LYON, France — The novel monoclonal antibody to PCSK9 AMG 145 (Amgen) substantially reduced plasma LDL cholesterol in four of eight patients with homozygous familial hypercholesterolemia (HoFH), a new proof-of-concept study has shown.

Dr Evan Stein (Metabolic and Atherosclerosis Research Center, Cincinnati, OH) presented the Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities (TESLA) in a late-breaking trials session here at the European Atherosclerosis Society 2013 Congress .

PCSK9 inhibition has emerged as one of the most active lines of investigation in cholesterol research, with promising results in a number of phase 2 trials in heterozygous FH and in patients intolerant to statins. HoFH--a rare heritable disorder that leads to severely elevated LDL-cholesterol and CVD that typically manifests in childhood--is the latest testing ground for this new class of agent.

PCSK9 antibodies work by inhibiting the PCSK9 protein, which binds to LDL receptors, resulting in their degradation so that fewer are available on liver cells to remove excess LDL-C from the blood. Statins, by contrast, actually stimulate the production of PCSK9, which limits their own ability to lower LDL-C. By blocking the PCSK9 pathway, the new monoclonal antibodies upregulate the recycling of LDL receptors, thereby lowering LDL.

The problem, as Stein explained here, is that up to 70% of HoFH patients have defective LDL receptors and 10% are LDL-receptor negative (less than 2% function), so "it is unknown and uncertain whether PCSK9 inhibition will be effective in patients who have minimal or no LDL-receptor function," he said.

A Proof-of-Concept, Dose-Scheduling Study

Dr Evan Stein

In TESLA, eight patients with genetically confirmed HoFH, already taking other treatments, were treated with 420 mg of subcutaneous AMG 145 every four weeks for at least 12 weeks.

Initially, said Stein, the plan was to dose patients at the highest dose previously tested in clinical trials once every four weeks for 12 weeks. "However, we found that we were not binding all of the PCSK9 . . . so we modified the protocol to go to the same dose, but given every two weeks, and during the time we were adapting the protocol, we continued dosing for another 12 weeks, every four weeks."

After 12 weeks, mean LDL lowering was 16.5%, ranging from an increase of 5.2% to a decrease of 43.6%. Three of the eight patients had reductions >30%, while a fourth had a reduction of 15%. In the two patients with negative receptor function at baseline, however, no significant change from baseline was seen.

For the group as a whole, no meaningful differences were seen between the every-two-week vs the every-four-week dosing schedule. However, mean reductions of LDL over the 12-week treatment period in the six patients with defective but still functional LDL receptors were 19.3% and 26.3% with the four-week and two-week dosing, respectively," Stein said, a statistically significant difference.

Importantly, no side effects were seen, even at the every-two-weeks dose.

"The study demonstrates for the first time that significant LDL-C lowering is achievable with a PCSK9 monoclonal antibody in HoFH patients with defective LDL-receptor activity," Stein concluded.

On the basis of these results, a larger randomized, placebo-controlled trial is now under way, he added.

New Hope for HoFH

Two other drugs, lomitapide (Juxtapid, Aegerion Pharmaceuticals) and mipomersen sodium (Kynamro, Isis Pharmaceuticals/Genzyme), which reduce hepatic lipoprotein production (and are not dependent on LDL-receptor function) have recently been recommended for approval in the EU (lomitapide) and approved in the US. Concerns about side effects, however, mean that both, at least in the US, can be used only under a risk-evaluation and mitigation strategy (REMS) requiring strict dispensing and monitoring.

In an email to heartwire , Stein stressed that the patients in the study were already "maxed out" on other drugs, including high-dose statins, ezetimibe (Zetia, Merck), niacin, and bile-binding resins.This is also the first study that has looked at a PCSK9 inhibitor in HoFH, Stein noted; Regeneron/Sanofi and Pfizer are also developing a PCSK9 antibody.

Dr Børge Nordestgaard

Commenting on the study for heartwire , Dr Børge Nordestgaard (University of Copenhagen, Denmark) stressed that this particular group of patients "have such severe disease and until very lately, typically died very young."

The two drugs recently approved for this group represent "breakthroughs" he said, but "neither of these are without side effects.

"So there's really a need for other drugs, because I'm sure there will be lots of patients, even with these two products, who won't tolerate them or won't tolerate them long term." That said, the LDL reductions seen in the TESLA trial with PCSK9 were not as great as those seen in the trials of these other agents, Nordestgaard noted.

"But now, for the first time, we have some drugs that mean these patients have a chance to live longer and not die as teenagers or in their 20s. That's really something."

Stein's talk estimated that HoFH affects approximately one in a million people, but Nordestgaard said population-screening studies suggest the number is higher, perhaps as high as one in 40 000.

"The homozygosity is an unbelievably serious disease; it's like cystic fibrosis, with these patients dying at the same age. It's truly the worst disease related to cholesterol," he said. "But maybe in five years, or more, it won't be a problem to be a homozygous FH patient anymore."

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