TopoTarget reports new clinical data presented by NCI at the ASCO conference from Belinostat trials

TopoTarget A/S
Symbion
Fruebjergvej 3
DK 2100 Copenhagen 
Denmark
Tel: +45 39 17 83 92
Fax: +45 39 17 94 92
CVR-nr: 25695771

www.topotarget.com

To OMX Nordic Exchange Copenhagen
Announcement No. 21-08 / Copenhagen, June 2, 2008

TopoTarget reports new clinical data presented by NCI at the ASCO conference
from Belinostat trials in advanced myeloid neoplasms (in combination with
azacitidin) and in ovarian tumors 


Copenhagen, Denmark - June 2, 2008 - TopoTarget A/S (OMX: TOPO) announced that
NCI (National Cancer Institute) presented positive data at ASCO (American
Society of Clinical Oncology) on belinostat from two clinical trials; a Phase I
study of Belinostat (PXD101) plus azacitidine (AZC) in patients with advanced
myeloid neoplasms and a phase II trial of Belinostat in patients with platinum
resistant epithelial ovarian tumors and micropapillary/borderline (LMP) ovarian
tumors. 


Phase I study of Belinostat (PXD101) plus azacitidine (AZC) in patients
with advanced myeloid neoplasms


Background: The hypothesis was that targeting 2 pathways of epigenetic
silencing using BEL and the DNA hypomethylating agent AZC would lead to an
additive or synergistic effect in patients with advanced myeloid neoplasms. 

Methods: The primary objective of this first part of the study was to determine
the MTD of BEL when given with a fixed dose of AZC. 3 to 6 pts were enrolled
per dose level. Patients had relapsed or refractory AML (Acute Myeloid
Leukemia), intermediate or high risk MDS (Myeloid Dysplastic Syndrome) or
advanced Myeloproliferative disorder. AZC, 75 mg/m2/d, was given SC on days 1-5
followed by escalating doses of belinostat given IV over 30 minutes on the same
days in a 28 day cycle. 

Results: Belinostat dose levels were 150 mg/m2 (in 6 patients), 300 mg/m2 (in 5
patients), 600 mg/m2 (in 6 patients) and 1000 mg/m2 (in 6 patients). 70% of the
patients had AML 26%, had MDS/CMML and 4% had primary myelofibrosis. 78% had
primary refractory or relapsed disease; 43% had poor risk cytogenetics. 
Non-hematologic grade 1-2 toxicities included fatigue, nausea and vomiting,
diarrhea  and phlebitis. One DLT (grade 3 myalgia) was observed in cycle 2 at
the 1000 mg/m2 dose level. Among 21 evaluable patients who received at least 1
cycle (median-4; range 1-17) 2 CRs were obtained, 1 PR and 4 had hematologic
improvement; 3 occurred at the 1000 mg/m2 dose level. Median time to response
was 2 cycles (range, 1-4). Improved plateletcounts (mean 150%) at 4 weeks were
observed in one-third of pts, and at all dose levels studied. 

Conclusions: The combination of belinostat with AZC is feasible, was well
tolerated in full doses of both drugs and clinical activity was observed. A
randomized study is planned to assess the relative contribution of belinostat
to this combination. That phase of the study will evaluate the 1000 mg/m2 dose
level of PXD101 and include pharmacodynamic endpoints. Sponsored by NCI grant
5U01-CA69852-12 


A phase II trial of the Histone Deacetylase inhibitor Belinostat (PXD101) in
patients with platinum resistant epithelial ovarian tumors  and
micropapillary/borderline (LMP) ovarian tumors. 

Background: Patients with micropapillary/borderline (LMP) ovarian tumors
represent an understudied population whose tumors are intrinsically resistant
to radiation and chemotherapy. Patients with platinum resistant epithelial
ovarian cancer (EOC) have low response rates to conventional chemotherapy.
Histone deacetylation has been implicated in loss of tumor suppressor and pro
apoptotic genes in ovarian cancer cell lines. Belinostat is a pan hydroxamate,
histone deacetylase inhibitor which demonstrates anti tumor activity in
multidrug resistant ovarian cancer cell lines and in an ovarian cancer
xenograft model. 

Methods: The aim of this phase II study is to assess the activity of belinostat
in 2 patient populations: metastatic or recurrent platinum resistant
(progression within 6 months) EOC and LMP ovarian tumors. In both groups up to
3 prior lines of chemotherapy were allowed.  Primary endpoints are objective
response with a stopping rule, secondary endpoints include stable disease rate,
survival, tolerability and assessment of molecular changes with therapy.
Belinostat 1000mg/m2/day was administered iv on days 1-5 of a 21 day cycle.
Tumor response was assessed by RECIST (Response Evaluation Criteria in Solid
Tumours) and CA125 (a tumor marker in ovarian cancer) criteria every 2 cycles. 

Results: 18 patients with EOC, median age 59.5  (range 31-78) years received a
total of 50 cycles of treatment,. 9 patients have stable disease (SD), 6
progressive disease (PD), 3 are non evaluable (N/E) and 2 remain on study.  12
patients with LMP tumors received 68 cycles of treatment, median no. per
patient 4 (range 1 to 13) cycles. 1 patient had a partial response (PR), 9 SD,
and 2 are NE. 1 further patient had a CA125 response. 5 patients remain on
study.. The most common adverse events any grade (% of cycles) were fatigue
(80%), lymphopenia (65%), and nausea (51%).  Acetylation of histones H3 and H4
was measured in tumor biopsies and in the blood. 

Conclusion: Belinostat shows promising activity in LMP ovarian tumors,
recruitment is ongoing. 


TopoTarget A/S

	
For further information, please contact:

Ulla Hald Buhl 		Telephone	+45 39 17 83 92
Director IR & Communications		Mobile	+45 21 70 10 49

 

Background information

About Belinostat
Belinostat is a promising small molecule HDAC inhibitor being investigated for
its role in the treatment of a wide range of solid tumors and hematologic
malignancies either as a single-agent, or in combination with other active
anti-cancer agents, including carboplatin, paclitaxel, cis-retinoic acid,
azacitidine and Velcade® (bortezomib) for injection.  HDAC inhibitors represent
a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes,
and have been shown to arrest growth of cancer cells (including drug resistant
subtypes); induce apoptosis, or programmed cell death; promote differentiation;
inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance
when used in combination with other anti-cancer agents. 

Intravenous belinostat is currently being evaluated in multiple clinical trials
as a potential treatment for cutaneous and peripheral T-cell lymphomas, B-cell
lymphomas, AML, mesothelioma, soft tissue sarcoma, MDS, and liver, colorectal,
and ovarian cancers, either alone or in combination with anti- cancer
therapies.  An oral formulation of belinostat is also being evaluated in a
Phase I clinical trial for patients with advanced solid tumors.  In August
2004, CuraGen signed a Clinical Trials Agreement with the NCI under which the
NCI will sponsor several clinical trials to investigate belinostat for the
treatment of various cancers, both as a single-agent and in combination
chemotherapy regimens.  In May 2005, TopoTarget announced the signing of a
Cooperative Research and Development Agreement (CRADA) with the NCI to conduct
preclinical and nonclinical studies on belinostat in order to better understand
its anti-tumor activity and to provide supporting information for clinical
trials. 

About TopoTarget
TopoTarget (OMX: TOPO) is an international biotech company headquartered in
Denmark, dedicated to finding ''Answers for Cancer'' and developing improved
cancer therapies. The company is founded and run by clinical cancer specialists
and combines years of hands-on clinical experience with in-depth understanding
of the molecular mechanisms of cancer. Focus lies on highly predictive cancer
models and key cancer targets (including HDACi, NAD+, mTOR, FasLigand and
topoisomerase II inhibitors). TopoTarget has a broad cllinical pipeline with 9
products in development, including belinostat which has shown proof of concept
as monotherapy in treating haematological malignancies and positive results in
solid tumours where it can be used in combination with full doses of
chemotherapy. The company's first marketed product Savene®/Totect® was approved
by EMEA in 2006 and the FDA in 2007 and is marketed by TopoTarget's own sales
force in Europe and the US. For more information, please refer to
www.topotarget.com. 

TopoTarget Safe Harbour Statement
This announcement may contain forward-looking statements, including statements
about our expectations of the progression of our preclinical and clinical
pipeline including the timing for commencement and completion of clinical
trials and with respect to cash burn guidance. Such statements are based on
management's current expectations and are subject to a number of risks and
uncertainties that could cause actual results to differ materially from those
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that there can be no assurance that actual results or business conditions will
not differ materially from those projected or suggested in such forward-looking
statements as a result of various factors, including, but not limited to, the
following: The risk that any one or more of the drug development programs of
TopoTarget will not proceed as planned for technical, scientific or commercial
reasons or due to patient enrolment issues or based on new information from
non-clinical or clinical studies or from other sources; the success of
competing products and technologies; technological uncertainty and product
development risks;  uncertainty of additional funding; TopoTarget's history of
incurring losses and the uncertainty of achieving profitability; TopoTarget's
stage of development as a biopharmaceutical company; government regulation;
patent infringement claims against TopoTarget's products, processes and
technologies; the ability to protect TopoTarget's patents and proprietary
rights; uncertainties relating to commercialization rights; and product
liability expo-sure; We disclaim any intention or obligation to update or
revise any forward-looking statements, whether as a result of new information,
future events, or otherwise, unless required by law.