Collateral and Berlex Announce Positive Results From Angina Gene Therapy Clinical Trial
Collateral Therapeutics (Nasdaq: CLTX) and Berlex Laboratories, the U.S. affiliate of Schering AG, Germany (NYSE: SHR) today announced that results of a Phase 1/2 clinical trial of Ad5-FGF4 showed that the administration of the product appeared to be safe and well tolerated. Regarding anti-ischemic effects assessed by measuring exercise time (ETT) on a treadmill, the investigators reported positive results for Ad5-FGF4 when patients on active therapy were compared with the patients that received placebo. Ad5-FGF4 is a non-surgical angiogenic gene therapy product candidate being developed for the treatment of patients with stable exertional angina due to coronary artery disease. Study results were announced here today in a late-breaking clinical trials session at the 50th Annual Scientific Session of the American College of Cardiology.
Today’s presentation by Cindy Grines, MD, William Beaumont Hospital, Royal Oak, MI, was based on the Angiogenic GENe Therapy (AGENT) trial, a U.S.-based, randomized, double-blind, placebo-controlled Phase 1/2 study. The study evaluated the safety and anti-ischemic effects of five ascending doses of Ad5-FGF4 in 79 patients with chronic stable exertional angina, and identified potentially safe and effective doses for subsequent study. The AGENT trial is the first report of human data concerning the safety of a single, non-surgical intracoronary administration of a replication-deficient human adenovirus. A full report of the data is being prepared for publication in a peer-reviewed journal.
“The AGENT trial marks the first scientifically well-controlled clinical study of cardiovascular gene therapy,” said Dr. Grines. “A one-time administration during cardiac catheterization has the potential to be an important addition to current treatment options which include bypass surgery, angioplasty and drug therapy for the 6.2 million Americans who suffer from angina.”
AGENT Phase 1/2 Clinical Trial
The AGENT trial, which evaluated the effects of ascending doses of adenoviral-mediated human FGF4 gene transfer in patients with stable exertional angina, had two objectives: (1) to evaluate safety and anti-ischemic effects of ascending doses of adenovirus mediated FGF4 gene transfer in patients with stable exertional angina, and (2) to select potentially safe and effective dose(s) for subsequent study.
The product candidate appeared to be safe and well tolerated in this study. Similar to other adenovirus gene transfer trials, in some cases, an increase in liver enzymes and/or fever were considered product related. Myocardial inflammation was not observed. During long-term follow-up, two patients were subsequently diagnosed with cancer, which was considered not related to therapy. In another apparently unrelated event, one patient died from a cardiac arrest while awaiting CABG surgery for unstable angina approximately five months after the one-time treatment.
The Phase 1/2 clinical trial was a randomized, double-blind, placebo-controlled study. In total, the study enrolled 79 patients with stable exertional angina, chest pain caused by a lack of oxygen in the heart muscle, which is triggered by physical exertion or emotional stress. Patients were enrolled at the following U.S. medical centers: William Beaumont Hospital, University of Vermont College of Medicine, Minnesota Heart Clinic, San Diego VA Medical Center/University of California, San Diego, Johns Hopkins Hospital, Mount Sinai Medical Center — New York City, St. Vincent Hospital — Indianapolis, North Shore University Hospital, Jack D. Weiler Hospital of the Albert Einstein College of Medicine, University of Pittsburgh Medical Center, University of Minnesota Health Center, and Washington Hospital Center.
Since this was a first study in humans, the protocol was designed (for safety reasons) to initially evaluate lower doses than those found to be effective in animal studies. Doses were evaluated in ascending order in one-half log increments. The patients received a single, non-surgical, intracoronary administration of placebo or Ad5-FGF4 based on a double-blind randomization in a ratio of 1:3 (placebo: treatment) at 5 ascending doses advancing sequentially in one-half log steps from 3.2 x 10(8) to 3.2 x 10(10) viral particles (v.p.).
To identify appropriate Ad5-FGF4 doses to carry forward into larger clinical trials, researchers used, in addition to the assessment of safety, a dichotomous qualitative method setting a response level of ETT improvement of 20% at 4 weeks and 30% at 12 weeks after treatment (each about two times placebo). Based on this analysis, in patients treated with an Ad5-FGF4 dose of 10(10) v.p., 50% improved at 4 weeks and 45% improved at 12 weeks compared to improvement in 16% and 21% in the placebo group and 42% and 36% in all patients treated with the active product. In patients receiving Ad5-FGF4 (10(10) v.p.), the mean increase in ETT time was 1.5 min at 4 weeks and 2.0 min at 12 weeks compared to 0.7 min and 1.0 min at 4 and 12 weeks, respectively, in the placebo group. Researchers also observed that patients with a shorter baseline ETT (less than or equal to 10 minutes) had a better response to active treatment than placebo.
Based on the study results, investigators also reported that the AGENT trial had successfully identified two doses, a low dose (10(9) v.p.) and a high dose (10(10) v.p.), to be advanced into a larger Phase 2b/3 clinical trial.
“Much progress has been made over the past five years under Schering’s angiogenic gene therapy research collaboration with Collateral, and we look forward to advancing Ad5-FGF4 into further clinical studies,” noted Dale Stringfellow, Ph.D., President and Chief Executive Officer of Berlex Laboratories Inc. “With the results reported today, this angiogenic gene therapy may hold the potential to become a new therapeutic approach for the treatment of certain forms of heart disease.”
“Our clinical trial has yielded important data upon which we will advance Ad5-FGF4 into a larger-scale Phase 2b/3 clinical trial,” noted Jack W. Reich, Ph.D., Chairman and Chief Executive Officer of Collateral Therapeutics. “With these positive results on the safety and utility of a single intracoronary administration of non-surgical angiogenic gene therapy, we are excited about the planned development of Ad5-FGF4, and plan to develop additional therapeutic approaches in the field of cardiovascular gene therapy and angiogenesis.”
AGENT Phase 2b/3 Clinical Trial Plans
A protocol for a Phase 2b/3 clinical study has been submitted for review to the U.S. Food and Drug Administration (FDA). The study will be structured as a randomized, double-blind, placebo-controlled study to evaluate two dose levels (10(9) v.p. and 10(10) v.p.) of Ad5-FGF4 in patients with stable exertional angina due to coronary artery disease. This study, which will continue evaluating safety in a larger number of patients long-term, will have as its primary efficacy endpoint, prolongation of exercise duration on a treadmill. Additional assessments will include anginal frequency, quality of life, anti-anginal medication usage and long-term coronary events. This study is expected to be initiated in the first half of this year. This study is designed as one component of a series of clinical studies which will be integrated into a product license application, intended to provide regulatory authorities with information to evaluate the safety and efficacy of Ad5-FGF4. It is planned that the Ad5-FGF4 clinical program will be conducted in multiple medical centers in the United States and abroad.
Ad5-FGF4 Product Candidate
Ad5-FGF4 is a non-surgically administered gene therapy designed to stimulate angiogenesis (new blood vessel growth) which may provide alternate routes for blood to flow into oxygen-deprived ischemic areas of the heart due to blocked or narrowed arteries. Envisioned as a procedure that could be administered by interventional cardiologists, Ad5-FGF4 involves a one-time, non-surgical administration of an adenoviral gene therapy vector containing the human Fibroblast Growth Factor-4 (FGF4) angiogenic gene delivered into the coronary arteries through a standard catheter. Ad5-FGF4 is used in this release as a generic term for a product candidate consisting of a human replication-deficient serotype 5 adenovirus in which the E1A/E1B genes are replaced by the human FGF4 gene driven by a CMV promoter.
Coronary Artery Disease
Angina, a symptom of coronary artery disease, is chest pain caused by myocardial ischemia, a condition in which the amount of oxygen the heart muscle requires exceeds the amount available due to coronary artery blockage (atherosclerosis). According to the American Heart Association (AHA), angina affects approximately 6.2 million Americans, with 300,000 new cases diagnosed each year. Coronary artery disease (CAD) affects more than 12 million Americans and is a leading cause of death in the United States. Current treatment options for CAD include drug therapy or invasive procedures that could require hospitalization, including angioplasty and bypass surgery. According to the AHA, approximately 480,000 angioplasty procedures and nearly 600,000 bypass surgery procedures are performed each year in the United States. Angiogenic gene therapy is being developed to potentially reduce the need for these interventions by offering an effective and safe addition to current treatment options.
About the Companies
Committed to developing novel diagnostics and therapeutics that address unmet medical needs, Berlex Laboratories, Inc., the US affiliate of Schering AG, Germany, researches, develops, manufactures, and markets ethical pharmaceuticals in five strategic areas: Female Healthcare, Diagnostic Imaging, Dermatology, Oncology and Therapeutics for life-threatening and disabling diseases. Berlex Laboratories, Inc., has business operations in Montville and Wayne, New Jersey and Richmond, California. For more information about Berlex and its products, you may visit the Berlex website at www.berlex.com.
Collateral Therapeutics, Inc., headquartered in San Diego, is a leader in the discovery and development of innovative non-surgical gene therapy products for the treatment of cardiovascular diseases. Collateral Therapeutics is developing non-surgical cardiovascular gene therapy products focused on: (1) angiogenesis, as a treatment for coronary artery disease, peripheral vascular disease and congestive heart failure; (2) myocardial adrenergic signaling, as a treatment for congestive heart failure; and (3) heart muscle regeneration, to improve cardiac function for patients who have suffered a heart attack. For more information about Collateral and its research, you may visit the Collateral website at www.collateralthx.com.
Statements in this press release that are not strictly historical may be “forward-looking” statements, which involve risks and uncertainties. There can be no assurance that Collateral Therapeutics, Inc. will be able to advance or commercially develop cardiovascular gene therapy products, that necessary regulatory approvals will be obtained or that any clinical trials will be successful or that the proposed treatments will prove to be safe and/or effective. The actual results may differ from those described in this press release due to risks and uncertainties that exist in Collateral’s operations and business environment, including, without limitation, Collateral’s early stage of product development and the limited experience in development of gene therapies in general, its dependence upon proprietary technology and current competition, history of operating losses and accumulated deficits, Collateral’s reliance on collaborative relationships, and uncertainties related to clinical trials, safety, efficacy, the ability to obtain the appropriate regulatory approvals, patent protection and market acceptance, as well as other risks detailed from time to time in Collateral’s filings with the Securities and Exchange Commission. Collateral undertakes no obligation to release publicly the results of any revisions to these forward-looking statements to reflect events or circumstances arising after the date hereof.
Certain statements in this press release that are neither reported financial results nor other historical information are forward-looking statements, including but not limited to, statements that are predictions of, or indicate future events, trends, plans or objectives. Undue reliance should not be placed on such statements because, by their nature, they are subject to known and unknown risks and uncertainties, and can be affected by other factors that could cause actual results, as well as the plans and objectives of Schering AG, or its US subsidiary, Berlex Laboratories Inc., to differ materially from those expressed or implied in the forward-looking statements. Certain factors that may cause such differences are discussed in Schering AG’s Form 20-F registration statement. Schering AG and Berlex Laboratories undertake no obligation to update publicly or revise any of these forward-looking statements, whether to reflect new information or future events or circumstances or otherwise.
SOURCE Collateral Therapeutics, Inc.
CONTACT: investors, Christopher J. Reinhard, ACC, 858-663-9855, or office, 858-794-3420, or media, Audra Nass, ACC, 415-602-8711, or office, 415-431-1747, both of Collateral Therapeutics, Inc.; or Jeanine O’Kane of Berlex Laboratories, ACC, 201-315-9424, or office, 973-487-2095
Web site: http://www.berlex.com
Web site: http://www.collateralthx.com (CLTX SHR)
