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:
- 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).
- 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.
- 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.
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.
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.
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.