Small but Promising Signal Holds Up for Add-on Evinacumab in Homozygous Familial Hypercholesterolemia

Patrice Wendling

May 03, 2017

PRAGUE, CZECH REPUBLIC — The investigational monoclonal antibody evinacumab (Regeneron) reduced baseline LDL-cholesterol levels by an average of 49% at week 4 when added to standard cholesterol treatment in patients with homozygous familial hypercholesterolemia (HoFH), in a small, ongoing proof-of-concept study[1].

"You may offer this option to patients affected by this disease in association with or in place of other agents," lead author Dr Daniel Gaudet (Université de Montreal, ECOGENE-21 Clinical Research Center and Lipid Clinic, Chicoutimi, QC) said in a late-breaking session at the European Atherosclerosis Society (EAS) 2017 Annual Congress.

The US Food and Drug Administration granted evinacumab breakthrough-therapy designation last month for the treatment of HoFH, a rare genetic disorder that occurs in about one in 160,000 to 300,000 persons and is characterized by high LDL-C levels and premature heart disease if left untreated.

Most of the nine patients were already on high-dose statins and three were receiving a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.

Unlike PCSK9 inhibitors, evinacumab works by targeting angiopoietinlike protein 3 (ANGPTL3), a circulating protein synthesized in the liver that inhibits lipoprotein lipase and endothelial lipase.

During a discussion of the results, Gaudet said initially they thought there was a synergy between evinacumab and evolocumab but that they are dealing with small patient numbers and aren't sure whether it's additive or not.

At last year's EAS Congress, investigators reported that adding evinacumab to standard lipid-lowering therapies led to an average 55% reduction in LDL-C levels at week 4 in the first four patients.

Patients received 250-mg evinacumab subcutaneously at baseline followed by a 15-mg/kg intravenous infusion at week 2. The first two patients also received 450-mg evinacumab subcutaneously once weekly at weeks 12 to 15, but this dose was stopped due to pharmacokinetic data and the study amended, Gaudet said.

The mean baseline LDL-C was 9.7 mmol/L (375 mg/dL) among the nine patients now enrolled and 15.5 mmol/L (599.3 mg/dL) among three of these patients with homozygous null-allele mutations. Triglycerides were low at 0.8 mmol/L (70.8 mg/dL) and 1.2 mmol/L (106.2 mg/dL), respectively.

Background therapies included atorvastatin 20 and 80 mg; rosuvastatin 20 and 40 mg; ezetimibe (Zetia, Merck) 10 mg; lomitapide (Juxtapid, Aegerion Pharmaceuticals) 20 mg; the PCSK9 inhibitor evolocumab (Repatha, Amgen) 140 and 420 mg/mL; and lipoprotein apheresis.

The mean reduction in LDL-C increased from 49% at week 4 to 52% after 6 weeks, with a mean peak reduction of 58% between weeks 4 and 12. "So the effect was sustained," Gaudet said.

Commenting on the data in another session at the congress, Dr G Kees Hovingh (Academic Medical Center, Amsterdam, the Netherlands) noted that while LDL-C was reduced 49% overall at week 4, there was a wide variation between patients (from roughly 25% to nearly 90% at week 4), likely based on the background therapy that was being given.

"So I think it's really intriguing data, and for me it is driving the observation and the need to gather all the data to generate good thoughts," he added during his talk on the recently launched HoFH International Clinical Collaboration (HICC) Registry.

Other mean percent changes in lipids/lipoproteins observed at week 4 were:

  • -39% apolipoprotein A1.

  • -46% apolipoprotein B.

  • -47% total cholesterol.

  • -19% lipoprotein(a).

  • -36% HDL cholesterol.

  • -47% triglycerides.

Session cochair Dr Sotirios Tsimikas (University of California, San Diego) told heartwire from Medscape the low HDL-C levels are not that surprising given the drug's mechanism of action and that it also recapitulates the clinical phenotype of HoFH, where many of these lipoproteins are diminished.

He said the data look "promising," especially because a lot of these patients are still on apheresis. The cost of a monoclonal antibody will be a part of the equation, but unlike statins where millions of patients are treated, this is a very rare disease.

As to the safety of the drug, there were 49 adverse events, of which one (CAD due to underlying disease) was serious but was not considered related to the study drug. Six events were considered related to evinacumab; two mild injection-site reactions, one moderate-severity myalgia, two mild hot flushes, and one severe epistaxis.

"It's very early, you have only nine patients, so it's very hard to know anything about safety and tolerability; you just have to wait for larger studies," Tsimikas said.

Regeneron has announced it is currently planning a phase 3 trial.

The study was funded by Regeneron Pharmaceuticals. Gaudet reports serving as a consultant/advisory panel member for Sanofi, Regeneron, Amgen, Novartis, Ionis, Catabasis, Aegerion, Omthera, Uniqure, Chiesi, Gemphire, and Cymabay. Hovingh reports his institution has received payment for conducting clinical trials from Sanofi, Regeneron, Amgen, Pfizer, Kowa, Genzyme, Isis Pharmaceuticals, Roche, Eli Lilly, Aegerion, Synageva, and AstraZeneca; and for lectures and/or advisory panel participation from Amgen, Sanofi, Pfizer, Regeneron, and Roche. Tsimikas currently has a dual appointment with the University of California, San Diego and as an employee of Ionis Pharmaceuticals.

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