TESLA and RUTHERFORD-2: Two FH Studies Highlight Evolocumab's Efficacy

October 01, 2014

JOHANNESBURG, SOUTH AFRICA — Two new studies testing evolocumab (Amgen), an investigational human monoclonal antibody for proprotein convertase subtilisin-kexin type 9 (PCSK9), both show the drug significantly reduces LDL-cholesterol levels in individuals with inherited genetic disorders that result in elevated cholesterol levels[1,2].

Published October 1, 2014 in the Lancet, the TESLA study, which tested evolocumab in homozygous familial hypercholesterolemia (FH), and RUTHERFORD-2 , which tested evolocumab in the more common heterozygous FH, showed the PCSK9 inhibitor reduced LDL-cholesterol levels by as much as 60% compared with placebo-treated patients.

The largest reduction in LDL cholesterol was observed in patients with heterozygous FH, but the homozygous FH patients, all of whom were treated with high-intensity statins and most with ezetimibe (Zetia, Merck/Schering-Plough), did have a 23% average reduction in LDL from baseline to week 12. When compared with placebo treatment, which resulted in an 8% increase in LDL cholesterol from baseline, evolocumab treatment difference translated into a 30% reduction in LDL cholesterol.

In an editorial accompanying the studies[3], Dr Raul Santos (University of São Paulo Medical School Hospital, Brazil) and Dr Gerald Watts (University of Western Australia, Perth) write that if "proven to be safe and efficacious in the long term, as well as cost-effective, PSCK9 monoclonal antibodies might be the best standard of care for many patients with severe forms of familial hypercholesterolemia."

The drugs might even prove to be useful in high-risk patients with elevated cholesterol levels, including those with statin-induced myopathy, state the editorialists. However, a wider application of the PSCK9 inhibitors as an add-on to statin therapy will depend on large-scale cardiovascular-outcomes studies, such as the ODYSSEY trials with alirocumab (Sanofi/Regeneron), FOURIER with evolocumab, and SPIRE-1 and SPIRE-2 with bococizumab (Pfizer).

In TESLA and RUTHERFORD-2, evolocumab appeared to be safe. The most commonly reported side effects were upper-respiratory-tract infections, influenza, gastroenteritis, and nasopharyngitis. There were no deaths, no neurocognitive adverse events, and no patient stopped treatment because of an adverse event.

TESLA Also Analyzed by Mutation Status

The TESLA study, which included 49 homozygous FH patients, including 33 treated with evolocumab 420 mg monthly and 16 treated with placebo, was presented earlier this year at the European Atherosclerosis Society (EAS) scientific sessions by Dr Frederick Raal (University of Witwatersrand, Johannesburg, South Africa).

The mean baseline LDL-cholesterol level was 348 mg/dL (9.0 mmol/L). By week 12, as noted, evolocumab reduced LDL cholesterol by 23%. There was a significant reduction in apolipoprotein B levels, but the reduction in apolipoprotein A was not statistically significant.

As reported by heartwire at that time, the researchers also analyzed the treatment effect by LDL-receptor mutation status. For homozygous FH 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. Apolipoprotein A was reduced in individuals with at least one defective LDL-receptor mutation.

These patients with defective mutations, in which the LDL receptor still works to some degree, had the best response to treatment, note the investigators. For patients with even a single LDL-receptor-negative mutation, the response to treatment was significantly less. For the one patient with a negative/negative mutation status, evolocumab had no effect and LDL cholesterol increased 10% from baseline.

"This trial shows that genetic information provides incremental insight into homozygous familial hypercholesterolemia and possible response to treatment," according to the TESLA investigators.

More Than 60% Get to <70 mg/dL in RUTHERFORD

The RUTHERFORD-2 study, which was also led by Raal, included 331 heterozygous FH patients randomized to evolocumab 140 mg every two weeks, to evolocumab 420 mg monthly, or to matching placebo. At baseline, the mean LDL was 155 mg/dL (4.0 mmol/L) despite all patients receiving statin therapy, including 87% with high-intensity statin therapy, and 62% also receiving ezetimibe.

As reported when the results were announced in January 2014, treatment with evolocumab significantly reduced LDL-cholesterol levels, down 61% from baseline with the 140-mg twice-weekly dose and 56% from baseline with the 420-mg monthly dose. By week 12, 68% of the 104 patients who received the 140-mg twice-weekly dose achieved an LDL cholesterol <70 mg/dL (<1.8 mmol/L), as did 63% of the 103 patients treated with the 420-mg monthly dose. The response to evolocumab was independent of the genetic variant in the LDL receptor.

In their editorial, Santos and Watts say that molecular testing or an assessment of LDL-receptor function might be useful in homozygous FH to determine who would respond to therapy, but this would be unnecessary in heterozygous FH patients. The editorialists state that there is also a need to test evolocumab in a setting where homozygous FH patients are treated with LDL apheresis.

In the US, the Food and Drug Administration has approved mipomersen (Genzyme), which inhibits apolipoprotein B synthesis, and lomitapide (Aegerion Pharmaceuticals), which inhibits the microsomal triglyceride transfer protein, for the treatment of homozygous FH. The European Medicines Agency has approved only lomitapide.

Raal has received consulting fees from Amgen and Sanofi related to PCSK9 inhibitors and from Genzyme (a Sanofi company) related to apolipoprotein B inhibitors. His institution has received research funding related to PCSK9-inhibitor clinical trials from Amgen and Sanofi and from Isis and Genzyme for trials related to mipomersen. Santos has received honoraria related to consulting or speaking from AstraZeneca, Aegerion, Amgen, Eli Lilly, Bristol-Myers Squibb, Boehringer-Ingelheim, Biolab, Genzyme, Merck, Nestlé, Novartis, Novo-Nordisk, Pfizer, Regeneron, Sanofi, Torrent, and Unilever. Watts has received honoraria related to consulting or speaking from Amgen, Abbott, AstraZeneca, Merck Sharp & Dohme, Novartis, and Sanofi.

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