Raising money in a field that has been over-hyped – such as biologics – isn’t easy, according to David Ringler, head of corporate communications for Theregen (San Francisco). But he says the company’s recently launch of its first-in-man trial of its biologic patch for the heart isn’t hype, but will provide solid evidence and bring in significant new funding. Theregen bannered the first procedure as “a living patch of human cells . . . successfully placed for the first time on a patient’s diseased heart.”

A surgical team led by Yale University (New Haven, Connecticut) medical researchers recently performed the procedure at the Veteran’s Administration Hospital (West Haven, Connecticut), using Anginera, the company’s cell-based cardiovascular patch. Ringler told Cardiovascular Device Update that the trial will include 12 patients, the procedures performed at Yale and the University of Maryland (Baltimore). The next trial will be a “combination of safety and limited efficacy, not a full-blown trial,” followed by additional efficacy studies.

The patch material is based on DermaGraft, the skin-substitute product developed by Advanced Tissue Sciences, a company that went under in 2004, with the product now owned and marketed by Smith & Nephew (London). When previously named Iken, Theregen acquired the licensing rights to Dermagraft for use in the current cardiovascular strategy.

That strategy is to use the product’s ability to produce angiogenesis when placed onto the surface of a damaged heart. The platform is the culturing of human fibroblasts grown on a 3-D bioabsorbable scaffold material to create viable tissue. When applied as an epicardial patch to an ischemic area of the heart, the tissue provides a source of the cytokines and growth factors leading to tissue repair, according to the company. Ringler emphasizes that the clinical trial path will be that which is required of a pharmaceutical, since Anginera is a biologic material, with the regulatory application made to the Center for Biologics of the FDA.

The Anginera patch is used in conjunction with a coronary artery bypass graft (CABG) procedure, with the patch applied “in areas that surgery is not appropriate – where there are open ischemic areas.”

“Dermagraft,” Ringler says, “was used to stimulate blood vessel formation and tissue and wound repair. That technology led us to run experiments on the heart in animals. We found compelling evidence of angiogenesis. Certain cells – in our case fibroblast cells – secrete these various proteins and cytokines that appear to help stimulate blood vessel formation. We’ve done this in several different models and it certainly deserves a chance in this very finicky environment.”

The general endpoint for the company’s work is to improve the patient’s “quality of life [as] the first and foremost measure,” Ringler says.

Results of one of the earliest studies in mice was published in an issue of Circulation in 2001 – while still being developed by Advanced Tissue Sciences – and demonstrated an ability to improve the function of damaged heart tissue with no adverse effects.

Theregen in January received $1.5 million in equity funding from Sanderling Ventures to support the trial, which received go-ahead from the FDA in 2005, and Guidant (Indianapolis) made an investment in the company – the amount not disclosed – in early February. Ringler said that the company has “sufficient funds to move forward.”

WorldHeart garners 50% paring of trial

Circulatory support system maker WorldHeart (Oakland, California) last month received FDA approval of a clinical trial patient enrollment reduction, which the company said could significantly reduce the time required to complete its Randomized Evaluation of the Novacor LVAS In A Non-Transplant Population (RELIANT) trial for use of the its Novacor left ventricular assist system as a destination therapy (DT). The FDA granted conditional approval of the company’s investigational device exemption (IDE) supplement for modifications to the trial, including a reduction in sample size, from 390 to 208 patients.

“This reduction in the required sample size by almost a factor of two will obviously have a pretty significant impact on the duration of the trial,” said Jal Jassawalla, president and CEO of WorldHeart, but declined to say exactly how much of a reduction in trial time the IDE might provide.

The FDA approval of the revised study is conditional upon submission of additional details related to the study’s statistical model, the incorporation of additional secondary analyses in the study protocol, and adjustment of the composition of the clinical events review committee.

The RELIANT trial, first unveiled in November 2003, has already enrolled nearly 20% of the newly required number. WorldHeart said the rate of patient enrollment has been increasing and is expected to accelerate as new centers complete the enrollment process and, it noted, the enrollment rate in 1Q06 was double the enrollment rate in the prior quarter.

The trial is designed to evaluate the Novacor for DT use by patients suffering from irreversible left ventricular failure who are not candidates for transplantation. Recipients are being randomized, on a 2:1 basis, to receive the Novacor or Thoratec’s (Pleasanton, California) HeartMate XVE LVAS. The goal of the trial is to show equivalency to the HeartMate XVE, which received a DT approval in April 2003. The FDA also expanded the inclusion criteria for the trial to include patients in NYHA Class IIIB heart failure, as well as currently included NYHA Class IV patients.

Under the newly approved IDE supplement, the primary endpoint for the trial – formerly only patient survival – is now a composite of patient survival, device replacement and neurologic events. The use of a composite primary endpoint accounted for the required patient enrollment. Secondary endpoints include quality of life, adverse events and cost effectiveness. The broadened patient inclusion criteria also include reduction of the total time of heart failure exposure from 60 out of 90 days to 30 out of 60 days, and the early identification of patients at risk. The company said that the added patient cohort allows DT patients currently supported by the HeartMate XVE in need of device replacement to electively receive the Novacor system.

Jassawalla said that after the trial is completed, WorldHeart expects to make a pulsatile ventricular assist devices (VAD) available to clinicians "which we believe will drive adoption in the destination therapy market."

The company is currently conducting a first-in-man feasibility study of its rotary VAD. Additionally, Jassawalla said that WorldHeart’s next-generation pulsatile pump, the Novacor II, has begun chronic animal trials.

As the only company with both rotary and pulsatile next-generation VADs under development, WorldHeart makes the claim that it is currently the VAD manufacturer best able to address the full spectrum of patient needs, from partial support to full functional support.

Cypher stent now in 2 million patients

Cordis (Miami Lakes, Florida) recently reported that 2 million patients have received the company’s Cypher sirolimus-eluting coronary stent since its market introduction in Europe in April 2002, a “first-time milestone for any company in the drug- eluting stent industry,” the company said.

“The Cypher stent represents an innovative advance in science that has significantly changed the practice of interventional cardiology,” said Professor Eduardo Sousa, MD, PhD, Institute Dante Pazzanese of Cardiology (Sao Paulo, Brazil). “It is a safe and effective treatment option for a wide range of patients and continues to be the top choice for interventional cardiologists globally.” Sousa was the first physician in the world to implant a Cypher stent.

Cordis also said it has submitted a premarket approval application to the FDA for a 2.25 mm version of its Cypher stent. “We will continue to work closely with the FDA through this approval process,” said Dennis Donohoe, MD, vice president, worldwide clinical and regulatory affairs for Cordis.

CABG winds down with liquidation plan

Shareholders of CABG Medical (Minneapolis) last month gave “overwhelming” approval to the company’s plan of liquidation and dissolution, and the company’s common stock ceased trading on the Nasdaq.

The company is closing down as a result of clinical trial problems with its main product, the Holly graft system, a drug-eluting graft designed to facilitate coronary artery bypass procedures.

The company projected an initial distribution of $1.47 per share will be made during the month of May 2006. After the company has completed the shut-down procedures, a second distribution of remaining funds, if any, will be distributed to shareholders and could range from $0.00 to $0.04.

The company also reported that Jay Graf, Archie Smith, Robert Munzenrider and John Babitt have resigned from the company’s board. Manny Villafana, company CEO and chairman, will continue as a director of the company until the final cash distribution and formal dissolution is completed.

Cardium reports rejection of appeal

The U.S. Court of Appeals for the Federal Circuit, which oversees appeals in all patent-related matters in the European Union, ruled in favor of Cardium Therapeutics (San Diego) in a case involving Arch Development and Arch’s licensee, Boston Scientific (Natick, Massachusetts). The appeal was brought by Arch and Boston Scientific after the Board of Patent Appeals and Interferences had ruled against them with respect to a series of patents and patent applications related to angiogenic treatments for coronary heart disease, including myocardial ischemia and angina.

Cardium is the exclusive licensee of a number of patents and patent applications of Dr. H. Kirk Hammond and colleagues at the University of California, directed to the intracoronary administration of adenovectors comprising angiogenic genes for the treatment of coronary heart disease and related conditions such as myocardial ischemia and angina.

“The completion of these important reviews of our intellectual property position, and consistent decisions in our favor, serves to underscore the value of our patent portfolio, which we believe reflects a best-in-class approach to the treatment of coronary heart disease,” said Dr. Tyler Dylan, chief business officer and general counsel of Cardium.

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