Pravafen is an oral controlled-release combination of 40 mg pravastatin and 160 mg fenofibrate currently being development for the treatment of mixed dyslipidemia

Combination of 40 mg pravastatin and 160 mg fenofibrate

1.   The Opportunity

Pravafen is poised to be the first fixed-dose statin-fenofibrate combination product on the market Pravafen was identified as one of the five most promising drugs entering into phase III trials by Thomas Pharma Quarterly Review in 2007:  The Ones to Watch

 

Pravafen is an oral controlled-release combination of 40 mg pravastatin and 160 mg fenofibrate currently being development by Sciele Pharma, Inc for the treatment of mixed dyslipidemia.  Mixed dyslipidemia is characterized by high triglycerides (TG), low high-density lipoprotein-cholesterol (HDL-C) and small dense low-density cholesterol (LDL-C) particles.

 Pravastatin, the generic name for Pravachol, is the most studied statin (cholesterol-lowering drug) in clinical trials. Pravastatin is often prescribed for patients requiring a reduction in LDL cholesterol andtriglyceride levels and an increase in the HDL cholesterol (the "good" cholesterol) level. Pravastatin generated $1.5 Billion in sales in 2008 (source NPA). Pravastatin has an excellent safety profile and is perceived by physicians to be the safest statin on the market. Many times, it is the initial statin of choice in patients with mildly elevated LDL. The US statin market was worth $20 Billion in 2008, representing a growth of 17% over 2007.

Fenofibrate is used in combination with a diet low in cholesterol and saturated fat to control elevated LDL and triglyceride levels.  Fenofibrates reduce triglyceride production by the liver and increase the elimination of circulating triglycerides from the blood.  Fenofibrates generated approximately $1.6 billion in sales (source NPA MAT Dec 2008) in 2008.  Prescriptions for the fenofibrate class had a growth rate of 17% in 2008.

Approximately 30% of patients on a fenofibrate are also co-administered a statin in order to manage their elevated LDL levels. Pravafen will offer a fixed dose combination of pravastatin and fenofibrate capable of decreasing LDL and triglyceride levels by a greater amount than either of the two medications prescribed alone.

Pravafen is currently in Phase III trials in the US, with trial completion scheduled for second quarter 2009.  NDA submission is scheduled for third quarter 2009 with anticipated approval and launch in Q3/Q4 2010.  While there are a number of fenofibrate and statin products available as monotherapies, there are currently no combination therapies available.  Therefore, Pravafen is poised to be the first fixed-dose statin/fenofibrate combination product on the market

 

2.   Market Overview:  Mixed Dyslipidemia

More than 100 million American adults have lipid problems, with 35% being treated Less than 30% of these patients at recommended levels for all three key lipids The prevalence of mixed dyslipidemia is currently more than 16 million patients in the U.S.

 

 More than 100 million American adults have lipid problems, and 35 percent reported being treated with lipid-altering medications. Of the patients being treated, fewer than one in three (30 percent) were at recommended levels for all three key lipids. Treatment guidelines endorsed by the National Cholesterol Education Panel, the American College of Cardiology and the American Heart Association have called for more aggressive management of lipids, including a lower LDL goal for many patients, as well as more aggressive management of HDL and triglycerides.

The National Cholesterol Education Panel (NCEP) Adult Treatment Panel III (ATP III) recognizes mixed dyslipidemia (atherogenic dyslipidemia) as the most common dyslipidemia associated with metabolic syndrome and diabetes. ATP III identifies low HDL-C as a major risk factor and elevated TG and small LDL-C particles as the emerging risk factors for cardiovascular disease (CVD).The prevalence of mixed dyslipidemia (characterized by elevated triglycerides and low HDL-cholesterol), is currently more than 16 million patients in the US and is rising in tandem with the ongoing obesity epidemic. 

Patients with mixed dyslipidemia are at high risk for coronary heart disease (CHD) events.  Coronary heart disease (CHD) causes significant morbidity and mortality. It is estimated that the direct and indirect cost of cardiovascular disease in the United States for 2008 will be $448.5 billion. In addition to lifestyle modification, the use of combination therapy in CHD is an acknowledged strategy in optimal management to prevent or delay the morbidity and mortality associated with CHD and its risk factors. Current recommendations for CHD prevention and treatment advise the use of combination drug therapy for high-risk patients, including those with mixed dyslipidemia.

 3.   Advantages of Pravafen

 

As Pravastatin is considered to be one of the "safest" statins, it is the best choice for a combination with a fenofibrate to reduce the risk of rhabdomyolysis Pravafen will reduce the pill burden for patients on multiple medications by providing a statin and a fenofibrate in one convenient capsule

 

It is well known that lipid-lowering drugs can cause rhabdomyolysis, the risk of which is increased by certain interactions with other drugs. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4.  Therefore, their plasma concentrations and risk of myotoxicity are greatly increased by other medications that strongly inhibit CYP3A4.  In addition, weak or moderately potent inhibitors of CYP3A4 must be given very cautiously with simvastatin, lovastatin, and atorvastatin (Neuvonen, PJ et al. 2006. Clin Pharmacol Ther. 80(6):565-81).  A number of medications often taken by patients with dyslipidemia, such as certain anti-hypertensives, niacin, and fenofibrates, are metabolized by CYP3A4 (Neuovenen et al. 2006; Miller, DB et al. 1998 Clin Pharmacokinet. 34(2):155-62.  However, Pravastatin is excreted mainly unchanged and its plasma concentration is not significantly increased by pure CYP3A4 inhibitors (Neuvonen et. al).  Therefore, there is less risk of interaction between fenofibrates and pravastatin with regard to CYP 3A4.  This is part of the reason why Pravastatin is considered by many to be one of the safest statins.

 Patients with mixed dyslipidemia often have co-morbid disorders including hypertension, atherosclerosis, diabetes, etc.  These patients need to take multiple medications daily.   Another benefit of Pravafen is that it will help lower the pill burden for these patients as they will receive two medications in one convenient capsule.  

 4.   Clinical & Regulatory Status

•  A pivotal Phase III clinical trial evaluating the safety and efficacy of daily administration of Pravastatin 40 mg versus Pravafen in the treatment of mixed dyslipidemia has been completed in Europe. 
• A fully enrolled, second Phase III trial is currently ongoing in the United States evaluating daily administration of Pravastatin 40 mg or Fenofibrate 160 mg or Pravafen in the treatment of mixed dyslipidemia.  This multi-center, double blind, prospective, longitudinal, randomized, 12-week study with a 52-week open-label follow-up to evaluate the safety and efficacy will be completed Q2/2009.
• NDA submission is scheduled for third quarter 2009 with anticipated approval and launch in Q3/Q4 2010. 

Phase III

 

Sciele believes the product will be eligible for 3 years of Hatch-Waxman market exclusivity based on meeting the requirements for such exclusivity.

 There is one issued and two pending patent applications protecting Pravafen in the U.S.:

 US Patent No. 5,545,628 expires January 10, 2015.  The claims cover the Pravafen composition; a method of use thereof, for the treatment of hyperlipidemia and/or hypercholesterolemia, and methods for making Pravafen.

 U.S. Patent Application No. USSN 10/486,219 will expire on August 7,2021when issued.  The claims cover the Pravafen composition and a method of use thereof, for the treatment of hyperlipidemia and/or hypercholesterolemia. 

 U.S. Patent Application No. 11/347822 will expire August 6, 2023 when issued.  The claims cover Pravafen and methods of using the compositions for the treatment of hyperlipidemia and/or hypercholesterolemia. 

Sciele is identifying selected potential partners to license Pravafen in the US.  Preferably, the partner will have experience in promoting cardiovascular or cholesterol lowering medications.

 The preferred transaction would include appropriate upfront, milestone, and royalty payments.  Sciele will provide finished product ready for labeling at a price to be determined.

 Since we are confident in the regulatory timeline for Pravafen, we would like to adhere to an expeditious transaction timeline.  Therefore, we are requesting the following timeline be adhered to by interested partners:

• A non-binding offer based on a confidential information package and Sciele presentation by July 1, 2009
• Selected potential partners will be invited for due diligence until August 15, 2009
• Target completion date for a transaction is September 30, 2009.