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May 18, 2010

Osiris’ Race to Market an FDA-Approved Stem Cell Product

Mesenchymal stem cell therapy Prochymal is in Phase III but still has challenges to overcome.

Osiris’ Race to Market an FDA-Approved Stem Cell Product

© Elena Pankova - Fotolia.com

  • While human embryonic stem cells have gotten the lion’s share of attention from the popular press and the public, companies developing stem cell therapies from other sources are advancing these products rapidly and reaping milestone payments from partnerships. Closest to an off the shelf stem cell product is Osiris Therapeutics’ Prochymal, a human mesenchymal stem cell (MSC) therapy.

    Prochymal is in development for multiple indications, the most advanced being graft vs. host disease (GvHD) and Crohn disease. It is already available under FDA’s expanded access program and has fast-track status for both indications. However, the company’s plans for an FDA approval and U.S. launch of Prochymal for GvHD last year were botched due to two clinical trial failures in that indication during 2009. 

    Osiris continues to assert, though, that MSCs from unrelated donors that are isolated from bone marrow and used in recipients without immune suppression offer a viable business strategy for the commercialization of stem cell therapies. The company's current focus, it says, includes the use of universal MSCs for bone marrow transplantation support in hematological malignancies, cardiac repair after acute myocardial infarction or congestive heart failure, and regeneration of meniscus after meniscectomy.

    Besides Prochymal, Osiris has a second MSC-based clinical candidate called Chrondogen, which is being tested as an arthritis treatment in Phase II. The firm’s first and only successful MSC product, Osteocel, was sold to NuVasive in 2008 and is now generating cash for that company.

    MSCs are nonhematopoietic stem cells present in the bone marrow as well as other tissues including cord and peripheral blood, fetal lung and liver, and adipose tissues. They can differentiate into multiple mesodermal cell lineages including osteoblasts, chondrocytes, endothelial-cells, as well as nonmesoderm-type lineages such as neuronal-like cells.

    Because of their relative ease of isolation and their extensive differentiation potential, MSCs were among the first stem cell types to be introduced in the clinic. Most critically, the cells do not provoke strong immune responses and therefore can be used for stem cell transplantation without the need for immunosuppressive drugs.

  • Prochymal’s Development Path

    In spite of its vast potential, Prochymal failed three clinical studies in 2009: a mid-stage trial in patients with chronic obstructive pulmonary disorder (COPD) and two Phase III studies in patients with steroid-resistant GvHD and acute GvHD. Phase III trials for acute and steroid-refractory GvHD are ongoing.

    The company’s luck with Prochymal in GvHD changed when on February 24, Osiris reported results from its protocol 275 study of the drug as a rescue therapy among 59 children with severe, treatment-resistant GvHD. The trial was carried out under a special allowance by the FDA. Prochymal achieved an overall response rate of 63%, and among children who showed a response to therapy, survival significantly improved, according to the company.

    Prochymal’s progress was stifled again, however, when an interim analysis of a Phase III trial evaluating patients with treatment-resistant Crohn disease showed that one of two dosing arms was unlikely to achieve the study endpoint of disease remission. The trial remained blinded to permit an evaluation of all 207 patients enrolled in the study. On May 5, the Phase III study was resumed based on preliminary data showing that despite initial concerns, the effect size, or difference between the Prochymal and placebo response rates, of one Prochymal dosing arm was consistent with the original statistical assumptions of the protocol and that Prochymal was significantly outperforming placebo.

    The trial is evaluating Prochymal in patients with severe Crohn disease who are unresponsive to steroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate), and biologic agents Remicade®, Humira®, and Cimzia®. The majority of patients enrolled thus far have failed at least two immunomodulators and two biological agents. 

    The company does not expect to receive approval through this restarted trial. “Our goal is to use the data from this well-controlled trial to appropriately design and power an efficient pivotal program to support product approval for this devastating disease,” remarked Douglas Jacobstein, M.D., Osiris’ medical director.  

    If the firm can get the trial design right, it would signal good news for Osiris and development partner, Genzyme. The companies formed an alliance in 2007 for the development and commercialization of Prochymal and Chondrogen, a stem cell preparation designed for intra-articular injection. In 2007, Osiris reported results from a six-month interim evaluation of a Phase I/II trial testing Chondrogen for the regeneration of meniscus in the knee. While the company said the product met its primary safety endpoint, it did not demonstrate a statistically significant increase in the volume of meniscus as compared to placebo. Chondrogen continues to undergo testing to establish its long-term safety.

  • Business Model

    In January 2008, the DoD commissioned Osiris and Genzyme in a deal worth $224.7 million to develop and stockpile Prochymal for the repair of gastrointestinal injury resulting from radiation exposure. Osiris reported revenues of $11.4 million in the first quarter of 2010, consisting primarily of up-front license fees from Genzyme and a $1 million milestone achieved under its collaboration with JCR Pharmaceuticals for development progress of Prochymal in Japan.

    The company also has an agreement with Boston Scientific to develop and commercialize a new therapy to treat cardiovascular disease. The alliance, which includes an equity investment, initially focuses on applying the MSC technology for heart attack patients.

    But did Osiris give up the big one in 2008? At the time, it had what looked like a successful product in Osteocel. Osiris’ president and CEO, C. Randall Mills, Ph.D., characterized the deal as a “landmark transaction for Osiris as it underscores the ability of Osiris to generate substantial revenue through our proprietary technology platform and underscores the commercial value of our products.” At the time Prochymal was in Phase III trials for acute and steroid-refractory GvHD and Crohn disease. 

    Osteocel, composed of unexpanded MSCs embedded in a matrix of cancellous bone, is delivered directly to a body site. It is marketed as a human tissue for transplantation. The product is not regulated by the FDA and did not require testing in clinical trials. 

    Osteocel, it turns out, had been around the block a couple of times before Osiris sold it.  In 2005, Blackstone licensed Osteocel from Osiris. Then, in 2006, Orthofix bought Blackstone for $333 million to gain access to the product. Orthofix shares hit an all-time high of $66 at the end of 2007. In July 2008, however, Osiris sold its Osteocel business to NuVasive. Orthofix tried but failed to get a federal court to block the deal and as a result, lost its right to sell Osteocel. It missed out on, according to Orthofix CEO, Alan Milinazzo, a potential annual market of about $300 million.

    Osiris has put its eggs squarely in the stem cell basket with Prochymal and Chrondogen. While it is indeed the closest to being able to market a stem cell product, the company does still need to surmount its clinical trial woes and the profound difficulties inherent in bringing an extremely complex therapy to market without any real clinical trial guideposts. A lot of unknowns remain in understanding how stem cells work, and a much more comprehensive view is needed before researchers and companies can fully translate its potential into the clinic and eventually onto the market.


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