Data from Phase 2a study released May 16, 2008
Investor Presentation: PS433540 Phase 2a Study Results (PDF File)
Need: Presently, an estimated 30 million American adults are diagnosed with hypertension across a broad range of medical conditions, with approximately 10 million of those individuals not achieving the desired blood pressure despite receiving multiple medications.
Potential: The worldwide hypertension market is estimated at nearly $25 billion and expected to surpass $30 billion by 2010. In addition, there are significant markets for conditions related to hypertension, including diabetic nephropathy and heart failure. Diabetes is the most common cause of end-stage renal disease. In the U.S. alone, the CDC estimates that there are 21 million diabetics and projects that number to increase to more than 30 million by 2030. Approximately 20 - 40 percent of diabetes patients are expected to develop diabetic nephropathy.
Therapeutic Targets: Angiotensin II (AII) and endothelin 1 (ET1) are two of the most potent endogenous vasoactive peptides currently known and are believed to play a role in controlling both vascular tone and pathological tissue remodeling associated with a variety of diseases including hypertension, diabetic nephropathy and heart failure. Currently, angiotensin receptor blockers (ARBs), which block the activity of AII, are widely used as a treatment for hypertension, diabetic nephropathy and heart failure. In addition, there is a growing body of data that demonstrates the potential therapeutic benefits of ET receptor antagonists (ERAs) in blocking ET1 activity.
It is also known that AII and ET1 work together in blood pressure control and pathological tissue remodeling. For example, ARBs not only block the action of AII at its receptor, but also limit the production of ET1. Similarly, ERAs block ET1 activity and inhibit the production of AII. Consequently, simultaneously blocking AII and ET1 activities may offer better efficacy than blocking either substance alone.
In well-validated rat models of human hypertension, the combination of an ARB and an ERA results in a synergistic effect. Furthermore, although ARBs are the standard of care for patients with diabetic nephropathy, improved efficacy with the co-administration of an ERA has been reported by a third party in Phase 2 clinical development.
Program Status: Pharmacopeia's lead internal development candidate (PS433540), which was licensed from Bristol-Myers Squibb, appears to block the activity of both AII and ET1 at the AT1 and ETA receptors, respectively. It is the first and only example of a single compound with dual-acting angiotensin and endothelin receptor antagonist (DARA) activity in development. Pharmacopeia views PS433540 as a first-in-class product candidate, which may represent a significant advancement in the treatment of cardiovascular disease. A number of preclinical studies using PS433540 have resulted in positive outcomes in multiple disease models and a positive preclinical pharmacokinetic and safety profile.
The company has announced positive results from multiple Phase 1 clinical studies for PS433540. Results from a single ascending dose study indicated that the compound was well tolerated at all six doses administered ranging from 20 mg to 1,000 mg and that the compound has a half-life that is consistent with once daily administration. In the multiple ascending dose study, five dose levels from 50 mg to 1,000 mg have not produced safety or tolerability issues. In an AII challenge study, PS433540 demonstrated its ability to block the increase in blood pressure induced by administration of angiotensin II (AII) to healthy volunteers. Numerous similar studies with other agents that block the renin-angiotensin system support that the result is a strong indication that PS433540 can be expected to lower blood pressure in hypertensive patients.
Pharmacopeia has initiated a Phase 2a concept validation study to evaluate the safety and efficacy in subjects with Stage 1 and Stage 2 hypertension. We expect to report results from this study in the first half of 2008.
To access an overview prepared by ClinicalTrials.gov of the ongoing Phase 2 DARA clinical trials in hypertension, please click the following link:
Phase 2ahttp://www.clinicaltrials.gov/ct/show/ NCT00522925?order=1 Phase 2b
http://www.clinicaltrials.gov/ct2/show/NCT00635232?term=PS433540&rank=1
You will be redirected to a page on http://www.clinicaltrials.gov that features key information on the trial. Please note that all information found at www.clinicaltrials.gov is provided by ClinicalTrials.gov.
