Plunging LDL-C Maintained Over a Year of Anti-PCSK9 Antibody Treatment

November 21, 2013

DALLAS, TX — In a yearlong efficacy-safety study of a cholesterol-lowering monoclonal antibody (MAb)[1], once-monthly injections of evolocumab (Amgen) consistently suppressed LDL-C levels by about 50% compared with a standard-care approach.

The LDL-C response was consistent across several distinct groups of dyslipidemic patients, including the statin-intolerant and those with familial hypercholesterolemia (FH). And the risk of adverse events didn't go up on treatment with the agent, a human MAb against proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of LDL-receptor levels. Evolocumab had previously gone by the name AMG145.

"The safety data are very clean. This is a very specific monoclonal antibody, and we're superpleased with the safety data and tolerability data that we're seeing so far," according to Dr Michael J Koren (Jacksonville Center for Clinical Research, FL).

Koren presented the trial, the "largest and longest efficacy and safety evaluation" of a PCSK9-inhibiting antibody at >1100 patients called Open-Label Study of Long-term Evaluation Against LDL-C (OSLER), here at the American Heart Association 2013 Scientific Sessions to coincide with its publication in Circulation.

Monoclonal antibodies for cholesterol lowering constitute a busy research area, with several companies pressing their own agents forward in the pipeline. Pfizer and Sanofi/Regeneron are also working on PCSK9 inhibitors, which are in various stages of development and in general have shown LDL-lowering prowess similar to evolocumab.

Pointing out the impressive phase 2 results for these agents, with cautious expectation that some or all will be approved, Dr Robert Eckel (University of Colorado, Aurora) asked, "Who will be candidates?" People with familial hypercholesteremia (FH) are an obvious choice. And millions of statin users are considered statin-intolerant, he noted, but pinning down a definition for intolerance will be challenge. "It's really a big dilemma, clinically. But if we have this many people with adverse effects, mostly myopathy, on two or more statins, ultimately we've got a large candidacy of people who require additional therapy." Eckel was the assigned discussant for Koren's presentation.

Another group: patients who fail to reach LDL-C goals despite best available therapy. "But what is goal today? Are we no longer treating to goal?" he asked. "Even though the guidelines indicate that the evidence is not to set goals, we practice medicine in the clinics. So goal setting has not been eliminated as a way to treat patients with lipid disorders. It's just not evidence-based."

Speaking with heartwire , Eckel said, "In my mind, the statin-intolerant may be the most important group, beyond the FH patients, who often need two or three [lipid-modifying] drugs. For them, this is going to be a lovely add-on."

Eckel also pointed out that in OSLER, lipoprotein(a) levels went down 20% compared with what was achieved with standard therapy. Statins don't much affect Lp(a), so people in whom it's elevated make up another potential candidate group.

OSLER randomized 1104 patients who participated in at least one of four smaller randomized phase 2 evolocumab studies to receive the MAb (420 mg subcutaneously every four weeks) on top of standard care or to standard care only. Randomization was carried out regardless of patients' treatment assignment in the preceding dyslipidemia trials and "ideally" within three days of their conclusion.

The preceding trials were: MENDEL , which tested evolocumab as monotherapy; LAPLACE-TIMI 57 , which tested the MAb added to statins, with or without ezetimibe; GAUSS , for statin-intolerant patients; and RUTHERFORD , which tested the drug in heterozygous FH.

In OSLER:

  • Patients on evolocumab for the first time showed a mean 52.3% fall in LDL-C at week 12 and at week 52 (p<0.0001 for both).

  • Those who continued taking the MAb after also taking it in the parent study maintained their reduced LDL-C levels, which had fallen to total of 52.1% by week 52 (p=0.31 for OSLER only).

  • Patients previously on evolocumab who were then randomized to standard management only saw their reduced LDL-C rise over time such that they were down a total of only 18% by OSLER week 4 and by 5.8% by week 12.

  • Adverse events, most often nasopharyngitis, upper-respiratory-tract infections, influenza, arthralgia, or back pain, occurred in 81.4% of evolocumab recipients and 73.1% of standard-management-only patients. In the researchers' judgment, those events were considered treatment related in only 5.6% of cases, they report.

  • 411 patients, nearly all randomized to evolcumab, attained LDL-C levels <50 mg/dL.

  • 98 patients, all on evolocumab, attained LDL-C <25 mg/dL.

  • 1.2% of evolocumab recipients and 2.2% of standard-management-only patients experienced an adjudicated cardiovascular event. One and two patients, respectively, had died by week 52.

The study wasn't powered for clinical outcomes, Koren noted.

Sometimes treatment with a MAb will elicit an immune response against it. "One thing I find very comforting is that we found no neutralizing antibodies against the antibody during one year of follow-up," he said.

Eckel was more circumspect. OSLER suggests that treatment with evolocumab "is effective and safe for one year. But what about longer treatment intervals?" For most patients, LDL-lowering therapy is a lifelong proposition. "One year's nice, but one year is not 20 years or even five years."

Koren discloses being an employee of Jacksonville Center for Clinical Research, which has received research grants from Amgen; disclosures for the coauthors are listed in the paper. Eckel had no conflicts of interest.

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