PCSK9 is a hot target for lowering cholesterol with Amgen Inc., Regeneron Pharmaceuticals Inc., Sanofi SA, Pfizer Inc. and many other companies developing drugs to inhibit the protein.

But with popularity comes competition and some companies have decided to avoid the frenzy by going after different targets to treat high cholesterol levels.

At the end of 2012, Aegerion Pharmaceuticals Inc., of Cambridge, Mass., gained FDA approval for Juxtapid (lomitapide) to treat patients with homozygous familial hypercholesterolemia (HoFH), a genetic disorder that causes extremely high cholesterol levels. Juxtapid inhibits microsomal triglyceride transfer protein, responsible for transferring the building blocks of LDL cholesterol out of the liver. (See BioWorld Today, Dec. 27, 2012.)

Juxtapid’s approval was quickly followed by the FDA approval of Kynamro (mipomersen), developed by Isis Pharmaceuticals Inc., of Carlsbad, Calif., and Genzyme, a unit of Paris-based Sanofi SA. Kynamro, an antisense drug, inhibits synthesis of apolipoprotein B, which is required for formation of LDL cholesterol. (See BioWorld Today, Jan. 31, 2013.)

Aegerion achieved $48.5 million in net product sales of Juxtapid last year, including $24.5 million in the fourth quarter. Sanofi hasn’t broken out sales of Kynamro, but Isis’ COO, B. Lynne Parshall, told investors on its fourth-quarter conference call that, “while the launch got off to a bit of a slow start, sales showed significant quarter-over-quarter growth in 2013, and we believe that sales will continue to increase significantly this year.”

Both HoFH drugs are also being tested in heterozygous FH patients, which could expand their market substantially.

CLEANING THE PIPES

Cerenis Therapeutics SA is taking a different approach to treating patients with high LDL cholesterol. Rather than inhibit the synthesis, Cerenis’ CER-001 seeks to remove the plaques caused by cholesterol buildup in patients’ arteries.

CER-001 is a pre-beta HDL mimetic, based on the major structural protein of HDL, apolipoprotein A-I. One of HDL’s functions – and the reason it’s called “good” cholesterol – is to mobilize cholesterol and deliver it to the liver where it’s eliminated.

In January, Cerenis, of Toulouse, France, and Ann Arbor, Mich., reported disappointing top-line results from a phase IIb trial dubbed CHI-SQUARE (Can HDL Infusions Significantly Quicken Atherosclerosis REgression?) in patients who had undergone an acute coronary syndrome episode such as a heart attack.

CER-001 failed to reduce Total Atheroma Volume (TAV), a measurement of coronary atherosclerotic plaque by intravascular ultrasound (IVUS), compared to placebo. Unfortunately the placebo group saw reductions in TAV, making the comparison not statistically significant.

An independent and blinded analysis of the data found one of the CER-001 dose levels did reach nominal statistical significance versus placebo. Cerenis President and CEO Jean-Louis Dasseux said the problem might be with the IVUS imaging to determine if the drug regressed the plaque. “There are a lot of improvements that can be done.”

Cerenis has two more trials testing patients with rare diseases in the lipid metabolism including HoFH patients. Given the higher need, Dasseux is more confident that the trials will be statistically significant. Those results, due in the coming months, will help guide the phase III program. “We do not necessarily want to abandon the rest,” Dasseux said, but as Genzyme, Aegerion, and Isis have shown, treating rare cholesterol diseases can be the easiest pathway to approval.

DUAL ACTION

Esperion Therapeutics Inc.’s ETC-1002 has a dual mechanism of action inhibiting ATP citrate lyase (ACL) and activating a complementary enzyme, 5’-adenosine monophosphate-activated protein kinase (AMPK).

ACL is part of the cholesterol-synthesis pathway, a couple of steps upstream from the enzyme inhibited by statins, such as Lipitor (atorvastatin, Pfizer Inc.) and Crestor (rosuvastatin calcium, Astrazeneca plc). ACL was investigated as a target by large pharmas including London-based Glaxosmithkline plc more than a decade ago but “because of success of statins were largely underfunded and ultimately abandoned,” Tim Mayleben, president and CEO of Esperion, told BioWorld Insight.

AMPK, which is also activated by metformin, has multiple effects on the body including inhibition of cholesterol synthesis and the breakdown of lipids and fatty acids.

Plymouth, Mich.-based Esperion has run seven clinical studies on more than 300 patients, seeing LDL cholesterol reductions of up to 43 percent and improvements in other cardiovascular risk factors including lowering of blood pressure and positive benefits on blood glucose levels.

Esperion is running one more phase IIb trial comparing a combination of ETC-1002 and Zetia (ezetimibe, Merck & Co. Inc.) to both drugs individually in patients with high cholesterol levels. Half of the patients enrolled will be intolerant to statins, mostly due to muscle pain and weakness.

“Zetia seems to have become the standard of care for statin intolerant patients,” Mayleben, “it was the right thing to do to introduce an active control.”

Top-line results for the ETC-1002/Zetia trial are expected in the fourth quarter of 2014, which will help shape the company’s phase III program.

THE COMPETITION

Neither CEO seemed very concerned about competition from PCSK9 inhibitors.

“Our treatment will work on top of any LDL-lowering drug,” Cerenis’ Dasseux said, explaining that the LDL-lowering drugs like statins and PCSK9 inhibitors are like turning off the sink tap while CER-001 is like opening up the drain. Both processes help keep the LDL-cholesterol sink from filling up.

For ETC-1002, which will have to compete with PCSK9 inhibitors, Mayleben said its oral formulation will give it an advantage over PCSK9 inhibitors that have to be injected or infused. “That’s what patients and physicians are used to,” he said.

The dual action of ETC-1002, activating AMPK, could also give the drug an advantage over PCSK9 inhibitors if Esperion’s phase III program can show that the drug improves other markers for cardiovascular outcomes.

ETC-1002 won’t have to compete with statins, many of which are available as generics, if Esperion targets the estimated five percent to 20 percent of people that are statin intolerant.

The upper level of that estimate could be reached if doctors follow new guidelines to push LDL cholesterol goals lower. As doses of statins are increased to lower cholesterol levels further, there’s an increasing likelihood of becoming intolerant.