AstraZeneca plans to submit an NDA for the oral direct thrombin inhibitor H376/95 in the second half of 2002.

A submission for the prevention of venous thromboembolism in orthopedic surgery was originally planned for 2001. Phase III trials of H376/95 administered post-operatively did not achieve statistical superiority over enoxaparin or warfarin, Global Product Director Ian Watts, PhD, told analysts during an R&D briefing Dec. 12 in Molndal, Sweden.

Study 236, which compared H376 vs. warfarin administered post-operatively, showed a 25% greater reduction in venous thromboembolism. Watts characterized the study as "a near miss."

An analysis of the effect of treatment time on treatment effect suggests "the earlier the start of thrombin inhibitor treatment, the greater the antithrombotic efficacy."

Current U.S. practice is to treat post-operatively, while the European standard is to treat pre-operatively, Watts explained. Following a Phase II trial with pre-operative treatment, AstraZeneca decided on post-operative treatment for the Phase III program.

"We will get on and design new studies for Phase III and we will deliver the orthopedic indication," VP-Cardiovascular Therapy Area Hamish Cameron, MD, declared.

"We have not given up on superiority," particularly in comparison to warfarin, Watts added. Superiority over low molecular weight heparin "is probably not necessary given that we are comparing [an] oral against a subcutaneous product. The convenience factor speaks for itself."

The setback in filing for a prophylaxis orthopedic indication does not affect plans for chronic indications, Cameron said. "The real value of the product is that chronic oral indication. That is on track."

The submission for prevention of stroke in atrial fibrillation is expected in the second quarter of 2003.

Despite the delay in initial commercialization, CEO Tom McKillop, PhD, said "our megabrand aspirations for this product are undiminished."

A filing for AstraZeneca's HMG-CoA reductase inhibitor Crestor (formerly ZD-4522) is planned for the second quarter of 2001.

Phase III studies of Crestor compared the drug to Merck's Zocor and Bristol Myers-Squibb's Pravachol. Crestor 5 mg and 10 mg lowered LDL-C levels by 42% and 49% respectively. Zocor (simvastatin) 20 mg lowered LDL-C by 37% and Pravachol (pravastatin) 20 mg by 28%, AstraZeneca said.

Eighty-seven percent of patients on Crestor 10 mg achieved U.S. target reduction levels while 71% of patients on Crestor 5 mg achieved the LDL-C goal. LDL-C target reduction was met by 64% of patients in the simvastatin arm and 53% of patients on the pravastatin arm.

Data from comparative trials against Pfizer's Lipitor (atorvastatin) will be presented at the American College of Cardiology in March.

"We will make a very strong argument to keep away from any class labeling," Cameron stressed. FDA agreed up-front to a pooled analysis of each comparator, Cameron added.

Both Merck and Pfizer are preparing to respond to the introduction of Crestor (¹ Also see "Pfizer ACAT Inhibitor Phase III Underway; Zocor, Lipitor Prepare For Crestor" - Pink Sheet, 18 December, 2000.).

Cameron suggested that Merck's development of a combination of Zocor with Schering-Plough's cholesterol absorption inhibitor ezetimibe is "a patent defense strategy" for Zocor more than a market improvement.

AstraZeneca has received a number of co-promotion offers for Crestor, McKillop said. "Pretty well the whole world would like a piece of Crestor. Maybe not Pfizer," McKillop said. "We are open-minded, but I assure you, we have a very strong base from our own resources."

AstraZeneca is building its field sales force in anticipation of the launches of Crestor and the proton pump inhibitor Nexium. The company maintains that it will have the third-largest U.S. sales force, behind only Pfizer and the combined GlaxoSmithKline.

According to data presented by Pfizer during a Dec. 11 analysts briefing, AstraZeneca has about 4,126 reps, trailing J&J (4,538), Merck (5,244), Bristol (5,566), GlaxoSmithKline (6,663) and Pfizer (8,241). Merck announced Dec. 12 that it plans to add 1,500 new sales reps.

The sales force will adequately cover both the cardiovascular and gastrointestinal launches, McKillop said. "We have the flexibility to deploy those units of primary care sales forces in whatever mix we choose to go with, but it does not mean we have sales people only trained for cardiovascular" or GI. "A very good, primary care rep, well-trained, can easily move from one to the other," McKillop maintained.

AstraZeneca has benchmarked "very carefully" for both Crestor and Nexium launches. Most major pharmaceutical companies spend between $750 mil. and $1 bil. in the U.S. in the year before and the year after launch in a competitive, crowded market, AstraZeneca said.

Because the company already has a majority voice in the PPI market with Prilosec, AstraZeneca may not have to spend as much on Nexium, the company suggested. U.S. launch of the successor product Nexium is anticipated for early 2001 following an Oct. 3 "approvable" letter from FDA.

U.S. labeling will contain an intermittent dosing schedule, VP-GI Franchise Martin Nicklasson, PhD, said. The NDA submission contained an indication for "on demand" maintenance treatment of gastroesophageal reflux disease.

Nicklasson presented 10-week data following launch in the U.K. showing Nexium, which has about 240,000 total scripts. Nicklasson compared this with other U.K. launches such as Merck's Vioxx, with about 260,000 scripts, and Pfizer's Viagra and Glaxo's Seretide, each with about 110,000 scripts.

Nexium reduces overall medical costs by 14% by decreasing physician visits and endoscopies compared to Prilosec, Nicklasson maintained. He added that "on-demand" treatment with Nexium 20 mg as opposed to intermittent courses of Prilosec 20 mg reduced direct medical costs by 57%.

While AstraZeneca continues to defend Prilosec's patent, the company will immediately shift its focus to the successor product. Merck - which manufactures Prilosec for AstraZeneca - told analysts that its projections assume generic omeprazole will enter the market by the end of 2001.

AstraZeneca's post-Nexium GI generation includes a reversible acid pump inhibitor drug in Phase II. Using a medium dose, intragastric pH went from 1.8 to six in one hour following dosing. The pH remained above four in nine out of 24 hours. "We may have a drug that we can tailor-make to different conditions in acid-related diseases," Nicklasson suggested.

McKillop questioned the recent moves by several companies towards a more decentralized R&D structure.

The combined GlaxoSmithKline, for example, intends to reorganize its research and development program following the merger into centers of discovery organized by therapeutic area.

Novartis created specialty therapeutic units earlier this year that combine research and development as well as marketing (² Also see "Novartis Rx Exec Changes Include U.S. COO Epstein To Oncology Unit Head" - Pink Sheet, 17 July, 2000.).

"The notion that we should break those up into separate units and make them compete against each other is marred," McKillop declared.

"That was the model we had in the old Astra, productive but extremely costly," R&D Exec Director Claes Wilhelmsson, MD/PhD, said.

"I can't understand, honestly, why some companies are going back to the old Astra expensive model."

Wilhelmsson reported that ME609 in Phase III for topical herpes has been returned to Medivir. In the cardiovascular arena, research on the NPY antagonist H409/22 in Phase II has been discontinued.

Issues over the respiratory device used in the combination budesonide/formoterol product Symbicort have been resolved with FDA, Wilhelmsson said.

However, AstraZeneca is not projecting an NDA filing before 2003; the company must first complete studies on single-agent formoterol (³ Also see "AstraZeneca Symbicort U.S. Filing Awaits Results of Formoterol Trials" - Pink Sheet, 11 September, 2000.). Symbicort is the "lynch pin" for growth of the respiratory franchise, McKillop said.

A nearer-term filing is expected for the dual D2-dopamine receptor and beta-2 adrenoreceptor antagonist Viozan. AstraZeneca plans to file an NDA in the fourth quarter of 2001 for treatment of "the key symptoms" of chronic obstructive pulmonary disease.

AstraZeneca Anticoagulant NDA Delayed; Crestor v. Lipitor Data In March

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