CD&D

The FDA has placed a large speed bump in front of the plans for a confirmatory clinical trial by Vasogen (Mississauga, Ontario) for its heart failure treatment. The agency last month raised concerns about how the company plans to recruit patients for its Advanced Chronic Heart Failure CLinical Assessment of Immune Modulation Therapy (ACCLAIM II) trial, intended to support an application for U.S. market approval of the company's device technology, called the Celacade System.

Chris Waddick, president/CEO of Vasogen, told Cardiovascular Devices & Drugs that the FDA's communication came as a surprise, specifically in that the agency would not allow use of data from the first ACCLAIM trial.

"ACCLAIM missed its primary endpoint for the group as a whole, but in 700 patients we saw a significant impact," Waddick said.

The FDA's Center for Devices and Radiological Health said it is concerned with Vasogen's use of the Bayesian approach for analysis of its data that approach allowing researchers to combine data from prior studies with current information in both the design and analysis stages of a trial. That approach allows researchers to recruit a heterogeneous study population between ACCLAIM and ACCLAIM II, the issue that is now being questioned by the agency.

According to CDRH, when good prior information on clinical use of a device exists, the Bayesian approach may enable the agency to reach the same decision on a device with an enrollment of smaller size or shorter-duration.

The FDA apparently rescinded earlier communications with the company in which it agreed to the trial design (a horse-changing in mid-stream that both device and drug companies often complain of).

Celacade technology targets the inflammation underlying chronic heart failure. During a brief outpatient procedure, a small sample of a patient's blood is drawn into the Celacade single-use disposable cartridge and exposed to controlled oxidative stress using the Celacade, the company's proprietary medical device technology. 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 a month thereafter.

Oxidative stress is a factor known to initiate apoptosis (programmed cell death), a physiologic process that is inherently anti-inflammatory. ACCLAIM studied 2,408 subjects with chronic heart failure at 175 clinical centers in seven countries. ACCLAIM II was designed to assess the ability of Celacade to reduce the risk of death or first cardiovascular hospitalization.

The difference in time-to-death or first cardiovascular hospitalization (the primary endpoint) for the intent-to-treat study population was not statistically significant; however, the risk reduction directionally favored the Celacade group.

Vasogen said it will work with members of the ACCLAIM II Steering Committee to address the FDA's concerns. "The FDA had concerns that we will not be able to recruit a similar patient population," Waddick said.

The agency indicated there has been an evolution in heart failure care since the ACCLAIM trial was initiated that may result in a differently treated patient group. But, Waddick said, "We don't see where there's been a material change in heart failure carebecause in ACCLAIM, [patients] were on standard therapy, and it would be the same approach for ACCLAIM II."

The company received approval to proceed with the ACCLAIM trial in 2002. It was granted CE mark approval for Celacade therapy in 2004.

The has retained Berry Consultants and Donald Berry, MD, head of the Division of Quantitative Sciences and chairman of the Department of Biostatistics at The University of Texas M.D. Anderson Cancer Center (Houston), a recognized authority in the area of Bayesian and adaptive trial design.

Last May, Vasogen closed on $16 million in financing through the sale of common shares at $3.25 a share. Net proceeds were about $14.6 million. In 2003 it raised $37.5 million in a private placement, selling 9.375 million shares at $4 each.

Bioheart squeezes out $5.8 million in its IPO

A year after filing for an initial public offering, Bioheart (Sunrise, Florida) in February closed the deal by pricing 1.1 million shares at $5.25 each. But the gross proceeds of $5.8 million were a far cry from the $35 million the company had initially hoped for. And last fall, Bioheart raised its target to $53.6 million when it set terms at 3.575 million shares priced between $14 and $16 per share.

As of Sept. 30, the company reported $9.5 million in cash and equivalents after posting a loss of $9.2 million during the first nine months of 2007. After expenses, net proceeds from the IPO would be just $1.5 million, but expense prepayments will allow Bioheart to take home $4.6 million in cash proceeds. That take-home total could increase to $5.4 million if underwriter Dawson James Securities exercises its option to purchase an additional 165,000 shares to cover any overallotments.

Most of the money from the offering will support a Phase II/III trial of MyoCell, Bioheart's autologous cell-based treatment for heart failure. The product is intended to repair and regenerate heart muscle by taking myoblasts from a patient's thigh muscle, growing them in a cell-culturing process, and injecting them into scar tissue within the heart wall using the company's MyoCath catheter.

Data from the double-blind, randomized, placebo-controlled, 330-patient trial are expected in 3Q09. Primary endpoints include improvement in six-minute walk distance and quality of life, as well as safety. If the findings are positive, Bioheart said it intends to ask the FDA to consider the trial pivotal and a basis for approval.

The company plans to pursue limited approval in Europe as early as 2Q08 based on Phase II data. Due to a limited number of patients treated, the Phase II trial did not initially show statistical significance for any of the efficacy endpoints.

Behind MyoCell, Bioheart has earlier-stage autologous cell therapy programs for acute heart attack and abnormal heart rhythm as well as an adipose tissue processing system, endoventricular catheters and an allogenic myoblast program.

CardioNet files with SEC, pricing 6.6M share IPO at $22 to $24

CardioNet (San Diego), a provider of real-time outpatient management solutions for monitoring an individual's cardiac health, recently reported terms for its initial public offering in an SEC filing. The company plans to offer a total of 6.6 million shares, 3.6 million from selling shareholders, at a range of $22 to $24. The company said it stands to raise about $61 million in proceeds if the offering prices at the midpoint. CardioNet first filed for the offering in August.

CardioNet has granted its underwriters a 30-day option to purchase up to 990,000 additional shares of common stock to cover any over-allotments.

The CardioNet system incorporates a lightweight patient-worn sensor attached to electrodes that capture two-lead ECG data measuring electrical activity of the heart and communicates wirelessly with a compact, handheld monitor. The monitor analyzes incoming heartbeat-by-heartbeat information from the sensor on a real-time basis by applying proprietary algorithms designed to detect arrhythmias.

When the monitor detects an arrhythmic event, it automatically transmits the ECG to the CardioNet Monitoring Center, even in the absence of symptoms noticed by the patient and without patient involvement. At the monitoring center, certified cardiac monitoring specialists analyze the sent data, respond to urgent events and report results in the manner prescribed by the physician.

The company said that since its commercial introduction of the system in early 2003, physicians have enrolled more than 109,000 patients and have secured direct contracts with 169 commercial payors as of Dec. 31.

The company said it intends to use the proceeds from the offering to repay in full a term loan to Silicon Valley Bank and would make required payments to former stockholders of PDSHeart (West Palm Beach, Florida), which it acquired last March. The company also said it would use the funds for R&D; to increase its sales and marketing capabilities for the CardioNet system; to acquire or license products, technologies or businesses and for working capital and general corporate purposes.

The company said it has incurred net losses from its inception through Dec. 31, 2007, including losses of $11.5 million for the year ended Dec. 31, 2005, $7.6 million for the year ended Dec. 31, 2006, and $400,000 for the year ended Dec. 31, 2007.

The company filed to be listed on the Nasdaq under the ticker symbol BEAT.

DoD awards $1.9M grant to investigator for trial of Oxycyte

Synthetic Blood International (SBI; Costa Mesa, California) said the U.S. Department of Defense has awarded a $1.9 million grant to M. Ross Bullock, MD, PhD, of the University of Miami Miller School of Medicine (Miami), Department of Neurosurgery and principal investigator for the company's planned Phase IIb clinical trial with Oxycyte for the treatment of traumatic brain injury (TBI).

Oxycyte is SBI's perfluorocarbon (PFC) therapeutic oxygen carrier and blood substitute.

"With this grant, we will be able to double our planned enrollment in the Phase IIb trial to 200 TBI patients, providing a larger statistical basis for evaluating Oxycyte's effectiveness as a treatment in this indication," Bullock said. He also was a principal investigator in SBI's Phase IIa pilot study in TBI and serves as co-chairman of the company's scientific advisory board. "We are scheduled to commence the double-blind, placebo-controlled Phase IIb trial in April of this year."

Robert Larsen, interim president/CEO of SBI, said that if results from the Phase IIb trial are similar to the company's pilot study results, the company may be able to accelerate Oxycyte's market approval.

According to the company, positive data from the Oxycyte pilot study in TBI patients demonstrated that Oxycyte was more effective in increasing brain oxygen tension levels and impacting other brain chemistries that contribute to favorable clinical outcomes in TBI patients than breathing either 100% or 50% oxygen (Medical Device Daily, May 17, 2007).

Cryocor files vs. CryoCath charging unfair trade practices

CryoCor (San Diego), developing treatments for cardiac arrhythmias, said it has filed a complaint with the U.S. International Trade Commission (ITC) alleging that CryoCath Technologies (Montreal, Quebec) has engaged in unfair trade practices by infringing on several CryoCor patents with its cryoablation system. It is asking the ITC to issue an exclusion order to bar the importation into the U.S. of infringing CryoCath cryoablation products.

CryoCor's complaint covers three patents licensed to CryoCor in uses related to its Cardiac Cryoablation System, including those covering pre-cooling technologies that CryoCor says are important to CryoCath's cryoablation system.

CryoCor said that if the ITC accepts the complaint, it will institute a formal Section 337 investigation on a fast track, typically within 15 months of complaint submission. It said that if the ITC finds infringement by CryoCath products imported into the U.S., the ITC may order that CryoCath's cryoablation system be completely excluded from U.S. import.

Ed Brennan, PHD, president/CEO of CryoCor, said, "Importantly, an ITC investigation has a fast timeline for completion ... . We expect to hear from the ITC within 30 days and will provide an update upon their response."

In other patent news: Two consumer groups say they will continue their challenge of three overreaching patents on human stem cells held by the Wisconsin Alumni Research Foundation (WARF; Madison) despite a non-final decision by the U.S. Patent and Trademark Office allowing three amended claims in one of the disputed patents.

The Foundation For Taxpayer and Consumer Rights (FTCR; Santa Monica, California) and the Public Patent Foundation (PUBPAT; New York) said they would appeal any later final decision by the examiner supporting the claims to the Patent and Trademark Office's Board of Appeals.

"We won the first round when the PTO rejected all claims of the '780,'806 and '913 patents," said John Simpson, FTCR Stem Cell project director. "Now WARF has won the second round with respect to just one of the patents, but the battle is hardly over. We're in this for the longhaul."

The two groups noted that the patent challenge has improved the situation for stem cell researchers; shortly after the PTO said it would re-examine the three patents, WARF said a substantial easing of its licensing requirements.

"WARF executives were acting like arrogant bullies blinded by dollar signs," said Simpson. "Our challenge has engendered a more co-operative stance on their part."

CoreValve to 'vigorously defend' ReValving system in suit

CoreValve (Irvine, California) said that the lawsuit filed against it last week by Edwards Lifesciences (Irvine) is "without merit." Edwards filed the suit last week in the U.S. District Court in Delaware charging infringement of three of its Andersen family of patents for transcatheter heart valve technology by CoreValve's ReValving System.

CoreValve said it will "vigorously defend" against the suit and continue to develop its ReValving System for percutaneous aortic valve replacement in high-risk patients with advanced aortic valve disease.

Last May Edwards initiated litigation against CoreValve in the District Court of Dusseldorf, Germany, for infringement of a related Andersen patent, EP 0 592 410 B1; similar litigation is pending in the UK. These suits address the sale of CoreValve's alleged infringing valves, according to Edwards. It says that the suit just filed targets CoreValve's manufacturing of valves in the U.S. for export and sale in Europe.

U.S. patents, No. 5,411,552, No. 6,168,614 and No. 6,582,462 – part of the Andersen patent portfolio – relate to a valve prosthesis for implantation by means of a catheter.

Study of beta blocker in post-MI bracydardia or heart block

Feinberg School of Medicine at Northwestern University (Evanston, Illinois) reported receiving a $15 million grant from the National Heart, Lung and Blood Institute of the National Institutes of Health to conduct an international study investigating whether a pacemaker-enabled administration of beta-blockers in patients with post-myocardial infarction bradycardia or heart block will also improve survival rates.

Jeffrey Goldberger, M.D., professor of medicine at Feinberg and director of cardiac electrophysiology at Northwestern Memorial Hospital, is the principal investigator of the multi-center, randomized clinical research study.

The five-year study, titled the Pacemaker and Beta Blockers after Myocardial Infarction (PACE-MI.) trial will enroll 1,124 patients from around the country, in Canada and in Israel.

"The study will also help us determine more precisely how frequently low heart rates are a problem in heart attack patients. The current estimates are 5 to 10 percent of 1.5 million heart attack patients yearly," Goldberger said.

Northwestern Memorial Hospital is the local site and will enroll 20 to 30 patients. Other centers are in 27 states, including Michigan, Minnesota, Iowa, Wisconsin and Missouri.

"This research question addresses a significant public health issue," Goldberger said. 'As our population ages, we seek to address a question that could potentially improve post heart attack survival as well as improved the quality of life for heart attack patients. We have predicted and observed that the patient population for this study represents a group that is more elderly, with factors that influence eligibility and willingness to participate. The study should be offered for consideration to geriatric patients in order to gain knowledge about this treatment in elderly age group. Study oversight by an objective safety board assures ongoing review and monitoring for the safety of all study participants".

Goldberger said that most of the participants in the study will be patients identified in the hospital after a heart attack, allowing time to discuss the study with physicians, family and friends.

In brief ....

CardiacQA, (Newark, Delaware), a web-based provider of Quality Assurance Tools and Nuclear Reporting Solutions for cardiology practices, reported eclipsing the 20,000 mark on its Nuclear Report Generator.

The company says that its clients access CardiacQA solutions via the Internet, reducing the time and costs associated with similar local installations. CardiacQA sasys it supports customers of all sizes, with a focus in the outpatient cardiology market.

"For 2008, our goal is to ensure that our organization is not only capable of growing at this industry-leading pace, but is able to do so while sustaining high quality performance levels in our software delivery model and our client support processes," notes William Moore, VP, Business Development of CardiacQA.