ImaRx Therapeutics (Tucson, Arizona) last week reported passing a major hurdle in developing what would be the first therapy for ischemic stroke since tPA was introduced by Genentech (South San Francisco).

In data released from its Transcranial Ultrasound in Clinical SONolysis (TUCSON) trial, ImaRx demonstrated that patients can recover from ischemic stroke with its SonoLysis therapy combined with ultrasound.

However, the company has discontinued the TUCSON trial because an undisclosed number of patients in one of two trial cohorts experienced intracranial hemorrhage events, possibly related to the use of the tPA clot-busting drug.

tPA has been the primary mode of treating ischemic stroke, but it needs to be administered in a narrow, three-hour window after an attack. And most patients don’t receive it as a result of delays, primarily the difficulty of determining the exact nature of the stroke and whether tPA is the appropriate therapy. Thus, there has been a continuing effort – and a continually frustrated effort — to develop alternative and adjunctive therapies for stroke.

ImaRx is pitching its technology as potentially opening the three-hour window to nine hours, thus greatly expanding the timeline for treatment.

Concerning the hemorrhage events in TUCSON, ImaRx declined to disclose if any of those patients had died.

“We are terminating our current TUCSON trial,” Bradford Zakes, president/CEO of ImaRx, told Medical Device Daily. “We believe we’ve found the appropriate microbubble dose to carry on in future with another trial.”

ImaRx was launched, based on the microbubble technology, now called SonoLysis. It includes the administration of ImaRx’s MRX-801 submicron-sized bubbles and ultrasound to break up blood clots and restore blood flow to oxygen-deprived tissues with or without a thrombolytic drug.

The next trial, SonoLysis Embolis Dissolution in Acute Ischemic Stroke (SEDONA) will be launched in the second half of 2008.

“We will no longer use tPA,” Zakes said. “We did determine that there were a higher number of hemorrhage events in patients who received treatment in Cohort 2. It’s unclear if it was the microbubbles, tPA or ultrasound.

“We have chosen, going forward, to discontinue TUCSON, taking uncertainty of bleeding risk out of the equation and moving forward with the SEDONA program, offering a safer therapy without the thrombolytic.”

The therapy’s microbubbles are lipid shells encapsulating an inert biocompatible gas. The sub-micron size of the microbubbles allows them to penetrate a blood clot, so that when ultrasound is applied via the transcranial window of the skull, their expansion and contraction, or cavitation, can break the clot into very small particles.

In the TUCSON trial, treatment was restricted to a three-hour window following stroke. The SEDONA program will extend that treatment window up to nine hours.

“This is fundamentally different from what a lot of other companies are pursuing in ischemic stroke with a thrombolytic approach,” Zakes said. “We’re using an inert microbubble technology in combination with externally administered ultrasound, in a non-interventional approach.”

The TUCSON design included four dose cohorts of 18 subjects each, randomized to receive either treatment (MRX-801, ultrasound and tPA) or control (tPA alone). Safety was assessed by the incidence of symptomatic intracranial hemorrhage within 36 hours following the initiation of treatment.

Activity was assessed by recanalization, defined as increased blood flow in the occluded artery, which was viewed by clinicians as a key factor in improving the probability of complete clinical recovery.

Improvements in functional and neurological outcomes were measured by improvement in NIHSS and Modified Rankin scores, widely accepted instruments used to assess clinical outcomes for stroke. ImaRx completed enrollment for all 18 subjects in Cohort 1 (12 treated and six control) and 17 subjects in Cohort 2 (11 treated and 6 control).

Cohort 1 evaluated one vial of MRX-801. There were no unexpected safety events and there were signs of improved recanalization in treated patients compared to controls. In clinical recovery endpoints, the number and proportion of patients who experienced dramatic or early clinical recovery were higher in the treatment group compared to controls, Zakes said.

The second dose cohort evaluated two vials of MRX-801. Activity data from subjects in this cohort is still being collected and will be available in the second quarter of 2008. From a preliminary evaluation of the safety data that have been collected to date, there were a greater number of intracranial hemorrhage events observed in subjects receiving treatment relative to controls.

Garen Manvelian, MD, chief medical officer for ImaRx, said “We are very encouraged by the data from Cohort 1 and are pleased to have observed activity with the lowest dose of MRX-801. We have learned what we set out to accomplish through this clinical trial.”

ImaRx licensed the oxygen delivery technology incorporated with its SonoLysis therapy from Sonus Pharmaceuticals (Bothell, Washington) last year (MDD, July 12, 2006).

Zakes said the company has sufficient cash to complete preclinical requirements and regulatory submission activities to initiate the SEDONA trial.

“But,” he acknowledged, “prior to the end of 2008, we’ll need to raise additional money going forward,” adding that the company is in ongoing discussions with potential partners to develop the stroke therapy.

This past November, ImaRx and Royal Philips Electronics (Amsterdam, the Netherlands) signed a research alliance focused on using Philips’ ultrasound technology as part of ImaRx’ SonoLysis program (Medical Device Daily, Nov. 6, 2007).

ImaRx said it partnered with Philips specifically because Philips already has an emphasis on stroke and imaging of the brain. It’s one of the few areas where there’s a drug/device combination using the microbubble technology that’s therapeutic rather than diagnostic.

In July 2007, ImaRx launched an initial public offering seeking to raise $12.3 million and faced a deficit of $65.5 million (MDD, July 25, 2007).

Another company attempting to widen the ischemic stroke treatment window is CoAxia (Maple Grove, Minnesota). It is developing its NeuroFlo Perfusion Augmentation Therapy and says it is the first intervention which may improve blood flow to the brain up to 24 hours after the first signs of stroke.

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