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

JAMA: Letter to the Editor : Intracoronary Bone Marrow Mononuclear Cells After Myocardial Infarction

We picked up on a JAMA letter to the editor (below) that reviews data from the TIME trial that was presented last fall. The author, Drs Arshed Quyyumi (NeoStem PI) and Andrew Pecora (NeoStem CMO) clearly identify that the effective dose given in the "Late TIME" trial appears to have been low , (3.8 million CD 34 cells) versus data that the Amorcyte trial reported that an effective biological threshold exists at 10 million cells. The authors in the letter to the editor state:

In the LateTIME trial, treated patients received a median CD34 cell dose of 3.8±1.5 x106 cells, well below 10 x106 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: NeoStem (NBS)  and Baxter (BAX) are both pursuing the use of CD 34+ cells in STEMI and CMI (angina) respectively. CytoMedix just reported that ALD-br cells show hints of efficacy and Aastrom seems to be moving forward in DCM. All cardiology indications. The NeoStem message is focused on the dose, timing and method of delivery, biological effect and clinical outcome. We see this as a core strength and part of what Progenitor Cell therapy (PCT) brings to the company.

On a separate note we believe Cardiology is the next major breakthrough to be seen in the regenerative medicine space. While NeoStem is well positioned as a manufacturer for Baxter and their own Amorcyte the company also has attractive valuation measures. That is not to say that other players like Aastrom , Athersys and Cytori are likely to move forward with P2/3 plans in the cardiac care space. Also keep an eye out for MesoBlast which has seen a decline in valuation since the TIME (& their own data) was presented at AHA last fall.

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Intracoronary Bone Marrow Mononuclear Cells After Myocardial Infarction

View more documents from ProActive Capital Resources Group.

Baxter ($BAX) Signs with NeoStem ($NBS) for Manufacturing in their Phase III Trial - Also a CD 34+ Cell

Daily Dose Conclusion: Baxter (BAX) press release below, names NeoStem’ s (AMEX: NBS) Progenitor Cell Therapy (PCT) division as the selected manufacturer for their Phase III trial with the Baxter CD 34+ cell. We see this as validation for NeoStem on three fronts:

1. Great revenue source for PCT
2. Validation of NeoStem’ s own CD 34+ based Amorcyte trial, in market niche STEMI (heart attacks), and
3. Close relationship between these two companies ! NeoStem looks like a compelling value play with the expected divestiture of the China Generics business as the next major catalyst. 

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Baxter Initiates Phase III Adult Stem Cell Clinical Trial for Chronic Cardiac Condition

Study Aims to Deliver Adult's Own Cells As Treatment for Chronic Myocardial Ischemia

DEERFIELD, Ill., February 28, 2012 - Baxter International Inc. (NYSE:BAX) announced today that it has initiated a phase III pivotal clinical trial to evaluate the efficacy and safety of adult autologous (an individual's own) CD34+ stem cells to increase exercise capacity in patients with chronic myocardial ischemia (CMI).

Chronic myocardial ischemia (CMI) is one of the most severe forms of coronary artery disease, causing significant long-term damage to the heart muscle and disability to the patient. It is often diagnosed based on symptoms of severe, refractory angina, which is severe chest discomfort that does not respond to conventional medical management or surgical interventions.

"The prospect of using a person's own adult stem cells to restore and repair blood flow in CMI is a very exciting concept based on a biological regenerative approach," said Norbert Riedel, Ph.D., Baxter's chief science and innovation officer. "The goals of this phase III trial are aligned with Baxter's overall mission to develop life-saving and life-sustaining therapies and it will help us determine if the therapy can make a meaningful difference for CMI patients."

The trial will enroll approximately 450 patients across 50 clinical sites in the United States, who will be randomized to one of three arms: treatment with their own autologous CD34+ stem cells, treatment with placebo (control), or unblinded standard of care. The primary objective is to evaluate the efficacy of treatment with CD34+ stem cells to improve the functional capacity of patients with CMI, as measured by a change in total exercise capacity at 12 months following treatment. Secondary objectives include reduced frequency of angina episodes at 12 months after treatment and the safety of targeted delivery of the cells.

After stem cell mobilization, apheresis (collecting the cells from the body) and cell processing, participants will receive CD34+ stem cells or placebo in a single treatment via 10 intramyocardial injections into targeted areas of the heart tissue. Efficacy will be measured by a change in total exercise capacity during the first year following treatment and safety data will be collected for two years. Stem cell processing will be conducted in GMP facilities in the United States by Progenitor Cell Therapy (PCT), a subsidiary of NeoStem, Inc. To learn more or enroll, visit www.renewstudy.com or www.clinicaltrials.gov .

This trial is being initiated based on the phase II data, which indicated that injections of patients' own CD34+ stem cells may improve exercise capacity and reduce reports of angina episodes in patients with chronic, severe refractory angina.

"The phase II trial provided evidence that this strategy, leveraging the body's own natural repair mechanisms, can improve exercise capacity and reduce chest pain, the first time these endpoints have been achieved in a population of patients who have exhausted conventional treatment options," said Douglas Losordo, MD, vice president of new therapeutic development at Baxter.

CD34+ cells, which are blood-forming stem cells derived from bone marrow, are comprised of endothelial progenitor cells (EPCs), which develop into new blood vessels. Previous preclinical studies investigating these cells have shown an increase in capillary density and improved cardiac function in models of myocardial ischemia.

About Baxter
Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, infectious diseases, kidney disease, trauma, and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.

Baxter ($BAX) Completes Acquisition of Synovis

Baxter International Inc. (NYSE:BAX) announced that the company has completed its planned acquisition of Synovis Life Technologies, Inc. (NASDAQ: SYNO), following approval of the transaction by Synovis shareholders.  The acquisition expands Baxter's regenerative medicine and BioSurgery franchise by adding biological and mechanical products from Synovis used for soft tissue repair and microsurgery in a variety of surgical procedures.

"The acquisition enhances Baxter's ability to offer a broad range of tools used to repair and reconstruct soft tissue damaged by disease or injury, as well as specific tools used in a variety of microsurgical procedures," said Ludwig Hantson, president of Baxter's BioScience business. "We look forward to welcoming the Synovis employees and organization into Baxter as we begin the business integration process."

Baxter's technological leadership in the development of biosurgical and regenerative medicine products is grounded in advancing innovation, enhancing surgical techniques and improving patient outcomes. Baxter advanced the field of tissue sealing and hemostasis more than 30 years ago with the development of TISSEEL Fibrin Sealant (sold under the name TISSUCOL in several countries around the world). Today, Baxter is adding the Synovis soft tissue repair and microsurgery products to the company's existing line of biological products and delivery devices used for hemostasis, tissue sealing, adhesion reduction, and hard tissue regeneration.

Synovis shareholders approved the offer of $28 per share, which equates to $325 million of equity value or approximately $260 million after adjusting for the net cash. Synovis reported annual sales of $82.4 million for the fiscal year ending October 31, 2011.

Synovis develops, manufactures and markets medical devices used primarily in surgical procedures for soft tissue repair, including PERI-STRIPS DRY, TISSUE-GUARD and VERITAS Collagen Matrix. These products are used in a variety of surgical procedures, including obesity surgery; patching the lining of the brain, vessels, and cardiac defects; hernia repair; and vascular surgery. The Synovis portfolio also includes products used in microsurgery, such as the COUPLER, FLOW COUPLER and GEM MICROCLIP. These products are used for joining small diameter vessels during autologous tissue breast reconstruction; sealing small blood vessels; and head, neck and hand procedures. Its newest business area is orthopedic and wound management products, with applications ranging from the repair of rotator cuff and other tendon injuries to advanced wound management. These products are primarily used by reconstructive, orthopedic, sports medicine, podiatric, and vascular surgeons.

Daily Dose Conclusion: Baxter is quietly building a stronger position in the regenerative medicine space. We know that the company is also developing a CD34+ cell Therapeutic for cardiac ischemia and has brought Douglas Losordo MD, one of the best known cardiologists and cell biologist, stem cell pioneers. This tells us that the company is serious.  NeoStem (NBS) is a great value pure play using a similar technology.

Osiris (OSIR): Look's Like Sanofi (acquired Genzyme) is saying No to Prochymal

News is swirling on Osiris Therapeutics (NASDAQ: OSIR) that Sanofi (SNA) in the post Genzyme (GENZ) acquisition will discontinue Prochymal for GvHD. Prochymal is a mesenchymal cell (MSC) that is allogeneic. Similar to what Athersys (ATHX) is developing with multi-stem. Osiris has struggled with GvHD and even Biodefense company Soligenix (SNGX), just reverse split 20:1, saw Orbec, a locally acting steroid that had every indication of success fail when the pivotal trial was halted for futility. In Biotech land we often say that the "graveyard is full of companies who tried to develop xxx for yyy indication", in this case its GvHD.

We would advise investors to try to understand the following when evaluating a new cell therapy:

What is it? What we mean is "what is the active ingredient". An allogeneic MSC means a lot of things, it’s a heterogeneous cell population, and as such, just not that well defined, so from a starting point, other than saying there is a paracrine effect where the cells act like cellular Advil, it’s a tough climb to say, what is it ?

Next - What does it do exactly ? or What is the Biological Mechanism of Action (MOA) and as such, what is the clinical effect that will be measured in the trial ? How closely related are they ? Again, these are critical elements that the FDA will look for beyond, I squirt it in, and it works. Don't forget dose, homing, and integration.

Thus far developers of cell therapy seem to be struggling with these questions with a few exceptions. Baxter (BAX) and NeoStem (NBS) stand out, with a highly defined cell product (CD34+/CXCR4) cells for Preservation of Heart function. Islet BioSciences stands out with their porcine islet cells (pig) for diabetes.

Daily Dose Conclusion: OSIR has approx. $50 mln in cash as of Sept. 2011 against a $160 mln market cap. Prochymal is still being developed for a number of other indications from Crohn's disease, Type 1 diabetes and Cardiovascular indications. With that said, we need to do more analysis to understand the probabilities of success in these areas given the questions (what is it, MOA, clinical effect) that we raise above.

Cytori (CYTX) : FDA Green Lights the Start of a Trial based on an IDE

Cytori Therapeutics (NASDAQ: CYTX) received an Investigational Device Exemption (IDE) approval from the U.S. FDA to start their Phase 1 trial; "ATHENA". ATHENA will investigate the use of the Celution® System, (this is the "bedside centrifuge" that processes stem cells from fat (adipose-derived stem and regenerative cells ADRCs) to treat a form of coronary heart disease, chronic myocardial ischemia (CMI).

This IDE approval comes pretty quickly given that the application was originally submitted to the FDA in December 2011.

ATHENA is a multi-center, randomized, double blind, placebo controlled, pilot trial to investigate the use of autologous, clinical-grade ADRCs, processed at the point-of-care with the Celution® System. The trial will enroll up to N=45 patients with no-option CMI who have limited therapeutic options.

It will evaluate a variety of clinical and functional outcomes, including safety, peak oxygen consumption (mVO2), and clinical outcomes at 12-months.

Previously, Cytori reported six and 18-month trial data from PRECISE, a European clinical trial for this same indication showing improvement in mVO2. In Europe, Cytori has applied to expand its Celution® System CE Mark to include no-option CMI claims based on data from the PRECISE trial. Cytori is also enrolling ADVANCE, a European pivotal trial investigating the Celution® System for acute myocardial infarction (heart attacks).

Daily Dose Take-Away: This is an exciting and interesting approach. If the trial shows strong efficacy signals it has big implications for the space. The key issues here will be:

• Understanding what the cell population here actually is ?
  
• What is its effective dose ?
  
• How is biologic variability accounted for ?
  

For example, Baxter has completed a PII trial in the same indication, but with an enriched population of marrow derived cells (CD 34+) ? So the cell type, the active ingredient, the dose, the timing and delivery are critical variables (to name a few) for a large indication like this one.

Which Cell Therapy companies present the best value?

Which Cell Therapy companies present the best value?

We developed an analysis using public filings and annualizing the most recent quarters as of 12/31/11. As such, the accuracy is subjective to our proprietary algorithm, and this list is not mean to be all comprehensive.

We conclude that ex leaders Dendreon and MesoBlast make the space very inexpensive. The sample below represents just over $500 million in market cap for eight of the selected public companies (ex DNDN and MSB). These companies have 3 - PIII trials, 5 PII trials and several P1 trials (based on these crude metrics).

We conclude that is worth investors time to understand among these companies in terms of what they are doing and the associated probabilities of success of their trials. Recent data peaks from the Cardiology space suggests that Baxter (BAX) and their CD34 cell type may be very viable. NeoStem has a very similar approach. The retrenchment in MesoBlast shares since that company presented data at AHA in November is of concern. Cytori, Aastrom, Athersys all have active programs in cardiology while Athersys lead program is partnered with Pfizer for Ulcerative Colitis and Aastrom is entering a Phase 3 trial in CLI.

By price ($), Osiris, MesoBlast, and Dendreon are the highest $ priced stocks:

But that starts to change as we migrate to market cap:

And if we eliminate Mesoblast and Dendreon we get a better picture of the rest of the field:

And that picture changes as we adjust for debt and cash: (enterprise value). In all fairness here, we know that NeoStem with $20-$30 million in value from their China generic company, could be the cheapest name and others are / will raise capital but ex China, Athersys is the “cheapest name”.

Looking at R&D spending: IMUC, Prima and NeoStem are among the most efficient but in fairness one must adjust for the fact that Aastrom is embarking on a pivotal trial versus Prima just starting their P3 and NeoStem their P2.

Revenues: Here we have excluded NeoStem’s $65 million from China which means PCT (Cell Therapy CMO) is running at close to $10 million in annual revenues (currently).

Cell Therapy in Cardiology: Conference Begins in NYC Tomorrow

Just a reminder that tomorrow through Friday a very important conference in NYC takes place: The Conference on Cell Therapy for Cardiovascular Disease.

Web site: http://celltherapy.crf.org/conference/overview.html

This is an off-wall street conference that is focused on reaching the medical community: Clinicians and clinical investigators, interventional cardiologists, noninvasive cardiologists, cardiac surgeons, research associates, basic science investigators (cell and molecular biologists), hospital administrators, program directors, legislators, and regulatory agency personnel to name a few. We will be attending.

A few key panels to be aware of:

• Wednesday: Industry Session I. Focus on Acute Injury Technologies: 4:30 pm - 5:30 pm. The participants include Linda Marban, Alexander M Milstein, Andrew Pecora (NeoStem CMO), Kai Pinkernell, Anthony Ting, Christine Wallrapp
• Thursday: Acute Injury: STEMI and NSTEMI, 8:45 am - 10:15 am. Moderators: Timothy D. Henry, Andreas M. Zeiher. Participants: Henricus J. Duckers, Raj Makkar, Marc S. Penn, Arshed A. Quyyumi (PI in NeoStem’ s Amorcyte trial) , Warren Sherman, Wojciech Wojakowski. We note that Dr. Zeiher is a moderator. Dr Zeiher is concerned one of the most prominent thought leaders in cell therapy and cardiology.
• Thursday 10:45-12:15: CLI/CMI. Moderators: Douglas W. Losordo, Amit Patel. Discussants: Todd J. Brinton, Timothy D. Henry, Thomas F. O'Donnell, Emerson C. Perin, Christof Stamm, Gustav Steinhoff

On this panel we note the presence of Doug Losordo who is also one of the most respected key opinion leaders in cell therapy and is also a pioneer on CD34+ cells and cardiology. Dr. Losordo is the PI in Baxter's CD34+ trial. NeoStem also is running a CD 34+ trial.

• Trial 1: CD34+ Cells for Refractory Angina: ACT 34 CMI Update and Phase 3 Study Design. Timothy D. Henry
• Trial 2: Adipose-Derived Cells for Chronic Ischemia: The PRECISE Trial, Emerson C. Perin
• Trial 3: Update on Standardization of CD133 Intramyocardial BMSC for Intramyocardial Delivery, Gustav Steinhoff
• Trial 4: BMAC for CLI: A Phase III Trial, Thomas F. O'Donnell
• Trial 5: Placenta-Derived Cells for CLI, Christof Stamm