Merck and Schering-Plough are pricing Zetia so that combination use with Zocor 10 mg is attractive compared to high-dose Zocor monotherapy.

Zetia (ezetimibe) will be launched in mid-November at an average wholesale price of $57.90 for a 30-day supply. Zetia 10 mg was approved by FDA Oct. 25 as the first in a class of drugs that inhibits cholesterol absorption in the intestines.

Zetia co-administration with Merck's Zocor (simvastatin) 10 mg will carry an AWP of $133.72 for a 30-day supply, according to Red Book data. By comparison, Zocor 20 mg and 40 mg cost $124.90 as monotherapy.

The Zetia/Zocor 10 mg combination is significantly cheaper than Zocor 80 mg (two 40 mg doses), and labeling includes data showing equal efficacy.

Zetia is indicated for hypercholesterolemia both as monotherapy and in combination with statins. Zetia is also cleared for use with Zocor or Pfizer's Lipitor (atorvastatin) for cholesterol reduction in patients with homozygous familial hypercholesterolemia, and for reduction of elevated sitosterol and campesterol in patients with homozygous familial sitosterolemia.

Merck and Schering expect a large opportunity for Zetia as an add-on therapy for patients not reaching cholesterol reduction goals.

"This is a very large and rapidly growing market, with almost 13 mil. people being treated with statins right now, and by various estimates there could be as many as 6 mil. people on statins who are not at their cholesterol goal," Merck/Schering joint venture General Manager Bob McMahon said Oct. 28.

"That represents a tremendous opportunity in terms of getting those patients to goal, and Zetia represents a breakthrough in terms of the ability to use this product with statins in order to get those patients to goal."

Zetia is expected to be supported by three distinct sales forces upon launch: one contributed by Merck, one from Schering-Plough, and a third sales force under the Merck/Schering joint venture (¹ Also see "Merck/Schering Zetia (Ezetimibe) Will Be Supported By Three Sales Forces" - Pink Sheet, 17 December, 2001., p. 11). The companies formed a joint venture for Zetia in 2000 (see ² [A#00640440004]).

The timing of the approval allows Merck and Schering an opportunity to establish Zetia (and the Zetia/Zocor combination) well ahead of a Crestor launch by AstraZeneca. Crestor has been "approvable" at FDA since May 31; AstraZeneca plans to submit additional data in the first quarter (³ Also see "AstraZeneca Crestor Plan: Drop 80 Mg, Submit Lower-Dose Data In Q1" - Pink Sheet, 12 August, 2002., p. 27).

The Zetia approval comes at an opportune time for both Merck and Schering. Merck, which has been through a "transition year" in 2002, will need Zetia to achieve the double-digit earnings growth expected for 2003 (⁴ Also see "Merck Re-Sets Expectations For 2002: Zocor, Prilosec Are Possible Upsides" - Pink Sheet, 17 December, 2001., p. 9).

Schering is also relying on Zetia as the company prepares for Claritin to go over-the-counter at the end of the year. Schering has described Zetia as offering a greater potential to transform the company than Claritin had when it was launched in the early 1990s (⁵ Also see "Schering-Plough Zetia Could Be More Important Growth Product Than Claritin" - Pink Sheet, 22 July, 2002., p. 13).

While Zetia was studied in combination with other statins, the obvious focus of the joint venture will be on combination use with Zocor. The joint venture is developing a fixed-dose combination of the two drugs. "We are currently in Phase III in that clinical development program, and we are on target for a late 2003 filing," McMahon said.

Zetia's efficacy as an add-on lipid-lowering therapy was studied in four statins in separate 12-week trials in a total of 2,382 patients: Merck's Zocor (simvastatin), Pfizer's Lipitor (atorvastatin), Bristol-Myers Squibb's Pravachol (pravastatin) and lovastatin (Merck's Mevacor and generics).

In pooled data across all doses, Zocor/Zetia co-administration reduced total cholesterol by 37% from untreated baseline, versus 26% for Zocor alone. The combination reduced LDL levels by 51%, compared to 36% for Zocor monotherapy, labeling says.

Zocor/Zetia pooled data lowed triglyceride levels by 29%, compared to 20% with Zocor alone, and improved HDL cholesterol levels by 9%, compared to 7% with Zocor monotherapy.

Labeling illustrates that Zocor 10 mg/Zetia 10 mg is comparable to Zocor 80 mg, with both doses reducing total cholesterol 32% from baseline. Zocor 10 mg/Zetia 10 mg reduced LDL cholesterol 46% compared to a 45% reduction with Zocor 80 mg. HDL cholesterol levels rose 9% on the Zetia/Zocor combo versus 8% with the high-dose Zocor monotherapy.

As add-on therapy to Pfizer's Lipitor, Zetia reduced total cholesterol by 41% across all doses versus 32% with Lipitor alone. Patients on the combination therapy had a 56% reduction in LDL levels versus 44% of Lipitor monotherapy.

The ability to skip two or three titration steps is particularly relevant given the rhabdomyolysis incidence reported at high doses of statins. The adverse event led to the withdrawal of Bayer's Baycol (cerivastatin) in 2001. The side effect concerns are also the principle cause of the delay in approval of Crestor (⁶ Also see "AstraZeneca Crestor Plan: Drop 80 Mg, Submit Lower-Dose Data In Q1" - Pink Sheet, 12 August, 2002., p. 27).

As with the statin class, Zetia labeling includes statements on myopathy and rhabdomyolysis, although no "excess" cases of either adverse event were reported in trials, the precautions section says. The incidence of creatine phosphokinase of more than 10-fold was .2% for Zetia versus .1% for placebo, and .1% for Zetia/statin versus .4% for statin monotherapy.

While the companies are likely to push the efficacy benefit of administering Zetia with a statin, ezetimibe monotherapy appears to have at least one advantage: no need for liver function testing prior to treatment.

When administered alone, the incidence of serum transaminases three times the upper limit of normal in Zetia patients was similar to that of placebo, labeling says: .5% for ezetimibe versus .3% for placebo.

When co-administered with a statin, however, the incidence of serum transaminases 3xULN was 1.3%, compared to .4% for patients on a statin alone. As with statins, liver function tests should be conducted prior to initiation of Zetia/statin therapy, labeling says.

Merck and Schering agreed to conduct a Phase IV safety and efficacy study in non-Caucasian patients. The 12-week study must be submitted by Dec. 25, 2004. The NDA (21-445) was filed Dec. 27, 2001 and approval came on the 10-month user fee goal date.

The joint venture will manufacture Zetia in Singapore (where the companies have incorporated as MSP Singapore Co., LLC) and in Puerto Rico. Schering's Puerto Rico plants are covered by the company's recent good manufacturing practices consent agreement with FDA. However, the consent agreement specifies that pending NDAs are not to be subject to extra scrutiny (⁷ Also see "Schering NDAs Are Clear For Review Under FDA Consent Decree" - Pink Sheet, 27 May, 2002., p. 15).

Schering/Merck Zetia Clears FDA; Price Favors Combo With Low-Dose Zocor

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