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Executive Summary

Pfizer's nifedipine GITS (gastrointestinal therapeutic system) has shown "significantly better" reduction of systolic and diastolic blood pressure when compared to Inderal LA in a study of 62 mild-to-moderate hypertensive patients, according to a recent report by a clinical investigator of the controlled release dosage form. Albert Einstein School of Medicine professor William Frishman, MD, told a Nov. 3 securities analysts meeting in New York that his comparative study indicates that nifedipine GITS "was more effective than Inderal LA in this particular experience: 50-60% of the patients normalized or had a good therapeutic response with GITS vs. 25-28% on the beta blocker." Frishman also reported that the controlled release dosage form (developed for Pfizer by Alza) also significantly improves the side effect profile of the calcium channel blocker. "The side effects related to the rapid absorption of [nifedipine in an immediate release formulation] dissipate" with the controlled release system, Frishman maintained. He reported, for example, that reflex tachycardia with nifedipine is "rarely seen" (down from 7% with the immediate release dosage to 1% with the controlled release system). Similarly, palpitations as a side-effect declined from about 8% to 1.5% with the change in formulations. Frishman summarized the results of his clinical work at life sciences conference in New York sponsored by Smith Barney. Frishman contended that his clinical work with nifedipine GITS indicates that "one can take a medication that is essentially short-acting, that has a side effect profile related to its rapid absorption, put it in another formulation, change its absorption, change its side-effect profile and perhaps even change its efficacy." He declared that in his studies the sustained release version of propranolol "was behaving like a beta blocker; nifedipine GITS was not behaving like nifedipine." Alza President Jane Shaw told another session at the Smith Barney meeting that the nifedipine GITS controlled release system was designed specifically to eliminate the reflex tachycardia side effects associated with nifedipine in an immediate release formulation. "At one point" early in development, Shaw said, "we thought with the nifedipine GITS that we would put an overcoat on [it] and have an immediate release fraction." She noted, however, that after pharmacodynamic studies "there turned out to be a real added benefit to not having an immediate release of nifedipine." The comparative study results on nifedipine GITS vs. Inderal LA are noteworthy as an indication of the extent of clinical work on the product. Pfizer filed an NDA for the formulation at the beginning 1987. There are indications that the product may be progressing through the NDA review process expeditiously. The once-a-day formulation of nifedipine is important to Pfizer to counter once-a-day verapamil (Calan-SR and Isoptin-SR) and potential upcoming versions of twice-a-day diltiazem (Cardizem) and once-a-day nitrendipine (Baypress). Alza says that three dosage strengths of nifedipine GITS are being studied: 1.7 mg, 3.4 mg, and 5.1 mg. One sign of the regulatory status of the nifedipine GITS NDA may be the recent meeting between two senior Pfizer execs and FDA Deputy Commission John Norris and a staff aide. Pfizer Pharmaceuticals President William Steere and VP/General Counsel Paul Miller met with the FDA officials on Nov. 3. The topic of their conversation was "electronic NDAs." The nifedipine GITS NDA is one of the first electronic NDAs. While it is not typical for Pfizer top execs to visit FDA on general subjects, a Pfizer spokesman said that the meeting with FDA was on the general topic of electronic NDAs and was not focused on the nifedipine GITS application. The apparent improvement in nifedipine's activity and side effect profile in the Alza dosage form was cited by Shaw as evidence of an increased awareness by the major drug companies that it is important in drug development to study the "pattern" of administration of an active compound. Shaw reported that 25% of the projects that Alza is working on in conjunction with other partners are for new chemical entities. Shaw said that major companies are aware of working on optimum dosage delivery systems prior to marketing a compound as well as trying to "fix up problems when seen in the marketplace." In response to a question the Alza president pointed out the maturing approach to controlled release product development. Shaw was asked if the nifedipine GITS system would experience regulatory problems like the earlier indomethacin OROS dosage (Osmosin). Discussing the Osmosin experience, Shaw maintained that "we hadn't surveyed the appropriate drug program" for indomethacin. Osmosin was a constant release product, she noted, "and it may be for the intestinal barrier to protect itself maybe you need some drug holiday." The nifedipine GITS NDA is one of a series of filings pending at FDA for Alza-developed formulations. The company has apparently had a particularly fruitful year with submissions to FDA. At the beginning of 1987, Alza said it (or its partners) planned to submit NDAs for six human drug products. By Nov. 3, NDAs for at least half of those products had been submitted. Overall, Alza has disclosed pending NDAs for eight products. In addition to the nifedipine GITS, the pending human NDAs include: * a Pfizer NDA for 24-hour prazosin in a GITS formulation (three dosage strengths, 2.5 mg, 5 mg and 10 mg); * a Glaxo NDA for controlled release albuterol (Volmax, approved in Denmark on Aug. 17 and recently launched); * a potassium supplement; * a brompheniramine/pseudoephedrine cough/cold combo; * a controlled release chlorpheniramine; and * a transdermal testosterone (once-a-day, can "oscillate patients through what is very close to a normal circadian rhythm"). Shaw maintained that the Alza oral release system for the cough/cold combo allows for differing release rates for the two components. Each of the ingredients has an immediate release dosage followed by a constant release over approximately 24 hours. She said the product shows the "degree of complexity [which can be built] into a single tablet -- the ability to have an immediate release fraction followed by a constant release fraction and to deliver two drugs at totally different rates simultaneously." Alza-Developed Products Now Generating $350 Mil. Sales Worldwide Worldwide sales of approved Alza delivery system products will reach about $350 mil. in 1987, Shaw told the analysts. She pointed out that consensus outside estimates put the company's earnings for this year in the $15 mil. aftertax range. Two delivery systems nearing the NDA stage are a temporary periodontal implant and a transdermal fentanyl patch. Filings for both systems were described by Shaw as "imminent." The periodontal product is a site-specific release mechanism for antibiotic treatment of gum disease. The product is a polymeric fiber which releases an antibiotic at a controlled rate when in an aqueous environment. "The aqueous environment that this is developed for," Shaw said, "is the pocket that develops around the gum associated with the development of periodontal disease." She said that oral administration of antibiotics for periodontal disease is made difficult by the poor circulation in the gums. "There is real value," she maintained, "to being able to put it in a delivery system that will deliver it locally for a prolonged period of time." With fentanyl, Alza is attempting to take the short-acting drug out of the anesthesia class and move it into the analgesic area for acute and chronic pain by putting it in a controlled release patch dosage form. The company is studying a three-day dosage form for post-operative use and for terminal cancer patients. "Dosage forms like this," Shaw said, "are drastically going to change the whole concept of delivery of narcotic agents." ALZA PRESIDENT SHAW EXPLAINS OSMOSIN EXPERIENCE The following explanation of the Merck experience with Alza's OROS system for indomethacin is taken from a transcription by "The Pink Sheet" of comments by Alza President Jane Shaw at a meeting sponsored by Smith Barney on Nov. 3. Shaw was asked why the adverse reactions experienced by the Osmosin system would not be repeated by nifedipine GITS. Shaw has not had the opportunity to read or edit these remarks from a spontaneous question and answer period. Indomethacin is a non-steroidal anti-inflammatory drug and by virtue of its systemic action can cause ulceration of the gastrointestinal tract as can any NSAID like aspirin. Alza, working with Merck, developed an OROS version of indomethacin which was introduced in the U.K., Sweden and Germany. The yellow card [adverse reaction reporting] system in the U.K. picked up on what they perceived to be a high incidence of adverse reactions which were the normal effects of indomethacin. Unfortunately, with the yellow card system you do not know what the denominator is. You know what the experience was in terms of the yellow cards appearing, but you don't know what the denominator was. . . . Merck chose to withdraw the product while they sorted [the situation] through. They were asked by the DHSS to prove that the incidence of perforations was not greater with this dosage form than with any other dosage form. Since the incidence was 1 in 10,000, that turned out to be a potentially huge clinical study to undertake and they just chose not to undertake it. The adverse reactions which were associated with Osmosin were due to the drug and not to dosage form. They were due to systemic effects of indomethacin. There might have been a number of reasons for that. First of all, we hadn't surveyed what the appropriate drug program should be. So it was constant release of indomethacin. And it may be for the intestinal barrier to protect itself maybe you need some drug holiday through the day. They only had one strength available, 75 mg., which they had moved forward on the basis of showing equivalent area under the curve to 25 mg tid. And it is very likely, therefore, that was an overdose situation, giving people 75 mg of indomethacin. There was no lower dose to give people. And then Merck did a very aggressive launch in the UK and people were found, although it was a once-a-day dosage form, taking it like an immediate release dosage form. It was promoted under the name of Osmosin and people were not told that it was yet another dosage form of indomethacin so they were on both indomethacin and Osmosin.

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