Keryx Biopharmaceuticals, Inc. Initiates Pivotal Phase 3 and Phase 4 Clinical Program of KRX-101 for Treatment of Diabetic Nephropathy
Wednesday, June 29, 2005 08:15 ET
NEW YORK, June 29, 2005 /PRNewswire-FirstCall via COMTEX/ --Keryx Biopharmaceuticals, Inc. (Nasdaq: KERX) announced today the initiation of its pivotal Phase 3 and Phase 4 clinical program with KRX-101 (oral sulodexide gelcap), the Company's lead drug candidate, for the treatment of diabetic nephropathy. This program is being conducted under the Subpart-H guidelines for accelerated approval pursuant to a Special Protocol Assessment (SPA) with the Food and Drug Administration (FDA).
The Phase 3 portion of the program is a randomized, double-blind, placebo- controlled study comparing 200 mg daily of KRX-101 versus placebo, with a 1:1 randomization between the two arms, in patients with persistent microalbuminuria. The Phase 3 study is designed to enroll approximately 1,000 patients and it is expected that it will take approximately 12-18 months to recruit for this study. The Phase 4 portion of the program, which is also being initiated today, is a randomized, double-blind, placebo-controlled study, also comparing 200 mg daily of KRX-101 versus placebo, with a 1:1 randomization between the two arms, in patients with persistent macroalbuminuria or overt nephropathy. The Phase 4 study is designed to enroll approximately 2,200 patients and it is expected that it will take approximately 24 months to recruit for this study. See the "About the Phase 3 and Phase 4 Clinical Trials" section below for more information.
The KRX-101 pivotal program is being conducted by The Collaborative Study Group (CSG), the world's largest standing renal clinical trial group, whose execution of the angiotensin-converting enzyme (ACE) inhibition trial of captopril in Type 1 diabetic nephropathy and the angiotensin II receptor blocker (ARB) trial of irbesartan in Type 2 diabetic nephropathy (I.D.N.T. study) both led to FDA approval and the recommendation of these agents as standards of care by the American Diabetes Association.
The lead investigator for these studies is Dr. Edmund J. Lewis, Director of Nephrology at the Rush-Presbyterian-St. Luke's Medical Center in Chicago and Co-Chairman of the CSG. In North America, the principal-investigators are Dr. Larry Hunsicker, Professor of Medicine at the University of Iowa College of Medicine and Co-Chairman of the CSG, and Dr. Julia Lewis, Professor of Medicine at Vanderbilt University and a leading member of the CSG.
In Europe, the principal investigators are Dr. Dick de Zeeuw, Professor and Head of the Department of Clinical Pharmacology at the University Medical Center in Groningen, the Netherlands, and Dr. Itamar Raz, Professor of Medicine and Head of the Diabetes Center at the Hadassah Hebrew University Hospital in Jerusalem, Israel. Dr. de Zeeuw served as one of the lead investigators in the pivotal Phase 3 study for losartan, an ARB, in Type 2 diabetic nephropathy (R.E.N.A.A.L study), which led to FDA approval of losartan. Dr. Raz played a major role as co-principal investigator in the I.D.N.T. study. Captopril, irbesartan and losartan are the only three drugs approved for the treatment of diabetic nephropathy.
The Asian-Pacific principal investigator is Dr. Robert Atkins, Professor of Medicine, Director of Nephrology at Monash University, in Melbourne, Australia. Dr. Atkins also played a major role, as co-principal investigator, in the I.D.N.T. study.
Participating in the KRX-101 studies are over 250 U.S., European and Asian-Pacific clinical centers.
Michael S. Weiss, Chairman and CEO of Keryx, commented, "We are very excited to be initiating this pivotal program and are enthusiastic about the strong support for these trials from many of the top clinical investigative sites from around the world." Mr. Weiss continued, "If the results of the Phase 3 trial mirror those of the interim Phase 2 data reported at the NKF Spring Clinical Meetings, we should have a highly statistically significant result and, assuming recruitment rates are in-line with our expectations, we could be launching KRX-101 in late 2007."
Dr. Edmund J. Lewis stated, "We are very encouraged by the recent interim data from the KRX-101 Phase 2 study, which give us a high level of confidence that we will be successful in improving the care for those patients that have persistent proteinuria despite treatment with maximum approved doses of ACEi or ARBs. We are very excited to be leading this pivotal program along with our colleagues worldwide, which will hopefully lead to the approval of this drug for the treatment of this devastating disease."
ABOUT THE PHASE 3 AND PHASE 4 CLINICAL TRIALS
The Phase 3 portion of the program, entitled "The effect of sulodexide in patients with type 2 diabetes and microalbuminuria," is a randomized, double- blind, placebo-controlled study, comparing 200 mg daily of KRX-101 versus placebo, with a 1:1 randomization between the two arms. The objective of this study is to determine the safety and efficacy of sulodexide in the treatment of patients with type 2 diabetes and persistent microalbuminuria, despite being treated with a maximum approved or tolerated dose of an angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme (ACE) inhibitor. The study is designed for patients to be on treatment for six months, followed by two months of evaluation off-treatment. During the treatment and off- treatment evaluation period, all patients in the study population are expected to continue to receive maximum approved or tolerated doses of ACEs or ARBs. Patients who are not already on maximum approved or tolerated doses of ACEs or ARBs for 120 days are required to go into a 120 day run-in period prior to randomization. This run-in period is designed to stabilize blood pressure and to confirm persistent microalbuminuria while the patients are treated with maximum approved or tolerated doses of ACEs or ARBs. The primary endpoint for the study is "therapeutic success" at 6 months, where therapeutic success is defined as (i) conversion from microalbuminuria to normoalbuminuria as measured by albumin/creatinine ratio (ACR) with at least a 25% reduction in ACR relative to baseline ACR, or (ii) a 50% reduction in ACR relative to baseline ACR. This primary endpoint is the same as the primary endpoint being evaluated in the on-going Phase 2 study.
The Phase 4 portion of the program, entitled "The effect of sulodexide in overt type 2 diabetic nephropathy," is a randomized, double-blind, placebo- controlled study, comparing 200 mg daily of KRX-101 and placebo, with a 1:1 randomization between the two arms, in patients with persistent macroalbuminuria or overt nephropathy. The objective of this study is to determine the efficacy of sulodexide in reducing the rate of progression of renal disease and adverse clinical sequelae in patients with diabetic nephropathy due to type 2 diabetes, despite being treated with a maximum approved or tolerated dose of an ARB. All patients in the study population are expected to continue to receive maximum approved or tolerated doses of ARBs during the course of the study. The Phase 4 study is expected to be completed post-FDA approval of KRX-101 based on the results of the Phase 3 clinical trial.
ABOUT THE SPA PROCESS AND SUBPART-H GUIDELINES
The SPA process is a procedure by which the FDA provides official evaluation and written guidance on the design and size of proposed protocols that are intended to form the basis for a new drug application (NDA). Subpart-H guidelines allow for the use of surrogate endpoints in pivotal Phase 3 trials to support NDA approval, with confirmatory studies completed post- approval.
ABOUT KRX-101
KRX-101 is a first-in-class, oral heparinoid for the treatment of diabetic nephropathy, a life-threatening kidney disease caused by diabetes. More than 20 studies have been published assessing the safety and efficacy of KRX-101 in diabetic nephropathy and other vascular conditions. A randomized, double- blind, placebo-controlled, Phase 2 study of the use of sulodexide for treatment of diabetic nephropathy was conducted in 223 patients in Europe, and was published in the June 2002 issue of the Journal of the American Society of Nephrology. The results of this Phase 2 study showed a dose-dependent reduction in proteinuria or urinary albumin excretion rates.
In the third quarter of 2003, we announced that the CSG, the world's largest standing renal clinical trial group comprised of academic and tertiary nephrology care centers, would conduct the U.S.-based Phase 2 clinical program for KRX-101 for the treatment of diabetic nephropathy. The CSG has previously conducted multiple large-scale clinical trials resulting in over 40 publications in peer-reviewed journals. In addition, the CSG conducted the pivotal studies for two of the three drugs that are currently approved for treatment of diabetic nephropathy. In the fourth quarter of 2003, Keryx announced the initiation of the Phase 2 study.
In March of 2005, Keryx announced that it had finalized a SPA agreement with the FDA for the Phase 3 and Phase 4 clinical trials of KRX-101. The clinical plan to support an NDA approval for KRX-101 under Subpart H (accelerated approval), as agreed upon with the FDA under an SPA, consists of: (i) a single Phase 3 trial in patients with microalbuminuria based on the surrogate marker of regression of microalbuminuria as the primary endpoint; (ii) supportive data from previously conducted clinical studies; and (iii) substantial recruitment into our Phase 4 confirmatory study that will measure clinical outcomes in patients with overt nephropathy, or macroalbuminuria.
In May of 2005, an interim data analysis, assessing the safety and efficacy of KRX-101, from on-going U.S.-based Phase 2 study was presented at the National Kidney Foundation Spring Clinical Meetings conference. The data presented confirmed the activity of KRX-101 as a potentially effective treatment for diabetic nephropathy in patients who are on maximum approved or tolerated doses of ACEs and ARBs.
Keryx holds an exclusive license to KRX-101 in the territories of North America, Japan, Australia, Israel and certain other markets.
ABOUT DIABETIC NEPHROPATHY
According to the American Diabetes Association, there are an estimated 18 million people with diabetes in the United States, of which 90%-95% are people with Type II diabetes. Approximately 50% of all people with diabetes develop diabetic kidney disease (source: DataMonitor), a condition known as diabetic nephropathy. Diabetes is the most common cause of End Stage Renal Disease, or ESRD, and is accountable for approximately 45% of all new cases of ESRD in the U.S. Despite advances in clinical care, including improvements in glycemic (blood sugar) and blood pressure control, the number of diabetes-related cases of ESRD continues to rise. In particular, the incidence of Type II diabetes- related ESRD is rapidly increasing. Less than 20% of diabetics on dialysis in the U.S. survive for five years, making the mortality of ESRD in this group higher than in most cancers. Principally due to age and concomitant vascular disease factors, renal transplantation is an option for less than 20% of patients with ESRD from diabetes (as compared to patients with ESRD caused by other non-diabetes conditions, of whom 40-50% may benefit from renal transplantation). Thus, despite recent advances, diabetic nephropathy remains a potentially catastrophic illness for which partial, but insufficient treatment is available today.
ABOUT KERYX BIOPHARMACEUTICALS, INC.
Keryx Biopharmaceuticals, Inc. (Nasdaq: KERX) is focused on the acquisition, development and commercialization of novel pharmaceutical products for the treatment of life-threatening diseases, including diabetes and cancer. Keryx lead compound under development is KRX-101 (sulodexide), a novel first-in-class oral heparinoid compound for the treatment of diabetic nephropathy, which is in a Phase 3-4 pivotal clinical program under an SPA with the FDA. Additionally, Keryx is developing clinical- stage oncology compounds, including KRX-0401, a novel, first-in-class, oral modulator of Akt and other important signal transduction pathways, currently in Phase 2 clinical development. Keryx also has an active in-licensing and acquisition program designed to identify and acquire clinical-stage drug candidates. Keryx Biopharmaceuticals is headquartered in New York City.
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