Santaris Pharma presents positive clinical data on SPC2996 in Chronic Lymphocytic Leukaemia

First RNA Antagonist medicine to be tested in patients reduces severity of adult leukaemia

Copenhagen, 6th June 2007 - Santaris Pharma, the Danish biopharmaceutical company, announced today that SPC2996, the Company’s new RNA Antagonist of Bcl-2, has shown early evidence of efficacy in an initial Phase I/II clinical study in Chronic Lymphocytic Leukaemia (CLL). The results of the study were reported this week at the 2007 Annual Meeting of the American Society of Clinical Oncology, held in Chicago, Illinois.

The clinical trial was conducted in patients with advanced CLL, the most common form of adult leukaemia, and involved 12 centres in France, Britain, Denmark, and the USA. Conclusions from the study were as follows.

•A reduction in the number of cancerous B-lymphocytes (white blood cells) and a beneficial effect on lymph nodes and overall tumour response was observed in patients given 6 repeated doses of drug at 4mg/kg/infusion over a two week period, with the effects on lymphocytes being seen within 24 hours of the first dose.

•A relationship between dose of SPC2996 and activity was observed in the study, with higher doses giving improved effects on lymphocyte counts, lymph nodes, time to progression and overall tumour response.

•SPC2996 treatment was associated with statistically significant reduction in mean Bcl-2 levels in white blood cells from CLL patients, supporting the intended mechanism of action of the drug.

Commenting on the results, Prof Bertrand Coiffier, from the Hospices Civils de Lyon, University of Lyon, France, the international coordinating investigator for the study, said:

“These results are early stage but promising. All patients came into this study with clinically progressing CLL. Despite this, patients receiving the drug at an effective level had rapid and sustained falls in circulating cancerous lymphocytes. There also appeared to be evidence of drug induced tumour responses. We look forward to further studies with this interesting new agent in CLL.”

The Phase I/II study was primarily aimed at finding the optimum dose of drug to be given in longer term, more rigorously controlled trials in CLL and Lymphoma, a related and more common tumour type. Dr Lene Worsaae Dalby, Santaris Pharma’s Vice-President of Clinical Development, said:

“We are encouraged by the data from this safety and proof of principle study. We are currently conducting a second trial with SPC2996 to optimise dose scheduling in favour of fewer doses of the drug given at higher concentrations. Following this second Phase I/II study, Santaris expects to commence randomised Phase II studies in CLL and to investigate the drug also in follicular lymphoma”.

The trial of SPC2996 in CLL is the first time an RNA targeted antisense drug containing the potent RNA analogue, Locked Nucleic Acid (LNA), has been evaluated in man for safety and efficacy. SPC2996 was well tolerated and infusions were unproblematic. Dr Henrik Orum, Santaris Pharma’s Chief Scientific Officer, commented:

“This clinical trial confirms that LNA-based drugs can be given safely to patients, can reach the site of action in cancer cells and are potent enough to induce clinically relevant benefits, even when given for only a brief period. This is encouraging for the rapidly advancing new field of RNA targeted medicines and for the future of RNA Antagonists in particular. We look forward to further human studies with this and other LNA-based drugs.”

- ENDS -

For further information, please contact:

Dr Keith McCullagh
President & CEO, Santaris Pharma,
Tel +45 4517 9819 (direct line) +45 4517 9820 (Company)
Mobile/Cell +44 7939 573548 e-mail km@santaris.com 

Prof Bertrand Coiffier
International Coordinating Investigator for the Study, Hospice Civils de Lyon, University of Lyon, France,
Tel +33 609 412414 (mobile),
e-mail bertrand.coiffier@chu-lyon.fr
 
For media relations, contact:
Adam Michael, a.michael@northbankcommunications.com , +44 (0)20 7268 3002
Annabel Entress, a.entress@northbankcommunications.com,  +44 (0)20 7268 3002

Regulatory Statements

SPC2996 is a new investigational drug which is at an early stage in clinical development. It has not been approved as safe and effective for human use by any regulatory authority and Santaris Pharma is therefore unable to make it available to patients outside its clinical trial protocols.

This written announcement contains forward-looking statements, identified by the use of words such as "believes," "expects," "may," "will," "should", "potential," "anticipates," "plans" or "intends" and similar expressions. Such forward-looking statements involve risks, uncertainties and other factors that may cause actual results, events or developments to be materially different from the future results, events or developments indicated in this announcement. Such factors include, but are not limited to the timing, success and cost of clinical studies; the ability to obtain regulatory approval of products, market acceptance of and future demand for Santaris products and the impact of competitive products and pricing. These factors should be considered carefully and readers are cautioned not to place undue reliance on such forward-looking statements. No assurance can be given that the future results covered by the forward-looking statements will be achieved. All information in this press release is as of the date of this press release and Santaris does not intend to update this information.

TECHNICAL NOTES FOR EDITORS

Chronic Lymphocytic Leukaemia
Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in adults in western Europe and North America, new cases occurring at an annual incidence of 3 to 5 per 100,000 persons in the population. The condition occurs primarily in older people with a median age at diagnosis of 66 years. Men are twice as likely as women to develop the disease. The clinical course of the condition varies widely with some patients showing rapid disease progression and early death, despite intensive chemotherapy, and others surviving for decades without any treatment. CLL is characterised by excessive numbers of functionally incompetent long-lived B-lymphocytes (small white blood cells) circulating in the blood, sometimes also causing swelling of lymph nodes, spleen and other organs. The failure of these cancerous B-CLL cells to die is generally thought to be due at least in part to over expression of the Bcl-2 gene characteristic of the disease.

About Bcl-2
The protein Bcl-2, first identified in B-cell lymphoma/leukaemia cells from which its name derives, is one of a family of intracellular proteins regulating cell survival and cell death. Some types of cells in the body, for example blood cells, are programmed to die after a few weeks of life, in the case of blood cells to be replaced in the circulation by fresh cells produced in the bone marrow. This process of programmed cell death is known as apoptosis. Bcl-2 is an apoptosis suppressor protein, i.e. it extends the lifespan of the cell in the presence of normal apoptosis stimuli. The levels of Bcl-2 within the cell are frequently over-expressed in malignant cancers, and this is particularly the case in human chronic lymphocytic leukaemia and lymphoma where it acts to prolong the life of malignant white blood cells. Drugs which lower the concentration of Bcl-2 or inhibit its function may therefore have therapeutic benefit by inducing cancer cell death and removal without resorting to chemotherapy.

About SPC2966
SPC2996 is the first of a portfolio of novel experimental drugs blocking harmful gene expression being designed and developed by Santaris Pharma. The drug belongs to a new class of drugs called RNA Antagonists, proprietary to Santaris Pharma, based on the novel three-dimensional analogue of RNA known as Locked Nucleic Acid (LNA). The drug binds with high potency and specificity to the messenger RNA for Bcl-2 and destroys it within the cell, resulting in a reduction in Bcl-2 protein concentration. SPC2996 is an investigational product which has not yet been approved by any regulatory agency as effective or safe for patient use but the novel agent is currently being evaluated in international Phase I/II studies in human CLL in centres in Denmark, France, UK and the USA.

About Santaris Pharma
Santaris Pharma is a clinical-stage biopharmaceutical company focused on developing a new class of drugs intended to switch off the expression of harmful genes. Called RNA Antagonists, these new drugs are being developed by Santaris and its corporate partners for the treatment of cancer and metabolic disorders. Created in May 2003 and backed by a broad group of leading international life science venture capital investors, Santaris Pharma completed a Euro 40m second round of equity financing in May 2006. In July 2006, the Company entered into a global partnership with Enzon Pharmaceuticals of New Jersey to co-develop and commercialise a series of Santaris RNA Antagonists for improving the treatment of cancer.

Santaris Pharma’s RNA Antagonist drug pipeline is based on its unique LNA technology. LNA drugs, with their high potency and biostability, have the potential to transform the field of RNAi medicines, making specific and effective gene silencing a reality in human medicine. If this potential is realised, even in part, it may be possible to design new drugs to treat the underlying genetic causes of disease rather than just the physical symptoms. Santaris Pharma holds the world wide patent rights to the exploitation of LNA in pharmaceuticals and presently has three drugs in preclinical or clinical development. The lead drug candidate, SPC2996, is currently undergoing international, multicenter, phase I/II clinical studies in Chronic Lymphocytic Leukemia (CLL).

For further company information see www.santaris.com 

Detailed results of the Phase I/II Study
A PDF of the results presented at the American Society of Clinical Oncology (ASCO) in poster format can be viewed and/or downloaded from the News section of the Company’s website, www.santaris.com .

The Clinical Trial reported here was an open-label, international, multi-centre, dose-escalating study in 25 patients with relapsed or refractory Chronic Lymphocytic Leukaemia, requiring treatment. Twelve expert haematology-oncology specialists participated, including:

• Prof Bertrand Coiffier, Centre Hospitalier, Lyon-Sud, France (International Coordinating Investigator);

• Prof Hervé Tilly, Centre Henri Becquerel, Rouen, France (ASCO Presenter);

• Dr Bruno Cazin, Hopital Huriez, Lille, France;

• Prof Mauricette Michallet, Hoptial Edourd Heriot, Lyon, France;

• Prof John Radford, Christie Hospital NHS Trust, Manchester, UK (Prinicipal Investigator, UK);

• Dr Claire Dearden, The Royal Marsden NHS Foundation Trust, Surrey, UK;

• Prof Peter Hillman, Leeds General Infirmary, Leeds, UK;

• Prof Martin Dyer, MRC Toxicology Unit, Leicester, UK;

• Dr Christian Geisler, Rigshopitalet, Copenhagen, Denmark (Principal Investigator, Denmark);

• Dr Ole Gadeber, Vejle Sygehus, Vejle, Denmark;

• Dr Annemarie Dalseg, KAS Herlev, Herlev, Denmark;

• Dr Brian Link, Holden Comprehensive Cancer Center, University of Iowa, USA (Principal Investigator, USA)

SPC2996 was given by intravenous infusion on 6 repeated occasions over a two week period. Five different dosage levels were investigated. At the top dose of 4mg/kg/infusion, all 6 of the 6 patients studied showed a decrease in the severity of their leukaemia, with a rapid reduction in the numbers of circulating lymphocytes (white blood cells) being observed within 24 hours of the first administration of the drug. Five out of the 6 patients in this group showed a maximal reduction in lymphocyte count of 50% or more, indicating a clinically beneficial effect. See figure 1 attached.

A dose response to drug was also observed with patients treated with SPC2996 at 2 mg/kg/infusion having a transient reduction in lymphocytes of up to 30% and doses of 1 mg/kg/infusion having no effect.

Reductions in lymph node swelling was also observed in these patients, 2 out of 4 patients receiving drug at 4mg/kg/infusion and 1 out of 4 at 2 mg/kg/infusion showed a reduction in lymph node diameters of 50% or more. Overall, using standard clinical assessment procedures, 2 of the 6 patients treated with the top dose of drug showed a partial tumour response, one of 28-42 days and one of more than 182 days, and 3 patients had stable disease for periods of between 28 and 70 days. Mean time to disease progression was approximately twice as long (122 days) in the group receiving drug at 4mg/kg/infusion as in the groups receiving 2 or 1mg/kg/infusion (42 and 79 days).

Mechanism of Action
In cell culture and experimental models of disease, SPC2996 inhibits the production of the protein Bcl-2 and its beneficial effects in patients are thought to be due to the drug reducing Bcl-2 levels within cancerous CLL lymphocytes by binding specifically to and inactivating the messenger RNA for Bcl-2. High levels of Bcl-2 in CLL cells are associated with resistance to cancer cell death and poor disease outcome. To confirm the effects of the novel RNA Antagonist SPC2996 on Bcl-2 levels in CLL patients, Bcl-2 mRNA levels were determined in extracted RNA from blood samples from patients in this study. As shown in figure 2 attached, there was a statistically significant down regulation of Bcl-2 mRNA (expressed as a ratio to 18S ribosomal RNA, a measure of total blood RNA) in patients receiving drug at 4mg/kg/infusion, over the 2 week course of therapy. Such patient data supports the view that SPC2996 is working through specific antagonism of Bcl-2 mRNA.

Safety
SPC2996 was well tolerated. All infusions were unproblematic and there were no signs of cytokine release or complement activation. Two patients had rises in serum alanine aminotransferase (ALT) following the last dose (i.e. after a total dose of 24mg/kg) which were transient and the patients recovered fully. Two cases of grade 3 thrombocytopaenia were reported. In the 2mg/kg/infusion group, one patient was diagnosed to have Tumour Lysis Syndrome following 2 infusions of drug.

- ENDS -