If Acusphere (Watertown, Massachusetts) succeeds in its quest to secure FDA approval for its Imagify contrast agent, it says that testing for coronary artery disease (CAD) could be much simpler and less expensive, as opposed to today's gold standard of nuclear stress perfusion testing.

Acusphere CEO Sherri Oberg kicked off a conference call to investors Tuesday morning to release in detail the results of its RAMP-2 test, its second Phase III clinical trial of Imagify (perflubutane polymer microspheres) injectable suspension. The company said that the data results exceeded the criteria for superiority to nuclear testing in two primary endpoints, accuracy and sensitivity, in RAMP-2.

But since a third endpoint was not met — superiority in predicting the absence of heart disease — investors were not so upbeat about the trial results. The company's share price dropped nearly 30%, falling to $1.14 to $2.85 in the day's trading.

Acusphere, however, bannered the results as supporting ultimate FDA approval.

"We are thrilled with these results, because the goal of the Phase III program was to demonstrate non-inferiority to nuclear stress, and we believe we've accomplished that goal," Oberg told call listeners.

Acusphere describes Imagify as the first ultrasound contrast agent designed to assess myocardial perfusion, blood flow in the heart muscle and considered a sensitive marker for coronary artery disease (CAD).

Currently, according to Acusphere, perfusion information is not available using cardiac ultrasound but must be obtained using a nuclear stress test.

Oberg told listeners that ultrasound is "much less expensive, at half the cost; it is much faster, taking only 30 minutes; and it does not involve" nuclear material.

Nuclear testing, she said, costs about $800 and takes about five hours to complete. It also involves the injection of a radioactive contrast agent, which she described as a "hazardous waste that has to be handled and disposed of by licensed professionals . . . "

"These RAMP-2 results suggest that the perfusion information that Imagify adds can enable ultrasound to detect disease just as well as nuclear, but with many other advantages," Oberg said.

Acusphere believes the "potential market" for Imagify includes 10 million CAD evaluations "representing an annual opportunity of more than $2 billion," Oberg said.

In RAMP-2, all three of the ultrasound-blinded readers had superior sensitivity and non-inferior accuracy to nuclear stress, the most frequently used imaging procedure.

The endpoint not achieved in RAMP-2 was specificity, though the company had previously reported superior specificity for Imagify in its RAMP-1 trial, those results reported last June. High accuracy and sensitivity were the top priorities in RAMP-2.

Richard Walovitch, PhD, senior VP of clinical research at Acusphere, who oversaw the design and management of the Phase III program, said during the conference call that the company is in a "position to move forward towards filing a strong NDA for Imagify." He also said the "efficacy analysis plan" for both Ramp-1 and Ramp-2 was very similar.

"In these trials, the first question we asked was, 'Is Imagify enhanced ultrasound as accurate as nuclear imaging?' Accuracy is a term that defines how many of the patients were correctly diagnosed," he said. "In our trial, accuracy is the principle primary endpoint, and if accuracy is not met, there is no reason to ask questions regarding sensitivity and specificity."

In a statement, Walovitch said that cardiologists place greater importance — for patients with a higher risk of disease — on sensitivity, the ability to detect existing disease. They place greater importance — in patients with a lower risk of disease — on specificity, the ability to rule out disease when it is not present.

RAMP-1 focused on lower-risk patients, and Oberg said in that trial the company "demonstrated superior specificity."

RAMP-2 focused on higher risk patients.

"Perfusion, that is, myocardial blood flow assessment, has been a key goal for heart ultrasound for years," said Michael Picard, MD, director, Clinical Echocardiography at Massachusetts General Hospital (Boston) and clinical monitor for the RAMP-2 trial. "Cardiologists use ultrasound for diagnosis and management of many conditions, and the addition of perfusion information would be a breakthrough. This would allow us to identify in a single, convenient, non-invasive test the patients at risk for a heart attack. Currently, this same assessment often requires multiple tests or invasive tests."

"These trial results, especially for sensitivity, are exciting because they offer the prospect of a new approach for detecting heart disease," he added.

In the RAMP-2 clinical trial, the company said Imagify was well tolerated, with the majority of adverse events (AEs) reported being "mild in intensity, transient and resolved without residual effects." The most common AEs reported were headache, increased white blood cell count, flushing, nausea, and chest pain. Each patient in the trial was subjected to pharmacological stress to assess myocardial perfusion.

The majority of these AEs occurred following the administration of the dipyridamole pharmacologic stress agent. Serious adverse events (SAEs) were reported in six patients. All SAEs were non-life threatening. Seven of the 457 patients enrolled discontinued dosing in the clinical trial due to AEs/SAEs. Imagify has now been cumulatively studied in over 1,000 patients being evaluated for coronary artery disease.

In Real-time Assessment of Myocardial Perfusion-2 (RAMP-2), 457 patients were studied at 11 clinical sites located in the U.S. and Europe. All of the patients enrolled in the trial were suspected of having coronary artery disease based on a variety of symptoms such as chest pain.

In accordance with the trial design, patients who did not have a nuclear stress test or whose nuclear stress test was not in accordance with the trial protocol were evaluated for safety but excluded from the primary efficacy analysis. The reported efficacy results from RAMP-2 are based on 377 patients. All ultrasound images were interpretable. Coronary angiography was used in 98% of the patients studied as the truth standard to determine which patients actually had disease and which did not.

The company said it is now working with its clinical investigators to prepare a more detailed description of the trial results for submission to a peer-reviewed journal in the next few months. In the meantime, it is also working with its clinical investigators to support them in their preparations for various upcoming scientific meetings.

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