Investors hailed Esperion Therapeutics Inc.'s success with ETC-1002, the firm's dual-action cholesterol-lowering pill, sending upward the Ann Arbor, Mich.-based firm's stock as onlookers sought to gauge the drug's chances in a market that already includes generic therapies and could soon include proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

Shares of Esperion (NASDAQ:ESPR) closed Thursday at $27, up $2.58, or 10.6 percent, after trading as high as $30.

"The team just found out these results over the weekend, so we're still digesting them," CEO Tim Mayleben said during a conference call with investors Wednesday afternoon, though the company was pleased. "Certainly, nothing really stands out as saying 'Oh, we've got to take a hard right in our strategy.' Now that we've seen this drug in 500 patients, it really has confirmed this attractive safety and tolerability profile," especially given that most have been dosed for 12 weeks.

The 300-patient study, known as ETC-1002-008, tested the compound as a monotherapy compared with Zetia (ezetimibe, Merck & Co. Inc.) alone in patients with hypercholesterolemia, with or without statin intolerance. Top-line results showed the 12-week study met its primary endpoint of greater LDL-cholesterol (LDL-C) lowering from baseline with ETC-1002. Specifically, patients given ETC-1002 turned up 27 percent and 30 percent reductions in LDL-C at doses of 120 mg and 180 mg, respectively, as compared to ezetimibe alone (p = 0.0008 and p < 0.0001, respectively).

Patients given the combination of 120 mg of ETC-1002 and 10 mg ezetimibe showed LDL-C drops of 43 percent, again significantly different from ezetimibe alone (p < 0.0001). When the combo of 180 mg of ETC-1002 and 10 mg ezetimibe was tried, LDL-C went down 48 percent as compared with ezetimibe (p < 0.0001). Those dips in LDL-C took place within the first two weeks of dosing and continued through the treatment period, Esperion said, noting that the drug was well tolerated.

Company officials were "blown away" with the combo's outcome, Mayleben said. "That was an amazing result." The Merck comparator in the trial sells nearly $3 billion per year, and with ETC-1002 gaining "twice the efficacy and comparable safety and tolerability," the newer drug seems more than viable, Mayleben said. ETC-1002 monotherapy and the ezetimibe combo also yielded significantly greater LDL-C drops than ezetimibe by itself in high-sensitivity C-reactive protein, a marker of inflammation in coronary disease.

In the liver, ETC-1002 inhibits ATP citrate lyase (ACL) and activates 5'-adenosine monophosphate-activated protein kinase. Preclinical studies showed that ETC-1002 is converted to a derivative coenzyme, ETC-1002-CoA, which directly inhibits ACL, a key enzyme that supplies substrate for cholesterol and fatty acid synthesis, as well as glucose production.

"Our thinking over the last several years has evolved," Mayleben said, and Esperion has determined that inhibiting ACL is the drug's primary mechanism of action. "We can say [that] more convincingly than ever now." It's "a well-known target, going back 40 years" in big pharma, which struggled to increase bioavailability of prospective drugs, he said. Esperion's first chore was "breaking the code on that bioavailability," Mayleben added, and the new task is understanding exactly how ETC-1002 works. "Of course, we'll continue to publish on this in the years ahead. This is what pioneers do. This is what we find ourselves doing."

Esperion is developing the drug for statin-intolerant patients to provide cholesterol-lowering benefit without the muscle-related side effects associated with statins. ETC-1002 will be approved by the FDA for "LDL-C lowering, period," Mayleben predicted, though the commercial strategy will focus on statin-intolerant patients. Differentiating the regulatory from the marketing approach is "not a change, but more of a refinement of what we've been saying," he said.

CV OUTCOMES TRIALS UNLIKELY

Coming up fast in the cholesterol space are PCSK9 inhibitors. Later this month, the FDA is expected to let the world know whether Thousand Oaks, Calif.-based Amgen Inc.'s biologics license application (BLA) for AMG-145 is accepted, and whether the compound gets priority review. Regeneron Pharmaceuticals Inc., of Tarrytown, N.Y., with Paris-based partner Sanofi SA, is expected to file a BLA for its PCSK9 candidate by the end of the year, and will deploy a special voucher acquired from Biomarin Pharmaceutical Inc., of Novato, Calif., which means both PCSK9 contenders would end up with a PDUFA date in the summer of 2015, said RBC Capital Markets analyst Michael Yee. "Our call is that Amgen gets standard review, both share an FDA advisory committee meeting, and the FDA approves both around the same time, without cardiovascular outcomes and because they are safe (do no harm)," he wrote in a research report. (See BioWorld Today, Nov. 6, 2012, and Aug. 1, 2014.)

During a second quarter earnings call with investors, Marianne Andreach, vice president of strategic marketing and product planning for Esperion, said the firm is watching for data from Whitehouse Station, N.J.-based Merck's IMPROVE-IT study, due at the American Heart Association meeting in Chicago in mid-November, along with Regeneron/Sanofi data with its PCSK9 drug in patients with statin intolerance. "We look at those studies with, as you would suspect, a high degree of interest," she said. IMPROVE-IT compared the effect on cardiovascular (CV) outcomes of the statin simvastatin with Vytorin (simvastatin/ezetimibe, Merck & Co. Inc.) in more than 18,000 patients with acute coronary syndromes.

Because the FDA also is requiring that CV outcomes trials be started for PCSK9 inhibitors before approval – and demanding that 20 percent to 25 percent of events in those studies be gathered before such drugs can reach the U.S. market – some observers have worried that a similar requirement will be levied on Esperion with ETC-1002. Mayleben thinks not. The FDA, he said, has been very public about guidance changes, and the agency has not revised its belief that lower LDL-C is a marker for CV benefit.

"We like to remind everybody that 15 LDL-C-lowering drugs have been approved over the last 27 years," he said. "In not one case has the FDA required those drugs to start or complete a CV outcomes trial prior to approval." PCSK9s, he pointed out, are brand new, large-molecule biologics "that have never been tested before," and with chronic therapy with antibodies, "one of the things we all are concerned about is long-term safety." If oral ETC-1002 prices like other small molecules, it should have an edge in the space, given the efficacy and safety profile so far.

Another potential complication for Esperion, detailed in SEC paperwork, could be the FDA's finding in 2009 that ETC-1002 may agonize the peroxisome proliferator activated receptor (PPAR). Data "appear to demonstrate the absence of PPAR-mediated pharmacology (triglyceride decreases, adiponectin increases, mild alanine transaminase increases) or toxicity (weight gain, edema, creatinine kinase/creatinine increases) in humans," Esperion said in a filing. "This is supportive of the conclusion that the weak PPAR alpha/gamma activities observed in animal models preclinically are not observed with therapeutic doses of ETC-1002 in humans," though such effects "will continue to be monitored."

The FDA "requires us to conduct two-year rat and mouse carcinogenicity studies before initiating phase III clinical trials of longer than six months," Esperion said. Those studies were due to finish in April and May of this year, with draft reports due about six months later. Mayleben said the company is on track to submit the results of the carcinogenicity studies to the FDA in December.

Another phase IIb study is ongoing. Called ETC-1002-009, the experiment is designed to test the potential of ETC-1002 to provide incremental LDL-C lowering for patients already taking a statin and who are not at their LDL-C goals. The randomized, double-blind, parallel-group, multicenter study is evaluating parallel doses of ETC-1002 in about 132 patients with hypercholesterolemia over a 12-week period.