To NASDAQ OMX Copenhagen A/S
Announcement No. 20-10 / Copenhagen, 21 May 2010
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

TOPOTARGET A/S ANNOUNCES BELINOSTAT ABSTRACT AT THE 2010 ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
?
Abstracts Now Available for Viewing at ASCO.org
?
Phase 2 Study of Belinostat Monotherapy in Relapsed/Refractory PTCL
demonstrated 32% Objective Response Rate
?
Additional Information to be Provided During ASCO Annual Meeting
Copenhagen, Denmark - 21 May 2010 - Topotarget A/S (NASDAQ OMX: TOPO) ,
announces that clinical data on belinostat will be presented at the 2010 Annual
Meeting of the American Society of Clinical Oncology (ASCO), to be held June
4-8, 2010 at the McCormick Place Convention Center in Chicago, Illinois, as
part of the ASCO proceedings.
Shown below is the summary abstract on the currently enrolling pivotal,
registrational PTCL trial being conducted under a Special Protocol Assessment,
as well as 4 other abstracts that are now available for viewing on the ASCO.org
website (www.asco.org).
A Multicenter, Open-Label Trial of Belinostat in Patients with Relapsed or
Refractory Peripheral T-Cell Lymphoma
?
Owen A. O'Connor - NYU Cancer Institute, New York, NY
?
Pier Luigi Zinzani - University of Bologna, Bologna, Italy
The study is a global, multicenter, single arm efficacy and safety study of
belinostat monotherapy in patients with relapsed or refractory peripheral
T-cell lymphoma (PTCL) who failed at least one prior systemic therapy. Main
aims are to determine objective response rate and time-related response
parameters.
Belinostat is a hydroxamate, class I & II histone deacetylase inhibitor
(HDACi). Pre-clinically, belinostat has a broad antineoplastic spectrum at
sub-micromolar concentrations including T-cell lymphoma lines. Phase 1 and 2
trials are ongoing in multiple indications and in more than 500 patients.
Belinostat treatment was safe and well tolerated, and the most common events
included nausea, fatigue, and vomiting. A Phase 2 study of belinostat
monotherapy in relapsed/refractory PTCL demonstrated in 19 evaluable patients
an objective response rate of 32% and a median response duration of 268+ days.
The results led to the present pivotal trial in PTCL as agreed with FDA under a
Special Protocol Assessment.
Page 1 of 5
TOPOTARGET A/S ANNOUNCES BELINOSTAT
ABSTRACT AT THE 2010 ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Eligible patients have received at least one prior systemic chemotherapy and
have histologically confirmed diagnosis of PTCL of one of the subtypes:
?
Anaplastic large cell lymphoma (ALK-positive or negative),
?
ALK-negative,
?
Angioimmunoblastic T-cell lymphoma
?
Enteropathy-associated T-cell lymphoma
?
Extranodal NK/T-cell lymphoma
?
Nasal type,
?
Hepatosplenic T-cell lymphoma
?
Peripheral T-cell lymphoma
?
Not otherwise specified (NOS) or
?
Subcutaneous panniculitis-like T-cell Lymphoma
The diagnosis should be confirmed by a positive set of T-cell markers and
negativity of B-cell markers. A pathology panel will review all diagnosis
specimens.
Belinostat will be administered as a 30-minute IV infusion of 1000 mg/m2 on
days 1-5 of every 3-week cycle until disease progression or unmanageable
treatment-related toxicities.
As of January 4, 2010, 19 patients have been included in the trial. The primary
study endpoint is objective response rate (ORR). The sample size was based on a
2-stage optimal design with a hypothesized ORR of p1=20% for B and a minimal or
"uninteresting? ORR of p0=9%. At least 14 confirmed objective responses in 100
evaluable patients are required to confirm a 20% target response rate with an
alpha of 0.05 assuming a power of 90%.
Pharmacokinetic data will be collected to explore exposure-response
relationships.
Monday, June 7, 2010 - 8:00am - 12:00pm
Trials in Progress Poster Session - Special Session, Clinical trials - S Hall A2
Abstract #TPS185: An Open-Label Randomized Phase 2 Trial Of Belinostat (PXD101)
In Combination With Carboplatin And Paclitaxel (BelCaP) Compared To Carboplatin
And Paclitaxel In Patients With Previously Untreated Carcinoma Of Unknown
Primary.
?
Karim Fizazi - Institut de Cancerologie Gustave Roussy, Villejuif, France
?
John Hainsworth - Tennessee Oncology Sarah Canon Research Institute, US
Treatment options for patients with cancer of unknown primary (CUP) are
limited; carboplatin and paclitaxel combination being one of the options.
Belinostat, is a hydroxamate, class I and II histone deacetylase inhibitor
(HDACi) with a broad antineoplastic activity. Phase I and II trials are ongoing
in multiple indications and in more than 500 patients the most common adverse
events have been nausea, vomiting and fatigue. Preclinical data shows
synergistic effect when combined with carboplatin and paclitaxel in vitro and
in vivo. In a Phase I study for patients with pretreated advanced solid tumors,
BelCaP was well-tolerated and active with objective responses seen in
pancreatic and rectal cancer patients. A patient with CUP (3 prior chemotherapy
regimens) had disease control during 29 months of treatment. Therefore, we are
conducting a randomized Phase 2 study (N~88) of CaP with or without belinostat
in CUP patients.
Randomized, global, multicenter Phase 2 trial in 19 centers. Inclusion criteria
include: a confirmed diagnosis of CUP, no prior therapy, ECOG PS 0-2, age > 18
years. Eligible patients are randomized to receive either arm A or B.
?
Arm A: BelCaP; belinostat as a 30-min i.v. infusion once daily (1000 mg/m2)
on days 1-3, Announcement No. 20-10 Page 2 of 5
TOPOTARGET A/S ANNOUNCES BELINOSTAT
ABSTRACT AT THE 2010 ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
followed by belinostat 2000mg orally once daily on days 4-5, with paclitaxel
(175 mg/m2) administered 2-3 hours following belinostat on day 3 and
carboplatin (AUC6) following directly after paclitaxel, up to 6 cycles. From
cycle 7: belinostat 750 mg is administered orally once daily x 14 days.
?
Arm B: Paclitaxel (175 mg/m2) administered day 1 and carboplatin (AUC6)
following directly after paclitaxel. Cycles repeated every 3 weeks.
Primary endpoint is progression free survival (PFS) and secondary endpoints
assess additional efficacy parameters and safety. Response is evaluated
according to RECIST criteria. 33 patients have been randomized as of
06-Jan-2009.
Monday, June 7, 2010 - 8:00am-12:00pm
General Poster Session - Developmental Therapeutics - S Hall A2
Abstract #2585 - Phase 1 Pharmacokinetics and Metabolic Pathway of Belinostat
in Patients with Hepatocellular Carcinoma.
?
L. Z. Wang, et al.
Metabolic inactivation of several hydroxamic acid-derived histone deacetylase
inhibitors (HDACi) involves glucuronidation. Vorinostat, a pan-HDACi, undergoes
glucuronidation by UGT2B17. We studied the pharmacokinetics and metabolic
pathway of belinostat (PXD101).
In vitro glucuronidation of belinostat was investigated; plasma
pharmacokinetics of belinostat was studied in a phase I study in patients with
hepatocellular carcinoma. Seventeen patients were treated with belinostat at
escalating doses of 600 (n = 3), 900 (n = 3), 1200 (n = 6), 1400 (n = 5) mg/m2
daily by intravenous infusion over 30 minutes for 5 days every 21 days; blood
was drawn on day 1 before infusion, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5 and 24
hours after the start of infusion, plasma was isolated for determination of
belinostat and identification of its metabolites using LC-MS/MS.
Pharmacokinetics of belinostat was studied using non-compartmental methods.
Using a panel of 12 UGT isoforms, UGT1A1 was found to be the predominant enzyme
for glucuronidation of belinostat with one third of unmetabolized belinostat
left after 1 h incubation at 37 ºC. Belinostat glucuronide had no activity
against HONE1 cell line at 10 ?M, compared to an IC50 of 1.59 ± 0.90 ?M for
belinostat. Belinostat AUC increased linearly with dose, with a mean clearance
of 34.34 ± 10.56 L/h/m2 and terminal half-life of 2.94 ± 0.48 h. Five
metabolites in human plasma were identified. Glucuronidation was the most
significant pathway of belinostat metabolism; 2 alternate biotransformation
pathways involved methylation to methylated belinostat and reduction of
hydroxamic group to its corresponding belinostat amide. In addition, two minor
metabolites were found to be belinostat N-glucoside and belinostat acid.
Belinostat glucuronide increased in levels shortly after administration,
reaching the maximum concentration at 1 h from start of infusion.
Phase II biotransformation played a key role on belinostat disposition, with
UGT 1A1 likely involved in the major pathway. Further studies should explore
the role of common polymorphisms of UGT1A1 on belinostat disposition and
pharmacodynamics.
Saturday, June 5, 2010 - 8:00am-12:00pm
General Poster Session - Leukemia, Myelodysplasia, and Transplantation - S Hall
A2
Abstract #6607 - Phase 2 Study of the Histone Deacetylase (HDAC) Inhibitor
Belinostat for the Treatment of Myelodysplastic Syndrome (MDS)
?
Amanda Cashen, MD, et al.
Announcement No. 20-10 Page 3 of 5
TOPOTARGET A/S ANNOUNCES BELINOSTAT
ABSTRACT AT THE 2010 ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Inhibition of HDAC can induce differentiation, growth arrest, and apoptosis in
cancer cells. Belinostat is a potent inhibitor of both class I and class II
HDAC enzymes. This Phase II study was undertaken to estimate the efficacy of
belinostat for the treatment of MDS.
Adults with MDS (any WHO classification, plus at least 1 significant cytopenia
if <5% bone marrow blasts) were eligible if they had ? 2 prior therapies for
MDS, adequate renal and hepatic function, and ECOG 0-2. The primary endpoint
was proportion of confirmed responses (CR, PR, and hematologic improvement
[HI]) during the first 12 weeks of treatment. Patients were treated with
belinostat 1000 mg/m2 as a 30 min IV infusion on days 1-5 of a 21 day cycle for
4 cycles. Responding patients could receive additional cycles until disease
progression or unacceptable toxicity. 21 patients were to be enrolled in the
first stage, and if 3 or more responses were observed, an additional 29 would
be enrolled in stage 2.
21 patients (median age, 67 years) were enrolled, and all are evaluable.
Patients were a median 13.4 months from diagnosis (range, 0.3-210) and had bone
marrow blasts of <5% (n=14), 5-9% (n=6), and 10-19% (n=1). 13 patients (62%)
had good risk cytogenetics, and 7 (33%) had poor risk. 17 patients (81%) were
transfusion dependent. Prior therapy included azacitidine (n=7) and
chemotherapy (n=8). Patients were treated with a median 2.5 cycles (range, 1-8)
of belinostat. There was one confirmed response - HI in neutrophils - that
lasted 2.1 months, for an ORR of 5% (95% CI, 0.2-23). Median Overall Survival
was 14.5 months. Median time to progression was 15.5 months. Grade 3-4
toxicities considered at least possibly related to belinostat were: neutropenia
(n=10), thrombocytopenia (n=9), anemia (n=5), fatigue (n=2), febrile
neutropenia (n=1), and headache (n=1). 2 patients had Grade 2 cytokine release
syndrome during belinostat infusion, and 2 patients had QTc prolongation.
Because the study met the stopping rule in the first stage of enrollment, it
was closed to further accrual.
Although well-tolerated, belinostat does not have sufficient efficacy to
warrant further investigation as a single agent in MDS. Supported by NCI
N01-CM62205
About Belinostat
Belinostat (PXD 101) is a Class I and II HDAC inhibitor that is being studied
in multiple clinical trials as a single agent or in combination with
chemotherapeutic agents for the treatment of various hematological and solid
cancers. Its anticancer effect is thought to be mediated through multiple
mechanisms of action, including the inhibition of cell proliferation, induction
of apoptosis (programmed cell death), inhibition of angiogenesis, induction of
differentiation, and the resensitization of cells that have overcome drug
resistance to anticancer agents such as platinums, taxanes and topoisomerase II
inhibitors. Belinostat is the only HDAC inhibitor in clinical development with
multiple potential routes of administration, including intravenous
administration, continuous intravenous infusion and oral administration.
Belinostat is currently in a registrational trial, under a Special Protocol
Assessment (SPA), as a monotherapy for relapsed or refractory Peripheral T-Cell
Lymphoma (PTCL), an indication for which it has been granted Orphan Drug and
Fast Track designation by the U.S. Food and Drug Administration. The Company
currently plans to file a New Drug Application (NDA) in 2011. Belinostat is
also under investigation in a randomized Phase 2 trial, as a combination
therapy with carboplatin and paclitaxel, for cancer of unknown primary (CUP).
Additionally, the National Cancer Institute is currently conducting several
clinical trials of Belinostat in a variety of hematological and solid tumors,
both as monotherapy as well as combination therapy.
Announcement No. 20-10 Page 4 of 5
TOPOTARGET A/S ANNOUNCES BELINOSTAT
ABSTRACT AT THE 2010 ANNUAL MEETING OF THE
AMERICAN SOCIETY OF CLINICAL ONCOLOGY
Announcement No. 20-10 Page 5 of 5
Topotarget A/S
For further information, please contact:
Francois Martelet, CEO: Direct: +45 39 17 94 99; Mobile: +45 31 36 83 41
Anders Vadsholt, CFO: Direct: +45 39 17 83 45; Mobile: +45 28 98 90 55
Background information
About Topotarget
Topotarget (NASDAQ OMX: TOPO) is an international biotech company headquartered
in Denmark, dedicated to improve cancer therapies. Topotarget currently
focuses, in collaboration with Spectrum Pharmaceuticals, Inc., on the
development in pivotal studies of its lead drug candidate, belinostat, which
has shown proof-of-concept as monotherapy in treating haematological
malignancies and positive results in solid tumours. Belinostat can be used in
combination with full doses of chemotherapy, and is currently in a pivotal
trial within PTCL (peripheral T-cell lymphoma). Topotarget's key cancer drugs
target HDAC, NAD+, mTOR, Fas ligand and topoisomerase II. 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 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
described in the forward-looking statements. Topotarget cautions investors 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 exposure; 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.

announcement no 20-10 topotarget announces belinostat abstract at the 2010 annual meeting of the american society of clinical oncology.pdf