BioWorld International Correspondent

Santaris Pharma A/S gained commercial validation for its Locked Nucleic Acid (LNA) oligonucleotide analogue chemistry through a co-development and commercialization oncology deal with Enzon Pharmaceuticals Inc., which is worth well in excess of $200 million in up-front fees and milestone payments.

Bridgewater, N.J.-based Enzon is licensing two preclinical LNA-based drug candidates from Santaris: SPC2968, an antagonist to hypoxia inducible factor-1alpha (HIF-1alpha); and an antagonist to the anti-apoptosis protein Survivin, called SPC3042. In addition, it is generating six more LNAs to oncology targets specified by Enzon. The latter company will fund all research and development activities and will obtain exclusive commercialization rights outside of Europe. Copenhagen, Denmark-based Santaris, has retained European rights to all compounds emerging from the alliance. It also is banking an up-front payment of $8 million and will gain an additional $3 million on production of the additional six LNAs. The rest of the money - at least $189 million in milestone payments - will come as the company hits pre-specified discovery, development and regulatory achievements. Enzon also will pay Santaris royalties on net sales in non-European territories of products resulting from the collaboration.

Santaris CEO Keith McCullagh said that his firm expects to secure a milestone payment of about $5 million from an investigational new drug application filing this year for the lead compound in the alliance, SPC2968. "Enzon will be filing an IND prior to the end of this year. That is the plan," he said.

The agreement marks the first major drug development deal to involve LNA, a highly stable antisense technology jointly discovered in 1998 by Jesper Wengel while at the University of Copenhagen (now at the University of Southern Denmark, Odense) and Takeshi Imanishi at Osaka University, Japan.

Santaris, formed through the merger in 2003 of Vedbaek, Denmark-based Cureon A/S and Copenhagen-based Pantheco A/S, has sole rights to therapeutic applications of LNA. Vedbaek-based Exiqon A/S, the original parent of Cureon, holds rights to diagnostic applications.

"We have quite a number of deals in the pipeline. This is the first one to come to fruition," said McCullagh. Santaris aims to structure additional deals in a similar fashion. It wants to retain European rights to all oncology programs and molecules it partners as it aims to build a pan-European sales and marketing team in this area. "It's a very strong belief of mine that you create value in a biotechnology business by retaining marketing rights," he said. Moreover, the oncology market is quite restricted. "You can cover the whole of Europe with a sales force of 50 or 60. You don't need a big organization," he said.

Enzon will make available, without charge, its full NDA dossier to Santaris, which then can adapt it for the European drug regulator, the London-based European Medicines Evaluation Agency. "We have an opportunity to bring these products to market in Europe without the development costs associated with them," McCullagh said. At most, Santaris may be required to undertake additional bridging studies, he added.

Although Santaris has generated promising preclinical data, which suggest that LNA may be orders-of-magnitude more potent than other antisense compounds, it has yet to obtain proof-of-concept data in man. An ongoing Phase I/II clinical trial in 42 patients with chronic lymphocytic leukemia (CLL) of its lead product based on the technology, the Bcl-2 antagonist SPC2996, is scheduled to deliver interim data in the fall and will be completed by the first quarter of 2007, McCullagh said. The dose-escalating, open-label study will measure as a surrogate marker levels of Bcl-2, an anti-apoptosis protein expressed in most cancer cells. Although it also will follow clinical parameters, McCullagh said, the study is not powered to determine clinical efficacy.

The company already is planning a combination study of SPC2996 with fludarabine in CLL, and is considering one involving rituximab (Rituxan), which is marketed by Genentech Inc., of South San Francisco, and Biogen Idec Inc., of Cambridge, Mass. "If we can enhance responses to both of these, we will have a major opportunity," McCullagh said.

In separate news, Enzon out-licensed a preclinical, anticancer fusion protein, SS1P, to Cambridge, UK-based Cambridge Antibody Technology plc (CAT), which was recently acquired by London-based AstraZeneca plc.

SS1P, which CAT has redesignated CAT-5001, originally was discovered and developed by the National Cancer Institute, of Bethesda, Md. It comprises an antibody fragment that recognizes mesothelin, a cell-surface antigen overexpressed in several cancers, linked to the Pseudomonas exotoxin PE38. The latter mediates its toxic effects once the fusion protein has been internalized by targeted tumor cells. CAT aims to move the compound into a Phase I clinical trial early next year. Financial terms were not disclosed.