WASHINGTON -- Evolocumab (Repatha), an injectable cholesterol-lowering drug, appears to be beneficial, but the drug's sponsor may not have studied the appropriate population, according to FDA reviewers.
The FDA released its review of evolocumab, a self-administered injectable drug made by Amgen, on Monday in advance of a of the agency's Endocrinologic and Metabolic Drugs Advisory Committee. The committee will vote on whether the drug should be approved in light of its risk-benefit profile. A similar injectable biologic, Regeneron's alirocumab (Praluent), will be .
Statins have been the first line of treatment for patients with high cholesterol since the late 1980s, but this new drug class could offer an alternative to statin patients who experience unpleasant side effects.
These are monoclonal antibodies -- lipid-altering therapies known as proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors -- that act by identifying and knocking out PCSK9 enzymes in the liver. This action lowers the amount of low density lipoprotein (LDL) cholesterol in the blood, reducing the risk of clogged arteries and heart attacks.
Amgen, of Thousand Oaks, Calif., has proposed evolocumab for treating adults with standard lipid disorder -- including patients who are statin-intolerant -- as well as for treating individuals ages 12 or older with the rare and life-threatening condition known as homozygous familial hypercholesterolemia (HoFH), according to .
Evolocumab's efficacy was studied in four phase III double-blind, randomized, placebo or active control (ezetimibe) trials spanning 12 weeks. The trials involved more than 3,100 patients, and roughly 1,800 of those received evolocumab. The co-primary endpoint for all thee trials was percent change in LDL cholesterol from baseline to 12 weeks and from baseline to the average of weeks 10 and 12.
The drug was administered at a dose of 140 mg every 2 weeks or 420 mg once a month.
In these trials evolocumab was used in four discrete population groups:
- As a stand-alone therapy in low-cardiovascular-risk subjects
- In conjunction with statins
- In patients reported to be "statin intolerant"
- In patients with HoFH whose LDL cholesterol levels were less than or equal to 100 mg/dL
In addition, the sponsor conducted a 52-week, double-blind, randomized, placebo-controlled trial of 901 subjects, of which 599 received the study drug. Patients were screened and titrated to LDL-cholesterol goals and given one of four background therapies tailored to their risk category -- ranging from diet alone for the lowest-risk participants to maximal drug therapy including atorvastatin and ezetimibe for the highest-risk participants -- before receiving evolocumab or placebo. The primary endpoint for this trial was percent change in LDL cholesterol from baseline to 52 weeks and the trial used only the 420-mg-per-month dose.
At doses of 420 mg per month, the study drug showed "statistically significant reductions" in LDL cholesterol of about 60% in both the 12-week and 52-week trials. The 140 mg biweekly dose produced similar reductions. Briefing documents noted the drug's efficacy across all four subgroups "with no significant differences." The reviewer also noted greater efficacy -- LDL-cholesterol reduction -- in subjects with lower BMI.
For the second indication patients with HoFH, the study drug at doses of 420 mg per month "significantly reduced" LDL cholesterol by 31% at week 12, compared with placebo. The mean change among the evolocumab subjects was -23% compared to +8% among those who received the placebo.
The most common adverse events in the evolocumab group were nasopharyngitis, upper respiratory tract infection, back pain, and nausea. Adverse events of special interest in this population included those common among other lipid-lowering therapies, such as diabetes, liver, muscle, and neurocognitive events, and those common to injectable protein therapies, such as hypersensitivity and injection site reactions.
In terms of serious nonfatal events, the reviewers noted that "Although the numbers were small, there was a numeric increase in the evolocumab group in the incidence of cardiac disorders (particularly angina and myocardial infarction), pancreatitis, appendicitis, pneumonia, and back pain."
The safety database was described by reviewers as "adequate but limited in long-term placebo-controlled data." Reviewers were especially concerned that many subjects in the 52-week trial had "low or moderate cardiovascular risk." And that "the most appropriate population" for an add-on therapy to statins would have included those "at high [cardiovascular] risk with substantial [cardiovascular disease] burden on maximally tolerated statin therapy."
The limited safety and efficacy data for the 420 mg biweekly group was called "problematic" in light of the drug's intended population, which includes children 12 or older.
If the drug is approved, however, any potential safety issues could be managed through proper labeling, monitoring, and healthcare provider support, the reviewers said. Ongoing studies were also recommended. Possible safety concerns included findings of pancreatitis, renal disorders, and the "possible increased incidence of new-onset diabetes" as well as the potential for drug-induced hepatoxicity, among other issues.
In a memorandum, deputy director for the Division of Metabolism and Endocrinology Products (DMEP) at the Center for Drug Evaluation and Research (CDER), said the FDA has wrestled with whether to use LDL cholesterol as a surrogate endpoint instead of cardiovascular outcomes. Statin manufacturers were not mandated to conduct post-approval cardiovascular outcomes trials.
Smith also highlighted the issue of designating the correct patient population. He noted that evolocumab could be viewed as a "practical monotherapy" in statin-intolerant patients. However, many patients reporting "statin intolerance" are "not truly intolerant of the pharmacological class," he said.