TAUSSIG Hints at Fewer CV Events With Add-On Evolocumab in Homozygous Familial Hypercholesterolemia

June 02, 2016

INNSBRUCK, AUSTRIA — A bit more is known about the longer-term effects of adding a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor to standard intensive lipid-lowering drug therapy in a particularly high-risk population, predominantly young patients with homozygous familial hypercholesterolemia (HoFH).

One of the first and largest studies to assess clinical outcomes in this group showed a 23% drop in LDL-cholesterol levels with no deaths, MIs, or hospitalizations for unstable angina over 48 weeks with open-label treatment with evolocumab (Repatha, Amgen). About a third of the 106-patient cohort was also on apheresis[1].

Investigators from the Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders (TAUSSIG) thereby estimated an annualized cardiac event rate of 2.14% for their patients taking evolocumab. The researchers, their study lacking a control group, compared that rate with an annualized mortality of 3.5% and a cardiovascular event rate of about 11% per year in other studies of HoFH patients on a statin plus ezetimibe (Zetia, Merck) but not apheresis.

The trial followed patients a mean of 1.7 years. "Two needed a stent, one needed a bypass, and one had a stroke, out of 106 patients in 2 years of treatment. Which is remarkable," senior investigator Dr Frederick J Raal (University of Witwatersrand, Johannesburg, South Africa) told heartwire from Medscape.

Dr Frederick J Raal

Such patients will likely never achieve conventional LDL-C targets using current therapies, he said. But even the reductions seen in TAUSSIG should "drop the event rate quite remarkably, because they're on such a high cardiovascular-risk curve." That is, the expected clinical benefit from the LDL-C and apolipoprotein B (apoB) reductions seen with evolocumab in the trial should be magnified in HoFH compared with conventional dyslipidemia, because as the biomarkers rise, risk climbs more sharply in HoFH.

Although 106 patients with HoFH is an impressively large cohort, TAUSSIG's clinical-outcomes conclusions should be interpreted cautiously, Prof Erik Stroes (University of Amsterdam, the Netherlands), not connected with the study, said to heartwire . Event-rate estimates for HoFH based on the literature are limited because "the event rate has not been studied by a lot of groups."

In TAUSSIG, "the data are strong, but obviously they are flawed by lacking any controls and having just historical comparisons," Stroes said. The observed and projected clinical-event rates "should for now be considered speculation."

HoFH Becomes More Like HeFH?

With PCSK9-inhibitor therapy added to standard intensive lipid-modifying agents, Raal said, it's as if the cardiovascular risk profile of patients with HoFH becomes more like that of patients with heterozygous FH. "You're converting them from that extremely high-risk group, dying in their teens, to now living into their 30s, 40s, and 50s," he proposed.

Still, even with PCSK9 inhibitors, "you're not curing this condition. I think that the treatment of homozygous FH is going to be multidrug therapy," according to Raal. "They're going to have to have a statin, ezetimibe, and because of the safety of this drug and ease of use, [PCSK9 inhibition] would be third line. But even then, you still are going to probably add a [yet-undetermined] fourth or fifth drug for these patients."

Change in Lipid Markers from Baseline to Week 12 on Evolocumab in TAUSSIG, N=106

Parameter Baseline Wk 12 (% change)
Mean LDL-C 8.4 mmol/L -20.6
Mean apoB 200.7 mg/dL -15.0
Median Lp(a) 77.0 nm/L -7.7

Raal reported TAUSSIG in two presentations, one on lipid effects and the other focused on clinical outcomes[2], this week here at the European Atherosclerosis Society 2016 Congress. At the society's 2014 congress, he reported a smaller but placebo-controlled 12-week Trial Evaluating PCSK9 Antibody in Subjects With LDL-Receptor Abnormalities (TESLA). With 49 HoFH patients not on apheresis, it had seen reductions of 23% in LDL-C from baseline in patients taking evolocumab and of 31% compared with the control group.

Both evolocumab and alirocumab (Praluent, Sanofi/Regeneron) are in their second year of clinical use on both sides of the Atlantic, based on demonstrated LDL-C–lowering effects but without completed randomized trials with clinical end points. Another, bococizumab (Pfizer), is in development. The three agents are antibody inhibitors of an enzyme that elevates LDL-C by downregulating cellular LDL receptors.

A randomized cardiovascular-outcomes trial is under way. The Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) study with >22,000 patients with standard dyslipidemia is comparing evolocumab against statins with a primary end point of cardiovascular death, MI, unstable angina, stroke, or revascularization. Results aren't expected for at least 2 more years.

Reductions Maintained to Week 48

TAUSSIG entered patients at least 12 years of age (mean 34; 51% female) on stable standard LDL-C–lowering therapy (90% were on high-intensity statins) for at least a month to receive evolocumab in a 420-mg injection every 2 weeks if they were on apheresis (n=34) or every month if not on apheresis (n=72). Nonapheresis patients were allowed uptitration to 420 mg every 2 weeks after the first 12 weeks of treatment.

Overall, the mean 21% reduction in LDL-C at week 12 was essentially maintained, for a total 23% reduction, at weeks 24 and 48. The 7.7% reduction in Lp(a) at week 12 had dropped by a total of 12% by weeks 24 and 48. Reductions were similar for patients older than 18 years vs those 18 or younger.

The four independently adjudicated cardiovascular events in four patients over the average follow-up of 1.7 months included two PCIs, one in each of the apheresis and nonapheresis groups; and one surgical revascularization and one stroke, both in nonapheresis patients.

The only two patients to discontinue evolocumab, both only temporarily, did so after developing a mild rash. Separately, one patient developed antibodies to evolocumab, detectable at week 12 but not thereafter, that were not associated with adverse events. There were no observed adverse neurocognitive effects.

Other Potential Benefits?

Unlike TESLA, TAUSSIG took "all comers" with HoFH, in hopes that with added PCSK9 inhibition, "if you're on apheresis, we may be able to decrease the frequency or come off apheresis," according to Raal. Of the 34 who were on apheresis at entry, two were able to stop apheresis and four reduced their frequency of apheresis treatments. "Instead of once a week, they went to once a fortnight."

Stroes agreed that, given the LDL-C lowering seen for HoFH in TAUSSIG, "you will never, ever get patients to target levels with only PCSK9 inhibitors. So the chance that those who are on apheresis can discontinue apheresis is highly unlikely."

It seems more promising, however, that PCSK9 inhibition could make apheresis less frequent for those who need it, Stroes said. Apheresis can cut LDL-C levels by 70% to 80%, "but in our experience, they rebound within 3 days."

However, "If just after apheresis you give a PCSK9 inhibitor, then actually the speed of recurring, going back to the baseline high levels, is delayed."

A similar strategy demonstrated success for patients with heterozygous FH taking alirocumab with apheresis in the ODYSSEY ESCAPE trial, as recently reported by heartwire . A trial of the strategy in HoFH is planned, according to Stroes.

But using it in clinical practice, he said, he has been able to stretch the time between apheresis treatments in HoFH to about the same extent seen in TAUSSIG. "From 50 to 25 sessions in a year? That's significant."

TAUSSIG is sponsored by Amgen, for which a number of coauthors are employees. Raal discloses receiving grants or research support from Amgen and Sanofi; being on speaker's bureau for AstraZeneca, Pfizer, Merck, and Amgen; receiving honoraria from AstraZeneca, Pfizer, Merck, Amgen, and Sanofi; and serving as a consultant or on an advisory board for AstraZeneca, Pfizer, and Merck. Stroes has disclosed consulting for Servier; receiving honoraria for speaking from Genzyme; and participating in clinical trials for Servier, Genzyme, Merck, and Sanofi.

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