MADRID, SPAIN — Homozygous familial hypercholesterolemia (HoFH) patients treated with the novel proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab (Amgen) on top of optimal medical therapy had a significant 31% reduction in LDL-cholesterol levels compared with patients who received placebo, a new study shows.
In addition, investigators also reported that evolocumab significantly reduced apolipoprotein B (apoB) levels 23% compared with HoFH patients treated with placebo.
The study, known as the Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities (TESLA), was presented this week at the European Atherosclerosis Society 2014 Congress (EAS 2014) by Dr Frederick Raal (University of Witwatersrand, Johannesburg, South Africa).
HoFH is a rare but serious genetic lipid disorder characterized by minimal LDL-receptor function, markedly elevated LDL-cholesterol levels, and premature cardiovascular disease that often results in death at a young age, said Raal.
"Heterozygous patients, we know, respond very well to evolocumab," Raal told heartwire . "They get about a 60% average reduction in LDL cholesterol. What we have shown with this proof-of-concept study is that we get about a 23% reduction [overall], but we also showed that we get about a 40% reduction in those homozygotes with defective LDL receptors. So, for homozygous FH, you'd put them all on high-dose statins, add ezetimibe [Zetia, Merck/Schering-Plough], and then hopefully add a PCSK9 inhibitor. With the addition, the vast majority, about 80%, will get nearly a 40% further reduction."
In the addition to the overall reduction, the researchers analyzed the treatment effect by LDL-receptor mutation status. For HoFH patients with an LDL-receptor gene defective in at least one of the two affected alleles, treatment with evolocumab reduced LDL cholesterol 41% compared with placebo. For those with defective LDL-receptor genes in both alleles, treatment reduced LDL cholesterol 47% compared with placebo.
"It was the patients who had two defective mutations—but they still worked to a degree—who had a really good response with evolocumab," said Raal. These HoFH patients, he noted, are more common than those without any LDL receptors.
Very High Baseline LDL Cholesterol Levels
In the present study, which included 49 patients with a mean age of 31 years, 43% had existing coronary artery disease, and 25% had already undergone CABG surgery. All patients were treated with a statin, and 94% were also treated with ezetimibe. At baseline, the mean LDL-cholesterol level in the placebo- and evolocumab-treated patients was 348 mg/dL (9.0 mmol/L).
After 12 weeks of treatment with 420 mg of evolocumab once monthly, LDL-cholesterol levels were reduced 23%. In contrast, the placebo-treated patients experienced an 8% increase in LDL cholesterol.
To heartwire , Dr Antonio Gotto (Weill Cornell Medical College, New York), who was not affiliated with the study but chaired the late-breaking session where the data were presented to a packed house, said the emerging PCSK9 results are exciting, especially since these are hard-to-treat patients who often have to resort to LDL apheresis.
He was surprised by the increase in LDL cholesterol among the placebo-treated patients, an increase that ultimately makes the LDL differential between treatment and placebo appear larger. The LDL reduction from baseline with evolocumab, as noted, was 23%. He said that other factors, including diet and the length of the washout period, might have had an impact on the LDL increase in the placebo arm.
The most common side effects noted during the 12-week trial were upper-respiratory-tract infections and influenza. No adverse neurological side effects were observed during the trial. If the drug were approved, and it still has a way to go before it gets there, Raal says it likely would be added after statins and ezetimibe. PCSK9 inhibitors appear to be safe and less toxic than other FH drugs like mipomersen (Kynamro, Isis Pharmaceuticals) and lomitapide (Juxtapid, Aegerion), he said.
"The big difficulty is that you have to identify these patients early," he told heartwire . "The risk is really related to what we call their 'cholesterol-years score': how high their cholesterol has been and for how long. Their cholesterol levels are, on average, four times normal. This means when we're 80 years old we've been exposed to a certain amount of cholesterol and when they're 20 years old they've been exposed to same amount of cholesterol hitting their arteries. We need to get them early and change the angle of their event curve."
Outcomes studies with evolocumab are under way. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study is a 22 500-patient trial testing evolocumab against statin therapy for the reduction of the primary composite end point of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization.
Although it is ongoing, full results of this study testing the PCSK9 inhibitor in patients at high risk for cardiovascular events won't be available until 2018 at the earliest. Raal, for his part, suspects the trial, which is an event-driven study, won't be completed until after 2018, given that event rates among these patients have been significantly lowered with statin therapy.
Other companies, including Pfizer and Sanofi/Regeneron, are working on PCSK9 inhibitors, which are in various stages of development and in general have shown LDL-lowering prowess similar to evolocumab.
Raal reports honoraria/expenses from KANEKA Medix, Merck, Astellas Pharma, Kowa, Pfizer, Takeda Pharmaceuticals, Sanofi, and Novartis. He reports research funding from KANEKA, Merck, and Astellas and royalties from KANEKA.
Heartwire from Medscape © 2014
Cite this: TESLA: Evolocumab Significantly Reduces LDL Cholesterol in Homozygous FH Patients - Medscape - Jun 02, 2014.