Novel Thrombolytic Microplasmin Safe in Acute Ischemic Stroke

Susan Jeffrey

October 02, 2008

October 2, 2008 (Vienna, Austria) — Phase 2 results with microplasmin, a novel thrombolytic agent that is thought perhaps to have some neuroprotective properties, have shown that the treatment was well tolerated and demonstrated "reasonable safety" when given out to 12 hours after symptom onset, researchers report.

Treatment was also associated with reduced induction of matrix metalloproteinases (MMPs), they note. These latter findings are "interesting and might suggest more protection of the blood-brain barrier," lead author Vincent Thijs, MD, from the University Hospitals Leuven, in Belgium, told attendees here. MMP activation plays a role in brain edema and hemorrhagic transformation after ischemic stroke.

Recanalization and reperfusion rates were on the order of about 30% and higher than with placebo, Dr. Thijs added. "Although I think these results are encouraging, we obviously need more studies to further develop this compound."

The results, from the Microplasmin in Treatment of Ischemic Stroke — Intravenous trial (MITI-IV), were presented here at the 6th World Stroke Congress. The trial was funded by ThromboGenics (Leuven, Belgium), manufacturer of the agent.

 

The future of microplasmin for this indication, though, appears to be uncertain. In a statement from ThromboGenics issued at the time these findings were released, Patrik De Haes, MD, chief executive officer of the company, says that he is "very pleased that we have been able to successfully conclude this study of microplasmin in patients with stroke."

However, he adds, "As we have stated previously, our current view is that it makes sense for ThromboGenics to move forward with the development of microplasmin for vascular indications only in cooperation with a partner, given the costs and risks involved." Instead, the company intends to focus its efforts on on phase 3 investigation of microplasmin in eye disease, he says, "where we already have generated encouraging clinical data."

Contacted by Medscape Neurology & Neurosurgery, Dr. De Haes confirmed that they have no plans to pursue the stroke indication themselves but have not yet established a partner. "Potential partners were awaiting these results, and in the coming months we will know more about their real interest," he said.

Bypassing the System

In the thrombolytic system, plasminogen is activated into plasmin by tissue plasminogen activator (tPA), Dr. Thijs explained. Plasmin then further decreases fibrin into degraded peptides.

"In order to bypass this system, you could infuse plasmin directly," he said, but noted that plasmin is difficult to produce in sufficient quantities. "Therefore, the sponsor of this trial designed a recombinant drug called microplasmin, which is a truncated form of plasmin," he said. The drug retains all protease activity and is able to degrade fibrin.

In preclinical tests, microplasmin reduced infarct size in different stroke models "and was potentially less neurotoxic than tPA," Dr. Thijs noted. "Some studies suggest less breakdown of the blood-brain barrier, and this may lead to possible increased safety."

In this phase 2a trial, 40 patients with ischemic stroke from 8 centers in Austria, Germany, and Belgium were enrolled between 3 and 12 hours after symptom onset and randomized to receive placebo or 1 of 3 ascending doses of microplasmin. Treatment was given as a 15-minute intravenous bolus infusion of 1 mg/kg, followed by a 1-hour infusion of 1, 2, or 3 mg/kg, respectively. The first 8 patients enrolled received the lowest dose (6 active, 2 placebo); the next 16 received 2 mg/kg (12 active, 4 placebo); and the last 16 patients received the highest dose (12 active, 4 placebo).

Patients were enrolled if they had a baseline National Institutes of Health Stroke Scale (NIHSS) score between 6 — later amended to 4 — and 22, he noted, and had to have a perfusion deficit on magnetic resonance imaging (MRI), although they did not require the presence of perfusion/diffusion weighted mismatch for inclusion. Exclusions were standard for the use of thrombolytic agents.

MRI was repeated within several hours of treatment to assess recanalization and reperfusion and at 7 days to estimate final infarct size. They also assessed clinical outcome at 30 days, but the primary analysis was of safety. Patient groups were well balanced, with a mean NIHSS score of 12; most were treated within 8 to 9 hours of symptom onset.

In terms of safety, there was 1 symptomatic intracerebral hemorrhage in the highest-dose group, which was fatal, and none with placebo. A second death occurred in the treated group, from pneumonia, toward the end of follow-up. There were no deaths in the placebo group. There were no cases of systemic bleeding with treatment vs placebo.

Biomarkers for Activity

Although underpowered to look at efficacy, they did examine some surrogate biomarkers that might give some hint of the drug's activity, including fibrinogen and MMP, he noted. They found significant depletion of fibrinogen with treatment in a dose-dependent fashion vs placebo. MMPs increased significantly in the placebo group, while in the treated group there was an again dose-dependent reduction.

Other clinical end points, including recanalization and reperfusion at follow-up, lesion growth from baseline to day 7, and improvement on the NIHSS of 8 points or achieving a score of 0 or 1, indicating good outcome, showed some trends toward efficacy, although clearly none were statistically significant in this small trial.

For example, lesion growth on MRI was slightly but nonsignificantly reduced with treatment vs placebo. Reperfusion within 8 hours of treatment was seen in 23% of treated patients vs 10% of those receiving placebo. In patients with TIMI 0 flow, indicating total occlusion, recanalization was achieved in 33% with treatment vs 14% in the placebo group.

At day 30, however, more patients in the placebo group had improved by 8 points or achieved an NIHSS of 0 or 1, occurring in 40% of placebo patients vs 30% in treated patients. When they used improvement by 8 points or an NIHSS of 0 to 2 as the end point, the results were switched, with 37% for treated patients and 30% for placebo patients. Again, none of these results were statistically significant, nor was there a difference in outcomes using the modified Rankin Scale.

"When you design a trial like this you mainly aim for safety and maybe some hint that there might be something interesting about the compound, and I think we achieved both goals," Dr. Thijs told Medscape Neurology & Neurosurgery. "The rate of bleeding even with this extended time window was quite low, and second, there were some hints — we also have some pharmacokinetic and pharmacodynamic data that I couldn't go into during the presentation — that it has some potential not only for clot breakup . . . but for the [blood]-brain barrier breakdown."

He also noted, however, that the future of this drug is unclear given the company's decision to concentrate its efforts on the eye-disease indication. "Of course, it's a huge cost to go from a 40-patient trial to the probably several-hundred-patient trial that would be needed to show biological efficacy in a phase 2b study." The company is looking for partners to further develop the compound in stroke.

Obscuring Potentially Good Effects?

During the session, Dr. Thijs was asked why trials such as this are trying to recanalize patients so late after their strokes, out to 9 and 12 hours, when all that might be accomplished is to obscure potentially good results that might be seen with these agents if they were delivered earlier.

"Of course you're right that these compounds need to be tested earlier in time, but you also need to establish some sense of safety, and since we think it's ethically impossible to randomize patients within 3 hours with an unproven drug, this is the only way to go at this moment," Dr. Thijs replied.

The study was supported by ThromboGenics. Dr. Thijs reports no conflict of interest.

6th World Stroke Congress: Abstract PL03-05. Presented September 27, 2008.

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