Keryx announces positive final results from Phase 2 clinical study for
KRX-101 (sulodexide gelcaps) for the treatment of diabetic
nephropathy
KRX-101 (200mg) demonstrates statistically significant advantage over Placebo
in patients with protocol defined diabetic microalbuminuria
Data Presented by Dr. Edmund Lewis at the American Society of Nephrology's
Renal Week conference
Keryx to host investor conference call to discuss the Phase 2 study results on
Monday, November 14, 2005, at 8:00 AM EST
New York, NY, November 11, 2005 - Keryx Biopharmaceuticals, Inc. (Nasdaq: KERX)
today announced positive final efficacy results from its Phase 2 study entitled:
"An exploratory, randomized, double-blind, multiple dose study of KRX-101
(sulodexide gelcaps) for the treatment of type 2 diabetic nephropathy patients
with persistent microalbuminuria." In a presentation today at the American
Society of Nephrology's Renal Week conference in Philadelphia, Pennsylvania,
Edmund J. Lewis, MD, head of the Collaborative Study Group and the principal
investigator of the Phase 2 study, presented final data from the study.
Study Result Highlights:
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The following are selected highlights from the Phase 2 study. For a more
detailed explanation of the study design and the results, please refer to the
sections below entitled "Design of the Phase 2 Study" and "Phase 2 Data
Analysis."
Table 1--Primary Endpoint Analysis (Therapeutic Success at 6 months) (200mg vs.
Placebo)
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Number of Patients Placebo 200mg p value
(Placebo/200mg) Fisher's
Exact Test
(2-sided)
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Per Protocol 36/36 11.0% 33.0% P=.045
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Intent to Treat 42/44 14.0% 32.0% P=.074
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Design of the Phase 2 Study
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The Phase 2 study was designed as a pilot for the fully-powered pivotal Phase 3
study, which is currently ongoing.
In this Phase 2 study, two doses of KRX-101 (200 mg and 400 mg) were compared to
placebo in patients with diabetic microalbuminuria on maximal therapy with an
angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker
(ARB). Patients were treated with KRX-101 or placebo for six months and followed
for an additional two months post-treatment. Patients were randomized 1:1:1,
placebo, 200mg and 400mg of KRX-101, respectively.
In this Phase 2 study, the primary endpoint for the study was the percentage of
patients achieving "Therapeutic Success" at six months. This is also the
endpoint in the protocol for the KRX-101 Phase 3 clinical trial now recruiting
patients, and which was agreed to with the FDA under a SPA. A patient is
considered a "Therapeutic Success" if they achieve one of the following outcomes
following 6 months on study:
(1) 50% reduction in albumin to creatinine ratio or "ACR"--ACR is a
standard measurement used to assess the level of kidney disease in
these patients. ACR measures the level of albumin protein in urine,
also referred to as "albuminuria," or
(2) Normalization of ACR with at least a 25% reduction in ACR--in this
study the normal laboratory range for albuminuria was defined as less
than 20mg of albumin to 1g of creatinine.
Phase 2 Data Analysis
- ---------------------
A total of 149 patients were randomized into the study. All patients evaluable
for Therapeutic Success at 6 months (i.e. all patients with a baseline ACR and a
6-month ACR) were included in the Intent to Treat analysis, for a total of 136
patients in the Intent to Treat population. All patients in the Intent to Treat
population that at baseline were within the target eligibility range of
microalbuminuria as defined in the protocol (ACR 20mg/G to 200mg/G) were
included in the Per Protocol analysis, for a total population of 117 patients in
the Per Protocol population.
All of the primary and secondary analyses shown were pre-specified. For the
primary endpoint analysis, statistical nominal p values have been provided for
informational purposes only since this Phase 2 study, as a pilot study, had less
than a 20% power to show statistically significant results for these endpoints.
The data is being presented in two ways. First, the 200mg arm is compared to
placebo because the 200mg is the dose in our Phase 3 and Phase 4 protocols, as
agreed to with the FDA under the SPA. Next, the data is presented as Active
(200mg and 400mg) vs. Placebo; this was the primary endpoint defined by the
Phase 2 protocol. Information on the effects of the 400mg arm alone can be found
in the footnotes to the tables. The dose response relationship of KRX-101
previously demonstrated up to 200mg was not observed from 200mg to 400mg in this
study. .
Table 1--Primary Endpoint Analysis (Therapeutic Success at 6 months) (200mg vs.
Placebo)
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Number of Patients Placebo 200mg p value
(Placebo/200mg) Fisher's
Exact Test
(2-sided)
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Per Protocol 36/36 11.0% 33.0% P=.045
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Intent to Treat 42/44 14.0% 32.0% P=.074
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Table 2--Primary Endpoint Analysis (Therapeutic Success at 6 months) (200mg and
400mg(1) vs. Placebo)
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Number of Patients Placebo Active p value
(Placebo/Active) (200mg and 400mg) Fisher's
Exact Test
(2-sided)
- ----------------------------------------------------------------------------------------------------
Per Protocol 36/81 11% 25% P=.136
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Intent to Treat 42/94 14% 26% P=.180
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1. For the 400mg group alone, the Therapeutic Success was 20% on intent to
treat basis and 18% on a per protocol basis.
Table 3--Secondary Endpoint Analysis at 6 months (Intent to Treat)
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Active
Placebo 200mg (200mg and 400mg(1))
n=42 n=44 n=94
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>50 % reduction in ACR 12.0% 27.0% 22.0%
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Normalization of ACR 9.0% 23.0% 17.0%
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1. For the 400mg group alone, the 50% reduction and normalization were 18% and
10%, respectively.
Table 4--Average Changes of ACR Over Time (Intent to Treat) (1)
- --------------------------------------------------------------------------------
200mg vs. Placebo vs. 200mg vs.
Placebo Baseline Baseline
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Two months -17.00% -4.0% -21.00%
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Four months -25.78% 7.5% -18.28%
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Six months -28.03% 12.57% -15.46%
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Eight months (2 months -28.98% 18.5% -10.48%
off therapy)
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1. The average changes from baseline over time for the 400mg dose group were
3.4%, 3.24%, 5.59% and 12.59%, respectively.
There were no serious adverse events (SAEs) that were deemed by the
investigators to be related, probably related or possibly related to the study
drug. A full analysis of the safety database will be conducted in the coming
months.
Michael S. Weiss, Keryx's Chairman and Chief Executive Officer, said, "We are
very excited by these final efficacy data from our Phase 2 study. We are
extremely pleased that despite the relatively modest size of the study, we
achieved a statistically significant benefit in the 200mg
group over placebo for the protocol defined patients with microalbuminuria and
demonstrated a very strong trend, nearing statistical significance, in the
intent to treat population. These results confirm our belief that KRX-101 is an
active agent in the treatment of diabetic nephropathy and gives us a high degree
of confidence that we will be successful in our Phase 3 and 4 pivotal program.
We are also encouraged by the compelling effects seen across the entire
population in the 200mg dose vs. placebo as demonstrated by the on average
reduction/progression comparison which we believe shows that the clinical
benefit of KRX-101 is not necessarily limited to those patients who achieve a
Therapeutic Success. We are very appreciative of the outstanding support,
guidance and dedication that the CSG has provided to the KRX-101 program."
Dr. Edmund Lewis, Co-Chairman of the Collaborative Study Group, commented,
"These results re-affirm our belief in the activity of sulodexide as an
important and novel treatment approach for patients with diabetic nephropathy.
The level of activity and durability of effect following removal of the drug are
impressive, particularly when one considers the level of renal damage you would
expect in a patient with persistent microalbuminuria despite being on maximal
doses of ACEi or ARBs. If we are able to replicate these results in our broader
Phase 3 and Phase 4 clinical program, we believe it will represent a major step
forward in our fight against diabetic kidney disease and will offer an entirely
new treatment approach to patients who desperately need additional treatments
for this devastating disease. We now look forward to completing the phase 3 and
phase 4 studies as soon as possible."
Dr. Larry Hunsicker, Co-Chairman of the Collaborative Study Group, commented,
"We are very pleased with these Phase 2 study results. The endpoint used in this
study, Therapeutic Success, was designed to create a high threshold and rigorous
test of whether a patient obtained a clinical benefit from therapy. It is
generally recognized that lowering pathological urinary albumin by greater than
50% or normalizing abnormal levels of urinary albumin is associated with a
clinically beneficial outcome for a patient. We believe the results of this
Phase 2 study are medically important and we look forward to confirming these
results in our on-going Phase 3 and Phase 4 clinical trials."
Dr. Julia Lewis, Co-Principal Investigator of the Phase 2 and of the Phase 3 and
4 pivotal program, commented, " I believe that the Phase 2 results further
magnify the potential clinical importance of sulodexide. Achieving a 2-3 fold
increase in the primary endpoint of Therapeutic Success in what is effectively a
second line population is very exciting. As clinicians, we often go through the
frustration of seeing patients progress despite being on high doses of ACE
inhibitors or ARBs, the only available treatments. In patients with early stage
kidney disease, like the ones in this Phase 2 study, the only way to know these
patients are progressing is by following their rising levels of urinary albumin,
as these patients exhibit no other overt symptoms of their disease. Lowering
urinary albumin is the primary goal of intervention, which is supported by
several large randomized clinical trials showing a direct linear correlation
between reduction of urinary albumin and long-term clinical outcomes. I believe
that the ability to lower albuminuria by 50% or normalize patients' albuminuria
in the magnitude demonstrated in this study should translate into a long-term
clinical benefit. I believe the approach of aggressively treating patients with
early kidney disease is the key to preventing or significantly delaying the
onset of end-stage renal disease and dialysis."
Conference Call Information
Keryx will hold a conference call accompanied by a PowerPoint presentation on
Monday, November 14, 2005, at 8:00 AM EST, to discuss the study results. To dial
in, please call 1-800-862-9098 (if calling from the U.S.), or (+1) 785-424-1051
(international). During the call, the speakers will be referring to a PowerPoint
web presentation, which can be accessed during the call on Keryx's website
homepage: www.keryx.com. This web presentation and an audio rebroadcast of the
conference call will also be available on the Keryx homepage for 15 days
following the conference call.
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 THE COLLABORATIVE STUDY GROUP
- -----------------------------------
The Collaborative Study Group (CSG), the largest standing renal clinical trials
group, is comprised of academic and tertiary care physician-researchers
interested in collaborative clinical trials investigating new therapeutic
approaches in the treatment of kidney disease. Since 1979 the CSG has conducted
multiple large-scale clinical trials resulting in over 40 major publications in
peer-reviewed journals. The CSG trial of ACE Inhibition in Type 1 Diabetic
Nephropathy and the recently completed trial of Irbesartan in Type 2 Diabetic
Nephropathy (I.D.N.T.) led to FDA product registration for new indications and
the recommendation of these agents as standard of care by the American Diabetes
Association. The results of each of the CSG's last 3 major clinical trials were
published in the New England Journal of Medicine. The IDNT multi-national trial
in collaboration with Bristol-Myers Squibb and Sanofi-Synthelabo is the largest
trial in renal disease to date, consisting of 1,715 patients from 210
investigative sites worldwide.
ABOUT KRX-101
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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 June 2005, we announced the initiation of our pivotal Phase 3 and Phase 4
clinical program for KRX-101. The Phase 3 portion of the program is a
randomized, double-blind, placebo-controlled study comparing a 200 milligram
daily dose of KRX-101 versus a placebo in patients with persistent
microalbuminuria. The Phase 4 portion of the program is a randomized,
double-blind, placebo-controlled study comparing a 200 milligram daily dose of
KRX-101 versus a placebo in patients with persistent macroalbuminuria. The CSG
conducted the Phase 2 trial and is conducting the pivotal Phase 3 and Phase 4
clinical program of KRX-101 for the treatment of diabetic nephropathy.
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 2 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 (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 2 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. is focused on the acquisition, development and
commercialization of novel pharmaceutical products for the treatment of
life-threatening diseases, including diabetes and cancer. Keryx's lead compound
under development is KRX-101 (sulodexide), a first-in-class, oral heparinoid
compound for the treatment of diabetic nephropathy, a life-threatening kidney
disease caused by diabetes. KRX-101 is in a pivotal Phase 3 and Phase 4 clinical
program under a Special Protocol Assessment with the Food & Drug Administration.
Additionally, Keryx is developing clinical-stage oncology compounds, including
KRX-0401, a novel, first-in-class, oral modulator of Akt, a pathway associated
with tumor survival and growth, and other important signal transduction
pathways. KRX-0401 is currently in Phase 2 clinical development for multiple
tumor types. Keryx also has an active in- licensing and
acquisition program designed to identify and acquire additional drug candidates.
Keryx is headquartered in New York City.
Cautionary Statement
- --------------------
Some of the statements included in this press release and made by our management
on the conference call, particularly those anticipating future financial
performance, clinical and business prospects for KRX-101,and KRX-0401, may be
forward-looking statements that involve a number of risks and uncertainties. For
those statements, we claim the protection of the safe harbor for forward-looking
statements contained in the Private Securities Litigation Reform Act of 1995.
Among the factors that could cause our actual results to differ materially are
the following: our ability to successfully complete the pivotal Phase 3 and
Phase 4 clinical trials for KRX-101; the final results from the KRX-101 pivotal
Phase 3 clinical trial may not track the results of the Phase 2 clinical trial;
we may not be able to meet anticipated development timelines for KRX-101 due to
recruitment, clinical trial results, manufacturing capabilities or other
factors; and other risk factors identified from time to time in our reports
filed with the Securities and Exchange Commissions. Any forward-looking
statements set forth in this press release speak only as of the date of this
press release. We do not intend to update any of these forward-looking
statements to reflect events or circumstances that occur after the date hereof.
This press release and prior releases are available at http://www.keryx.com. The
information in our website is not incorporated by reference into this press
release and is included as an inactive textual reference only.