Biotech Values

[DewDiligence]

NUVO’s phase-2 data are OK:

[But I don’t think these data are going to blow anyone away. The knock on NUVO’s Alfimeprase has been that the therapeutic window is narrow (giving too much can cause intracranial bleeding) and these data don’t fully put this issue to rest.]

http://biz.yahoo.com/prnews/040930/sfth002_1.html

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Nuvelo Phase 2 Clinical Trial Results Show Potential of Alfimeprase to Treat Acute Peripheral Arterial Occlusion, Also Known as 'Leg Attack'

New thrombolytic shows potential to restore blood flow to patients within four hours of initiation of dosing

WASHINGTON, Sept. 30 /PRNewswire-FirstCall/ -- Nuvelo, Inc. (Nasdaq: NUVO - News) today announced that Phase 2 trial results showed the potential of its lead product candidate, alfimeprase, to treat acute peripheral arterial occlusion (PAO), also known as "leg attack." The results were presented today at the Cardiovascular Research Foundation's (CRF) Sixteenth Annual Transcatheter Cardiovascular Therapeutics Scientific Symposium (TCT 2004), in Washington, D.C.

Full analysis of the multi-center, multi-national, open-label, dose- escalation study, NAPA-1 (Novel Arterial Perfusion with alfimeprase-1), revealed that alfimeprase showed potential for thrombolysis (breaking up of a blood clot) with rates of up to 76% and restoration of arterial flow with rates of up to 60% based on intention to treat analysis. Furthermore, all thrombolytic activity and restoration of flow was recorded within four hours of initiation of dosing. Most plasminogen activator type thrombolytic agents may require a prolonged infusion of 24 to 36 hours in patients with leg attack.

"Based on these data, I believe alfimeprase presents an opportunity to shift the paradigm of treatment for this very sick patient population," stated Dr. Kenneth Ouriel, chairman of the division of surgery at the Cleveland Clinic and principal investigator for Nuvelo's Phase 1 and 2 alfimeprase trials in PAO. "This is reflected in alfimeprase's potential to offer significant advances in the rapid resolution of a clot while minimizing systemic side-effects such as intracerebral hemorrhage and other bleeding complications. I therefore believe alfimeprase warrants further study in acute PAO."

"The opportunity to restore arterial blood flow within four hours of initiation of dosing with alfimeprase is remarkable," said Steven R. Deitcher, M.D., vice president clinical and regulatory affairs for Nuvelo. "As in heart attack, rapid restoration of blood flow is critical to reducing morbidity and mortality in leg attack. There is a real unmet medical need to address leg attack. While avoidance of open-vascular surgery with the use of currently available thrombolytics can reduce the risk of peri-operative morbidity and mortality, use of these plasminogen activator-based therapies presents unavoidable risks of major bleeding and intracerebral hemorrhage. Unlike these thrombolytics, alfimeprase shows the potential to avoid a systemic lytic state as its suggested lytic activity is localized to the site of drug delivery."

Nuvelo is scheduled to meet with the Food and Drug Administration (FDA) to discuss the initiation of a Phase 3 trial that will be designed to further assess the efficacy and safety of alfimeprase in acute PAO patients.

About the Study

The 24-center, open-label, dose-escalation study conducted in the United States, Europe, Hungary, Russia and South Africa evaluated the safety and activity of alfimeprase in acute PAO patients. The study was led by Dr. Ouriel and Dr. Jacob Cynamon, professor of clinical radiology and director of the division of vascular and interventional radiology at the Montefiore Medical Center.

Patients were randomized to receive one of three doses of alfimeprase, 0.1 mg/kg, 0.3 mg/kg or 0.6 mg/kg. Doses were administered via a side-hole catheter in two separate, five to fifteen minute pulsed infusions, giving 2/3 of the dose up front, followed by the remaining 1/3 of the dose after two hours. Angiograms were taken at baseline (time zero), one hour and two hours with the final and conclusive angiogram taken at four hours after initial dosing.

Primary endpoints included: adverse event (AE) rate, serious adverse event (SAE) rate and major bleeding, including intracerebral hemorrhage (ICH), up to 30 days after dosing. Secondary endpoints included determination of alfimeprase activity; open-surgery free survival at 14 and 30 days; patency, as defined by restoration of flow; increase in ankle-brachial index (ABI) by greater than or equal to 0.15; and reduction in severity of planned surgical interventions.

Full analysis of the 113 subjects revealed that there were no ICHs or deaths. Hypotension rates in the lower doses (0.1 mg/kg and 0.3 mg/kg) were approximately 3% or 2 patients, one of whom was categorized by the investigator as not related to alfimeprase. AE, SAE, major hemorrhage and hypotension rates were dose-related and hypotensive episodes were not associated with any clinical sequelae. Of the 16 SAE level bleeding events reported, seven were major bleeds and nine were minor bleeds. Of the seven major bleeds, six were unrelated to alfimeprase and only one was categorized by the investigator as possibly related (a groin hematoma). Of the nine minor bleeds, three were categorized as possibly related to alfimeprase and six were unrelated or unlikely to be related to alfimeprase as determined by investigators. From 52% to 69% of study patients were able to avoid surgical intervention.

Upcoming Event

Today, from 12:00 p.m. to 2:00 p.m. ET, Dr. Kenneth Ouriel, chairman of the division of surgery at the Cleveland Clinic and a principal investigator for Nuvelo's Phase 1 and 2 alfimeprase PAO trials, will present this Phase 2 data at a meeting for the financial community in Washington, D.C.

A simultaneous webcast of Dr. Ouriel's presentation will be available live, starting at approximately 12:15 p.m. ET, and via replay in the Investor Relations section of Nuvelo's Web site at www.nuvelo.com.

About Alfimeprase

Alfimeprase is an enzyme produced by recombinant DNA technology. It is a thrombolytic agent or blood clot dissolver that is intended to directly degrade fibrin when delivered through a catheter at the site of a blood clot. Thrombolytics currently on the market such as Abbokinase® or Activase® are plasminogen activators which rely on the plasminogen system to degrade fibrin. The activity of plasminogen activators is impacted by the amount of plasminogen found in the blood clot and may require prolonged infusions when dissolving very large clots such as those found in patients with acute PAO. Alfimeprase directly degrades fibrin, producing a rapid dissolution of blood clots. In preclinical and clinical studies, alfimeprase has been shown to have the ability to degrade large arterial clots within four hours of initiation of dosing. In addition, alfimeprase possesses a unique mechanism of action. Preliminary testing suggests that its lytic activity is localized to the site of delivery. Alfimeprase is inhibited within seconds of moving away from the clot and into the general circulation by alpha-2 macroglobulin, a naturally occurring protein in our blood. This clearance mechanism helps focus the thrombolytic activity to the site of delivery and in preclinical and clinical testing, appears to minimize bleeding side effects.

About Leg Attack

Acute PAO, also known as "leg attack," which affects more than 100,000 people in the United States per year, is the blocking of arterial blood flow to the lower limbs by a clot. Leg attack is the result of underlying peripheral arterial disease, in which chronic fatty plaque buildup restricts blood flow. The classic early symptom of leg attack is leg pain or fatigue during activity that subsides with rest. Continued restriction of blood flow leads to pain at rest and, if the ischemia continues, to ulcers, gangrene, tissue death and if untreated, foot or leg amputation.

Bypass surgery, angioplasty and off-label use of thrombolytics are established treatments for leg attack. There are currently no approved, widely used products on the market to treat leg attack. With the limited treatment options currently available, alfimeprase has received orphan drug designation for leg attack.
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