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

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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 ($PSTI) versus Aastom ($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.

PluriStem ($PSTI) : Letter to Shareholders

Pluristem Therapeutics (PSTI) provided a Letter from the CEO (the quarterly update), and it’s a good and comprehensive piece. Our take-away is as follows: Pluristem has cash ($43 million), the company is hiring great talent, and is making clinical progress. Their allogeneic product has the potential to be very unique, as an immuno privledged allo cell therapy product. In English what that may mean is the best of both worlds. An autologous like product (auto being self, like your own cells) but with a low cost of goods, "cells in a bottle, like pills in a bottle". With that said it is early days, as Pluristem marches forward in their lead indication, Critical Limb Ischemia (CLI). Aastrom (ASTM) is in the lead as they begin their Phase III trial (see today's prior note). There is no question in our mind that Pluristem's product may have the lowest cost of goods sold, which in CLI may be a critical factor. Other indications, muscle injury, et al, add additional catalysts to watch.

From Pluristem's News Letter:

Clinical Trials Update: Muscle Injury:

Pluristem plans to initiate a Phase II dose escalation trial using its PLX cells in muscle injury.

Its PLX cells will be administered into muscle routinely traumatized during hip replacement surgery in an effort to improve and shorten the rehabilitation time for the patient.

The study will enroll an estimated 18 patients and be conducted at the Klinik für Orthopädie, Charité Hospital, Berlin, Germany.

Pluristem has filed the Investigational Medicinal Product Dossier (IMPD) with the Paul-Ehrlich-Institut and will initiate the study upon regulatory approval.

Clinical Trials Update: Peripheral Artery Disease (PAD):

Pluristem plans to  initiate three clinical trials in the PAD area.

Clinical Trials Update: Intermittent Claudication (IC):

Pluristem plans a dose escalating Phase II trial in IC involving several clinical sites in the United States and Europe.

PSTI has finalized the study protocol, and will initiate the study upon regulatory approval of the Investigational New Drug (IND) Application in the United States and the IMPD in Europe.

Clinical Trials Update: Buerger's Disease:

The company plans to initiate a clinical trial in the U.S., Europe and India upon approval of the regulatory applications.

Clinical Trials Update: Critical Limb Ischemia (CLI):

Pluristem is planning a Phase II/III pivotal trial at multiple sites in the USA and Europe for CLI

The endpoint for this pivotal trial will be amputation free survival (AFS).

Based on recommendations of regulatory experts and potential collaborative partners, Pluristem has made the strategic decision to use only commercial-grade PLX cells for this pivotal clinical trial.

These cells will be manufactured in our new facility scheduled to be completed towards the end of 2012.

PSTI will then file the necessary documentation with the U.S. FDA and European Medicines Agency (EMA) and upon regulatory approval, will begin this important trial.

Clinical Trials Update: Radiation Exposure

In preclinical studies, Pluristem's PLX cells demonstrated statistically significant improvement as mitigators of the acute radiation syndrome (ARS) and as protectants of the bone marrow following radiation exposure in animals.

Manufacturing Update: The new manufacturing facility is on schedule with the build-out. Pluristem is one of the few cell therapy companies (other than NeoStem) that is focused on manufacturing at an early stage.

Financial Update:  In PSTI's recently released 10-Q quarterly report the company had approximately $43 million in cash and deposits.

Medistem ($MEDS) Initiates Collaboration With Chinese Conglomerate Aimed at Clinical Development of Endometrial Regenerative Cells for Critical Limb Ischemia

Medistem Inc. (OTC: MEDS) announced today initiation of joint efforts with the Chinese conglomerate, Shanghai Jia Fu Medical Apparatus Inc, in developing the Endometrial Regenerative Cell (ERC) “universal donor” stem cell product for the Chinese market. The initial focus of the collaboration will be treatment of critical limb ischemia, an advanced form of peripheral artery disease.

Medistem has previously received FDA clearance to begin a Phase I clinical trial using the ERC stem cells in this patient population. A scientific publication providing the rationale and supporting data for utilization of ERC in treatment of critical limb ischemia may be found at http://www.translational-medicine.com/content/pdf/1479-5876-6-45.pdf.

Video on MediStem's Source of Cells:

Daily Dose Conclusion: Critical Limb Ischemia (CLI) is getting crowded. Aastrom (ASTM) is in the lead in the US with a P3 FDA trial in motion. With that said the market capitalization for Aastrom has fallen sharply as trial has been expanded and costs rising. Definitive Phase II data should have translated into a pharma partnership but the Phase IIB data read missed the primary endpoint as the AFS (Amputation free survival rate) of the control group fell (it was unusually high in the PIIa read-out). As such it seems that Aastrom has to go it alone now. Also aggressive in the CLI space is Pluristem (PSTI), Aldagen (now part of Cytomedix: OTC/BB:CMXI) and even device company Thermogenesis (KOOL) announced CLI data from a trial in India. We believe that in CLI COGS (cost of goods sold) and the ability to retreat patients will be significant factors.

Aastrom (ASTM) fall in market cap appears over-done at this point but smart investors will wait for a financing to be completed before jumping in. Data is at least 2 years away so there is no rush. Ditto for the other CLI players. In terms of Cytomedix we are very concerned that the strategy is flawed as Aldagen's product (ALDH-br cells) look expensive to make and are in early stages behind Aastrom and Pluristem. Is Cytomedix funded for a phase II CLI program ?  Stay tuned.