An intriguing "excellent outcome" in certain patients plus Multistem's clean safety profile may let Athersys Inc. and Japan partner Chugai Pharmaceutical Co. Ltd. refine the targeted patient population for better results in future trials, but for now the cell therapy has failed overall in top-line data from an exploratory phase II study in ischemic stroke.

"The results are consistent with our view regarding Multistem's ability to modulate the immune system following stroke," William Lehmann, chief operating officer, told BioWorld Today. "Unfortunately, we just didn't have the [treatment] window right for this study."

Shares of Cleveland-based Athersys (NASDAQ:ATHX) closed Friday at $1.40, down 78 cents, or 35.8 percent, after the firm disclosed that the study missed the primary endpoint of global stroke recovery and the secondary endpoints of performance on individual components. But when the analysis was limited to patients who got Multistem within 36 hours (n = 27), the response rate improved markedly on the primary endpoint (odds ratio 2.21, p = 0.07) and on the proportion of subjects described as doing especially well (p = 0.03), gaining an "excellent outcome." The company also pointed out that Multistem treatment was associated with lower rates of mortality and life-threatening adverse events, infections and pulmonary signals.

"Our design was developed based on our preclinical work, but recent third-party work suggests that earlier treatment (sub-36 hours) can be important in acute neurological trauma, and our results seem to confirm this," Lehmann said. "The other evidence – lower mortality, lower infection and pulmonary events, and even trends to benefit in excellent outcome in the full patient group – confirm activity and are consistent with our view of immune system modulation." Among all subjects who received Multistem treatment, 15.4 percent achieved the excellent outcome, defined clinically as attaining mRS 0-1, NIHSS 0-1 and BI ≥95, compared to 6.6 percent of patients that received placebo, (p = 0.10).

Caused by a blockage of blood flow in the brain, ischemic stroke accounts for more than 85 percent of all strokes in the U.S., according to the American Heart Association. More than 2 million people suffer a first-time ischemic stroke each year in the U.S., European Union, and Japan combined, and more than 15 million people globally.

The stroke blowup follows another phase II Multistem failure in ulcerative colitis (UC) last April, when the product failed to moderate the severity of disease in patients with treatment-refractory disease. In the fully enrolled phase II study of 128 patients with chronic, advanced UC, a single administration of Multistem did not show statistically significant improvement compared to placebo in either of two primary efficacy endpoints: change in endoscopic (modified Baron) score from baseline at eight weeks and change in Mayo rectal bleeding subscore from baseline at four weeks and eight weeks. (See BioWorld Today, April 29, 2014.)

New York-based Pfizer Inc. partnered with Athersys in a 2009 deal valued at a potential $111 million, though the company received just $6 million up front. The pharma giant also selected the inflammatory bowel disease indication. "UC was a different type of study with a very different patient population – chronic disease, with patients on alternative immune-modulating treatments for many years, over 10 years on average," Lehmann said. "Our takeaway from the results was that repeat dosing could be necessary to treat these patients." (See BioWorld Today, Dec. 22, 2009.)

PHASE II ONGOING IN AMI

Early last month, Tokyo-based Chugai and Athersys disclosed their partnership and licensing pact to exclusively develop and sell Multistem for stroke in Japan, where the aging population means an increasing health care burden, with the indication on the rise. Athersys has begun preparations for clinical development in Japan, including engagement with the Japanese Health Authority.

Chugai will be responsible for the development and commercialization of Multistem for ischemic stroke in Japan, and Athersys will have responsibility for product supply, collecting an up-front cash payment of $10 million from Chugai, with more payments as the program advances. Athersys could get development and regulatory milestone payments from Chugai of up to $45 million, and up to about $150 million more if sales goals are reached.

For stroke, the gold standard tissue-plasminogen activator (tPA, sold as Activase by Roche AG) is only for patients who are treated three to four hours after a stroke, i.e., about 5 percent of patients. Athersys enrolled 126 ischemic stroke patients to receive a single intravenous dose of Multistem or placebo within 24 hours to 48 hours after the event (average 30 to 34 hours in trial). The subgroup where researchers found encouragement "also excluded patients who received both tPA and mechanical re-perfusion," noted Piper Jaffray analyst Edward Tenthoff, and "had less than half the initial Multistem cohort (27/65), severely limiting power. This analysis indicates that Multistem may still increase the therapeutic window for stroke patients ineligible for tPA, however more studies will need to be conducted to confirm this effect." Tenthoff wrote in a research report that, "including the Chugai up-front [payment], we estimate Athersys holds pro forma cash of $36 million, so will likely need to raise additional capital." He maintained his "overweight" rating on the company's shares but cut the price target from $4 to $2.

Multistem is a biologic product manufactured from human stem cells from adult bone marrow or other non-embryonic tissue sources. Unlike other cell types, after isolation from a qualified donor Multistem may be expanded on a large scale and stored in frozen form until needed. Cells obtained from a single donor need no genetic modification and may be used to produce banks yielding hundreds of thousands to millions of doses of Multistem, an amount far greater than other stem cell types can achieve, Athersys noted.

"We will continue to move forward with our current programs, while determining the right path for stroke," Lehmann said. "We believe there is good potential for Multistem in acute myocardial infarction [AMI], based on earlier clinical trial results, and also for the pulmonary area given our nonclinical study results and the impact on mortality and stroke comorbidities in this stroke study." A phase II trial in AMI is "progressing, and our target is to have top-line results in 2016," he said. In the summer of 2013, the company disclosed that it was awarded a Small Business Innovation Research Fast Track grant from the National Heart, Lung, and Blood Institute to support the experiment, providing up to $2.8 million in support over the course of the study as progress is made.