Data From American College of Cardiology: $NBS, $BAX, $ASTM, $CMXI

Data came out over the weekend in Advance of the American College of Cardiology meeting in Chicago. The article reviews the Focus-CCTRN trial which uses autologous bone marrow to treat heart disease in a Phase II trial.  Specifically the trial evaluates the injection of bone marrow in ischemic cardiomyopathy.   This trial is similar to what Baxter is working on in their phase III trial using not bone marrow but what they believe is the active cell in marrow, CD 34+ cells. Incidentally this is similar to what NeoStem is doing with the Phase II Amorcyte Heart Attack “PRESERVE” trial which is using IRA (Infarct related artery) injection of CD 34+ cells (NeoStem is also doing the manufacturing for Baxter).
 
The results of the study are fascinating. They showed that the greatest efficacy was shown in those patients who received the greatest number of CD 34 cells.
 
Specifically the article states: 

"A regression analysis showed that higher CD34 cell or CD133 cell counts were associated with greater absolute unit increase in LVEF. The range of CD34 was 0.5% to 6.9% (SD, 1.2%). Assuming that differences of 1.96 for SD or 2.4% are more likely due to biological variability, the effect of differences in CD34 cell level beyond that expected due to natural variability was examined, using a 3% level to be conservative. Every 3% higher level of CD34 cells was associated with on average a 3.0% greater absolute unit increase in LVEF in a multiple variable model that included age and treatment as predictor variables (3.06 [95% CI, 0.14-5.98];P=.04)."

This article seems to confirm what NeoStem’s Chief Medical officer, Andrew Pecora MD, and Phase II Trial Investigator, Arshed Quyyumi MD, FRCP wrote in their Letter to the editor (Published in JAMA, March 14, 2012) that reviews the results from another Bone Marrow Trial (The Late TIME trial) that was presented last Fall at the American Heart Association (AHA).

“In the Late TIME trial, treated patients received a median CD34 cell dose of 3.8±1.5x106 cells, well below 10x106 CD34 cells. Additionally, in vitro SDF-1 mobility of the infused cells was not measured and may have been adversely affected by the absence of autologous serum in the infused product. Future studies must account for the quantity and mobility of infused (potent) cells before conclusions regarding efficacy are made.”

Daily Dose Conclusion: A lot of work has been done with Bone Marrow cells and its all shown trends but there have not been any home runs. The data seems to be pointing to the active ingredient (there may be more than one, that’s for sure) is CD 34+ cells. Patinets with greater numbers of these cells  are showing efficacy. The Amorcyte Phase 1 data was very compelling showing a statistically valid correlation between the number of CD 34 + CXCR4+ cells and the effect on both perfusion and infarct size. The fact that Baxter is also pursuing a CD 34+ cell approach is validating. The trial is being run by Dr. Doug Losordo  who is considered a Key Opinion Leader (KOL) and Pioneer in cell therapy. Dr. Losordo’s team last summer published the results of experiments that showed that among all the various cells present in marrow, it is the CD 34+ cells that generate the greatest amount of blood vessel growth.

Daily Dose Equities - Effect of Transendocardial Delivery - CCTRN TrialThis article showed in a sub-group analysis that patients with higher numbers of CD34+ cells did best.

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Daily Dose Equities - Exosomes from Human CD34 + Stem Cells

This article is published by Dr. Doug Losordo, who since the article was printed, has joined Baxter to run their CD 34+ Cardiac Ischemia Trial (Angina – heart pain).

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Daily Dose Equities - Intracoronary Bone Marrow

Two Letters to the Editor of JAMA; 1) Dr Hung Q Ly MD, MSC, FRCPC and 2) Drs. Arshed Quyyumi and Andrew Pecora (NeoStem) discuss the flaws in the LATE-Time trial.

View more documents from ProActive Capital Resources Group

Key markets covered include:

• Stem Cell Research
• Cardiac Heart Repair
• Benefits of using your own cells
• Stem Cell Trials
• Heart Attack Cell Therapy
• Proof of Concept
• Clinical Trial Data

Pluristem Therapeutics to Present at Three Conferences in April ($PSTI)

Pluristem Therapeutics Inc. (NasdaqCM: PSTI; TASE: PLTR) is a leading developer of placenta-based cell therapies. The company's patented PLX (PLacental eXpanded) cells drug delivery platform releases a cocktail of therapeutic proteins in response to a variety of local and systemic inflammatory diseases. PLX cells are grown using the company’s proprietary 3D micro-environmental technology and are an off-the-shelf product that requires no tissue matching or immune-suppression treatment prior to administration.

 

Pluristem has announced that The Company's Sr. VP of Corporate Development, William Prather RPh, MD, will present at three upcoming financial and scientific events in the U.S. 

According to the press release, "Dr. Prather will be "outlining the progress that Pluristem has made on the development of its PLacental eXpanded (PLX) cell product candidates," as well as speaking about "the recently announced pre-clinical data on acute radiation syndrome (ARS) and acute myocardial infarction (AMI), the construction of Pluristem's state-of-the-art cell therapy manufacturing facility, as well as the company's strategy of partnering with pharmaceutical companies for the marketing of several of its potential cell therapies." 

Below is the schedule of events where Pluristem will be delivering presentations:

Needham Healthcare Conference - April 3 at 2:00PM - 2:40PM in Henry New York Palace Hotel, Manhattan, New York City

Imperial Capital's Healthcare Investor Forum - April 17 at 10:15AM - 10:45AM, New York Palace Hotel, Manhattan, New York City

8th Stem Cell Summit - April 19 at 3:15PM - 5:45PM session and on April 20 at 10:45AM - noon session, Hyatt Harborside Hotel, Boston, MA

Read more at MarketWatch.com. 

Pluristem's ($PSTI) PLX Cells Effective in Treatment of Acute Myocardial Infarction (AMI) in Animal Trial

Daily Dose Conclusion: The stock has moved up well here in midday trading as investors are excited that PSTI is exploring other indications beyond just CLI. Pluristem data helps raise the questions (and the makes the boundaries a bit more foggy) between autologous and allogeneic pro's and con's. This is clearly an allo product (pills in a bottle if you will) but the cells are from the placenta and PSTI claims they are immuno-privledged. Other companies have shown definitively that only autologous cells remain resident and provide functional ongoing neo-angiogenesis. Pluristem has said their cells are cleared, so as such we are concerned that PSTI's allo-cells are cellular short term approach (maybe very beneficial near term) but unlikely to show long term benefits in man. We just don't know.  Certainly the animal data presented look's good.

Of greater focus for investors should be PSTI's start of the CLI trial ? Is this on hold until manufacturing is cleared in the new facility, or will it start prior  ?  Keep an eye (or a heart out) for data from ASTM on DCM - dialtaed cardio-myopathy, NeoStem NBS in AMI-STEMI, Baxter-CMI, Cytori (AMI) and MesoBlast and Athersys, both AMI too.

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Significantly Improved Cardiac Function, Smaller Infarct Size With Greater Regional Left Ventricle Wall Thickness and the Pronounced Stimulation of New Vessels Formation Were Observed in Animals Treated With PLX Cells

Pluristem Therapeutics, Inc. (Nasdaq:PSTI) (TASE:PLTR) today announced that its PLacental eXpanded (PLX) cells, tested in a preclinical animal model of acute myocardial infarction (AMI), proved to effectively improve several cardiac hemodynamic parameters in animals that received those cells. The study was conducted in collaboration with Professor Christof Stamm, MD and Professor Carsten Tschope MD and their respective staffs at the Center for Regenerative Therapies (BCRT), Berlin, Germany.

Twenty mice suffered an AMI by ligating the left anterior descending (LAD) coronary artery via thoracotomy. Immediately following the AMI, animals were given either PLX cells (n=10) or cell-free medium as a control (n=10) into the border zone of the infarct. Additionally, five animals underwent a sham (placebo) operation by incurring the thoracotomy but without ligation of the LAD.

After 4 weeks, transthoracic echocardiography was performed, the mice were sacrificed and their hearts examined histologically. Hemodynamic studies demonstrated improved cardiac contractile function in the mice which received the PLX cells as compared to control-treated mice. The improved cardiac contractile function included a statistically significant increase in stroke volume (p=0.01) (fig. 1) and ejection fraction (p=0.06) (fig. 2). Additionally, PLX cell-treated hearts had significantly smaller infarct sizes (p=0.04) and greater regional Left Ventricular (LV) wall thickness (fig. 3). Histological analysis indicated that those animals treated with PLX cells displayed a statistically significant higher number of mature arterial vessels in the infarct border zone than in control animals (p=0.004) and suggests that PLX cells induce the formation of new blood vessels into ischemic myocardium (fig. 4). Charts and images accompanying this release are available at http://media.globenewswire.com/cache/11974/file/12981.pdf

See the full press release @ NASDAQ.com

Cytomedix ($CMXI) in American Heart Journal For Positive Phase I Clinical Data Using ALD-201 to Treat Ischemic Heart Failure

Cytomedix, Inc. (OTCBB: CMXI) develops, sells and licenses regenerative biological therapies primarily for wound care, inflammation and angiogenesis. The Company markets the AutoloGel™ System, a device for the production of autologous platelet rich plasma ("PRP") gel for use on a variety of exuding wounds; the Angel® Whole Blood Separation System, a blood processing device and disposable products used for the separation of whole blood into red cells, platelet poor plasma ("PPP") and PRP in surgical settings; and the activAT® Autologous Thrombin Processing Kit, which produces autologous thrombin serum from PPP. The activAT® kit is sold exclusively in Europe and Canada, where it provides a completely autologous, safe alternative to bovine-derived products. On February 8, 2012 Cytomedix closed the acquisition of Aldagen, a biopharmaceutical company developing regenerative cell therapies based on its proprietary ALDH bright cell ("ALDH(br)") technology, currently in a Phase 2 trial for the treatment of ischemic stroke.

Daily Dose Conclusion: This is not new news for Aldagen (now part of CytoMedix) but does remind us that among the various cells in bone marrow, there are specific populations of cells, in this case, ALD-br cells, that are prolific elicitors of neoangiogenesis (capable of forming and fostering new blood vessel formation) . Our expectation is that CytoMedix will focus on CLI trial. Recall that Aastrom is now in a pivotal trial with their bone marrow (expanded cells) and PluriStem (PSTI) is hoping to begin their Phase II trial with their placental derived (allogeneic) cell product. From a COGS view point it’s likely that PSTI's product will be the cheapest to make, and Aastrom has the lead to the marketplace. Also know that in the wings are the adipose derived players such as Cytori and even device make Thermogenesis (KOOL). This could be local processing and also a very cheaply produced product. As such we have our concerns regarding the classic SWAT (Strength, Opportunities, threats & Weakness) and how each of the CLI players will score on these metrics.

Today's Press Release: CMXI announced that positive data from a Phase 1 clinical trial of ALD-201 to treat ischemic heart failure were published in the March 2012 online edition of the American Heart Journal. In the study, ALD-201 was considered safe and demonstrated initial evidence of improved blood flow and improved clinical status. ALD-201 is a population of biologically instructive adult stem cells (aldehyde dehydrogenase bright cells, or ALDH(br)) that are selected from the patient's own bone marrow using the ALDH enzyme as a marker. The article is titled:

"Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure." 

The randomized, double-blind, placebo-controlled Phase 1 study included 20 heart failure patients with no treatment options. The primary end point was safety and secondary end points included several well-accepted clinical measurements. The patients received either an injection of ALD-201 directly into the heart muscle, or an injection of an equivalent volume of placebo using the same catheter delivery system. Investigators assessed patients for endpoints for the first six months after the injection and then followed them for an additional six months.

In the study ALD-201, including injection into the myocardium, was considered to be safe and well tolerated. After six months, the subjects who received ALD-201 demonstrated an improvement in MaxVO2, a measure of the body's ability to take up oxygen during exercise, while the placebo group did not. These findings support the ability of ALDH(br) cells to promote angiogenesis and restore blood flow to the ischemic heart muscle.

Commenting on the results of the Phase 1 study, Principal Investigator, Emerson C. Perin, M.D., Ph.D., Director of the Stem Cell Center at the Texas Heart Institute at St. Luke's Episcopal Hospital, and the Adult Cardiology Texas Heart Institute at St. Luke's Episcopal Hospital in Houston, noted,

"The preliminary evidence suggests improved perfusion and a trend toward improved functional capacity in no-option heart failure patients treated with ALDH(br) cells. Importantly, we presented a unique approach for selecting a diverse population of active cells for cell therapy by using a physiologic rather than a single phenotypic marker, which may result in the isolation of a more efficacious population comprising the multiple cell types required for ischemic repair."

About Ischemic Heart Failure

Ischemic heart failure is caused by a reduction of blood flow to the muscles of the heart, which is most commonly caused by an obstruction of the arteries feeding blood to the heart tissue. As a result, the insufficient provision of oxygen and nutrients reduces the heart's ability to pump blood efficiently to the rest of the body. Current treatment options for ischemic heart failure include surgical procedures, bi-ventricular pacers, drug therapies, implantable cardiac defibrillators, and ventricular assist devices. For some patients, these treatments are not effective or appropriate. Once ischemic heart failure patients have exhausted all potential revascularization options, their only other option is a heart transplant, if they are eligible.

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Aastrom (ASTM): Reports the Quarter, JMP Makes Positive Comments

Aastrom (ASTM): Reports the Quarter its great to have the cash but...

Highlights As follows:

1. The company ended 2011 with cash of $5.5MM which, together with $40MM raised last week should fund current operations through mid 2013.
2. The Phase III trial for ixmyelocel-T in critical limb ischemia (CLI) has begun. Enrollment will be monitores (this is a large trial, how long will it take ?).
3. Aastrom is planning to move ahead with a phase IIb trial in dilated cardiomyopathy (DCM) by this summer. Reesults from the Phase 1b trial are expected this quarter.

Daily Dose Conclusion: Its great that Aastrom is financed but we convertible debt is atypical for Biotech's and raises the importance of the CLI trial. We believe the trial is highly powered and if all goes well will show good results but as mentioned previously, the "B" in binary just got a bit Bigger.  CLI is an unmet medical need. Aastrom does appear to have the jump on the field (versus Pluristem (PSTI) and Aldagen / Cytomedic

Pluristem Begins Up Scaling Its PLX Cell Bioreactors - $PSTI

Scale Up of Bioreactors to Allow Production of About 30 Billion Cells With Each Reactor Run

Pluristem Therapeutics, Inc. (Nasdaq:PSTI - News) (TASE:PLTR) today announced that it has initiated the process of scaling up the Company's manufacturing bioreactors from their current size of 5 liter (L) to 15L. The up scaling process is being coordinated to go on-line as part of Pluristem's current plant expansion. With the completion of the scaling up process, Pluristem will be positioned to become the leading manufacturer of cells for a variety of product candidates.

The 15L bioreactors will accommodate the commercial production of Pluristem's PLacental eXpanded (PLX) cells that will be used in both the Company's upcoming pivotal Critical Limb Ischemia (CLI) clinical trial and the subsequent commercial sales of the cell product once approved.

Utilizing Pluristem's proprietary 3D manufacturing technology, a 15L bioreactor will yield approximately 30 billion PLX cells per reactor run, enough PLX cells for 100 doses at a dose of 300 million cells, the dose that will be used in the CLI clinical trial.

"The large-scale manufacturing of our PLX cells is vital to the success of our clinical trials and subsequently important for the potential commercialization of our PLX products," said Zami Aberman, Chairman and CEO of Pluristem. "Today, we initiated an additional important step in our industrialization process, where we utilize our proprietary 3D production technology, in order to manufacture trillions of cells in a stable, fully controlled and cost effective manufacturing operation. I believe that these competitive advantages strongly position us to provide viable therapies to millions of patients around the world once our products are fully developed and approved."

Daily Dose Conclusion: PluriStem many not be as far way from starting the Phase II CLI trial as was implied from the quarterly CEO's letter that seemed to say that new production for the trial would come from the new plant which is being done at commercial scale. Our biad remains positive on PSTI.

About Pluristem Therapeutics

Pluristem Therapeutics Inc. (Nasdaq:PSTI - News) (TASE:PLTR) is a leading developer of placenta-based cell therapies. The company's patented PLX (PLacental eXpanded) cells drug delivery platform releases a cocktail of therapeutic proteins in response to a variety of local and systemic inflammatory diseases. PLX cells are grown using the company's proprietary 3D micro-environmental technology and are an off-the-shelf product that requires no tissue matching or immune-suppression treatment prior to administration. The PLX-PAD comprehensive clinical development plan has been recognized by both the EMA and FDA, targeting a sub-population of 20 million patients in the Peripheral Artery Disease (PAD) market.

Data from two Phase I clinical trials indicate that Pluristem's first PLX product, PLX-PAD, is safe and potentially effective for the treatment of end stage PAD. Pluristem's pre-clinical animal models have demonstrated PLX cells are also potentially effective in nerve pain and muscle damage when administered locally and in inflammatory bowel disease, MS and stroke when administered systemically.

Pluristem has a strong patent portfolio, company-owned GMP certified manufacturing and research facilities, strategic relationships with major research institutions and a seasoned management team. For more information visit www.pluristem.com, the content of which is not part of this press release. Follow Pluristem on Twitter @Pluristem.

CLICK HERE to watch a video where CLI patients and doctors involved with the clinical trials share their stories. CLICK HERE to see Pluristem's cell therapy product animation on YouTube.

Aastrom ($ASTM) Raises Capital - $40 MLN Private Placement

Aastrom Biosciences (ASTM) completed a $40M private placement with Eastern Capital ($1.81 -$0.01) Net proceeds to Aastrom, after placement fees and other offering expenses, are ~$38M.

The company intends to use the net proceeds from the financing for general corporate purposes, including research and development expenses related to the pivotal Phase 3 REVIVE-CLI clinical trial with ixmyelocel-T initiated in February 2012.

At closing, Aastrom issued approximately 12,300 shares of Series B convertible preferred stock to Eastern Capital at a price of $3,250 per share.

The shares will accrue dividends at a rate of 11.5% per annum during the 5-year term.

The Series B preferred stock is convertible into shares of the company's common stock only after 8-Mar-17 at a rate of 1,000 common shares for one preferred share.

There were no warrants issued in connection with the financing and Eastern Capital will not take a board seat.

Daily Dose Conclusion: This strikes us as a last resort financing. Aastrom has the capital to see the CLI trial to its conclusion, and if the trial hits, they can pay off this "expensive financing" and if it does'nt its essentially the end of Aastom. As such we view this deal as raising risk for investors and making the "B" in Binary now a capital letter.

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Pluristem ($PSTI) versus Aastom ($ASTM) in CLI

 

We had two stories yesterday, one on Aastrom (NASDAQ: ASTM) and one on PluriStem (NASDAQ: PSTI). Aastrom has started their phase III trial. PluriStem updated their progress on several trials including CLI. 

Both companies are marching forward. Aastrom in a Phase III trial, Pluristem in a Phase II that they hope will morph into a Phase III (PII/III) trial and can be used as part of a registration package.

Here is how we read the Critical Limb ischemia indication:

1. It’s a difficult indication to prove efficacy because the endpoint is amputation free survival (AFS). AFS itself is a very variable endpoint and not easy to predict with accuracy who will be amputated versus whose limbs can be saved. 
2. Aastrom ran a Phase II trial. The interim analysis showed great separation between the control (placebo) are and the active (cell / drug) arm. So much so, that ASTM halted enrollment early. Unfortunately when Aastrom looked at the data again, Phase IIb look, the placebo arm did better and there was not a statistically significant difference in AFS between the two arms. Too bad they got head faked by the first data look. The problem is what do they do now ? Run another Phase II trial or run a Phase III with lots of power (patients) to get statistical significance between the active and placebo arms. Answer: They are going for it. Time is money in biotech and its hard raising capital (that’s what been weighing on ASTM shares). So the cost to do a Phase II get great data, then run a phase III while less risky from a science viewpoint, is too long too expensive versus risk a large phase III and hope you hit your endpoint. 

Aastrom Conclusion: This is a situation that investors hate being in, they have to gamble that the Phase II signal seen, will show up in a better powered phase III trial but these risks are now reflected in ASTM's low valuation. Investors now will have to own it and wait the 2 years for data that leads to the binary announcement, success or failure. 

What about Pluristem (PSTI) ? They are smart enough to have learned from Aastrom’ s mistake. The plan is move forward with a well powered ?, well designed phase II trial with the goal of announcing both a stat. significant result and a morph to Phase III. In that way it may be possible (our opinion) for the PII plus the PIII to act as an approval package. Pluristem did imply in their letter to shareholders that the new facility will supply the CLI trial.  The ramp up time for that to come on-line may be faster than people expect.  If so it will help mute any time advanatge Aastrom now has.

1. Given the PSTI PII/III goal one might conclude that Aastrom really does not have a significant time advantage versus pluristem (PSTI).
2. Which product is cheaper? No question in our mind that PSTI's allogeneic, 3d-fermentation style product will be significantly less expensive to manufacturer. The hope is that these placental cells are unique and immuno-privledged and are "autologous" like in their properties versus Aastom's expanded autologous cells.
3. Is there an engraphment advantage of auto versus allo? Yes, always there is But in CLI engraftment may not be the issue as it is in cardiology (heart repair). If the cells help vascularize a bad limb and go away, and patients can be re-treated multiple times (PSTI says yes they can, on retreatment they have not seen immune reactions) then auto may not have a keen advantage versus allow in CLI and COGS here could be the critical factor. 
4. What about the rest of the field? Investors should note that Cytomedix acquired Aldagen who is also hoping to kick of a Phase II trial. This will be with autologous cells but enriched for ALDH-br cells. It looks like this would be the third product to the marketplace and the most expensive, so can Cytomedix (CMXI) show an efficacy advantage over Aastrom or pluristem. We conclude that is very unlikely. Thermogenesis also had need recently about an adipose (fat derived) autologous (but cheap, bedside processed) product, also chasing CLI with a small proof of concept study in India.

Last Point: Its full speed ahead for both Aastrom and Pluristem in CLI. See our recent comments on both, but in weighing the products, the associated cogs, the indications, the cash on their respective balance sheets we conclude that PSTI is strongly positioned.