Raul D. Santos, MD, MSc, PhD
New data from an open-label study is shedding light on the long-term safety and efficacy of evolocumab (Repatha) for the treatment of familial hypercholesterolemia (FH)
Results of the study supported the use of evolocumab for FH—finding the therapy was both well-tolerated and showcased the ability to reduce plasma LDL-C levels in patients with either phenotype of FH over a median of 4.1 years of follow-up.
With evolocumab being the only PCSK9 inhibitor therapy currently approved as an adjunct to diet and maximally tolerated statin therapy for both homozygous FH (HoFH) and heterozygous FH (HeFH), an international team of investigators, led by Raul D. Santos, MD, MSc, PhD, sought to assess the long-term efficacy and safety of the therapy through a single-arm, open-label study.
The Trial Assessing Long Term Use of PCSK9 Inhibitor in Subjects with Genetic LDL Disorders (TAUSSIG) was designed by investigators to assess evolocumab in 300 patients—of which 106 had HoFH and 194 had HeFH.
For inclusion in TAUSSIG, patients needed to be at least 12 years of age and to have received lip-lowering therapy for 4 weeks or longer. Participants were also required to have a baseline LDL-C of 130 mg/dl or more; baseline LDL-C of 100 mg/dl or more with a diagnosis of coronary heart disease or risk equivalent; or to have been undergoing biweekly aphaeresis treatment.
Study protocol dictated visits would occur every 12 weeks until the end of the study. Assessments of fasting lipids, adverse events, and antievolocumab antibodies were performed at each visit. The study was designed to last until week 260 but investigators noted it was terminated early as Amgen—the trial’s sponsor—determined sufficient data on the long-term safety and efficacy had been collected.
Two dosing regimens were established for the study. Patients received subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis—after 12 weeks, patients not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint of the study was the incidence of treatment-emergent adverse events and the secondary outcomes were changes in LDL-c and other lipids at each visit.
At the end of the study, the median follow-up time was 4.1 years and 268 (89.3%) of patients experienced treatment-emergent adverse events and 11 people discontinued evolocumab and a result of the adverse event. The most common type of adverse event was nasopharyngitis followed by influenza, upper respiratory tract infection, headache, myalgia, and diarrhea.
When examining changes from baseline in LDL-C, a mean reduction of 59.8 mg/dl was noted from baseline to week 12 in patients with HoFH and a 104.4 mg/dl reduction was seen in those with severe HeFH. At week 216, the mean reduction was 47.2 mg/dl in the HoFH group and 90.6 mg/dl in the severe HeFH group.
Between week 12 and week 216, LDL-C reductions of 15% or more were noted in 56.7% to 72.2% of patients with HoFH and in 88.5% to 99.0% of patients with severe HeFH. Investigators pointed out LDL-C reductions for patients receiving apheresis at enrollment were similar to nonapheresis for both groups.
A cohort of 32 patients had positively adjudicated cardiovascular events, which correlated with an annualized event rate of 2.7 per year—2.8% in the HoFH group and 2.6% in the severe HeFH group. Additionally, 48 nonapheresis patients up-titrated to 420 mg every 2 weeks and this resulted in a subsequent LDL-C change from baseline of -19.6% at week 12 to -29.7% at week 24.
Investigators noted multiple limitations in their analysis, including a lack of a control arm; early termination of the trial; lack of blinding; and the small number of patients who could be assessed beyond 4 years. Furthermore, the 420 mg every 2 weeks dosing is currently not approved in the US and other countries.
In an accompanying editorial comment
, P. Barton Duell, MD, and Sergio Fazio, MD, PhD, of the Knight Cardiovascular Institute at Oregon Health and Science University, wrote the TAUSSIG study highlighted the ability of evolocumab to achieve meaningful, long-term improvements in LDL-C.
“The results from this study demonstrated robust LDL-C lowering in patients with heterozygous FH and more modest results in patients with homozygous FH, but with sustained LDL-C lowering efficacy and safety up to 5 years,” the duo wrote. “New experimental therapies are under development that may enhance our capacity to achieve excellent LDL-C lowering in these high-risk patients, but in the meantime, specialty providers need to use all available LDL-C lowering medications.”
The study, “Long-Term Evolocumab in Patients With Familial Hypercholesterolemia
,” was published online in JACC.