BioWorld International Correspondent

Santaris Pharma A/S raised €40 million (US$48.2 million) to fund clinical development of a pipeline of RNA antagonist drug candidates, which are based on locked nucleic acid (LNA) oligonucleotide analogues, and it has given early warning of an IPO.

If its clinical program goes according to plan and market conditions are right, the company aims to go public next year, CEO Keith McCullagh told BioWorld International.

Santaris, of Hørsholm, Denmark, is midway through a Phase I/II trial in chronic lymphocytic leukemia (CLL) with its lead molecule, SPC 2996, which down-regulates translation of the anti-apoptotic protein Bcl-2. Because it has been well tolerated in man so far, the company filed a protocol amendment to enable it to extend the current study to higher doses.

"Following this Phase I/II study, if it’s successful, we may go straight to a Phase II/III clinical trial," McCullagh said. The FDA is reviewing a new drug application filed by Genta Inc., of Berkeley Heights, N.J., for another antisense CLL drug that targets Bcl-2, Genasense (oblimersen sodium). "All our data show that 2996 is far superior than Genasense in potency and efficacy in down-regulating the Bcl-2 target in primates and other animals," McCullagh said.

Two other molecules are in late preclinical development. SPC 2968, which targets hypoxia inducible factor-1alpha (HIF-1alpha), is in development initially for renal cancer and multiple myeloma, and is due to enter the clinic in the second half of the year. The company is looking for an early stage partner for SPC 3042, which targets the anti-apoptosis protein survivin, as the development costs of that program are higher.

Santaris was formed in 2003 following the merger of Cureon A/S, a company spun out of Vedbaek, Denmark-based Exiqon A/S to develop therapeutic applications of LNA, and Copenhagen-based Pantheco A/S, which had been developing therapeutics based on another oligonucleotide analogue, peptide nucleic acid (PNA). McCullagh, formerly CEO of what was once the UK sector’s flagship company, British Biotech plc (now Vernalis plc, of Guildford, UK), joined Santaris on a consultancy basis initially, to help the enlarged entity develop its strategy. After serving as interim CEO for several months, he dropped "interim" from his title in June 2004. (See BioWorld International, March 12, 2003.)

The company has since de-emphasized its interest in PNA. "We still own those IP assets, but we’re not developing them," McCullagh said. "I just don’t think it has the attributes that make LNA so special." Moreover, intellectual property rights to PNA are shared by several companies, including Isis Pharmaceuticals Inc., of Carlsbad, Calif., and Applied BioSystems Group, of Foster City, Calif. LNA was 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; patent rights were assigned to Exiqon. The latter company now holds rights to diagnostic applications, while Santaris holds rights to all therapeutic applications.

The very high binding affinity of physiologically active antisense LNAs, combined with their small size, thermal stability and resistance to enzymatic degradation, are all factors that make them potentially superior to siRNA. "The great challenge all the siRNAs have is they are very unstable and are not very good if you give them systemically," said McCullagh. "Because we don’t have that problem, we can go after cancer."

Although LNAs, like siRNAs, carry a negative charge, which makes delivery across the cell membrane difficult, their potency and stability compensate. In animal experiments, a single intravenous dose of SPC 2968 down-regulated angiogenic factors for four to five days, McCullagh said.

HIF-1alpha, which is down-regulated by SPC 2968, is upstream of vascular endothelial growth factor (VEGF), the target of Avastin (bevacizumab), marketed as a metastatic colorectal cancer treatment by Genentech Inc., of South San Francisco. McCullagh said SPC 2968 also effects expression of VEGF receptor, metalloproteases and other genes associated with a malignant phenotype. "We think it’s likely to have superior activity in a number of cancers to Avastin, or it may even be synergistic," he said.

Santaris now is funded to mid-2008. The €40 million includes a conversion to equity of about €8 million worth of convertible debentures issued by existing shareholders during 2005. The current round was led by ABN AMRO Capital Life Sciences, of Amsterdam, the Netherlands. Other new investors included Munich, Germany-based Global Life Science Ventures, Copenhagen-based V kstfonden and Paris-based SPEF Venture.