12:00 AM
Apr 30, 2012
 |  BioCentury  |  Product Development

Beyond statins: LDL diversity

Beyond statins: PCSK9 inhibitors slash LDL; but not for all patients

No fewer than 20 companies are working on next-generation lipid-lowering agents intended to improve upon the benefits of statins, which lower LDL-C and reduce the risk of cardiovascular events but still leave millions of people above target LDL-C levels. While most are developing their compounds in similar settings - generally as add-ons to high-dose statins in patients not achieving LDL-C goals - emerging data suggest different mechanisms may turn out to be appropriate for different populations.

In March two mAbs that inhibit proprotein convertase subtilisin/kexin 9 made headlines with new clinical data.

As reported as the American College of Cardiology (ACC) meeting, REGN727 (SAR236553) from Regeneron Pharmaceuticals Inc. and Sanofi, and Amgen Inc.'s AMG 145 both showed some of the highest reductions in LDL-C seen in patients on high-dose statins.

The mAbs are at the front of at least eight programs targeting PCSK9 (see "PCSK9 Bandwagon," A10) .

"The PCSK9 pathway is in my opinion one of the most exciting in cardiovascular drug development and perhaps in all of drug development today," Amgen SVP of Global Development and CMO Michael Severino told BioCentury.

However, researchers who spoke to BioCentury noted other emerging therapeutic classes may be more appropriate for patients with mixed dyslipidemia and for patients with the most severe forms of hypercholesterolemia that are caused by deficiencies in LDL receptors.

Compounds with potential in the former group include thyroid hormone receptor beta agonists and AMP-activated protein kinase (AMPK) activators.

Patients with severe disease caused by defective or missing LDL receptors are being targeted with inhibitors of microsomal triglyceride transfer protein (MTP) and apolipoprotein B-100 (APOB-100). This group includes patients with severe heterozygous and homozygous familial hypercholesterolemia (FH).

Anti-PCSK9 mAbs also may face competition from cholesteryl ester transfer protein (CETP) inhibitors. This class of small molecules is known more for raising HDL levels, but some compounds have been shown to significantly lower LDL-C as well (see BioCentury, Nov. 21, 2011).

Picking PCSK9

The ACC data were greeted with excitement because the meeting provided confirmatory data on Regeneron's mAb while the Amgen results provided the first clinical data on a second candidate against the target.

PCSK9 first emerged as a target for hypercholesterolemia in 2003 with the discovery of a few French families who carry a gain-of-function mutation in the PCSK9 gene that caused hypercholesterolemia. Subsequently, individuals with loss-of-function mutations were discovered to have low LDL-C levels and particularly low risk of coronary heart disease (CHD).

The loss-of-function mutations have not been associated with disease in either humans or animals, which supported the idea that targeting PCSK9 pharmacologically could be a safe method for lowering LDL-C.

When PCSK9 was discovered to play a role in the same pathway as statins, the hypothesis was that blocking it could enhance their cholesterol-lowering effects.

Statins inhibit HMG-CoA reductase, which leads to increased expression of LDL receptors, which in turn remove LDL-C from circulation. PCSK9 essentially counteracts statins by enhancing the degradation of LDL receptors, thus increasing plasma levels of LDL-C.

In fact, said Dayami Lopez, an assistant professor of pharmaceutical sciences at North Carolina Central University's Biomanufacturing Research Institute and Technology Enterprise: "The body's natural response to statin therapy is to start producing more PCSK9, so adding a PCSK9 inhibitor should be a great complement."

The first Phase II POC data were reported by Regeneron and Sanofi in November 2011. Two studies showed twice-monthly subcutaneous REGN727 significantly reduced LDL-C in patients who had baseline LDL-C of 100 mg/dL or more despite already being on lipid-lowering therapy (see BioCentury, Nov. 21, 2011).

In one trial in 75 patients with heterozygous familial hypercholesterolemia...

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