HZT-501
Phase 3 Trials Meet Primary Endpoints
Horizon Therapeutics' lead investigational product candidate, 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.
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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Over 1500 patients across the United States participated in the "REDUCE" trials |
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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
HZT-501 Meets Primary Endpoints in Two Pivotal Trials
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. The studies recently completed in 2008. The trials were conducted via a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA).
The Registration Endoscopic Study to Determine Ulcer Formation of HZT 501 Compared to Ibuprofen: Efficacy and Safety Study (REDUCE 1 and REDUCE 2) were two randomized, double-blind, controlled trials that enrolled more than 1,500 patients in the United States. The primary efficacy objective of REDUCE-1 was to evaluate HZT 501 in reducing the proportion of patients who develop endoscopically diagnosed gastric ulcers during the 24-week treatment period, as compared to ibuprofen, in patients at risk for NSAID-induced ulcers. The primary objective of REDUCE-2 was to evaluate HZT 501 in reducing the proportion of patients who develop endoscopically diagnosed gastric and/or duodenal ulcers during the 24-week treatment period, as compared to ibuprofen, in patients at risk for NSAID-induced ulcers.
Patients, who had mild-to-moderate pain, including those with osteoarthritis, were randomly assigned, in approximately a 2:1 ratio, to receive HZT 501 (800 mg ibuprofen and 26.6 mg famotidine) or ibuprofen (800 mg) alone orally three times daily for a 24- week treatment period or until patients developed either an endoscopically diagnosed upper gastrointestinal ulcer and/or prohibitive toxicity. Patients received endoscopies at baseline and weeks 8, 16 and 24.
In REDUCE-1, 24-week treatment with HZT 501 resulted in a statistically significant reduction in gastric ulcers versus treatment with ibuprofen alone. In REDUCE-2, 24-week treatment with HZT 501 resulted in a statistically significant reduction in gastric and/or duodenal ulcers versus treatment with ibuprofen alone.
Treatment with both HZT-501 and ibuprofen alone were well tolerated in the studies. The majority of adverse events were mild to moderate in severity. There were no significant differences between the two treatment groups' adverse event or serious adverse event profiles.
Horizon Therapeutics plans on submitting HZT 501 Phase 3 results to U.S. and European regulatory authorities in 2009.
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 can be effective. 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.