Disappointing Results for “Prochymal” trials
In a recent article I described a hopeful new technology called “Prochymal” that I hoped would much improve control of graft-versus-host disease – the single most important hurdle standing in the way of safer stem cell transplants. I reviewed very encouraging results reported from Phase – II trials and I hoped the company’s pivotal Phase – III trials would confirm the earlier results and thereby earn rapid FDA approval.
I am sorry to tell you that the just announced results sound a whole lot less encouraging than I hoped. Below is a excerpt from the company’s statement.
Osiris Therapeutics, Inc.today announced preliminary results for two phase III trials evaluating Prochymal for the treatment of acute graft versus host disease (GvHD). GvHD, the most common complication of bone marrow transplantation, is a life-threatening disease for which there is currently no approved treatment. Prochymal showed significant improvements in response rates in difficult-to-treat liver and gastrointestinal GvHD, however neither trial reached its primary endpoint.
Key findings from the GvHD trials include:
- There was no statistical difference between Prochymal and placebo on the primary endpoints for either the steroid-refractory (35% vs. 30%, n=260) or the first-line (45% vs. 46%, n=192) GvHD trials.
- The primary endpoint for the steroid-refractory GvHD trial (durable complete response) for the per-protocol population approached statistical significance(40% vs. 28%, p=0.087, n=179).
- In patients with steroid-refractory liver GvHD, treatment with Prochymal significantly improved response (76% vs. 47%, p=0.026, n=61) and durable complete response (29% vs. 5%, p=0.046).
- Prochymal significantly improved response rates in patients with steroid-refractory gastrointestinal GvHD (88% vs. 64%, p=0.018, n=71).
- In pediatric patients, Prochymal showed a strong trend of improvement in response rates (86% vs. 57%, p=0.094, n=28).
Bitter Reality
One more time, I (we) have to face the reality that it is not a done deal until the last bit of information is in, until well designed and well conducted late stage clinical trials prove new drugs are really as good as they seem to be at first blush. The FDA is rightly unimpressed by trials that do not meet their primary endpoints. Neither am I. Of course, these results will be parsed every which way by experts and company spokespersons. But it seems clear Prochymal flunked a couple of very important tests.
We have been here before. Remember Genitope, their custom made “MyVax” vaccine was going to cure CLL with little to no toxicity? The company went out of business after it failed to show benefit in a pivotal trial. How about Genta’s “Genasense” (oblimersen)? It too failed to meet it pre-defined primary endpoints. So many drugs fall by the wayside when they face late stage trials. The list is depressingly long. Even my favorite Ofatumumab is teetering on the edge, FDA approval has been delayed longer than I hoped.
I try hard not to get too enthusiastic about Phase -II trial results. I have been burned too many times, I have come by my cynicism the hard way. But some times it is hard to resist the possibility of breakthrough good news just around the corner. Hope springs eternal, especially when there is precious little else to keep us going. I was really rooting for Prochymal’s successful completion of their Phase – III trials. So many patients with aggressive CLL need transplants. But until we learn to control GVHD more effectively, transplants will continue to be the toughest therapy decisions patients and their families have to face.
Well guys, I think we can put Prochymal on the back burner for now. Sorry. I wish I had waited a little longer, waited for the Phase – III results before publishing my glowing review just a few weeks ago. The least I can do is bring this disappointing sequel to your attention as well, hot off the presses.
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14 comments on "“Prochymal”: Less Than We Hoped For"
We certainly can’t blame you (or anybody) for being optimistic, but now we know. As you said, that is why we do trials. On the positive side, the more products we test the better the possibility of finding one that works.
Chaya, Thank you for keeping everyone current! Hope is something everyone needs, even if the end brings disappointment. We know that attempts are being made to solve the problems and answer the questions of why things fail. Even in failure there is sometimes a light that leads to success. And, that is what we all hope for.
Maryann
Failure is a critical part of any scientific advance. If this is truly a dead end, then it is best that the researchers know it now and re-orient their work toward a more productive end.
Chaya, thanks for the update. As a scientist I always feel that any good data leads the way forward. There may be futile approaches that are abandoned early, details in the clinical data that lead to a more circumscribed application, leads on what to tweak next time. Everyone who worked to get the trial initiated and conducted, including the patients who participated deserve our thanks.
I must be missing something here, Chaya…the numbers above indicate to me a positive outcome for the trial.
With comments like,”significantly improved response”, and
“strong trend of improvement in response rates”, I can’t see how the treatment is a total failure.
I would think that with numbers like these for “steroid-refractory liver GvHD” producing “durable complete response (29% vs. 5%)” that it would be worth using in at least some cases.
Am I missing something?
Harley
Thank you for the latest information, Chaya. As a veteran science writer, I’ve written about countless “possible” cures or treatments that haven’t panned out, and often have felt guilty about raising people’s hopes despite the caveat “that more research needs to be done.” As they say in Hawaii, “Imua!” — Onward.
Chaya,
I have CLL and have been told I have four years until my next chemo. I have been feeling so much more ‘alive’ since your recent postings about transplants.The idea that there might actually be a glimmer of a cure on the horizon gave purpose and shape to my life. There’s nothing worse than standing looking down into the abyss,just waiting for the inevitable.A glimmer is mighty bright in such a dark place; please keep them coming.
Molly
Chaya, what are your thoughts on the Kanzius device and direction relating to carbon/gold nanoparticles and radio wave destruction for the treatment of cancer. Seems like plenty of attention is being drawn to it. Dr Steven Curry and other MD Anderson personnel seem very excited about this direction. Your thoughts would be appreciated. I personally think this has lots of momentum and is going in the right direction while all those drugs to slow the disease down get most of the attention. This is a whole new idea of treating cancer. Kanzius has got the idea. Joe B.
Chaya,
As Thomas Edison once said about the invention of the light bulb, “I have not failed. I’ve just found 10,000 ways that won’t work.” For each failure we are one step closer to success. At least when a phase III trial does not meet expectations, we move on to other promising trials. Eventually, we will get there. Faith Chaya, it is all we have to go on at the moment and I have faith that one day CLL will be curable. Please keep up the wonderful work you are doing for all of us!
Elaine
Chaya,
Have you seen any data on the effects of a stem cells transplant with a slight mis-match (9 point match mismatched on the A alle)as opposed to a cord blood transplant? I’m assuming the GvH would be a greater G v. H problem with the mismatch, but with no perfect match available one has limited choices, if any.
Pam
Chaya,
Any links to the actual articles?
I agree with Harley. It doesn’t look like a complete bust. Of course Wall Street may view the results differently!
CHAYA,
Change of subject. Has anyone been successfully treated for lung
granulomas? If so, what is the scoop?
Angie
Chaya, thank you again for keeping me/us up to date!
Not wanting to throw the baby out with the bath water, the take-away from the “failed” study is that it still seems that MSC therapy has promise for liver and GI tract GvHD – nasty forms of the disease even for steroid-responsive patients. It was considered for my wife nearly a year ago at MDA when she was about D+45, but study qualification was marginal, so finally opted for Infliximab with fortunate results. Steroid treatment is certainly no walk in the park for those who do respond, so alternatives to that course are always of interest to help wean patients off the steroids. If not the silver bullet, Prochymal might still be another useful weapon in the arsenal to be used in less broadly defined circumstances.
Eric
You guys are terrific!
Osiris and the failure of Prochymal is all the news in biotechnology world today. Here is the link to an article in the New Scientist on the subject. The article has further links to other sources and comments.
http://www.newscientist.com/blogs/shortsharpscience/2009/09/adult-stem-cell-therapy-fails.html
Harley, there is little doubt the results are disappointing. Look at the first bullet point in the company’s own statement (quoted in my review above). The rest of it is PR stuff, slicing and dicing the results to look at the three quarters empty glass in as optimistic a manner as possible. It is always possible to dissect any given set of data to find patterns that look favorable. But scientists (and the FDA) rightly look at such after-the-fact comparisons as so much technical spin. Clinical trials must prove success on points of comparison agreed to ahead of the test – the primary endpoints. Sub-set analysis is a weak attempt to salvage something from a bad situation.
Here is an analogy: let us say you were in a two man race, a 100 meter dash. You against the present champion. The race is run and he wins – perhaps not by a huge margin but clearly he wins. What would you think if I reported that yes, the other guy won, but you looked ever so much more handsome and non-sweaty at the finish line? These were not agreed to criteria for the race and they have little or no impact. If the good looks of the runners had been the point of the race, agreed to ahead of time, then the issue becomes relevant.
Kanzius machine: sorry to burst your bubble, I do not see much possibility of this approach even getting into late stage trials any time soon, let alone becoming commercially available. Even early stage human trials are down the road.
Lung granulomas – I do not know anything about this subject. Not our sand box, sorry.
Mis-matched (9 out of 10) is likely to cause more GVHD but it is important to know where exactly the mismatch is. We are learning more about the art of matching donor to host and some mismatches are more important than others. If no suitably matched adult donor is available, I strongly urge patients to consider a matched umbilical cord stem cell transplant. It is MUCH easier to find good matches using this source of stem cells.
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