Osiris Therapeutics Inc.'s double-barreled Phase III blowup last week with Prochymal for graft-vs.-host disease sent shivers through the stem-cell therapy community, vindicating nay-sayers who'd been predicting failure of the leading product candidate.

But the game, for Prochymal and for stem cells, is far from over.

"It's admirable that Osiris gave a shot to something that was a really bad inflammatory condition - something that was already exceedingly complex - and even in that arena shot for the moon," said Evan Snyder, director of the Del E. Webb Neuroscience, Aging and Stem Cell Research Center at the La Jolla, Calif.-based Burnham Institute for Medical Research.

"I don't consider this any kind of death knell" for research into mesenchymal or other stem cells, Snyder said. "If I were Osiris now, I would go back and look very carefully at [areas where Prochymal showed signs of efficacy], and figure out what were the good aspects, why didn't they get more. And then not give up."

Osiris is forging ahead. Based upon the results of the steroid-refractory GvHD trial, the company plans to file an amendment with the FDA to the expanded access program, broadening the entry criteria to include patients with severe GvHD of the liver - one area where Prochymal seemed to do better.

In the preliminary peek at data, both of Columbia, Md.-based Osiris' trials (one in steroid-refractory patients, one in acute first-line disease) missed their primary endpoints, though results were promising in a pair of subsets.

The 260-patient steroid-refractory trial got efficacy in 35 percent of patients on Prochymal vs. 30 percent given placebo, while the first-line study, with 192 patients, garnered a 45 percent number with drug, compared to 46 percent with placebo.

In the steroid-refractory trial, though, the primary endpoint in the per-protocol population of 179 patients neared statistical significance on the primary endpoint of durable complete response: 40 percent on drug vs. 28 percent on placebo (p=0.087).

Prochymal significantly improved the response in 61 patients with steroid-refractory liver GvHD, where the numbers were 76 percent vs. 47 percent (p=0.026), with the counts in durable complete response reaching 29 percent vs. 5 percent (p=0.046).

The news was brighter in 71 patients with steroid-refractory gastrointestinal disease, too: 88 percent vs. 57 percent (p=0.018). Pediatric subjects, 28 in all, showed a strong trend of improvement, as well, with 86 percent benefiting from the drug and 57 percent responding to placebo (p=0.094).

Osiris' protocol 265 tested Prochymal in the acute population when combined with steroids. Most patients in this trial were suffering from skin GvHD, which responded significantly better to steroids than had been previously reported in controlled trials, the company said.

The company made the most, too, of findings from protocol 280 - in the steroid-refractory GvHD setting - where the benefit of adding Prochymal to second-line treatment garnered a result that landed in the neighborhood, at least, of statistical significance in the per-protocol group, i.e., those patients who met inclusion and exclusion criteria.

But officially, Prochymal failed. Again.

The fizzle followed news in June that the drug did not significantly improve lung function in a Phase II trial in chronic obstructive pulmonary disease. In March, Osiris stopped a Phase III trial in Crohn's disease, blaming a higher-than-expected placebo effect. (See BioWorld Today, June 25, 2009, and March 30, 2009.)

Snyder called the GvHD results "promising" anyway, and said the same about the stem-cell field in general. Another company to make headlines last week, The Woodlands, Texas-based Opexa Therapeutics Inc. - which trumpeted positive Phase IIb results with its multiple sclerosis therapy Tovaxin, an autologous T cell vaccine - not long ago scored a $50 million stem cell deal with Novartis AG, of Basel, Switzerland, and the research area is staying strong. (See BioWorld Today, Aug. 10, 2009.)

Another firm favored by Snyder is Stem Cells Inc., of Palo Alto, Calif., which earlier this month in Cell Stem Cell published preclinical data showing that transplanted purified human neural stem cells delayed the loss of motor function in a mouse model of infantile neuronal ceroid lipofuscinosis, also known as Batten disease. The rodents turned up a statistically significant reduction in cellular waste buildup, protection of critical host neurons and delayed loss of motor function compared to the control group.

Batten disease afflicts infants and young children. Stem Cells Inc., with its approach, is bound for "modest success. It's not going to look as if they saved these kids, but [research] is going to show that these cells can make enzymes and factors that might be useful. They're on the road" to a viable therapy, Snyder said.

"The whole notion that stem cells make factors - and this goes beyond [Osiris'] trial and beyond mesenchymal stem cells - is really where the stem cell field is moving," he told BioWorld Insight. "It's more achievable in the short term than trying to replace cells."

Prochymal is partnered with Cambridge, Mass.-based Genzyme Corp. outside the U.S. and Canada. Oppenheimer analysts noted "minimal" impact for Genzyme as a result of the two trial failures, but Wall Street's view for Osiris was dimmer. Charles Duncan, with JMP Securities, found encouragement in the subset results but assumed another Phase III trial to replicate those data, which means a delayed launch of Prochymal.

Lazard Capital Markets was even less optimistic. Analyst Joel Sendek deemed it "likely" that the FDA will not grant broader entry to the expanded-access program (as Osiris plans to ask), and may even stop the program entirely. "While the company claims that a high placebo rate is the cause for trial failure, and not the lack of Prochymal efficacy, we believe this argument is a stretch and unsubstantiated," Sendek wrote in a research report, adding that Prochymal's latest failure in GvHD signals that the treatment probably won't succeed in anything else either.

Snyder, though, characterized Prochymal's latest woes as "a bump in the road" for stem-cell therapy. "You always swing for the fence," he said. The GvHD attempt with Prochymal "seemed logical, but [the disease] has so many organs involved. When you inject the cells intravenously, it gets stuck in many places. Most of them will get stuck in the lung. They won't make it to the gut or liver, and that could easily be what happened with them. Lungs are not the major area for GvHD, so now they have to figure out how to deliver the cells in a more targeted fashion."

Overall, stem cells "will be useful in inflammatory diseases like arthritis - things in that category, perhaps even helping with bone repair," Snyder said. "Neural stem cells and others might be useful in neurodegenerative diseases, and protect certain nerve cells from dying [in conditions such as] Lou Gehrig's disease, Parkinson's and spinal cord injuries."

The strategy holds potential in some aspects of MS and Alzheimer's disease, too, "where you're really trying to not necessarily cure the disease but short-circuit some of the expression of that disease," he said.

Precision stands as the main stem-cell challenge, Snyder said.

"There will be a flurry of trials with vascular administration," he predicted. "Some will be unsuccessful, some will be moderately successful. Then people will start figuring out easier ways to deliver the cells [efficiently]. For example, you can take neural stem cells and stick them into the ventricles. It just needs a little more work."

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