PCSK9 inhibitors have hit their stride. Phase II data from Amgen’s AMG 145 in statin-intolerant patients and familial hyperlipidaemia might enable the project to become the second antibody in the class to be advanced into phase III, and the results have done little to quell the growing excitement about this class of drug.
This means that by next year’s end AMG 145 could be leading a close three-way race to bring a potent new low-density lipoprotein cholesterol (LDL-C) lowering agent to the market. “The levels of reduction are dramatic,” said Dr William Zoghbi, director of the imaging institute at the Methodist DeBakey Heart and Vascular Centre in Houston, Texas. “You’re down 70% or so. We haven’t seen that in anything else.”
If the darling of the 2011 American Heart Association scientific sessions was Regeneron Pharmaceuticals and Sanofi’s REGN727/SAR236553, this year it was the turn of AMG 145 to take a bow (Therapeutic Focus - PCSK9 inhibitors showing promise with early data, November 18, 2011). With Pfizer waiting for the results of a phase IIb study in 350 patients, expected in June 2013, before making its decision to advance RN316 into a pivotal trial, the three compounds are will be neck and neck.
Data from the phase II Gauss trial of AMG 145 in 157 statin-intolerant patients indicated up to a 63% reduction in LDL-C after 12 weeks, in an arm with a maximal dose of 420mg once every four weeks and also taking Zetia. Even the lowest-dose arm as monotherapy, 280mg once every four weeks, showed a statistically significant 41% improvement in LDL-C when compared against Zetia alone.
Three patients developed creatine kinase elevations above five times the upper limit of normal, two of them above 10 times. Myalgia developed in 13 of the 125 patients randomised to take AMG 145. The safety data gave cause for caution, but analysts from UBS wrote that the myalgia finding “does not represent a threat to approvability”.
Separately, the California group reported data from its Rutherford trial in patients with heterozygous familial hypercholesterolaemia (HeFH), which yielded statistically significant reductions in LDL-C at both the 420mg and 350mg dose, 55% and 43% respectively, compared with placebo.
Amgen executives said the data supported moving into phase III in monotherapy and combination therapy, in statin-intolerant patients, in HeFH and in secondary prevention of cardiovascular events. Meanwhile, Sanofi and Regeneron outlined plans for the phase III Odyssey Outcomes trial of ‘727, known generically as alirocumab, which will recruit 18,000 patients with the goal of showing a reduction in cardiovascular events in patients who have suffered acute coronary syndrome and have not reached an LDL-C goal.
PCSK9, or proprotein convertase subtilisin/kexin type 9, is an enzyme that binds to LDL-C receptors primarily in the liver, and inhibits their ability to metabolise the so-called “bad cholesterol”. Blocking the enzyme’s action, such as through binding with an antibody, would thus improve cholesterol metabolism.
Inhibitors of PCSK9 are primarily being considered for patients unable to achieve LDL-C reduction goals even on maximum statin doses, or in patients who are intolerant to statins because of muscle-realted side effects. An estimated 10-20% of patients are unable to achieve the LDL-C goals.
Pfizer also announced its presence in the space with 12-week data from an iv formulation of RN316 that significantly lowered LDL-C at a 3mg and 6mg per kilogram dose when compared with placebo in patients already on high-dose statins.
The New York group is testing a subcutaneous formulation, which will likely be the commercial focus given that both Regeneron and Amgen are testing subcutaneous candidates.
“Given the worldwide population not controlled or intolerant of statins, we are bullish on the PCSK9 class, but recognize that Pfizer is currently third in this race,” UBS wrote in a note after Pfizer’s presentation.
Getting to goal
Dr Gregg Fonarow, a cardiology professor at University of California-Los Angeles, said the potential entry of the class onto the market could allow cardiologists to shift their thinking in how they approach treating patients who have not achieved LDL-C goals.
“Those cardiologists who have been focused on not lowering LDL more aggressively … and start focusing on HDL raising have left a lot of potentially preventable events on the table,” Dr Fonarow told EP Vantage. “Had they been more aggressive on LDL they would have done much better for their patients.”
Dr Zoghbi notes, however, that there is still a great deal of potential for reducing cardiovascular mortality with statins by making sure a larger share of the population knows their risks.
“If you’re working in a silo, and you develop all these drugs and you don’t affect delivery … you’re not going to be able to affect practice,” Dr Zoghbi says.
To contact the writer of this story email Jonathan Gardner in Los Angeles at firstname.lastname@example.org