HZT-501
Phase 3 Enrollment Closed: Clinical Data Expected Fall 2008
Horizon Therapeutics' lead product, HZT-501, is a proprietary fixed dose combination product containing the world's most prescribed traditional NSAID, ibuprofen, with a high dose of the most potent H2 antagonist, famotidine. HZT-501 entered Phase 3 clinical trials in March 2007 for reduction of the risk of development of ibuprofen-associated upper gastrointestinal (i.e., gastric and/or duodenal) ulcers. Enrollment is now closed to new patients with clinical results anticipated in the second half of this year.
Ibuprofen has proven anti-inflammatory and analgesic properties, whereas famotidine reduces the stomach acid secretion that can cause gastric and duodenal ulceration. By combining ibuprofen and famotidine into a single product, it is anticipated that ibuprofen's gastrointestinal safety profile will be improved - without altering its ability to reduce pain and inflammation.
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Famotidine was highly effective in lowering the incidence of gastric and duodenal ulcers where high dose (80mg daily) was added to the NSAID |
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It is anticipated that HZT-501 will provide a potential near term solution to a widespread need in the mild to moderate pain market:
- Safe, effective pain relief
- Prevention of severe (ulcer) NSAID induced GI side effects
- Treatment of chronic and acute pain indications
- Ensured patient compliance with an optimal dosing regimen for both ibuprofen and famotidine in a single pill
- Convenience and reduced pill burden
Phase 3 Trials Enrollment Closed: SPA in Place
An end-of-phase 2 meeting with the FDA resulted in acceptance on material design of Phase 3 trials for HZT-501. The Company has initiated Phase 3 clinical trials under Special Protocol Assessment from FDA, with first patient dosed in March of 2007. Enrollment is now closed with clinical results expected in the second half of 2008. Horizon has successfully completed early supportive clinical studies on HZT-501 to:
- Verify and define the effects on gastric pH
- Confirm that no significant drug-drug interactions exist between ibuprofen and famotidine
- Establish the comparative bioavailability of HZT-501 to approved reference drug products
Proof of Concept in Clinical Trials: NEJM Study
In the May 30, 1996 edition of the New England Journal of Medicine, an article, "Famotidine for the Prevention of Gastric and Duodenal Ulcers Caused by Non-steroidal Anti-inflammatory Drugs" was published by Taha, et. al. The study was a randomized, controlled trial including 285 arthritis patients. The primary endpoint was the measurement of the cumulative incidence of endoscopically diagnosed gastric and duodenal ulcers at 4, 12 and 24 weeks in patients treated with an NSAID alone vs. those treated with NSAID plus a total daily dose of either 40mg or 80mg of famotidine.
The cumulative incidence of gastric ulcers was 20% in the NSAID-alone group and 8% in the 40-mg BID famotidine plus NSAID group (p = 0.03). The cumulative incidence of duodenal ulcers was 13% in the NSAID-alone group and 2% in the 40-mg BID famotidine plus NSAID group (p = 0.01). There also were significantly lower rates of gastric and duodenal ulceration combined (28% for the NSAID-alone group vs. 11% for the 40-mg BID famotidine plus NSAID group; p = 0.003).
Overall key conclusions were as follows:
- Famotidine was highly effective in lowering the incidence of gastric and duodenal ulcers where high dose (80mg daily dose) was added to the NSAID.
- There were little to no side effects or adverse events.
- These reductions were significant and were in the range of levels reported later in studies supporting the GI protective effects of the Cox-2 inhibitors.
Cumulative Incidence of Gastric and Duodenal Ulcers at 4, 12 and 24 Weeks in Patients with Arthritis Receiving Long-Term NSAID Therapy
Source: Taha, A. S et. Al. N Engl J Med 1996 ; 334 : 1435-1439
Well Known Trusted Compounds with Long Term Safety History
Both ibuprofen and famotidine have well documented and excellent long-term safety profiles, and both compounds have been demonstrated effective when administered individually. Both products are approved over-the-counter, and have been used for many years by millions of patients worldwide. Single ingredient ibuprofen products do carry warnings regarding the risks of stomach ulcerations and bleeding. The most frequent adverse effects reported with the use of single ingredient famotidine include headache.
Ibuprofen: The World's Most Widely Prescribed NSAID
Ibuprofen continues to be the most widely prescribed NSAIDs worldwide. In the U.S. alone, there were over 26 million prescriptions written for ibuprofen in 2005. Ibuprofen volumes in Europe equal those in the U.S., with volume in Japan approximately 1/3 that of the U.S. In the U.S., both the 600 mg and 800 mg doses together account for approximately 90% of total prescriptions. In addition, ibuprofen's flexible TID (three times a day) dosing allows it to be used extensively for both chronic (arthritis, chronic back) and acute (sprains, strains) conditions.
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In the U.S. alone, there are over 26 million prescriptions |
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Famotidine: Proven Safe and Effective GI Protection
Famotidine was chosen as the ideal GI protectant in combination with ibuprofen. High dose famotidine has been shown in a clinical trial to be effective in reducing the incidence of NSAID induced ulcers. In addition, famotidine is a well studied compound that provides other distinct advantages:
- The most potent of the H2 antagonists
- Excellent long term safety profile - over 20 million patients have been treated worldwide:
- OTC approved
- Demonstrated safety up to 10x the approved Rx dose for up to six months
- Additional data supporting low/no risk of serious adverse events
Benefits of a Fixed Dose Combination Therapy
Numerous studies in other treatment areas have demonstrated that fixed dose combination therapy is more effective and convenient than combination therapy with the same drugs taken separately. A single pill formulation can improve compliance which is often associated with enhanced outcomes. Fixed dose combinations can also reduce the number of pills and ensure the correct dosage of each component is taken at the correct time.
HZT-501 - Convenient and Optimal Dosing Regimen
HZT-501 has been formulated to provide an optimal combined dosing regimen of ibuprofen and famotidine together in the convenience of a single pill. It is anticipated that this innovative new therapy will provide safe and effective pain relief - while reducing the stomach acidity caused by the NSAID during the critical peak time of risk of ulceration.
Note: All NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. The presence of famotidine in HZT-501 will not reduce this risk.
REFERENCES:
Berardi et al. "Comparison of Famotidine, with Cimetidine and Ranitidine" Clin Pharm. 1988; 7(4): 271-284.
Product Labels: Proton Pump Inhibitors and Famotidine
Robinson et al. "Clinical Pharmacology of Proton Pump Inhibitors: What the Practicing Physician Needs to Know" Drugs 2003; 63(24): 2739-2754.