Pfizer will receive Phase III data on the anti-atherosclerotic agent avasimibe during 2001, Worldwide Development President Peter Corr told a Pfizer securities analysts meeting Dec. 11 in New York City.

The selective ACAT inhibitor has the "potential to be the first direct-acting antiatherosclerotic agent" to reach the market, Corr said. Avasimibe is being studied in two Phase III trials to prevent progression of atherosclerosis, and "perhaps" to induce plaque regression, he added.

The studies are using intravascular ultrasound to test plaque volumes, positron emission tomography to measure blood flow and exercise tolerance as a clinical endpoint.

The company expects initial Phase III results by mid-2001, with additional data later in the year.

Avasimibe appears to be Pfizer's nearest-term pipeline project to build on its leading presence in the cholesterol market with the HMG-CoA reductase inhibitor Lipitor (atorvastatin). The effect of avasimibe is "additive" to Lipitor, Corr noted.

The company is also developing a fixed-dose combination of Lipitor with the antihypertensive Norvasc (amlodipine), and is developing a CETP inhibitor (CP-529,414) as a potential HDL-elevating therapy.

CP-529,414 raises HDL levels by up to 70%, Pfizer maintained. The drug is currently in 8-week Phase II studies, and Pfizer is considering a fixed-dose combination with Lipitor.

Merck's near-term plans to build on its HMG-CoA reductase franchise Zocor also involve combination therapy. Merck has formed a joint venture with Schering-Plough to develop the cholesterol absorption inhibitor ezetimibe as a single agent and in combination form with Zocor (¹ Also see "Merck/Schering Ezetimibe Deal Is Part Of Growing Ties Between Firms" - Pink Sheet, 29 May, 2000.).

In ongoing Phase III studies, ezetimibe 10 mg has been found to lower LDL cholesterol levels by an additional 18% when used in combination with any statin, including Zocor, Merck Research Labs President Edward Scolnick told analysts during Merck's Dec. 12 business review in Whitehouse Station, N.J. Total cholesterol is lowered by 12%-13%, he said.

A combination of 10 mg each of ezetimibe and Zocor results in a 47% reduction in LDL, compared to 37% with Pfizer's Lipitor at 10 mg, Scolnick maintained. Ezetimibe 10 mg/Zocor 20 mg yields a 54% LDL reduction. Ezetimibe with a 40 mg Zocor dose results in a 59% LDL reduction, and an 80 mg Zocor starting dose would result in a 65% reduction, Scolnick said.

Scolnick suggested that physicians may prefer to add ezetimibe to low-dose statin therapy rather than go through the three dose titrations that would be necessary to achieve comparable LDL reduction levels with statin monotherapy.

"When you get to the highest doses of monotherapy in statins, you run into problems because their mechanism-based side effects are the liver and muscle," Scolnick said. "There's no way to overcome that with any statin that exists today."

"If you add ezetimibe to 40 mg or 80 mg of Zocor, you'll get to LDL [levels] that are better than any statin that exists, safely," he declared. With the ezetimibe/Zocor combo, "you don't have to block synthesis of all the metabolites in the liver," but only "block absorption of one of the metabolites that controls the LDL receptor."

As a result, "you get additive effects of cholesterol lowering without blocking the rest of the pathway. In our opinion, that's going to be the way to do it most safely and with most efficacy," Scolnick maintained.

The deal's exclusivity arrangement means that while ezetimibe could be prescribed in combination with any statin, Merck will hold rights to the only ezetimibe/statin single-pill combination therapy.

"Whilst you will be able to use ezetimibe concomitantly with Lipitor when it's available as a monotherapy," Merck Human Health-Americas President David Anstice said, Pfizer cannot "put Lipitor and ezetimibe into a fixed-dose combination."

During the Dec. 11 meeting, Pfizer professed to be unconcerned by the potential Zocor/ezetimibe combination.

"We don't think a combination of Zocor and ezetimibe is a particularly threatening combination," Pfizer President Henry McKinnell declared. "What this does is it attempts to match in a combination product what Lipitor already delivers," he maintained.

For its part, Merck was asked whether Pfizer's CEPT inhibitor could allow the company to "turn the tables" on Merck again in the cholesterol market.

"We have other compounds with varying mechanisms trying to improve HDL elevations," Scolnick said. "We have enough going on in research and in the clinic already that I don't think we'll be caught flat-footed."

Scolnick suggested that Zocor already has an advantage over Lipitor in terms of HDL levels. "As you go up in dose with Lipitor, the clinical data show that the HDL levels go down, whereas in Zocor they rise," he maintained.

Pfizer maintains that no published data "have demonstrated any statin's ability to significantly elevate HDL cholesterol."

Both Pfizer and Merck are preparing for the launch of AstraZeneca's statin Crestor (formerly ZD-4522), which the company has touted during development as a "super-statin" (² Also see "AstraZeneca Anticoagulant NDA Delayed; Crestor v. Lipitor Data In March" - Pink Sheet, 18 December, 2000.).

Pfizer U.S. Pharmaceuticals President Karen Katen pointed to the wealth of outcomes data released and pending for Lipitor, noting that there are currently 180 trials ongoing in over 100,000 patients. "This is what makes a super-statin, as opposed to a superfluous statin," Katen commented.

"Lipitor will continue to lead this market," McKinnell declared. "Lipitor achieves the desired lipid-lowering effect right across its dosage range," he said. "It has a clinical trial program really second to none," pointing to " that array of trials that will be reading out around the time of new product launches."

Merck is also continuing to roll out long-term studies of Zocor, and the company is boosting its U.S. sales presence by hiring 30% more reps.

Merck highlighted the four-year SEARCH study in 12,000 post myocardial infarction patients comparing Zocor 80 mg versus 20 mg.

While many studies have demonstrated the benefit of lowering LDL levels, the SEARCH effort is the first that "actually quantifies the increased benefit of lowering LDL and raising HDL," Scolnick maintained. Initial results are expected to be released next year.

"If the SEARCH study actually demonstrates that more LDL lowering has real benefit on clinical outcomes and that leads to even lower guidelines for getting LDL down, Zocor/ezetimibe as a combination will be a unique treatment paradigm and will dominate the field," Scolnick maintained.

Educating physicians on the outcome of the SEARCH results would be expected to be an essential part of Merck's future marketing program for Zocor.

To boost its overall physician-directed efforts, Merck is adding 1,500 sales representatives to its 5,000-rep U.S. base over the next 18 months. "With this expansion, Merck will have more than doubled the U.S. sales force over a six-year period," Chief Financial Officer Judy Lewent said.

The domestic sales force expansion is Merck's most substantial increase in the past few years. While the company announced additions for 1998 and 1999, no new sales members were added in 2000. Pfizer has the largest sales force in the industry, with over 8,000 U.S. reps.

In addition to boosting the support for Merck's in-line products, the new sales reps will help support Merck's projected 2001 product launches, including the hospital drugs Invanz (ertapenem, MK-826) and Cancidas (caspofungin), Lewent said.

Merck submitted an NDA for the injectable antibiotic Invanz in November for once-daily intravenous or intramuscular dosing. Indications include complicated intra-abdominal infection, community-acquired pneumonia, complicated urinary tract infection and acute pelvic infection.

The second Merck drug slated for 2001 introduction, the cidal antifungal therapy Cancidas, has a 41%-43% success rate in aspergillosis patients who either failed or were intolerant to prior therapy, Merck said. Cancidas has also demonstrated efficacy against esophageal Candida infection, Merck said.

The Cancidas NDA was submitted in July and an FDA advisory committee meeting is planned for Jan. 10. Merck is also continuing studies for systemic Candida infection and empiric therapy in patients suspected to have fungal infection.

Pfizer ACAT Inhibitor Phase III Underway; Zocor, Lipitor Prepare For Crestor

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