Long-term Evolocumab Safe, Effective for Familial Hypercholesterolemia Treatment

Evolocumab can reduce LDL cholesterol and the need for lipoprotein apheresis long-term in patients with severe familial hypercholesterolemia (FH) that has been incompletely responsive to standard lipid-lowering therapy, according to a new analysis.

Patients with FH have been shown to derive cardiovascular benefit from statin therapy, but many never achieve the target low LDL levels even with the addition of ezetimibe. FH is traditionally thought to be comprised of two phenotypes: severe heterozygous FH and the even rarer, more difficult to control homozygous variety.

When PCSK9 inhibitors came to market in 2015, they became an important option for FH patients “because in the past, less than 5% of the heterozygous FH patients were able to attain the recommended LDL-cholesterol levels,” lead author Raul Santos, MD, PhD (University of São Paulo Medical School Hospital and Hospital Israelita Albert Einstein, Brazil), told TCTMD. “Now, with this drug it's up to 70% of them [in whom] we can really reduce LDL to adequate levels. For the homozygotes, it's harder because their baseline LDLs are very high and actually the PCSK9 inhibitors do have a long way to go.”

For the open-label TAUSSIG study, published in the February 18, 2020, issue of the Journal of the American College of Cardiology, Santos and colleagues included 300 FH patients (35% with homozygous FH) at least 12 years of age who had been receiving stable lipid-lowering therapy for at least 4 weeks plus either a baseline LDL level ≥ 130 mg/dL, a baseline LDL level ≥ 100 mg/dL with a diagnosis of coronary heart disease or risk equivalent, or undergoing biweekly apheresis treatment.

Those on apheresis began with subcutaneous evolocumab (Repatha; Amgen) 420 mg once every 2 weeks, while everyone else received the same dose once monthly. Clinicians could up- or down-titrate the dose at their discretion.

When your LDL is 300 plus, getting a nearly one-quarter reduction is a very large reduction and should translate into a reduction in morbidity and mortality. Steven Nissen

Over a median 4.1 years, the incidence of treatment-emergent adverse events was similar for both homozygous (88.7%) and severe heterozygous FH patients (89.7%), and altogether only 11 patients (3.7%) discontinued the drug due to these. The most common events were nasopharyngitis, influenza, upper respiratory tract infection, headache, myalgia, and diarrhea.

The researchers identified no neutralizing anti-evolocumab antibodies. While binding antibodies developed in eight patients, they were present at or before baseline (n = 3) or were transient with a negative result when last tested (n = 5).

For homozygous and severe heterozygous FH patients, mean LDL-cholesterol reductions were 21.2% and 54.9%, respectively, from baseline to week 12 and 24.0% and 47.2% at week 216. There were also persistent mean changes in apolipoprotein B—from -15% at week 12 to -21% at week 216 in homozygous FH and from -35% to -44% between the same time points for severe heterozygous FH. Median changes in lipoprotein(a) between week 12 and week 216 went from -7.0% to -23.6% for homozygous and from -0.7% to -32.4% for heterozygous FH.

Of the 48 patients with homozygous FH who were up-titrated, the mean change in LDL cholesterol improved from -19.6% at week 12 to -29.7% after 12 weeks of the more frequent dose of evolocumab. Additionally, 16 of the 61 patients receiving apheresis at enrollment discontinued the treatment by the end of the study.

The annualized cardiovascular event rate was 2.7%—2.8% for those with homozygous and 2.6% for severe heterozygous FH.

Variable Response

The study shows that “PCSK9 inhibitors work” in patients with FH, however, “there's a variable response” dependent on genetics, Santos said. “We might have patients who do not respond at all, but might have patients we can still have up to a 60% reduction. So this is good news.”

Additionally, the findings for the first time show that these effects can be sustained long-term without the development of antibodies, he noted. Evolocumab might have even “reduced the risk of events because when we compare our patients with historical controls actually our rates of events are significantly lower than those when we had . . .  only statins,” said Santos. “So, this suggests that actually the drug is protecting the patients against cardiovascular complications.”

Does this mean every FH patient should be given a script for a PCSK9 inhibitor? Not exactly, Santos asserted. For those at high risk of developing cardiovascular disease, which depends on their LDL level and other risk factors, “statins and ezetimibe might be enough,” he said. “But in my opinion, for FH patients who already have cardiovascular disease, FH patients who persist with extremely high LDL-cholesterol levels despite treatment, or those who have a very bad family history of coronary heart disease or have other risk factors, they should take the PCSK9 inhibitor.

“If there's one disease that PCSK9 inhibitors are meant for it’s heterozygous FH,” he continued. “For the homozygotes, I think it's a little bit more complicated.”

Clinical Implications

In an accompanying editorial, P. Barton Duell, MD, and Sergio Fazio, MD, PhD (both from Oregon Health & Science University, Portland), write that “the results from this study demonstrated robust LDL cholesterol-lowering in patients with heterozygous FH and more modest results in patients with homozygous FH, but with sustained LDL cholesterol-lowering efficacy and safety up to 5 years.” In the meantime, while new experimental drugs like evinacumab are in the works, “specialty providers need to use all available LDL cholesterol-lowering medications, possibly in combination with low-density lipoprotein apheresis, . . . in the quest to adequately lower the LDL-cholesterol concentration in patients with FH for whom this is the most extreme and often single risk exposure.”

If there's one disease that PCSK9 inhibitors are meant for it’s heterozygous FH. For the homozygotes, I think it's a little bit more complicated. Raul Santos

Commenting on the study for TCTMD, Steven Nissen, MD (Cleveland Clinic, OH), said the findings show that evolocumab “certainly is very effective” for FH, even though homozygous FH remains a challenge to treat. “We know statins don't work very well, and it was also believed that PCSK9 inhibitors would not be very effective in these patients. And what actually you see here is there is a modest but clinically significant reduction in LDL. . . . When your LDL is 300 plus, getting a nearly one-quarter reduction is a very large reduction and should translate into a reduction in morbidity and mortality.”

For those with severe heterozygous FH—"people that one might have guessed would be resistant to the effects of PCSK9 inhibitors”—a more than 50% reduction in LDL was “enormous,” Nissen said. “They started at nearly 200 for LDL cholesterol. So, the way I see it is this is a population that it's really kind of a no brainer that we should be using PCSK9 inhibitors in these severely hypercholesterolemic patients with receptors that are not normal. But it's nice to have the data that tells us that they're very efficacious.”