Therapeutic Focus - PCSK9 inhibitors showing promise with early data

For all their effectiveness in lowering low-density lipoprotein cholesterol (LDL-C), statins have not been the answer for every patient wanting to lower the risk of heart disease. Many are unable to achieve goal LDL-C levels on statins alone whilst others are unable to take them because of muscle pain, prompting pharma companies to look for new agents.

PCSK9 inhibitors are an emerging next weapon in the cardiology armoury, a potentially effective approach that is hoped will aid the liver’s metabolism of LDL-C. The hope is that PCSK9 inhibitors could be used as an adjunct to an estimated one in four patients taking statins who do not achieve LDL-C goals and alone in another 10% of patients who experience muscle pain.

“I find 30 to 40 percent of patients I see are statin intolerant,” Dr Robert Eckel, a University of Colorado heart disease specialist, told EP Vantage in an interview at the American Heart Association scientific meetings this week. “We get some people back on statins but often not at doses that are needed to get LDL to 'goal'. I need additional LDL lowering therapy.”

Add on

PCSK9 is an enzyme that otherwise binds with LDL-C receptors primarily in the liver, inhibiting their ability to metabolise the so-called “bad” cholesterol implicated in heart disease. Statins are known to stimulate production of PCSK9, thus limiting their effectiveness in lowering LDL-C. Thus an anti-PCSK9 agent would be a useful add-on to statin therapy.

There are only a handful of active experimental candidates aimed at blocking the activity of PCSK9 (see table below); the anti-PCSK9 monoclonal antibodies now in phase II all have big names backing them, indicating the level of excitement about this new approach and the commercial potential given the unmet need.

They are supported by some promising results so far, with data on two candidates unveiled at AHA. Sanofi - in partnership with Regeneron Pharmaceuticals - Amgen and Pfizer are testing monoclonal antibodies that bind to PCSK9, or proprotein convertase subtilisin/kexin type 9.

Regeneron released data from a phase I trial of REGN727 (SAR236553) indicating reductions in LDL-C of 35.6%, 50.2% and 57.5% for patients receiving three injections of 50mg, 100mg and 150mg in addition to statin. No serious adverse events were recorded, particularly liver-related abnormalities.

Preliminary phase II trial data published by Sanofi and Regeneron right before AHA suggested LDL-C reductions of a similar magnitude: after 16 weeks, a reduction of more than 65% in LDL-C levels when REGN727 was added to a regimen of 80mg of Lipitor, compared with 17% for 80mg Lipitor alone, for patients had previously been on a stable 10mg Lipitor dose. That trial also included an arm that added REGN727 to the 10mg Lipitor dose; a 65% reduction in LDL-C was registered.

Regeneron’s phase II programme consists of three trials and 347 patients, following on from a seven-trial phase I programme of 260 patients.

Meanwhile, at AHA Amgen released phase I data on AMG 145, which found reductions of up to 64% compared to placebo patients. Amgen has a phase II programme underway consisting of five trials and more than 1,600 patients.

Moving from a pill to an injection may be a big jump for many, however, notes Dr Sergio Fazio, a medical professor at Vanderbilt University. “I deal with so many patients who say no to insulin,” Dr Fazio said at an AHA session in which the PCSK9 data was discussed. “Just imagine what kind of job you have ahead of you.”

However, an oral approach may be difficult, says Clapton Dias, Amgen’s director of early development clinical pharmacology. “PCSK9 is a target that is not approachable by small molecules,” Mr Dias said in an interview.

Interference

Another approach being tried is RNA interference. Alnylam Pharmaceuticals’ ALN-PCS began phase I trials in September following pre-clinical data that showed a 90% reduction in PCSK9 serum protein levels on a dose that silenced 50% of the PSCK9 mRNA expression.

Santaris Pharma began phase I trials of RNAi candidate SPC5001 in May. In primates it reduced PCSK9 levels by an average of 50% and 74% in the highest responder.

Safety and preliminary efficacy data on both of the RNAi candidates is likely to be known within the next year, and will give specialists an early idea of how they will match up to the anti-PCSK9 antibodies.

Given the shortfalls of statins, specialists are anxious for products that can address the unmet medical need. PCSK9 inhibitors are showing promise, but await validation in large pivotal trials.