Staff Writer

SAN DIEGO - During the American Heart Association's 2009 International Stroke Conference, held last week, panel after panel bemoaned the fact that tissue-plasminogen activator (t-PA), marketed by Genentech Inc. as Activase (alteplase), is the only FDA-approved stroke drug, and its use is severely limited by a delicate risk-benefit balance and tight three-hour time window for administration. (See article this issue.)

Stroke meets many of biotech and pharma's requirements for an attractive development opportunity, explained Warren Wasiewski, vice president and chief medical officer of Neurobiological Technologies Inc. It's a large global market, but it can be penetrated by a niche sales force targeting stroke centers.

Additionally, with t-PA only being used in about 2 percent of stroke patients, there is a large unmet need and almost no competition.

But despite all that, big pharma has very little appetite for developing new stroke drugs, Wasiewski said during a panel. "There have been too many failures," he lamented.

Among the casualties are Neurobiological Technologies' own Viprinex (ancrod), which was the subject of two Phase III stroke trials that were halted in December after a futility analysis indicated they were unlikely to show benefit. (See BioWorld Today, Dec. 18, 2008.)

Other failures include Renovis Inc. and AstraZeneca plc's NXY-059, which was discontinued after failing a Phase III study, and Nuvelo Inc.'s alfimeprase, which had failed two Phase III studies in peripheral occlusion and catheter occlusion before being tried in stroke and eventually discontinued as Nuvelo did a reverse merger with ARCA Biopharma Inc. (See BioWorld Today, Oct. 27, 2006, and Sept. 26, 2008.)

There also have been plenty of smaller setbacks: Wyeth Pharmaceuticals ended a Hedgehog agonist partnership with Curis Inc. in stroke and other indications, and Ambit Biosciences Corp. discontinued a preclinical stroke program.

Meanwhile, a German study of anemia drug Eprex (epoetin alfa, Johnson & Johnson) in stroke caused an imbalance of deaths, and Stem Cell Therapeutics Corp.'s Phase IIb stroke trial, which also involves EPO, remains on hold. (See BioWorld Today, March 11, 2008, and Sept. 19, 2008.)

Some failed candidates continue to move forward: Paion AG's clot-buster desmoteplase failed a Phase III stroke trial and got dumped by partner Forest Laboratories Inc. only to be picked up by H. Lundbeck A/S, which started two new Phase III trials in December. (See BioWorld Today, June 4, 2007, Aug. 31, 2007, and Jan. 2, 2008.)

And sometimes moving forward in the face of a setback can pay off: ImaRx Therapeutics Inc. ran into trouble with intracranial hemorrhage associated with high doses of stroke drug MRX-801, but Phase I/II data presented at the conference showed that lower doses improved recanalization and clinical outcomes without bleeding problems. (See BioWorld Today, Jan. 7, 2008.)

Other acute stroke programs in development include ThromboGenics NV's Phase II microplasmin, Athersys Inc.'s Phase I adult stem cell product MultiStem, Remedy Pharmaceuticals' preclinical ATP gated channel program, and Aldagen Inc.'s preclinical adult stem cell program, while other companies are trying a preventative approach.

Why have there been so many failures?

Aside from the fact that nine out of 10 biotech products fail, and the brain is a particularly tricky organ that lowers those odds, Claiborne Johnston, of the University of California at San Francisco, said a review of more than 1,000 preclinical stroke drugs showed no difference in data indicating a likelihood of success for those that were advanced compared to those that were shelved.

Wasiewski also noted that a lot of companies tend to skip Phase II in stroke trials because the treatment effect is too small to achieve statistical significance in a small group of patients. Jumping from poor animal models and Phase I safety data into a large Phase IIb/III study can lead to late-stage failures, he said.

William Barsan of the National Institutes of Health's Neurological Emergencies Treatment Trials (NETT) Network said he thinks the problem is "an issue of trial design." Stroke trials often use arbitrary timing and doses, he said, and he encouraged sponsors to pursue more adaptive trial designs.

Barsan said NETT has not conducted any industry-sponsored trials yet, but the group could "essentially act as a CRO" for smaller biotech companies.

NETT is interested in large, Phase IIb/III or Phase III trials with simple protocols that are designed with clinical impact in mind, he said.

The network currently is participating in the ALIAS trial, which is looking at high-dose, intravenous human serum albumin in stroke.

Billy Dunn, a neurologist at the FDA, also noted that some Phase III stroke trials have failed because they've been based on post-hoc subgroup analyses from failed Phase II studies.

He encouraged stroke trial sponsors to maintain a "rigorous methodology" and to take advantage of tools such as Subpart E, fast-track, priority review, single-trial approval, treatment investigational new drug applications, and waivers of informed consent, as appropriate.