May 27, 2012 (Milan, Italy)Another phase 2 study showing impressive reductions in LDL cholesterol with the anti–proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) monoclonal antibody REGN727 /SAR236553 (REGN727) has been reported, and the companies developing the agent, Regeneron and Sanofi, have announced that phase 3 trials will begin June.

The phase 3 trials will include patients with high unmet medical need, such as patients with familial hypercholesterolemia (FH) or elevated cardiovascular risk who cannot reach their LDL-cholesterol goals with current standard therapies.

The latest study with REGN727, which is generating excitement due to the very large reductions in LDL it achieves, was presented yesterday here at the European Atherosclerosis Society 2012 Congress and published simultaneously in the Lancet [1].

As in previous studies, the 150-mg dose of the agent given every two weeks by subcutaneous injection gave the best results, and it therefore seems likely that it will be this dose that will be tested in phase 3. Giving higher doses every four weeks had less of an effect.

Presenting the study, Dr Evan Stein (Metabolic and Atherosclerosis Research Center, Cincinnati, OH) said: "LDL reductions averaged almost 100 mg/dL from baseline, and the mean on-treatment LDL was close to 50 mg/dL. Nothing has been shown to be this effective before." To heartwire , he added: "We've established that it's effective. Now we have to show to show safety. That is what the phase 3 trials are for."

A Sanofi representative told heartwire that the product had so far been tested in around 300 patients. Phase 3 trials would involve several thousand patients.

The monoclonal antibody is directed against the enzyme PCSK9, which inactivates hepatic LDL receptors, thereby reducing the removal of LDL cholesterol from the bloodstream. By blocking the PCSK9 enzyme, the monoclonal antibody accelerates the removal of LDL.

The current study, conducted at 16 centers in the US and Canada, involved 77 patients with familial hypercholesterolemia, most of whom were already taking high-dose statins as well as ezetimibe but who still had high LDL levels (mean 150 mg/dL). They were randomized to receive REGN727 150 mg, 200 mg, or 300 mg every four weeks, or 150 mg every two weeks, or placebo every two weeks.

The primary end point was mean percent reduction in LDL cholesterol from baseline at week 12 and showed the best results with REGN727 150 mg every two weeks.

Reductions in LDL With Various Doses of REGN727 vs Placebo

Dose, mg Reduction in LDL (%) % of patients reaching LDL<70mg/dL
Placebo 10.65 0
150/4 wk 28.9 13
200/4 wk 31.54 13
300/4 wk 42.53 47
150/2 wk 67.90 81

One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. One patient in the REGN727 300-mg group discontinued treatment because of an injection-site reaction.

Asked whether the antibody would require outcome studies for approval, Stein replied: "I'm not the FDA, but LDL is a well-accepted surrogate end point. It has reassuring genetics, and there is no offsetting morbidity in patients with low functional LDL. It hasn't led us astray before, and this antibody has a very specific LDL-receptor target. I feel it is likely that it may get approval based on the LDL reductions, provided outcome trials are under way."

Another question addressed the volume of the injection necessary to give the 150-mg dose. Stein answered: "I cannot say what the actual volume will be, but as a rule of thumb for monoclonal antibodies, you get about 150 mg of protein into 1 mL of injection."

In a Comment accompanying the Lancet paper [2], Dr Eric Sijbrands (Erasmus Medical Center, Rotterdam, the Netherlands) says the current study has the "strength" of having been conducted in patients with FH "who clearly need additional therapy to improve prognosis." But noting that FH patients require lifelong treatment, he adds that future studies must evaluate prolonged use of the agent.