How Celacade Technology Works

Our Celacade technology targets the inflammation underlying chronic heart failure. Inflammation is a normal response of the immune system to cellular injury caused by infection, trauma, or other stimuli. During the inflammatory process, immune cells release a number of factors, including cytokines – potent chemical messengers that modulate inflammation and facilitate the healing process. While this inflammatory process is usually self-limiting, it can persist, become chronic, and lead to a number of serious medical conditions.

During a brief outpatient procedure, a small sample of a patient’s blood is drawn into our Celacade single-use disposable cartridge and exposed to controlled oxidative stress utilizing our proprietary Celacade medical device technology. Oxidative stress is a factor known to initiate apoptosis (programmed cell death), a physiologic process that is inherently anti-inflammatory. The treated blood is then administered to the same patient intramuscularly. An initial course of treatment comprising three consecutive outpatient procedures is administered over a two-week period, and treatments are continued once per month thereafter.

During apoptosis, signalling molecules, including phosphatidylserine (PS), normally present on the inner surface of the cell membrane, become exposed on the cell surface. The PS molecules interact with specific PS receptors on the surface of antigen presenting cells (APCs) of the immune system, including macrophages and dendritic cells. The interaction with macrophages leads to an up-regulation in the production of the anti-inflammatory cytokines IL-10 and TGF-β. Dendritic cells that interact with apoptotic cells remain immature and, in the presence of anti-inflammatory cytokines such as IL-10 and TGF-β, cause the differentiation of some naïve T cells to regulatory T cells. These traffic through the tissues and inhibit inflammatory cells such as T1 cells by a process that includes cell-cell interaction and the production of anti-inflammatory cytokines by the regulatory T cells. The end result is a reduction in tissue levels of inflammatory cytokines such as TNF-α, IL-6, IFN-γ, and IL-1β, and a down-regulation of chronic inflammation.

Phase III ACCLAIM Trial

During 2006, we announced the results of our 2,408-patient phase III ACCLAIM trial of Celacade in patients with chronic heart failure. Please click here for a description of these results.

European Regulatory Status & Commercialization Agreement

Celacade has received E.U. regulatory approval as a medical device under the CE Mark, which enables marketing of Celacade for the treatment of chronic heart failure in the 27 member countries of the E.U. To our knowledge, Celacade is the only CE-Mark approved product that specifically targets the destructive chronic inflammation underlying the development and progression of heart failure. Under the CE Mark in Europe, Celacade is approved for the treatment of all NYHA Class II patients, and NYHA Class III, & IV heart failure patients who do not have a history of prior heart attack. As a result of our recent restructuring, (for additional details, please click here) we are no longer maintaining the necessary quality process/personnel to support European commercialization.

During 2007, we completed a collaboration agreement (the “Agreement”) with Grupo Ferrer to commercialize Celacade for the treatment of chronic heart failure in certain countries of the E.U. and Latin America. Under the Agreement, Grupo Ferrer has the exclusive rights to market Celacade for the treatment of chronic heart failure and other cardiovascular conditions in certain countries of the E.U. and Latin America. As a result of our recent restructuring, (for additional details, please click here) the commercialization of Celacade in the E.U. has been put on hold pending the outcome of a strategic review process.

U.S. Regulatory Status

At a May 2007 meeting with the FDA to discuss the ACCLAIM results, the Agency recommended that we conduct a confirmatory study (“ACCLAIM II”) to support a U.S. PMA filing for Celacade for patients with NYHA Class II symptoms and also recommended that we use a Bayesian statistical approach. This approach involves a trial design methodology that may allow for the utilization of prior trial results to contribute to the statistical power of a confirmatory study and therefore potentially provides the opportunity to significantly reduce the number of required patients, as well as the cost and duration of such study.

In preparation for ACCLAIM II, the FDA decided to review their jurisdictional designation for Celacade. The Celacade System was previously regulated as a medical device with the Center for Devices and Radiological Health (CDRH) acting as lead reviewer, with input from Center for Biologics Evaluation and Research (CBER). The FDA required several months to complete their jurisdictional review, resulting in delays in receiving further comments on the design of ACCLAIM II. As a result of this review, the FDA eventually concluded that Celacade will remain regulated as a medical device; however, CBER will take on the position of lead reviewer. The FDA indicated that transition process from CDRH to CBER was completed on February 29, 2008.

As part of the transition to CBER, CDRH communicated to us that they disagree with the use of a Bayesian approach because of a concern with being able to recruit a homogeneous study population between ACCLAIM and ACCLAIM II. This is contrary to the FDA’s original communication recommending that we use Bayesian study design. We are currently in discussions with the FDA to clarify their position regarding the Bayesian approach and determine the least burdensome trial design to support a PMA submission for Celacade in the United States.