conclude.

Sabatine has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca–Bristol-Myers Squibb Alliance, BRAHMS, Bristol-Myers Squibb–Sanofi Joint Venture, Critical Diagnostics, Daiichi Sankyo, diaDexus, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Ortho-Clinical Diagnostics, Roche Diagnostics, Sanofi, Singulex, and Takeda; he has consulted for Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Pfizer, Sanofi, Vertex, Zeus, Cubist, and Quest Diagnostics. Disclosures for the coauthors are listed on the journal website. Robinson reports grants and fees from Sanofi; research grants from Amarin, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, and Takeda/Zinfandel; and research grants from and consulting for Amgen, Merck, Pfizer, Regeneron/Sanofi, and Genetentech/Roche, all through her institution. Disclosures for the coauthors are listed on the journal website. Stone and Lloyd-Jones report they have no relevant financial relationships.


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