Washing cryopreserved cells. An emerging need or disappearing process?

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I’m not a fan of the allogeneic vs autologous business model debate because I don’t believe it’s a debate that rages other than at conference panel sessions.  Most investors, researchers, and executives recognize that there will almost certainly be room for both to succeed and that the winner in any particular indication will be largely determined by proven clinical efficacy over the standard of care and other available treatment alternatives.

Cryopreserved vs Fresh

The oft-touted primary commercial advantage of allogeneic cell therapy products over their autologous counterparts is the ability to inventory standardized products for later on-demand distribution and use.  This contributes to the ‘economies of scale’ advantage allogeneic products enjoy.  Certainly this is true.

Critics of the autologous business model cite the high cost of single-batch lot sizes and short shelf-life of autologous products- often shipped fresh - as the primary drivers of the high cost of these types of products and the variation in cell composition of therapeutic products derived from patient to patient.  Certainly also true.

Nonetheless, the two issues most involved in a debate comparing the business models are cost and price implications of the relative bioprocessing scalability and distribution costs of each model.  For sake of convenience it is most often assumed that allogeneic cell therapies are cryopreserved and autologous products are delivered fresh from the manufacturing site to the clinic for delivery to the donor-patient.  This is, of course, an over-simplification because it is not always true.    

Take, for instance, Opexa Therapeutics’ Toxavin which involves the cryopreservation of multiple doses (potentially representing several years) of treatment from a single patient apheresis.  This is in stark contrast with Dendreon’s Provenge which requires a new apheresis for each of three monthly treatments and a limited shelf-life of a fresh product of approximately 72 hours. One cannot avoid concluding that the likely cost implications of such a difference are bound to be significant considering the differences in upstream collection, processing, and distribution costs.

I want, however, in the last few paragraphs of this post to focus attention on a couple of aspects related to cryopreservation of cell therapeutics.  Firstly, as a digression, I am often left with the impression that executives and analysts alike often over-estimate the cost of shipping fresh products (with their temperature and time sensitivities) compared to the costs associated with shipping cryopreserved products which most often require heavy and bulky LN2 shippers as well as facilities and personnel experienced with receiving and handling cryopreserved products at regional repositories and local pharmacies.

 

Does the existence of cryoprotectant excipients dictate point-of-care cell washing?

Currently the short answer is “not necessarily”.  The primary point I want to address here, however, is related to the costs currently associated with balancing the excipient and processing requirements involved in cryopreserving, storing, and thawing cells on the one side with the need to have a product that is clinically safe, effective and well tolerated by the patient on the other side.  Companies developing cryopreserved cell therapies have three choices in this regard:

1. Infuse the patient with a product that includes cryopreservant excipients (almost always including some levels of DMSO being the overwhelmingly dominant reagent) recognizing the impact on patient experience and infusion volumes (a more significant concern in bodily regions where capacity is small (e.g., heart) or potentially sensitive (e.g., brain). 
2. Invest in developing an infusion-ready formulation that significantly minimizes the amount of excipients.  This may or may not involve a thaw or post-thaw dilution.  
3. Commit to a process that involves point-of-care, post-thaw washing and re-concentration of the product to remove excipients and minimize the volume size of the product to be infused.

In terms of examples, we believe Mesoblast is currently in the first camp, Celgene has pursued the second strategy, and Athersys is an example of a company using the 3rd approach.  Each have a similar cell type and all three are pursuing some of the same indications. 


Some companies have worked hard to bring to market cryoprservant formulations that reduce the amount of DMSO (e.g., BioLife Solutions).  Some predict that in the near future DMSO-free cryoprservants will be a real fourth option (e.g, Essential Pharma's Cryo-Ess currently for Research Use Only). 


These products will have to be pioneered by some early-adopters before they are readily considered by the majority of players in a field which is oft-defined both by its dogged pursuit of precedent and reticence to be mold-breaking and innovative.

Stem cell transplanters are also faced with deciding between first and third course.  While different considerations and drivers apply to them vs companies developing s.351/ATMP products, they are still faced with the decision to wash or not.

What factors to consider in the “to wash or not wash” debate?

Of the many and somewhat differing factors to take into account, cell therapy developers and stem cell transplanters share a number of common considerations when deciding how to treat cryopreservants in the clinical setting:

• Regulator’s general tolerance of DMSO in the final product formulation to-date.  Despite this record of tolerance, it is expected that for certain indications and/or for certain types of routes of administration, there may be significantly more regulatory scrutiny concerning injecting DMSO.  Indeed, DMSO is classified as a Class 3 (relatively low risk) solvent in ICH Q3C with a recommendation of 50 mg/day as upper threshold below which one does not need to ‘justify’ its presence.  The typical DMSO solutions used in cell therapy labs contain about 1 gram (not mg) per mL before dilution-- so if used at 10% in final product, this translates to 100 mg per mL. Therefore a 10 mL cell therapy product (at 10% DMSO) would contain 1000 mg (1 gram) of DMSO (20 times the ICH threshold).

It may be worth noting that apparent regulatory tolerance of the infusion of DMSO may be somewhat tied to the fact that most previous applications have involved the IV injection - allowing for excipients to e rapidly diluted in systemic circulation.  For cell therapies delivered some other way, potential toxicity may be a more significant concern.

• Concentrations of 10-20% DMSO has been traditionally used since the dawn of stem cell transplantation with minor reports of allergic reactions (e.g., hives, itching or facial or glottal edema) and only rare reports of more serious anaphylactic/oid reactions. Side effects of DMSO include hypernatremia, fluid overload, dysgeusia (distorted taste), nausea, vomiting, elevated liver enzymes, hemolysis, renal failure, and allergic reaction.  DMSO toxicity is the most common complication of stem cell transplantation with symptoms including flushing, rash, chest tightness, nausea and vomiting, an cardiovascular instability (as outlined in the Circular of Information for the Use of Cellular Therapy Products).  Ruiz-DelGado recently reported dimethyl sulfoxide-induced toxicity in cord blood stem cell transplantation and reviewed the literature (Acta Haematol. 2009;122(1):1-5).  The authors reported the incidence of any cord blood infusion reaction ranging from 4% to 65%, with life-threatening infusion reactions occurring in up to 4.6% of patients. 

It is worth noting that  the FDA’s Pharmacovigilance Review Memo, related to the FDA’s recently approval of the New York Blood Centers BLA for its cord blood progenitor product named “Hemacord”, includes the following statement:  

“Exposure to DMSO and Dextran-40, though not completely avoidable, can be limited by proper preparation before infusion of cord blood. Warnings and instructions for preparation (e.g. thawing, washing, dilution) should be included in the label.”

• Even for those patients who do not experience any toxicity, allergic, or anaphylactic/oid reaction, there is an undisputed and significant ‘garlic’ odor and taste experience by the patient as well as the issues related to having to consent around the infusion of such excipients.

• One of the outstanding regulatory questions is to what extent regulators will consider point-of-care washing steps to be a final manufacturing step.  Closely related, but not necessarily intrinsically tied to this issue, is the question of whether a final release assay will be required to test a final product which was washed and re-concentrated post-thaw.

• Finally, one is tempted to wonder whether to what extent regulatory opinion, commercial strategies, development pathways are influenced by what has been to-date a lack of commercially acceptable and viable technical solutions to post-thaw washing and re-concentration.

On this last note, Cell Therapy Group is working with Stem Cell Partners on bringing to market what we believe is potentially a simple, quick, cost-effective, easy-to-use density phase washing centrifugation device utilizing commercially available reagents and centrifuges – the EnsuraSep Cell Washer.  

Have a quick spin through the brief technology outline at www.cellwasher.com and I would be happy to discuss it further with anyone interested.  

We are working on different configurations and sizes of that device for different applications. Stem Cell Partners is working with our clients to design custom canisters and reagent-formulations to meet their specific requirements.  Stem Cell Partners is also working on alternative centrifugation-based device that has a wider-capacity range. 

While we believe the Ensura-Sep Cell Washer may enable a simple and rapid washing and concentration of a cell suspension in a single centrifugation step, CTG is also working with other companies who are pursuing other solutions using different technologies such as filtration.

There is currently much expert divergence on the question of what role point-of-care cell washing/concentration may play in the future of cell therapies.  I invite any and all comments or feedback on this post either using the comment function here or in the discussion thread mentioned below in the LinkedIn Cell Therapy Industry Group.

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Much thanks to a great discussion thread in the LinkedIn Cell Therapy Industry Group called “Clinical preparation of frozen cell therapy products” which inspired must of this content with a special nod to Jon Rowley, Reinout Hesselink, EJ Read, Christopher Bravery, and Ali Mohamed.

ISCT 2009 Corporate Tutorials and Symposia

Here is a listing of the corporate tutorial and symposia sessions being held at the International Society for Cellular Therapy conference Sunday-Wednesday in San Diego. For more information see www.celltherapy.org.

	ISCT 2009 Corporate Tutorial and Symposium Listing

			Sunday May 3, 2009 Time: 3:00pm – 5:00pm / Grand Ballroom B Miltenyi Biotec
			Emerging treatments enabled by cellular therapy ……………………………………………………………………………………………………………… Chairperson: Shelly Heimfeld, PhD, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Topics and Speakers: Notch-mediated expansion of human cord blood stem/progenitor cells: cell processing and translation to the bedside ……………………………………………………………………………………………………………… Shelly Heimfeld, PhD / Colleen Delaney, MD, MSc, Fred Hutchinson Cancer Research Center, Seattle, WA, USA NK cell therapy in the pediatric leukemia ……………………………………………………………………………………………………………… Wing H. Leung, MD, PhD, St. Jude Children's Research Hospital Memphis, Memphis, TN, USA Antiviral T cell immunotherapy—present and future perspectives ……………………………………………………………………………………………………………… Mark W. Lowdell, PhD, FRCPath, MICR, Royal Free & University College London, London, UK The role of cell processing in the emerging regenerative medicine applications ……………………………………………………………………………………………………………… Denis-Claude Roy, MD, FRCP(C), Hopital Maisonneuve-Rosemont, University of Montreal, Canada

Monday May 4, 2009 Time: 7:30am – 8:30am / Nautilus 4 WuXi AppTec

Topics and Speakers: Validation of a rapid PCR method for the detection of mycoplasma contaminants according to European Pharmacopoiea 5.8, 2.6.7, 2007. Use in release testing of cell therapy products. ……………………………………………………………………………………………………………… Garry B. Takle, Ph.D. Vice President, Operations. WuXi AppTec Philadelphia. Recent publication of a revised section for mycoplasma testing in the European Pharmacopoeia (5.8, section 2.6.7) has led to interest in validating a nucleic acid amplification technique for use in detection of mycoplasma contaminants in cellular therapies. The replacement or supplementation of the existing culture based methods with a PCR-based method has several advantages for the biopharmaceutical industry, mainly with respect to turnaround time for results, and cost. Replacement or substitution of existing methods by a PCR method requires the demonstration of equivalent assay LOD and specificity. The experimental requirements for this comparability validation have been spelled out in detail in the EP section referenced above. In this presentation, we describe the validation and comparability analysis of a PCR method exactly according to the EP guidance. Completion of this validation activity has resulted in the availability of an assay that meets or exceeds EP compliance requirements for a mycoplasma detection method. Comprehensive testing panels for cellular therapeutics. ……………………………………………………………………………………………………………… Chris Larson, MS., Lab Manager, Cell Biology and Flow Cytometry. WuXi AppTec, Philadelphia. In this presentation WuXi AppTec will describe the current regulatory landscape for appropriate testing programs for cellular therapies, focusing on safety and identity assays. A multiuse contract manufacturing facility for the production and release of cellular therapies. ……………………………………………………………………………………………………………… John Bermel, Sr Manager, Cell banking/Cell therapy. WuXi AppTec, Philadelphia. WuXi AppTec will present a summary of the design and operation of the contract GMP cell therapy and cell banking facility located within the Philadelphia site. Design, start up and validation activities will be discussed with reference to specific projects and case studies.

Monday May 4, 2009 Time: 12:15pm - 1:30pm/ Nautilus 2 CellGenix Technologie Transfer GmbH and American Fluoroseal Corporation

Topics and Speakers Application of DC Maturation and T Cell Expansion in a Clinical Setting ……………………………………………………………………………………………………………… Dr. Gunnar Kvalheim, Radium Hospital - Oslo, Norway Purpose: Description of methods and materials for DC maturation and autologous T cell expansion in cancer therapy and a report of clinical outcomes. Expansion of Young Tumor Infiltrating Lymphocytes (Y-TIL) as a Therapeutic Agent in Cancer Treatment ……………………………………………………………………………………………………………… Dr Nina Garlie, Aurora-St. Lukes Medical Center - Milwaukee, WI. Purpose: Description of materials and methods used for a therapeutic Y-TIL expansion protocol Description of Materials and Methods for Cord Blood Expansion with Clinical Outcomes ……………………………………………………………………………………………………………… Dr. Colleen Delaney, Fred Hutchinson Cancer Center - Seattle, WA Purpose: The application of double cord transplants with one expanded cord using cytokines and notch ligand, and one cord left unmanipulated in cancer therapy.

Tuesday May 5, 2009 Time: 7:30am – 8:30am / Nautilus 5 Invitrogen

Come join the leading innovators in cell therapy for a breakfast session on safer cell therapies. One of the key concerns of regulatory agencies around the world is ensuring that candidate cell therapies for clinical trials and ultimate approval have adequate safety profiles. During this session, four leading industry experts will share the technologies and strategies they have identified and employed at different stages of cell therapy development to ensure phase-appropriate safety profiles and streamlined regulatory review of their clinical products. Chair Eric Roos, Business Development Leader, Stem Cell Therapy, Life Technologies Corporation Panelists Leslie Wolfe, PhD, VP, Technology Development, Cellular Therapies, Genzyme Biosurgery Patricia Whelton, Senior Director, Regulatory and Process Development, Osiris Therapeutics, Inc. John T. Kemshead, PhD, Director, Clinical Affairs, Baxter Cellular Therapies For more information on the session: www.invitrogen.com/isctmeeting Register for the breakfast session: www.invitrogen.com/isct-register

Tuesday May 5, 2009 Time: 12:30pm – 1:30pm / Nautilus 1 Pall Medical

Culture and expansion of cord blood MNCs enriched by the Pall Purecell Select System, a new alternative to density gradient Description Enriched MNCs are used for variety of research and clinical applications. The new Pall Purecell™ Select System is a rapid, easy to use, single use disposable for the isolation of Mononuclear cells (MNC) from whole blood and other samples. Purecell Select System was evaluated for enrichment of MNCs from cord blood samples in two different research studies with direct comparison to cells isolated by density gradient method. In one study, enriched cells were subsequently used for CD34+ cell selection followed by hematopoietic progenitor cell expansion. In the second study, MNC enriched cells were used for production of Endothelial Colony Forming Cells (ECFCs®). Results of these studies will be presented and participants will walk away from the tutorial with an awareness of how the Purecell Select System can be suitable for certain research applications and it’s potential future use in clinical cell manufacturing processes. Speaker Christine Smith-Steinhart, PhD EndGenitor Technologies, Inc.

Tuesday May 5, 2009 Time: 12:30pm – 1:30pm / Nautilus 2 Biosafe SA

From Stem Cell Banking to Bedside Biosafe is honoured to have 2 renowned experts presenting some of the leading advances in the field of cellular therapy. Topics and Speakers Dr. Joanne Kurtzberg, Chief of Pediatrics and Blood & Marrow Transplantation at Duke University, NC, USA will provide an overview of the Carolinas Cord Blood Bank, one of the world’s largest and most respected public cord blood banks, before presenting recent developments in the use of cord blood to treat non-haematopoietic diseases. Dr. Riccardo Saccardi from the Haematology Department, Careggi University Hospital, Florence, Italy, will present the different work performed by his laboratory in the study and therapeutic use of cellular products. Careggi is Europe’s leading transplant centre for autoimmune diseases and Dr. Saccardi will go on to discuss the use of stem cells in the treatment of such diseases.

Tuesday May 5, 2009
Time: 12:30pm – 1:30pm / Nautilus 3


BioLife Solutions Inc.

Biopreservation Yield in Cell Therapy: Process Optimization From Source Material to Finished Product Description Participants in the Biopreservation Yield in Cell Therapy: Process Optimization workshop will experience presentation and discussion of a new class of preservation media products which result in the optimization of supply chain logistics and biopreservation processes in hypothermic storage and cryopreservation of various biologic source materials and manufactured cell therapy products. In addition, this workshop will provide a new and detailed understanding of preservation induced cellular injuries and the resultant impact on functional yield of source material and clinical therapeutic yield of manipulated cell therapy products. Critical analysis of traditional post-preservation assay type and timing and how the status quo impacts therapeutic effectiveness of cell therapy products will be introduced through the review of scientific data and selected case studies. This data will support cumulative yield improvements of source material and manufactured cell therapy products using BioLife Solutions’ HypoThermosol® and CryoStor™ products. Speaker Ian B. Nicoud, Ph.D., Director of Technology & Business Development Bio Dr. Nicoud served as an intellectual property and technology consultant for BioLife and joined the Company in September 2007. He has a strong background in transplantation medicine and preservation biology and holds a Ph.D. in Cancer Biology from Vanderbilt University and a B.S. in Biology from Saint Norbert College. He is a co-author of several of the Company’s recent patent applications and manages BioLife’s intellectual property portfolio and technology licensing activities.

Wednesday May 6, 2009 Time: 12:00pm – 1:00pm / Grand Ballroom B STEMCELL Technologies Inc.

Topics and Speakers Expansion of Mesenchymal Progenitor Cells (MPCs) in a Novel Serum- and Animal Component-Free Culture Medium ………………………………………………………………………………………………………………. Ravenska Wagey, PhD Senior Scientist, STEMCELL Technologies Inc. To address the need for serum-free MPC culture, STEMCELL Technologies has developed a novel serum- and animal component-free culture medium which promotes superior clonogenic growth and long-term expansion whilst maintaining multi-lineage differentiation potential of human bone marrow-derived MPCs. Dr. Ravenska Wagey will present performance characteristics of the medium as well as optimal procedures for the isolation, characterization and expansion of MPCs. A Rapid Hematopoietic Colony Assay for Measuring the Potency of Umbilical Cord Blood Grafts ………………………………………………………………………………………………………………. Michelle Bowie, PhD Global Product Manager, STEMCELL Technologies Inc. To meet the need for rapid and easy-to-use potency assays, STEMCELL Technologies has developed a new hematopoietic colony assay that can be completed in 7 days, is easier to score than standard CFU-assays and provides accurate measurement of hematopoietic progenitor cell frequencies in cord blood units that correlate well with results of standard CFU-assay formats. Dr. Michelle Bowie will present an overview of the hematopoietic CFU assay as well as the performance characteristics of STEMCELL’s 7-day CFU-assay.

Cell Therapy Industry HiLites 2009-02-20

Before we get started, here's some good advice:

• renew your membership or join ISCT (www.celltherapy.org)
• if you're on LinkedIn, join the Cell Therapy Industry Group
• register to go this year's ISCT CellTherapy 2009 conference in San Diego
• get on Twitter, and follow my stream (@celltherapy) for timely news and random thoughts
• tell someone you love them.
  
  
  
  

Ok. Another week, another conference, another controversy, another clinical hold...

This was the week of RRY Publications' 4th Annual Stem Cell Summit, organized by investor and analyst Robin Young. Once again, Monya Baker, of Nature's stem cell blog "The Niche" does an outstanding job of summarizing the conference content and tenor in a post called "Investors ♥ stem cells". My only humble comment is that it might have been more aptly named "Entrepeneurs ♥ stem cells" because I don't think the plethora of companies and technologies represented at the conference was due to a flood of investment but rather the irrational (thank God!) enthusiasm of biotech entrepreneurs that keep sectors like this afloat whilst risk-averse investors await the obvious to float to the surface.

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This issue is sponsored by the company setting a new standard for what you can expect in fresh cell and tissue storage.

You owe it to your cells to find out what they know.

www.biolifesolutions.com

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The big pile to hit the fan this week was the PLoS Medicine article published online February 17 describing a patient who developed “brain tumors” (glioneuronal neoplasms) after undergoing repeated transplants of “fetal neural stem cells” in Russia starting in 2001. Fellow bloggers Monya Baker @ the Niche (click here >>) and Alexey at Hematopoiesis.info (click here>>) both provide useful summaries and commentary .

Naturally it is a concerning report for the industry and the regulators. People jumped all over it touting their various perspectives and generating a veritable miasma of opinion. Indeed, so much so that Stem Cells, Inc (NASDAQ: STEM) was forced to publish a commentary on the report in an attempt to distinguish their product from what was apparently injected into the boy in Russia. STEM's commentary is worth the read.

What I will say here - apropos to my ongoing discussion about stem cell transplant clinics around the world enticing people to pay for a shot of stem cells because 'why not? these products are safe' - is that there are stem cells and then there are stem cells and then there are stem cell products. Products are well studied, well understood, well defined, well characterized, well controled, and well tested.

Ex-FDA, regulatory consultant Dr. Darin Weber (blogging at RegenmedGuru.com) has a great post on this whole issue that is well worth the read. He sums up his commentary by saying:

The bottom line is that if you wish to test stem cells in humans in the U.S., the FDA is going to require robust evidence of efficacy and safety in relevant preclinical animal models, regardless of the source.

Now the FDA has an clear example it can point to, for better or for worse, to justify the extensive preclinical studies it requires. The good news is that many developers of stem cell derived therapies, including Geron, have in fact been able to generate the preclinical efficacy and safety data needed to enter human clinical studies.

So why is the FDA "holding back" stem cell treatments that are available in other countries? Why should people think very carefully about their decision to go to a clinic offering stem cell injections for sale? Why is 'industry' critical of what some of these clinics are doing? Why should we be concerned about whether these 'treatments' are as safe as advertised? We now have an example of why.

This is no justification for being over-reactionary about the potential for cell therapy. This is not even a good reason to paint all unregulated stem cell treatments with the same brush. It is a reason to be ever-vigilant in ensuring we are doing our utmost to produce effective AND safe therapies. It is also reason support the dialogue ISSCR is attempting to stimulate to help people discriminate between those clinics following best practices and those which are not.

In the meantime, people are getting shot up with sheep stem cells in Mexico (check it out) ...

FINANCIAL

No news is not really good news here.

CLINICAL

Neuralstem, Inc. (AMEX: CUR) announced today its spinal cord stem cell trial to treat ALS has been put on clinical hold. This seems to be pretty par for the course at this stage. The question will be how long it takes to address the issues. Geron was able to get through their hold in under 9 months; ReNeuron submitted its IND to FDA in December 2006 and has yet to get it through despite being approved to proceed in the UK last month. See Monya Baker's commentary on Neuralstem's hold on Nature's stem cell blog, the Niche - click here >>.

Neuralstem was more forthcoming with details about their hold than Geron was when in the same position months ago. The FDA has reportedly provided the Company with specific comments, questions and recommendations for modifications to its protocol including requests for additional information regarding their product manufacturing process and pre-clinical studies, as well as their clinical delivery injection device and technique. The Company believes that it can "provide this information in an expeditious manner."

Apparently the Agency has also requested various modifications to the protocol and eligibility criteria for patients in the trial, as well as slight changes to the timing of the surgeries. Perhaps more interesting was the comments by President & CEO, Richard Garr that the "Agency had extensive 'non hold' comments, requests for information, and recommendations" which he characterized as issues which will need to be "addressed for final product manufacturing and testing". By that, I'm assuming he means the FDA raised several issues which wouldn't hold up phase I testing but certainly would need to be addressed in future stages.

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HepaLife Technologies, Inc. (OTCBB: HPLF) (FWB: HL1) (WKN: 500625) announced plans for a phase III clinical trial of its HepaMate™ Bioartificial Liver System. The HepaMate™ technology has previously been tested in clinical Phase I and pivotal Phase II/III studies involving more than 200 patients. However the last phase II/III study failed to achieve its primary endpoint. In October 2008, HepaLife announced completion of its acquisition of a liver support technology previously known as HepatAssist from Arbios Systems. It's not clear how, if at all, this is playing into HepaLife's current strategy.

As an extracorporeal cell-based bioartificial liver system, HepaMate™ is designed to combine blood detoxification with liver cell therapy to provide whole liver function in patients with the most severe forms of liver failure. HepaMate™ is comprised of a blood plasma separation cartridge, a hollow-fiber bioreactor filled with proprietary porcine liver cells, a charcoal column, an oxygenator, circuit tubing and a plasma reservoir. These components are assembled into a patented blood/plasma circulation system, which is placed on the HepaDrive™ perfusion platform.

A patented liver cell cryopreservation process provides for safe and easy storing and distribution of the liver cells which detoxify existing toxins, produce albumin and other liver-specific proteins when, during therapy, the patient’s plasma is separated from whole blood, exposed to the HepaMate™ bioartificial liver and returned to the patient.

The company claims only 90 minutes are required to assemble the system, prime the blood and plasma circuits and to process the liver cells due to the logistical advantages of its proprietary cryopreserved pig hepatocyte technology over the use of fresh cells from cell lines or liver tissue.
Thawing, loading and washing of the cryopreserved cells is reported performed at the patient’s bedside using a what the company describes as a proprietary, "FDA-approved" technique.

Apparently a retrospective statistical analysis of the previous pivotal Phase II/III clinical trial data, adjusted for the impact of liver transplantation on patient survival, revealed a statistically significant survival advantage for patients with fulminant and subfulminant hepatic failure when treated with HepaMate™ compared to controls receiving standard medical care alone. The company blames the previous trial's failure on the inclusion of a subset of 24 patients who had undergone a prior, failed liver transplant. It was these patients, the company postulates, that led the the phase II/III trial failing to achieve its primary 30-day survival endpoint in the overall study population. Based on the retrospective statistical analysis of the clinical trial data, HepaLife expects a new Phase III clinical trial without the inclusion of failed liver transplant patients to be successful.

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It's now clear why J&J is closing its Sydney, Australia operation which was investigating OZ1 as its lead product against HIV. Earlier this week a report came out entitled "AIDS: 'Major advance' seen in revolutionary gene therapy'. It was an interesting spin. What was learned from the study in question was a 'major advance' only in the minds of scientists who can chalk this study up to 'lessons learned' from less than positive results. We're no closer to a therapy based on this product.

The report indicated that the world's largest experiment using gene therapy to combat the AIDS virus yielded "a major advance," in demonstrating that the technique is valid, beneficial and safe. "It shows the potential of the gene therapy approach for the treatment of HIV and represents a major advance in the field... [it] can be developed as a conventional therapeutic product," the report stated. Yet later the report admited that while the treatment is safe efficacy was modest. Finally, the report states that in an interview, the principal investigator, Mitsuyasu, said they would not be proceeding past this Phase II trial to the final, third phase of the process. Instead, the team would learn from its experience, modify the technique and start again with tests on a smaller group of volunteers.

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This week NeuroGeneration put out a press release that boldly states it published long-term results of a successful phase I trial using autologous neural stem cells to treat Parkinson's disease. Despite the over-reaching headline, this is not the data from a completed phase I trial but rather the results from the trials' first (and only?) patient. Really more of a case report.

The paper was published in the February issue of the Bentham Open Stem Cell Journal. It outlines the long term results of the treatment of a patient for the treatment of Parkinson’s disease using autologous neural stem cells. According to lead author and NeuroGeneraton owner/founder, Michel F. Levesque, MD, FRCS(C), FACS, "We have documented the first successful adult neural stem cell transplantation to reverse the effects of Parkinson’s disease and demonstrated the long term safety and therapeutic effects of this approach."

The paper described a process by which tissue is taken from the patient's cerebral cortex and expanded for 6 months (yes, 6 month!) before injection. The paper's conclusions:

• Neural stem cells can be isolated from the human adult cerebral cortex, expanded in vitro using epigenetic factors, induced to differentiate into dopaminergic, GABAergic and other types of mature neurons, and selectively delivered back to striatal targets without immunosuppressant.
• Because of their biocompatibility, safety and potential integration into the host striatum, autologous neural stem cell-derived differentiatedneurons represent an alternative to current cell therapy aimed at the restoration of the nigro-striatal circuitry inParkinson’s disease.
  

COMMERCIAL

MaxCyte, Inc announced the introduction of its GT Flow Transfection System at the 4th Annual Stem Cell Summit held in New York, NY this week. The MaxCyte GT Flow Transfection System is marketed as a a validated, scalable technology for customizing the biological activity of cells for therapeutic use. The system, the subject of a US FDA Master File, is designed to enable rapid and efficient transfection of primary cell or cell line with reported >90% cell viability following loading with a broad range of molecules (proteins, drugs, plasmids, mRNA, miRNA, and siRNA) or combinations thereof, at volumes up to tens of billion cells.

What's not clear to me is how this system is different from the clinical scale, non-viral cell loading systems MaxCyte has been selling now for some time and a quick spin through their website has not helped shed any light on that question. Indeed there is nothing about a product launch on their website so this product "introduction" might just be clever spin around a talk about a product that has been on the market for some time. I'll try to find out...

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MedCell Bioscience Ltd (merged last year with NovaTherapy) announced they won the Hong Kong Grand Award for their NovaPod - a compact, manual feed, disposable, batch culture bioreactor that allows researchers and scientists working on stem cells to culture cells in three dimensions. The Hong Kong Grand Award for Industries, Machinery and Machine Tools was presented on 21 January 2009 at the Hong Kong convention and exhibition centre.

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Ok this isn't cell therapy but it's about the so-sexy, so-'now' iPS cells so I couldn't resist. The Japanese unit of German chemical giant Bayer A.G., Bayer Yakuhin Ltd, has announced it is selling a set of patents on producing iPS cells to a U.S. venture firm. The three patents to be sold to iZumi Bio Inc include Bayer Yakuhin’s main method of producing iPS, or induced pluripotent stem cells, which have the potential to grow into any type of human body tissue. Bayer Yakuhin filed for Japanese and international patents on the method in June 2007. The two other international patents are supportive ones for the mainstay one. Bayer Yakuhin’s move has been closely watched since it made patent applications months ahead of Kyoto University.

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StemCellDigest.net did a nice job this week of detailing the historic and rather complicated but much closer licensing relationship than I realized existed between Advanced Cell Technology Inc. (OCTBB: ACTC) , Biotime, Inc, (AMEX: BTX) and International Stem Cell Corp (OTCBB: ISCO). To read more, click here>> .

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ProtoKinetix, Inc (OTCBB: PTKX) issues a press release this week that their synthetic anti-aging glycopeptide, AAGP, is "Critical for Stem Cell Therapy" saying that tests of the compound in conjunction with stem cell preservation studies at all temperatures has shown an "impressive increase in survivability and viability". Reportedly, these results have been consistent regardless of the source of the stem cells. As an example, AAGP(TM) has been independently tested as a protective agent in the cryopreservation and subsequent thawing of umbilical cord blood in low concentrations of AAGP(TM) (4mg/ml). The resultant analysis reportedly revealed a more than double average increase over the control group (cells not protected with AAGP(TM)) in the yield, following thawing. Sounds impressive enough but they provide no links to publications and despite the headline that AAGP is 'critical' for stem cell therapy, I've not seen or heard them at any stem cell conference nor have I seen any of the data published in journals. Curious...

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Stem Cell Therapy International, Inc. (OTC BB:SCII.OB) - another of these companies marketing stem cell transplant treatments in clinics located in countries where they are allowed to do so - has filed its quarterly report. It is a long and twisted tale of corporate re-orgs, reverse mergers, subsidiaries, debt, financings, payments in salaries and consultanting fees, zero revenues, and a pending deal with the Korean company, Histostem Co., Ltd., that was first announced early last year and has yet to close because of some litigation that won't go away. As best I can tell from a quick scan of the SEC filings they did not treat a single patient in 2008 - perhaps that's the good news.

RESOURCES & EVENTS

MIT Enterprise Forum of Cambridge announced an upoming session (March 3rd) on the Future of Biotech with a panel of experts who will discuss Challenges and Opportunities in Stem Cell Therapy and Regenerative Medicine.

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The FDA has posted what could be a very useful presentation if the right (wrong?) circumstances: Writing An Effective 483 Response.

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Curt I. Civin and E. Albert Reece put out a piece this week in the Baltimore Sun entitled "The Stem Cell Opportunity" outlining some of their thoughts on the state, need, and potential for the sector.

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A summary of the most recent ISCT Cellular Therapy Liaison Meeting with the FDA has been posted on the AABB Web site, along with corresponding speaker presentations. Agenda items for the meeting, which was held in October 2008 at the AABB National Office, included "Adoptive T-Cell Therapy for Melanoma: Production Steps and Associated Costs," "Autologous Expanded T-Cell Therapy in Post-Transplant Setting," and "HESC-Derived Cell Therapies: Safety in Translation." View summary


Sign-off...

Well, that's a wrap to an a wee bit of an odd but not entirely bad week in the cell therapy industry. For those of you with any doubts, remember you heard it here first: cell therapy means business.

Cell Therapy Industry HiLites 2008-12-19

Ok so it's almost not Friday anymore even by my Pacific Time Zone but I promised to try to do this every Friday and so here I am. I will not be doing a HiLites next Friday however. I'm taking a break for the holidays.

For the week before Christmas this was one busy week!

I'll start this week's HiLites with a bit of a focus on Bioheart, Inc. (Nasdaq:BHRT). The company has been busy this week reinventing itself - just how much remains to be seen. As followers of the industry will recall, Bioheart had a disappointing IPO earlier in the year but was able to raise ~$1.8M in a private placement in October. This, I suspect, is not much more than survival money as they are financing a 330-patient phase II/III trial in US and Europe.

So the company's announcement this week came as no surprise that it intends intends o spin out or sell off its interest in several non-core technology platforms including:
- Biopace -- A biological pacemaker.
- MyoValve -- A cell seeding method for repairing and building biological heart valves.
- EndoCell -- A system for bedside preparation of adipose tissue for delivery of endothelial progenitor cells to the adventitia of coronary arteries for prevention of restenosis following
balloon angioplasty, stenting or atherectomy.
- AortaCel -- Cell compositions and delivery systems for repairing aortic aneurysms or for reinforcing the neck area in aortas repaired with an endovascular stent graft.

In addition, Bioheart is seeking a strategic partner for the development of its bi-ventricular pacemaker technology, called MyoStim, which utilizes a patented electrical stimulation software program and an additional pacemaker lead to enhance cell transplantation.

Understandably Bioheart is doing this in order to intensify its strategic focus on the treatment of patients suffering from heart failure. Interestingly, however, in their press release Bioheart made no mention of their cell therapy saying rather that Company is strategically focused on commercializing patented technologies for reducing and repairing heart muscle damage caused by heart attacks as well as marketing advanced heart failure monitoring devices including the Bioheart 3370 Heart Failure Monitor and the Bioheart-Monebo CardioBelt(tm) ECG Acquisition Device.

Then yesterday Bioheart announced it had had signed a deal with Life Technologies Corporation (Nasdaq:LIFE) (the new combined Invitrogen-Applied Biosystems entity) which provided Life the global distribution to Bioheart's myoblast cell-based research products to life science researchers. The deal is intended to "expand the number of therapeutic applications under development with this type of cell" but again no mention of Bioheart's own trial or product.

All of which leads to at least a couple questions we hope Bioheart will soon answer. Firstly, is the company positioning itself away from its lead product MyoCell®? Secondly, the deal with Life Technologies was described as a "distribution and OEM agreeement" but while there was discussion about the distribution aspects of the deal, there was no description of the OEM part. Given that neither company has any notable capacity or expertise in producing clinical-grade cells will this only encompass research-grade cells or are there other plans here not being discussed?

I'll move on to other news of the week.

In a move that will certainly enhance his legacy on his way out the door, Alan Lewis announced that Novocell, Inc. has entered into a non-exclusive drug discovery collaboration with Pfizer which gives Pfizer access to Novocell’s proprietary pancreatic progenitor cells derived from human embryonic stem (hES) cells. This appears to be an open-platform type of agreement (limited for now to 2 years). Novocell will receive an upfront payment, research funding, additional amounts payable upon the achievement of certain technical milestones, and payments relating to the sale by Pfizer of any exclusive therapeutic discovered as a result of the collaboration.

Novocell has shown it can coax human embryonic stem cells to become fully functioning pancreatic beta cells that secrete insulin in mice but about 15 percent of the animals got teratomas, a type of tumor. This, the company will have to learn to prevent or at least control before it gets approval to go to human clinical trials. For now, as Xconomy's Luke Timmerman says, "Novocell can take some comfort knowing that some of the deepest pockets in the pharmaceutical industry are shelling out at least a little spare change to help it crack daunting challenges like that."

BioLife Solutions Inc. (OTCBB: BLFS) announced that it has completed an initial series of small animal safety studies. The studies evaluated injections of HypoThermosol, CryoStor, or control phosphate buffered saline (PBS) into healthy rodents. The study was designed to mimic human clinical applications where stem cells isolated from cord or peripheral blood are re-suspended in a carrier solution and administered intravenously to treat patients suffering from a variety of diseases and disorders including leukemia, anemia, lymphoma, myeloma, and other cancers.
The results of these studies demonstrate- the Company claims - that infusion of HypoThermosol and CryoStor present no safety risk within the parameters of this two-stage evaluation in a rodent model. Data to be published and/or presented soon.

Avita Medical Ltd (ASX: AVH) says the French Ministry of Health is funding a 200 patient medico-economics study on the impact of Recell on burn wound healing. Avita said that the first patients were enrolled and had been treated in the study which was part of a French program “to advance the implementation of innovative technologies”. Avita said the primary goal was to demonstrate the medical effectiveness and economic benefits of the Recell technology to the hospital and health care system in the treatment of burns and wounds.

Recell, already commercially available in Australia, is a single-use medical device for harvesting autologous skin cells. Developed as an 'off the shelf' kit, ReCell enables a thin split thickness biopsy, taken at the time of procedure, to be processed into an immediate cell population for delivery onto the wound surface. Once processed, the cell suspension is available for immediate use and can cover a wound up to 80 times the area of the donor biopsy. ReCell enables the delivery of keratinocytes, melanocytes, fibroblasts and Langerhans cells harvested from the epidermal-dermal junction for application onto a wound surface in order to promote effective wound healing.

Pluristem Therapeutics Inc. (NasdaqCM:PSTI) (DAX:PJT) filed a European Investigational Medicinal Product Dossier (IMPD) to begin clinical trials of its placental-derived adherent stromal cell product, PLX - PAD, an allogeneic cell therapy, for critical limb ischemia. The company filed the IMPD application with the Paul Ehrlich Institute (PEI), the German competent authority in the European Union (EU). An IMPD is a harmonized procedure for the authorization to perform a clinical study in any one of the EU Member States. An IMPD is requested whenever the performance of a clinical study in any one of the EU Member States is intended, and it is similar to an Investigational New Drug (IND) Application that would be filed for the performance of a clinical study in the United States. Assuming approval of the IMPD by this authority, Pluristem said it plans to initiate the dose ranging clinical trial during the second quarter of 2009 at two sites in Berlin, Germany

Amgen lobbied this week for personalized medicine by presenting to the FDA the argument that one of its drugs should be used by just a subgroup of patients with colorectal cancer who appear to be most likely to benefit from it.

NeuralStem filed an IND to use its neural stem cell technology in a trial for Lou Gehrig’s disease in what it described as the first ALS trial using stem cells.

Progenitor Cell Therapy has brought in a new CFO with over 21 years of experience in the life sciences industry and fundraising. This will undoubtedly help them raise the funds needed for their continued US and European expansion plans.

StemCells, Inc (NASDAQ: STEM), which already has a trial underway for Batten disease, just received FDA approval to start a trial for Pelizaeus-Merzbacher Disease (PMD), also fatal brain disorder that affects mainly young children. The mechanism of the potential Batten disease therapy is to establish healthy neural cells that can help a patient’s own cells clear out some toxic garbage that builds up in the disease, the mechanism for PMD is to boost myelinization of neurons. StemCells uses cells originally derived from fetal tissue.

Although this news will be old to some I discovered this week Arteriocyte's announcement from November 10 that it had been awarded the DARPA Blood Pharming award to the tune of $1,950,000 which presumably it has to share with collaborators at Johns Hopkins University, The Ohio State University and INSERM, Paris. While this seems like a sizeably juicy award, the US Military's Defense Advanced Research Projects Agency (DARPA) has issued a tall order. DARPA wants a self-contained device small enough (≤47 ft3) to go into the military field and create at least 100 units of universal blood (i.e., can be transfused into anyone regardless of blood type) per week for eight weeks. The key ingredient to Arteriocyte's proposal and the company's Nanofiber Based System (NANEX) technology is umbilical cord blood stem cells.

While technically not a cell therapy play, both these players are notable enough in the cell-as-tools sector that we thought it worth noting that VistaGen Therapeutics has signed a deal with Wisconsin Alumni Research Foundation (WARF) to license WARF's human embryonic stem cell patents for the development and commercialization of stem cell-based research tools.

Winning this week's award for the press release with no news, is the annoucement from Advanced Cell Technology, Inc.(Other OTC: ACTC.PK) that "its technology platform, which utilizes a single cell biopsy that does not destroy the embryo, is well positioned to receive Federal funding under the new administration led by President-Elect Barrack Obama."

They made up for it the next day, however, by releasing news of new funding. Demonstrating, once again, their tenacious survivability, ACT announced it had licensed a "non-core technology" to one of its creditors, Ireland-based Transition Holdings, Inc, for $2.5 million - comprised of the extinguishment of $1.5 million of debt and an additional funding commitment of $1 million. The Company expects to apply the proceeds it receives in the future towards its retinal pigment epithelium (RPE) cells program.

Cytori has now launched a a 30-person clinical trial using adipose (fat) stem cells for chronic radiation induced injury.

Life Technologies announced its CIRM award will be used to develop human stem cell models of neurodegenerative diseases to advance drug development. The company intends to use human embryonic stem cells to develop new models of Lou Gehrig's Disease and other neurodegenerative diseases.

Inno Bio Diagnostics Sdn Bhd (IBD), which specialises in cell-based diagnostics and regenerative medicine, is investing RM4.58 million (~$1.3M) to set up a cell therapy centre at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC) in Kuala Lumpur, Malaysia. IBD, a wholly-owned subsidiary of Inno Bio Ventures Sdn Bhd, aims to create and develop business opportunities in stem cell technology in the area of cell-based diagnostics and therapy. The cell therapy centre, which is expected to start operations next year, will be jointly managed by IBD and UKMMC to develop human hepatocyte-like cells from stem cells that are derived from embryonic, bone marrow, mesenchymal and adipose tissues. The human hepatocyte-like cells can be used for in vitro assays for screening and testing potential drugs for the pharmaceutical and nutraceutical industries. According to Ahmad Zaharudin, the company is projecting a revenue of RM15 million to be generated from the product, knowledge transfer and licensing of technology as outcome of the partnership.

Genzyme Corporation announced that the U.S. Food and Drug Administration has granted marketing approval for Mozobil(TM) (plerixafor injection), a drug intended to be used in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). The product has also been granted orphan drug designation. Genzyme has submitted an application in Europe for approval of Mozobil and expects approval of the product in the second half of 2009. Genzyme recently filed applications in Australia and Brazil, and additional global applications in up to 60 countries are planned. Mozobil has received orphan drug designation in Mexico which allows the product to be commercialized in the country upon U.S. approval. Genzyme believes that Mozobil may have broad application outside the current indication. Early preclinical and clinical investigations are already underway to explore additional therapeutic indications for Mozobil, including mobilization of hematopoietic stem cells in allogeneic stem cell transplants and tumor sensitization in oncology/hematology treatments such as adult myeloid leukemia.

And finally... it looks like there's a showdown shaping up in Colorado. As disucssed previously on this blog, in July FDA CBER's Mary Malarkey sent a warning letter to Dr. Christopher J. Centeno, Medical Director of Regenerative Sciences, Inc (RSI), doing business as Regenexx. On a recent visit to the Regenexx website, we see that they state the following:

"The Food & Drug Administration's (FDA) role is to regulate the sale and distribution of drugs, devices, biologics and combination products, but not how these products are used by physicians. The FDA does not approve surgical procedures. RSI conducts all surgical procedures within the State of Colorado. There are no interstate aspects to the procedures conducted by RSI that invoke FDA jurisdiction under the Public Health Service Act (PHSA), which requires an interstate nexus. Our surgical procedure involve the use of autologous stem cell therapies (ACTs) consisting of products or treatments incorporating the in vivo use of a patient's own stem cells, following, in certain circumstances, ex vivo manipulation or processing, for the prevention, or treatment of disease. The surgical procedures conducted by RSI including surgery and bone marrow transplants are not performed as part of any research intended for FDA approval of a product that is under the jurisdiction of the FDA. Therefore, the stem cell procedures conducted by RSI are not under the jurisdiction of the FDA. Rather, the procedures conducted by RSI are considered the "practice of medicine," and is left up to individual surgeons' judgment and experience and oversight by the Colorado Board of Medicine." [emphasis added]


And that ends the way I saw the cell therapy industry this week.... More HiLites to come in 2009! Happy holidays to one and all.

--Lee

Cell Therapy HiLites 2008-11-07

I'm not going to turn this blog into a news service by any means, particularly since I wouldn't want to compete with what I already created in Cell Therapy News - still the single best news source for this sector. I'm going to aim, however, to put out a brief weekly email highlighting what I believe to be some of the key content I noticed during the week (news or otherwise).

For what it's worth, here's what I noted this week.

Athersys, Progenitor Cell Therapy, NeuroNova, Stem Cell Sciences, and Amorcyte featured in GEN article on regenerative medicines. GEN Oct 15 2008 (Vol. 28, No. 18)

Onyvax publishes data supporting the notion that the intersection of biomarkers, personalized medicine, and cell therapy is just around the corner and it will turn medicine on its head. They believe they have identified a biomarker profile that could be predictive of response to cancer vaccines.

Science Direct's Top25 Hottest Articles for 2008 Q2 have a very high ratio stem cell-related publications.

It was a big week for BioLife Solutions with several new adoptions of their preservation and storage media as well as the filing of their second MasterFile with the FDA.

On the economic front, the Genzyme-Osiris deal (worth a potential $1.4B) was obviously great news for a sector so keen to see signs that investors aren't shunning the field but on the other hand is something of a confirmation that companies will have to get creative to survive what Burrill projects will be a lengthy dry-spell in terms of biotech investment.

Invitrogen & Applied Biosystems resurrect the Life Technologies brand as the new name for their merged entity.

Sartorius Stedim relieves us of the confusion of having two Wave Biotech's out there with single use bioreactor systems (SUBs) by purchasing the European Wave Biotech AG. (full story)

The FDA takes a new approach to the annual HCT/P Establishment Registration Updates. (link)

Finally, if you haven't checked out www.biobusiness.tv yet you really must. Jean-Loup Romet-Lemonne has created a valuable biotech business video content channel that promises to focus a great deal on cell-based therapies because of Jean-Loup's experience in and passion for cell therapies.

Until next week...