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TOPIC: Aastrom CLI halted due to resource issues

Aastrom CLI halted due to resource issues 27 Mar 2013 11:55 #340

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Surely most of you read about this already- for those who did not- ASTM has the same issues in finding a partner apparently.
Zack´s Napodano was writing he foresaw a deal with Takeda on CLI.
Now you know the real story... :bye:

Aastrom Biosciences Announces Strategic Change in Research and Development Programs to Focus on Dilated Cardiomyopathy and Other Rare Disease Indications
Press Release: Aastrom Biosciences, Inc. – 2 minutes 17 seconds ago


Focus shifted to Phase 2b ixCELL-DCM clinical study and the development of ixmyelocel-T for dilated cardiomyopathy, an orphan drug indication.
Company to stop enrollment and end Phase 3 REVIVE CLI study following strategic program review.
Corporate restructuring will significantly reduce operating expenses and capital requirements.
ANN ARBOR, Mich., March 27, 2013 (GLOBE NEWSWIRE) -- Aastrom Biosciences, Inc. (ASTM), the leading developer of patient-specific expanded multicellular therapies for the treatment of severe chronic cardiovascular diseases, today announced a strategic change in its research and development programs to focus on the clinical development of its lead product, ixmyelocel-T, for the treatment of dilated cardiomyopathy (DCM). Aastrom, which recently initiated the Phase 2b ixCELL-DCM clinical trial, previously received a U.S. orphan drug designation for the use of ixmyelocel-T in the treatment of DCM. As a result of the strategic change, Aastrom will stop enrollment and end the Phase 3 REVIVE clinical trial in patients with critical limb ischemia (CLI). In addition, the company is executing a corporate restructuring that will reduce staff and operating expenses by approximately 50 percent.
Nick Colangelo, president and chief executive officer of Aastrom, stated: "We completed our strategic review of the CLI program, including an evaluation of the challenges in enrolling patients in the REVIVE study and a recent determination that the CLI program would not be supported by a partner in a timeframe that would impact the pace of enrollment of the study. Based on this review, we have decided that the best path to commercialization of ixmyelocel-T is to focus aggressively on the DCM program. We will begin treating patients in the Phase 2b ixCELL-DCM clinical study within the next few weeks. In our earlier Phase 2a DCM clinical trials, ixmyelocel-T was well-tolerated and efficacy observations were consistent with improved function of impaired myocardium in patients with DCM. In addition, preclinical results demonstrated that ixmyelocel-T was protective of ischemic heart tissue in a murine model of heart failure. These findings strongly support the decision to focus our resources on the development of ixmyelocel-T for the DCM orphan indication."
The ixCELL-DCM trial is a randomized, double-blind, placebo-controlled Phase 2b study. Approximately 108 patients will be enrolled at about 30 sites in the U.S. In the study, ixmyelocel-T is administered via catheter-based injections to patients with advanced heart failure due to ischemic DCM. The primary endpoint of the trial is the average number of events per patient, which include all-cause mortality, all-cause hospitalizations or unplanned hospital visits to treat worsening heart failure. Patients will be followed for a total of 12 months.
Mr. Colangelo added: "We appreciate the contributions of all of the participants in the REVIVE clinical program and continue to believe that ixmyelocel-T has great therapeutic potential to treat patients with CLI. Our Phase 2b results demonstrated that ixmyelocel-T was efficacious and well-tolerated in patients with CLI. However, we have determined that the optimal use of our resources at this time is to focus on the development of ixmyelocel-T for DCM and other rare disease indications where clinical development may require smaller studies with lower costs and a shorter path to regulatory approval. We also plan to continue to explore the use of our proprietary Aastrom Replicell system to develop new cell therapy products for other areas of unmet medical need."
He further stated: "This was a difficult but necessary decision, and I appreciate the diligence and support of my colleagues in our effort to define the best path forward for Aastrom. Based on all of these considerations, I believe this is the right course of action for our company and the best way to create sustainable long-term value for our shareholders."

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An early assessment what was about to happen 06 Apr 2013 13:07 #366

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Thank you Alexey- enjoyed the article too. Reading it, it brought back memories of communications I had in 2009/2010 with an industry insider of my own trade (financial-NOT medical) who since 1992 had been involved in the cell industry when a peripheral blood cell collector which was targeted for cancer applications. These discussions went anonymous over a board mail system and were private, so I would never disclose them, but I do recall he did write a public post after the initial P2 CLI results were announced in February 2010- I think it was. In retrospect I think those comments are worth sharing-
<What do you make of the Aastrom reported results?>

OK, I am going to get dressed in my flame-proof suit before answering this one. The rest of you please stand-by with fire hoses and lots of water; I may need it.

Objectively, based on this data Aastrom is well and truly screwed. These are terrible results that preclude any chance of getting a partner in either the CLI or DCM indications any time soon, if ever. My best advice at this point, and I am not exaggerating, is to sell what you have and move on with a view to reloading in two years. That is a sad epitaph for a once promising technology, but realistically more than 90% of all new technologies in the biotech world fail.

Why am I so down on Aastrom this morning? It is because the cells are obviously not generating new blood vessels and if the cells can't generate new blood vessels then the cells cannot heal either an ischemic limb or the heart. Aastrom has touted their technology for years as a replacement for large volume bone marrow so it is fair to ask “how do these results compare with large volume bone marrow?” Are they better, worse, or about the same? We would not expect better, but Aastrom should have demonstrated "about the same" efficacy. They didn't. Start by taking a sober look at the Japanese results published in 2002. I think the article is available on-line to anybody that wants to find it (not sure, I have a PDF saved on my computer). If not, most libraries can get reprint from back issues of Lancet. The citation is:

"Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial" Author is Tateishi-Yuyama, et al. Lancet; Vol 360, Issue 9331, Pages 427-435.

The problem with CLI patients is lack of blood flow to the peripheral limbs. The arteries clog up with plaque just like the arteries in the heart clog up. Indeed, most of the patients with CLI also have heart disease, and the vast majority have diabetes or some other systemic metabolic disease. Surgical interventions that increase blood flow, including peripheral stents, popliteal artery by-pass grafts, medications like Plavix, and growth factor therapies like Regranex are known to work. When blood flow increases the wounds heal and major amputation is avoided. The Japanese histology and imaging proved that endothelial-lineage cells differentiated into new blood vessels. In Aastrom's case there was no statistically significant difference in primary wound healing which is a clear indication that new vessels were not formed or, if they were, that they were not patent vessels.

The fine points of the science aside, what really matters to physicians, patients, and reimbursement is avoidance of major amputations. If a therapy only delays the inevitable for a short time, which is what Aastrom is saying here, it does not justify the cost of the treatment and it will not inspire widespread adoption in the market. Physicians are not going to put their patients through a very expensive and painful procedure only to cut the limb off two months later especially if the patient has continued rest pain.

The release did not mention any success with other quantitative measures (ankle-brachial index, transcutaneous oxygen pressure, etc.) which I interpret as statistical failure since if those had been positive Aastrom surely would have mentioned it. Most tellingly, the press release made no mention of the very important secondary functional endpoints (rest pain, pain free walking). If the patient remains bed ridden and in pain while awaiting amputation, the quality of life is quite arguably lower than with an earlier amputation. Who cares if the amputation is delayed if the patient is in pain and can't even walk across the room?

Worse yet, Aastrom ran this trial against a placebo (i.e. saline injection) while the randomized trial run by the Japanese used peripheral blood as an active control (peripheral blood contains at least a few stem cells). In Japan, 39 of 45 patients evidenced improvement in limb status (actually 39 out of 43 because two died from heart attacks and did not complete the follow-up). Given the data Aastrom released they did not do nearly so well even though the control was a placebo rather than a biologically active substance. Six months is plenty of time to show results (about 1.5 cycles of tissue remodeling) since the Japanese results were based on a 24 week follow-up period.

Why did this happen? Maybe the Aastrom process expands a lot of certain hematopoietic cells but fails to expand a sufficient number of endothelial-linage progenitor cells. Maybe too many cells die in transport from the Aastrom facility to the treating hospital. Maybe the therapy is highly technique dependent and the Japanese are better at this than the Aastrom centers. Regardless of the reason this product is not going to market as is. The company needs to sort out the root cause of these results, fix the problem if it is fixable, and restart Phase II. FDA would almost certainly let them proceed to Phase III given that the current product is safe, but that would be a horrible waste of money.

Aastrom is looking at adding at least three years to the time line and expenditure of at least $40 million, and even then success is not guaranteed. CLI is a much simpler condition to treat than DCM. Months ago I said that if the CLI results were strong then DCM had a chance of working, but that if the CLI results were bad or equivocal then DCM was almost certain to fail. I have not changed that view.

Sorry for the downer of a message, but I can’t come up with a better spin given this news. Aastrom cells failed to grow new blood vessels as well as large volume bone marrow, and at the end of the day that is all that matters.


Re: Too much guess work
As I said, I am out of Aastrom and this point and won't be returning here frequently from this point forward. Let me leave you with some thoughts and suggestions:

1. Read <b><u>ALL</u></b> the studies and ask the tough question: are the Aastrom results significantly better than other experimental therapies that are either cheaper or easier to administer? My conclusion is no, your conclusion may be different.

I read a <b>lot</b> of clinical studies involving a lot of different therapies for CLI and DCM, not just the stem cell trials. When somebody says "there are no other treatments available" then you need to keep your hand on your wallet. There are many companies working on alternatives for any unmet clinical need with a significant number of patients, whether that need is CLI, DCM or toenail fungus. Never believe any medical device, pharma, or biotech that says that they are the only game in town.

Last evening I had a chance to listen to some of the other parameters discussed in the conference call. While Aastrom's results to date are not horrible from a clinical perspective, they are similar to outcomes with other therapies. Since the therapy is more complicated, more invasive, and is certain to be more expensive the economic returns are likely to be ethereal.

2. Stem cells are the standard of care in Japan for CLI, and in Germany and some other countries for myocardial infarction. There are plenty of winners, and the data looks good at the five year follow-up, which is why there are 14 "centers of excellence" in Japan providing this therapy on a routine basis. Why it hasn't make it to the US is a mixture of "not invented here" syndrome, a historically complicated regulatory environment (recently this has gotten better), politics (which should not be an issue with adult bone marrow, but it is anyway), and the business model. Until pharma has a product where they can charge a premium price they are not going to throw their marketing muscle behind it, and there is no way to convince a hospital to pay big bucks for the patient's own tissue unless there is some value added. Bone marrow spun in a centrifuge and injected via syringe is not value added.

3. While I know it is tough for retail investors to assess, don't forget about the molecular biology and biochemistry. It is all about the biology. If Aastrom cells were creating new microvascular circulation, which means that they are delivering a threshold does of endothelial progenitor cells, they would have had much better wound healing and statistically significant improvements in limb salvage. rPDGF-BB does that, rVEGF does that, Aastrom did not. Until there is a credible explanation for those results, be cautious.

4. Don't be unduly influenced by the anecdotes. Six month and twelve month amputation-free survival for patients with CLI has been reported in the medical literature in the range of 65% to 75%, not 0% as some would have you believe. If two-thirds of properly treated patients don't get amputated, does an anecdote about a single patient that kept their leg tell you anything meaningful? Similarly, if one-third do get amputated would an anecdote about a patient that lost a limb be sufficient reason to panic? The answer in both cases is no.

I still believe in stem cells and I still believe that Aastrom had a scientifically sound approach to the field, despite the management issues. However, the proof of efficacy is not there in these cardiovascular indications so it is time for me to focus my energies on more promising investments. For those of you that choose to stay invested your patience might yet pay off when Aastrom has data from several hundred patients even though the odds have gotten longer.

I wish you all the best of luck; the world needs a stem cell success story.

<b>If they are not showing any statistical significance to overall healing, why then are they proceeding to take this to phase 3?</b>

Consider the alternatives:

1. Proceed to Phase III. As Admiral David Farragut said during the Battle of Mobile Bay "damn the torpedoes, full speed ahead." Tim is saying "damn the interim results, we are going to Phase III." Aastrom could not show efficacy with 46 patients but they think they can overcome the noise in the data with just 250? I have not seen the raw data or cranked my own size estimates, but at first blush that simply does not pass the statistical smell test.

History has shown that many small biotechs forge ahead to Phase III when a larger company with a more robust development pipeline would write it off at Phase II and move to the next opportunity. The failure rate in the overall drug industry at Phase II is 50%, but it is lower than that for small companies. Why is that? When a company is small and has only one product they tend to go all-in and play the cards they have been dealt to the bitter end. Unlike poker, you can't bluff the FDA so this strategy works on rare occassions. Not surprisingly, there is a strong inverse correlation between the rate of failure in Phase III and the market cap of the sponsoring company. Failure rates are especially high for small companies that press ahead without a large industry partner that has validated their business concept and technology.

2. Shut down the company. This might be the most rational thing to do. Close down, sell off the assets, and return the excess cash to the shareholders. However, that would require management to volunteer to become unemployed in a very iffy jobs market. Who wants to be out of a job in 2010, especially with other stem cell stocks failing (Osiris for example). Michigan is not a hotbed of biotech development or much of anything else these days. Try selling a house in the Detroit area so that you can move to Southern California where the biotech business is concentrated.

3. Find the problems with the technology and fix them. As I posted earlier, that would take time and money and the problems might not be fixable. The company may not be able to raise more money so this option might be more theoretical than practical.

Faced with those three alternatives what would your choice be if your name was Tim or Elmar?

That is all that is relevant- my take is that neither Tim or Elmar had the right answer- the new CEO did. :winky:
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Board moderator and Site-owner. I still regret the day I started analysing the prospects of MacroPore (now Cytori) back in 2004- a left-over from the tech-bubble at that time from the century change in my portfolio- and became addicted to Cytori´s fat cell technology. :cry:

An early assessment what was about to happen 08 Apr 2013 03:29 #371

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Very interesting posts concerning ASTM. Reassuring confirmation for adipose derived Stromal Vascular Fraction being a very cost effective treatment vis a vis the alternatives.

I particularly liked the following quote: "Stem cells are the standard of care in Japan for CLI, and in Germany and some other countries for myocardial infarction. There are plenty of winners, and the data looks good at the five year follow-up, which is why there are 14 "centers of excellence" in Japan providing this therapy on a routine basis."

The above quote indicates that their is considerable experience in Japan in the CLI indication. Given this experience it is quite reassuring to see CYTX having a trial up and running for a similar indication :

ir.cytori.com/investor-relations/News/news-details/2012/Multicenter-Investigator-Sponsored-Cell-Therapy-Study-for-Peripheral-Artery-Disease-Approved-in-Japan1131017/default.aspx

I would note that the lead investigator Toyoaki Murohara had tried bone marrow derived stem cells in the past but now seems to believe that ADRC are the way to go.

www.google.gr/url?sa=t&rct=j&q=toyoaki%20murohara%20bone%20marrow%20stem%20cells&source=web&cd=8&ved=0CIMBEBYwBw&url=http%3A%2F%2Fpdf.highwire.org%2Fstamped%2Fatvbaha%2F24%2F12%2FE192.full.pdf&ei=IntiUdzyK8e4O-fYgDg&usg=AFQjCNEvlvhIDpZEedweTOi-e2MGvCf8nQ&bvm=bv.44770516,d.ZWU

As the CYTX trial is a single arm trial with the longest review date being at 6 months we could "theoretically" receive trial data/information relatively quickly. However for data to be seen, CYTX has to have concluded a partnership deal that will provide it with financial resources sufficient to carry on in such a way that the market players will choose to align themselves with management, rather than against it. :vegas:

It will take a daring BP player to partner with CYTX........... lets not forget that Mesoblast partnered with TEVA, primarily a generic drug player, via Cephalon and a CEO who was dying but felt this was a must do deal. I think we are close to a deal. There are companies out there that are on the patent expiration cliff that cannot afford to wait :bang: any more least they be pushed off by newer aggressive players without a legacy business model to defend ......... or one they prepared to abandon if necessary.......

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