106 volume 27 number 2 february 2009 nature biotechnology

Osiris seals billion-dollar deal with Genzyme for cell therapy

the Cambridge, Massachusetts–based com-pany does get commercial rights to the MSC treatments in all other countries. Potential markets include osteoarthritis, and may ultimately expand to include cardiovascular disease, diabetes and chronic obstructive pul-monary disease.

Osiris was one of the first companies to work with adult MSCs and is “the leader in the space,” according to Chris Mason, Professor of Regenerative Medicine Bioprocessing at University College London with no financial ties to the firm. “It is a pragmatic company, they have done a good job of manufacturing high-quality cells leading to robust clinical data,” he adds.

“We’ve been talking to Osiris in one way or another for five or six years now because we’ve been in cell therapy for a long time ourselves,” says Stephen Potter, senior vice president for corporate development at Genzyme, which received approval for the first cell therapy (Carticel) ever approved by the US Food and Drug Administration (FDA), in 1997. But there was no real move-ment toward a deal “until we started to see the phase 2 data in their first GvHD trial,” he notes. “That really started to elevate our discussion, and I think they [Osiris] started

to see the value in having a partner who had a more global reach.”

Osiris has advanced its lead product Prochymal well into phase 3 clinical trials to treat severe refractory GvHD, a disease that causes life-threatening immune system reac-tions in the skin, gastrointestinal tract and kidney after a bone marrow transplant. Data from all three phase 3 Prochymal trials are expected mid-2009, after which the company expects to submit a biologic license application to the FDA. There is currently no approved drug to treat GvHD, and the FDA has granted Prochymal fast track designation and orphan disease status, which will expedite regulatory reviews and ensure marketing exclusivity for seven years. Prochymal has also been granted expanded access by FDA and Health Canada, so it is now available to any child aged 2 months to 17 years with end-stage GvHD without the need for compassionate-use paperwork.

In addition to GvHD indications, Prochymal is also in phase 3 trials for Crohn’s disease, a gastrointestinal tract disorder. Studies suggest that MSCs can help regenerate intestinal tis-sue damaged by Crohn’s that is necessary for absorbing nutrients. Prochymal is also in late-stage development for acute radiation syn-drome, a condition that shares similar clinical manifestations to GvHD and Crohn’s disease. In July 1997, Osiris and Genzyme entered an agreement to study radiation sickness. Then in January 2008, the partners were awarded a US Department of Defense contract worth $224.7 million to develop and stockpile Prochymal to counter nuclear terrorism and other radio-logical incidents. The biodefense deal was an important harbinger for Genzyme, says Potter. “It’s always nice to get a test drive,” he says.

Genzyme has a proven track record of mar-keting nonblockbuster products to produce good margins and returns for investors. More specifically, Genzyme’s extensive product portfolio includes Epicel (cultured epidermal autografts) for treating patients with severe burns and Carticel (autologous cultured chon-drocytes) marketed to the orthopedic surgery community for regeneration and repair of cartilage defects. This franchise complements Osiris’ other MSC formulation: Chondrogen, a meniscus regeneration product, which is virtually the same substance as intravenous-ly-administered Prochymal, except that it is formulated for direct intra-capsular injection into the knee.

The substance of this deal is MSCs made from adult volunteer bone marrow donors. Osiris selects donors from a pool of 18- to

The head office of Osiris in Columbia, Maryland. The company is pursuing adult stem cell formulations for a raft of indications including joint injury, cardiovascular disease and diabetes.

Adult stem cell products could be lining up to penetrate the inflammation and orthopedics markets, judging by the recent $1.38 billion paid by Genzyme for Osiris’s mesenchymal stem cell technology. Genzyme’s bid to develop and commercialize two of Osiris Therapeutics’ mesenchymal stem cell (MSC) products, announced in November, was hardly surpris-ing. With more than 10 years of experience in developing stem cells in the clinic, Columbia, Maryland–based Osiris Therapeutics has become a frontrunner among companies commercializing adult stem cells. The com-pany’s two stem cell therapies, Prochymal and Chondrogen, are well advanced into clinical studies for graft-versus-host disease (GvHD), Crohn’s disease and knee cartilage regen-eration. But one issue continues to puzzle researchers: no one is quite sure how these cell products work.

The deal with Genzyme places Osiris on a firm financial footing. As well as mile-stone payments, the $130 million up-front payment comes in addition to cash from a US Department of Defense contract for Prochymal use in acute radiation sickness. Although Genzyme has no equity stake in Osiris, which will keep all US and Canadian rights to its MSC products and indications,

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do see the MSCs go to the intestine,” says Mills. “They will engraft at the site of inflammation, but they don’t persist there.” The cells act more as a drug than as a reconstructing agent. “This is not strictly ‘regenerative medicine’, but it has that effect and the results are excellent,” Mason points out.

Whatever the reason, Prochymal appears to work. Phase 2 results in 32 adult patients with acute GvHD showed an overall response rate of 94%, with a complete remission or response rate of 77% representing 24 patients.

And results for end-stage refractory GvHD in 12 children, ranging from infant to 15 years, showed a 100% response rate with a complete remission or response in 58% or 7 children.

Osiris is also pursu-ing MSC formulations

for type 1 diabetes, chronic obstructive pul-monary disease and the prevention of heart failure following acute myocardial infarction, all of which are in phase 2 clinical trials. And there’s probably more on the way. “There’s a lot of animal data suggesting multiple sclerosis as a target,” says Mills. Rheumatoid arthritis, acute organ rejection and scleroderma are also targets. “Do I think the MSC therapy will be effective at counteracting a broad range of autoimmune diseases? Absolutely.”

George S. Mack Columbia, South Carolina

30-year-old individuals. The cells are first isolated by density gradient separation and further purified by a selective adherence tech-nique to eliminate non-MSC contaminants to 99.5% purity. From here, Osiris expands the culture to yield 10,000 doses of Prochymal from a single donor. According to University College’s Mason, the company’s novel method for expanding MSC cells, their experience in processing and packaging marrow-derived MSCs into an off-the-shelf product, was instrumental in clinching success. “The cells are high quality, the material is reproducible and the results excellent,” Mason adds. From the investor point of view, it makes for a highly scal-able and efficient busi-ness model.

When infused into the patient, the MSCs are drawn to the sites of damage and inflamma-tion, whether it is ischemic tissue in the myo-cardium immediately after a heart attack or the mucosal crypts in the colon of patients with Crohn’s disease or the tissues affected by GvHD, which occurs in ~50% of bone mar-row transplant patients. In fact, the colitis of Crohn’s disease can resemble the histopathol-ogy of the GvHD-affected colon, which is what originally prompted investigators at Osiris to explore and develop the product in the former indication.

Because Prochymal and Chondrogen are allogeneic, some degree of immune response might be expected, but to date it appears that MSCs are either immune privileged or they turn off or disable immune cells. Of ~850 patients treated with Osiris’s MSCs over the past decade, with some GvHD patients hav-ing received as many as 12 consecutive doses, there have been no infusion reactions either on initial or subsequent administration, even with doses given months later. “It’s an innate property, not something we do to them,” says Osiris CEO Randal Mills. “It’s the stem cell equivalent of O-negative blood. They just lack the cell surface antigens.”

MSCs seem to achieve their therapeu-tic effects by working as anti-inflammatory agents. Although the complete mechanism remains uncertain, MSCs down-modulate the immune response by suppressing tumor necrosis factor α and interferon γ production while boosting interleukin (IL)-10 and IL-4 secretion by T-helper 2 cells. Because of their pluripotency, MSCs might be expected to engraft the tissues they are intended to regen-erate, but in the case of infused MSCs, engraft-ment appears to be transient. “In Crohn’s, we

in briefGM poplars to grow next doorResearchers at the Ghent, Belgium–based Flanders Institute of Biotechnology (VIB) have gained ground in a long-running battle over the planting of genetically modified (GM) poplar trees by applying for permits to plant the trees across the border. The Belgian government initially refused VIB’s application to run field trials on home turf, but now the Dutch government, which has already issued a ‘positive opinion’, may grant them permission. The transgenic poplars are deficient in the enzyme cinnamoyl-CoA reductase, which reduces the lignin content making them more suitable for bioethanol production, although so far their benefits have only been demonstrated in the lab. The VIB had hoped for a green light from the Belgian Biosafety Council to run the trials closer to its research facilities and pilot-scale biorefinery. Instead, researchers will be forced to make regular trips to neighboring Holland to monitor and harvest the trees. Willy De Greef, secretary general of EuropaBio, the Brussels-based association for European bioindustry, says, “VIB is a public institute, which doesn’t have the resources of a multinational. I don’t even dare to think about what it does to their annual research budget.” He says if European laws governing the planting of GM field trials were more consistently adhered to across member states, such situations wouldn’t arise. A final decision from the Dutch government is due in spring 2009. –Hayley Birch

FDA goes public-friendlyIn an effort to reach out to the American public, the US Food and Drug Administration (FDA) in December announced a collaboration with online health information provider WebMD to disseminate health and drug safety information. The deal gives the FDA pages within WebMD’s website and print magazine. WebMD.com reaches a far larger audience than the FDA’s website with nearly 50 million unique visitors each month compared with the FDA’s 6 million. “It’s important to put the information where the people are going, and not expect them to come to us,” says FDA’s Jason Brodsky, director of consumer health information. The WebMD-FDA site http://www.webmd.com/fda/ links to the agency’s guides to reporting adverse events and understanding product recalls, and offers safety tips on drugs, medical devices, food and cosmetics. The agency plans to add multi-media content and features on the safe use of products. For example, the agency will offer a guide to parents on vaccines, warn consumers about unlawful distribution of unapproved drugs and answer questions such as, What are biologics? European agencies are also attempting to improve online access to health information. The UK’s National Health Service (NHS) plans to launch in April NHS Evidence, a web-based service that consolidates clinical data and experience, prescribing and safety information, and technology appraisals. And the European Commission in December adopted a legislative proposal aimed to improve patient access to information about drugs. –Emily Waltz

New product approvalsRoActemra (tocilizumab)/F. Hoffmann-La Roche (Basel) and Chugai (Tokyo)

The European Commission approved RoActemra for adult patients with moderate to severe rheumatoid arthritis (RA) who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs or tumor necrosis factor antagonists. RoActemra is the first humanized interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody developed for RA.

Stelara (ustekinumab)/Janssen-Cilag (Beerse, Belgium) and Centocor (Horsham, Pennsylvania)

The European Commission approved Stelara for moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA (psoralen plus ultraviolet A light). Stelara is a human monoclonal antibody that targets the p40 sub-unit of cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23). Centocor (a Johnson & Johnson subsidiary) discovered the drug and has exclusive marketing rights in the U.S.

“Do I think the MSC therapy will be effective at counteracting a broad range of autoimmune diseases? Absolutely.”

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