Santaris Pharma releases positive data on LNA-based survivin inhibitor

Nov 10 2008

Santaris Pharma announced today that SPC3042, a RNA-based antisense oligonucleotide developed using the company's proprietary Locked Nucleic Acid (LNA) technology, potently blocks survivin, a key survival protein in cancer cells, in both in vitro and in vivo models of prostate cancer. Importantly, SPC3042 works synergistically with the anticancer drug paclitaxel (Taxol) in both model systems.

The data on SPC3042 was published in the September 2008 issue of the journal Molecular Cancer Therapeutics.

"This publication marks a milestone in our efforts to develop LNA-based RNA antagonists," said Santaris Pharma's CEO S©ªren Tulstrup. "SPC3042 is one of the most advanced compounds in our development program. Combined with other data on this compound's pre-clinical safety and tolerability, these results are very encouraging as we work with our development partner, Enzon Pharmaceuticals, Inc. (Nasdaq: ENZN), to further explore SPC3042 in an oncology setting."

SPC3042 blocks survivin by binding to and inhibiting its messenger RNA (mRNA), the molecule that transmits the information for building survivin from the genome to the cell's protein building machinery.

"Survivin is a fundamental regulator of both programmed cell death, also called apoptosis, and the cell cycle," said Troels Koch, Msc, PhD, Vice President of Research at Santaris and the study's senior author. "While it is expressed widely during early human development, in adults survivin is almost exclusively found in cancer cells. This makes survivin a very attractive target for inhibition with LNA-based oligonucleotide therapeutics."

SPC3042 was compared in vitro in a prostate cancer cell line to five other anti-survivin mRNA oligonucleotides incorporating LNA modifications and other chemical modifications. Of the molecules tested, SPC3042 exhibited the most robust induction of apoptosis in vitro. Also, SPC3042 potently sensitized prostate cancer cells to the activity of paclitaxel in vitro, while displaying in vivo synergy with paclitaxel in a prostate cancer xenograft mouse model. While the two agents individually had little effect on tumor weight in this model, when given together they triggered a significant reduction in tumor weight with no pre-clinical adverse effects.

SPC3042 is one of eight LNA-based RNA antagonists being developed by Santaris Pharma and Enzon through in an innovative and comprehensive partnership. Under the terms of the agreement, Enzon licensed two of Santaris' compounds, SPC3042 and the HIF-1¥á antagonist SPC2968, as well as six additional proprietary RNA antagonist candidates, all to be directed against novel oncology drug targets selected by Enzon. Enzon will have exclusive rights to develop and commercialize these compounds in the U.S. and other non-European territories. Santaris will retain exclusive rights to commercialization in Europe.

LNA is an analogue of RNA (ribonucleic acid). The ribose sugar in LNA is 'locked' in the RNA conformation by virtue of its rigid bicyclic structure. The result is that when incorporated into oligonucleotides, LNA conveys dramatically enhanced binding affinity to complementary RNA sequences. Drug molecules with multiple LNA substitutions therefore have truly outstanding potencies. The greater potency of LNA in binding complementary RNA sequences means that LNA oligonucleotide drugs can be made significantly shorter than previous antisense or siRNA drugs. These shorter RNA antagonist drugs are taken up efficiently by cells and tissues, thereby overcoming many of the delivery problems of RNAi to date. In addition to greater potency than other oligonucleotide chemistries, LNA drugs are resistant to degradation when given systemically, have long tissue half lives, are taken up readily by many tissues, and have improved therapeutic ratios over first and second generation antisense drugs.

Messenger RNAs (mRNAs) are template molecules that transmit genetic information encoded in DNA to the cell's protein-manufacturing machinery. Inhibition of mRNAs stops the expression of disease-associated genes by preventing their translation into proteins. Santaris Pharma's unique LNA technology enables development of short, synthetic RNA-binding molecules that can effectively antagonize disease-causing mRNAs and other classes of RNA (e.g., microRNAs) and thus may yield patient benefits unobtainable by other therapeutic approaches.

MicroRNAs are a newly discovered class of small regulatory molecules which control many biological processes in cells. In addition, microRNAs have been implicated in many diseases, such as cancer, viral infections, cardiovascular disease and neurological disorders and, therefore, represent a new class of targets for therapeutic intervention. Santaris Pharma's unique LNA technology enables development of short, synthetic RNA-binding molecules that can effectively antagonize disease-causing microRNAs and, thus may yield patient benefits unobtainable by other therapeutic approaches.