TopoTarget
Encyclopedia
TopoTarget is an international biotechnology
company focused on the discovery and development of drugs and therapies to treat cancer
. While the company has offices around the world, its headquarters are based in Copenhagen
, Denmark
. It was founded in 2000 by a group of clinicians.
TopoTarget is involved in collaborations with both academia and industry. In 2001 they began collaborating with the National Cancer Institute
, a component of the US National Institutes of Health
. Since their acquisition of Prolifix, they have been collaborating with the Netherlands Cancer Institute. They also collaborate with Rigshospitalet
, the national hospital of Denmark. TopoTarget has also collaborated with other companies, including Novartis
since 2003, and Lundbeck
as of October 2007; Topotarget has been member of the Danish Innovation Network BioLogue since 2005.
. The company is publicly traded on the OMX
Nordic Exchange in Copenhagen under the symbol TOPO. They are a member of Medicon Valley Alliance
. The CEO is Peter Buhl Jensen, M.D.
, Ph.D.
(including assay
development, medicinal chemistry
, preclinical research, and clinical trials), marketing
, and sales. About 58% of employees are in medical and research fields. TopoTarget has public partners in many areas of the world, notably at Rigshospitalet, Copenhagen, Frankfurt University Hospital, Oxford University Hospital, and the National Cancer Institute, US
. This was followed by the purchase of G2M Cancer Drugs AG in Germany
in 2005. By 2006 TopoTarget had 125 employees specializing in most areas of drug discovery and development. In 2007, they acquired Apoxis, which has two products, APO010 and APO866. TopoTarget currently employs 146 people in Denmark, Germany, Switzerland
, UK and the USA.
Currently TopoTarget has nine drugs in clinical development, as well as an extensive portfolio of small molecule
drug candidates in the pre-clinical phase. Savene/Totect, TopoTarget’s first marketed product was released in October 2006 in Europe
and October 2007 in the United States causing a large jump in revenue from 2 million DKK in 2006 to 19 million DKK in 2007. In 2007, 293 patients were treated via drugs from TopoTarget’s pipeline.
Allowing each sector to focus on its specialty in the drug development timeline maximizes TopoTarget’s use of time and resources to increase productivity.
A number of in-licensing collaborations have expanded TopoTarget’s drug pipeline. In June 2004, TopoTarget entered a licensing and collaboration agreement with CuraGen Corporation with respect to research, development, and commercialization of a group of small molecules that inhibit histone deacetylase
(HDAC) enzymes. One of these drugs—Belinostat—has proved particularly promising and forms the basis of TopoTarget’s research collaboration with the National Cancer Institute in the USA. In October 2005, Astellas sold them the exclusive worldwide license for a group of compounds with potential anti-cancer or immuno-suppressive
activity which are currently undergoing further preclinical evaluation. LEO Pharma A/S sold TopoTarget the license to its preclinical HDAC inhibitor, which is also undergoing evaluation as a treatment for cancer and inflammatory conditions. As of April 2008, all sales rights for this compound were transferred to TopoTarget. In October 2007, H Lundbeck A/S sold the development rights for their sigma receptor
ligand
, Siramesine
. By licensing potential cancer therapeutics from external sources and developing drug candidates from within, TopoTarget hopes to establish a broad array of drugs that target the underlying molecular mechanisms of cancer.
Once the viability of a compound has been established internally, TopoTarget relays the remaining responsibilities of the development process to its commercial collaborators in out-licensing agreements. Three prominent bodies maintain such out-licensing contracts: the National Cancer Institute (USA), the Netherland’s Cancer Institute, and Righospitalet (Copenhagen, Denmark). TopoTarget has been working with the Division of Cancer Treatment and Diagnosis at NCI since 2001 to develop new anti-cancer agents. Currently, NCI is handling the clinical development of TopoTarget’s HDAC inhibitor Belinostat (PXD101). NCI’s efforts are focused on determining the molecular basis of Belinostat’s anti-cancer activity and the drug’s viability in combination drug therapy. The Netherlands Cancer Institute provides TopoTarget access to the extensive research conducted by the Division of Carcinogenesis, which uses advanced techniques in functional genomics to identify novel genes with roles in carcinogenesis. May 2003 saw the establishment of a five-year research collaboration agreement between TopoTarget and Copenhagen’s Rigshospitalet to test the drug Topotect for effectiveness against brain metastases. Such relationships allow TopoTarget to advance its products through clinical development where its immediate resources are insufficient for the task.
Inhibitors, APO200.
. Savene was developed by TopoTarget and authorized to be put on the market in July 2007 by the European Commission
for the treatment of anthracycline extravasation. Savene, developed by TopoTarget is used for the treatment of anthracycline extravasation, a rare complication to chemotherapy
. Anthracycline extravasation is defined as the unintentional installation or leakage into the perivascular or subcutaneous spaces during administration. Savene works by inhibiting DNA topoisomerase II, which is the target of anthracycline chemotherapy. The drug binds to DNA topoisomerase II at a different step in the catalytic cycle than anthracyclines, which locks the enzyme in a conformational form that is no longer affected by anthracyclines. The drug is delivered as a ready-to-use kit containing both Savene powder and Savene diluents., ppg. 12–13;
Belinostat (aka PXD101), pg. 15 is TopoTarget’s lead product that is currently in late-stage clinical development for the treatment of hematological malignancies and solid tumors
. Belinostat works through a new mechanism of action to restore cell control which has been shut down by cancer, as a histone deacetylase inhibitor
(HDACi). TopoTarget expects to launch an initial regulatory study using Belinostat as monotherapy to treat peripheral T-cell lymphoma
(PTCL) by the beginning of 2009. In October 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin
and paclitaxel
for relapsed ovarian cancer
. Final results in late 2009 of a phase II trial for T cell lymphoma were encouraging.
Belinostat has been granted orphan drug
and fast track
designation by the FDA. Belinostat is in a phase II pivotal trial with NDA
submission planned for 2011H2.
(FAP). Savicol delivers valproic acid
as a proprietary, which builds up on a specific pharmacokinetic release pattern that is projected to inhibit certain HDAC enzymes in a more efficient manner. Savicol has been entered into Phase II studies by TopoTarget for the treatment of colorectal polyps in FAP patients. Orphan drug status has been granted to Savicol in both the United States and in Europe.
(VPA) for the treatment of hyperproliferative skin diseases, including basal cell carcinoma
and pre-cancerous actinic keratosis
. VPA primarily targets HDAC class I enzymes that are involved in cell proliferation and tumorigenesis. Baceca is currently in Phase II clinical trials.
. Randomized Phase II clinical studies were performed with Avugane in April 2006 and further studies have been conducted since then to investigate the clinical utility of the drug. If the results are successful, TopoTarget may consider conduction trials on other diseases including psoriasis
and atopic dermatitis
.
) and is currently involved in Phase I clinical trials for the treatment of brain metastases, which are a common secondary condition to patients that have lung cancer
and breast cancer
.
-toxin for the treatment of specific types of cancers in the form of a protein product., pg 20 The recombinant protein product targets the ErbB2/HER2 receptor, which is overexpressed in 30% of breast cancer
and is often a marker of a more aggressive disease. This receptor is also believed to be involved in certain other cancers, including head and neck cancers. The next clinical studies of Zemab were expected to be initiated by the start of 2009. but no clinical trials were registered.
s on the surface of cancer cells inducing cell apoptosis
. A Phase I study is currently being conducted with APO010 on patients with untreatable, advanced or refractory solid tumors.
, called NMPRT
. The worldwide development and marketing rights to APO866 were acquired from Astellas in October 2005. APO866 is a drug that provides a new therapeutic approach to cancer with the potential of acting as both a monotherapy and in combination with other chemotherapeutic agents or radiotherapy. TopoTarget has opened three separate clinical studies of APO866. The clinical studies are (1) to assess APO866 as a treatment of advanced melanoma
, (2) to assess APO866 as a treatment of cutaneous T-cell lymphoma and (3) to assess APO866 as a treatment of refractory or relapsed B-chronic lymphocytic leukemia
.
) gene. This product is used to treat a rare human genetic disease linked with mutations in the EDA1 gene. The disease reduces a patient’s ability to sweat
and increases hypersensitivity to heat, aberrant dentition
, hairlessness, and dry skin. Completed pre-clinical development has shown the potential of APO200 in animal models of X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED). APO200 gained orphan drug status from the FDA in February 2006. TopoTarget plans to sell this project to another company or to out-license it.
A number of Heat Shock Protein 90 (HSP90
) small molecule inhibitors have been developed by TopoTarget, with several compounds showing high potency in several cancer cell lines, particularly those cell lines which over-express HER2 receptors. This project is still in pre-clinical trials and TopoTarget is in the process of out-licensing the product or looking for companies to collaborate with on the project.
(mammalian target of rapamycin) pathway to understand targets for anti-tumor drugs. Currently they are looking to find a lead compound in order to continue these studies. TopoTarget is also looking into more drugs that interrupt HDAC activity, not only for cancer therapy, but for diseases like malaria
and CNS disorders.
N.B. — full text not freely available online
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...
company focused on the discovery and development of drugs and therapies to treat cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. While the company has offices around the world, its headquarters are based in Copenhagen
Copenhagen
Copenhagen is the capital and largest city of Denmark, with an urban population of 1,199,224 and a metropolitan population of 1,930,260 . With the completion of the transnational Øresund Bridge in 2000, Copenhagen has become the centre of the increasingly integrating Øresund Region...
, Denmark
Denmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
. It was founded in 2000 by a group of clinicians.
TopoTarget is involved in collaborations with both academia and industry. In 2001 they began collaborating with the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
, a component of the US National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
. Since their acquisition of Prolifix, they have been collaborating with the Netherlands Cancer Institute. They also collaborate with Rigshospitalet
Rigshospitalet
Rigshospitalet - Copenhagen University Hospital, or simply Riget, is the national hospital of Denmark, located in the capital city of Copenhagen, between the streets of Blegdamsvej, Tagensvej and Nørre Allé...
, the national hospital of Denmark. TopoTarget has also collaborated with other companies, including Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
since 2003, and Lundbeck
Lundbeck
H. Lundbeck A/S is a Danish international pharmaceutical company engaged in the research and development, production, marketing, and sale of drugs for the treatment of disorders in the central nervous system , including depression, schizophrenia, Alzheimer’s disease, Parkinson’s disease,...
as of October 2007; Topotarget has been member of the Danish Innovation Network BioLogue since 2005.
Company profile
In 2007, TopoTarget’s revenue was 44,890,000 DKKDanish krone
The krone is the official currency of the Kingdom of Denmark consisting of Denmark, the Faroe Islands and Greenland. It is subdivided into 100 øre...
. The company is publicly traded on the OMX
OMX
OMX AB is a Swedish-Finnish financial services company, formed in 2003 through a merger between OM AB and HEX plc and is now a part of the NASDAQ OMX Group since February 2008.It has two divisions, OMX Exchanges, which operates eight stock exchanges mainly in the Nordic and Baltic...
Nordic Exchange in Copenhagen under the symbol TOPO. They are a member of Medicon Valley Alliance
Medicon Valley Alliance
Medicon Valley Alliance is the Danish-Swedish cluster organisation representing human life sciences in Medicon Valley. As a non-profit member organisation, Medicon Valley Alliance carries out initiatives on behalf of the local life science community in order to create new research and business...
. The CEO is Peter Buhl Jensen, M.D.
Doctor of Medicine
Doctor of Medicine is a doctoral degree for physicians. The degree is granted by medical schools...
, Ph.D.
Ph.D.
A Ph.D. is a Doctor of Philosophy, an academic degree.Ph.D. may also refer to:* Ph.D. , a 1980s British group*Piled Higher and Deeper, a web comic strip*PhD: Phantasy Degree, a Korean comic series* PhD Docbook renderer, an XML renderer...
Personnel
At the end of 2007, TopoTarget had a total of 146 employees who worked in drug developmentDrug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
(including assay
Assay
An assay is a procedure in molecular biology for testing or measuring the activity of a drug or biochemical in an organism or organic sample. A quantitative assay may also measure the amount of a substance in a sample. Bioassays and immunoassays are among the many varieties of specialized...
development, medicinal chemistry
Medicinal chemistry
Medicinal chemistry and pharmaceutical chemistry are disciplines at the intersection of chemistry, especially synthetic organic chemistry, and pharmacology and various other biological specialties, where it is involved with design, chemical synthesis and development for market of pharmaceutical...
, preclinical research, and clinical trials), marketing
Marketing
Marketing is the process used to determine what products or services may be of interest to customers, and the strategy to use in sales, communications and business development. It generates the strategy that underlies sales techniques, business communication, and business developments...
, and sales. About 58% of employees are in medical and research fields. TopoTarget has public partners in many areas of the world, notably at Rigshospitalet, Copenhagen, Frankfurt University Hospital, Oxford University Hospital, and the National Cancer Institute, US
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
History
TopoTarget was founded in 2000 by clinicians specializing in the molecular mechanisms of cancer. Since its start it has grown mostly through acquisitions of other companies. In 2002, TopoTarget acquired Prolifix Ltd. based in the United KingdomUnited Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
. This was followed by the purchase of G2M Cancer Drugs AG in Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
in 2005. By 2006 TopoTarget had 125 employees specializing in most areas of drug discovery and development. In 2007, they acquired Apoxis, which has two products, APO010 and APO866. TopoTarget currently employs 146 people in Denmark, Germany, Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....
, UK and the USA.
Currently TopoTarget has nine drugs in clinical development, as well as an extensive portfolio of small molecule
Small molecule
In the fields of pharmacology and biochemistry, a small molecule is a low molecular weight organic compound which is by definition not a polymer...
drug candidates in the pre-clinical phase. Savene/Totect, TopoTarget’s first marketed product was released in October 2006 in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
and October 2007 in the United States causing a large jump in revenue from 2 million DKK in 2006 to 19 million DKK in 2007. In 2007, 293 patients were treated via drugs from TopoTarget’s pipeline.
Collaborative research and business strategy
Since its inception in 2000, TopoTarget has developed a strong, two-pronged strategy for expanding its drug portfolio. TopoTarget splits its focus between in-licensing and out-licensing opportunities to maximize its utilization of available skills and resources. In-licensing takes advantage of internal talent and focuses on preclinical and early clinical development of small molecule drugs through Phase I trials. Out-licensing of its products to larger pharmaceutical companies, however, facilitates the progression of drugs with broad market potential through the final stages of clinical development, regulatory approval, and marketing by taking advantage of their established reputations and knacks for navigating the later stages of commercialization. To summarize its strategy, TopoTarget states:Allowing each sector to focus on its specialty in the drug development timeline maximizes TopoTarget’s use of time and resources to increase productivity.
A number of in-licensing collaborations have expanded TopoTarget’s drug pipeline. In June 2004, TopoTarget entered a licensing and collaboration agreement with CuraGen Corporation with respect to research, development, and commercialization of a group of small molecules that inhibit histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
(HDAC) enzymes. One of these drugs—Belinostat—has proved particularly promising and forms the basis of TopoTarget’s research collaboration with the National Cancer Institute in the USA. In October 2005, Astellas sold them the exclusive worldwide license for a group of compounds with potential anti-cancer or immuno-suppressive
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
activity which are currently undergoing further preclinical evaluation. LEO Pharma A/S sold TopoTarget the license to its preclinical HDAC inhibitor, which is also undergoing evaluation as a treatment for cancer and inflammatory conditions. As of April 2008, all sales rights for this compound were transferred to TopoTarget. In October 2007, H Lundbeck A/S sold the development rights for their sigma receptor
Sigma receptor
The sigma receptors σ1 and σ2 bind to ligands such as 4-PPBP, SA 4503, ditolylguanidine, dimethyltryptamine and siramesine.- Classification :...
ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
, Siramesine
Siramesine
Siramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressant effects...
. By licensing potential cancer therapeutics from external sources and developing drug candidates from within, TopoTarget hopes to establish a broad array of drugs that target the underlying molecular mechanisms of cancer.
Once the viability of a compound has been established internally, TopoTarget relays the remaining responsibilities of the development process to its commercial collaborators in out-licensing agreements. Three prominent bodies maintain such out-licensing contracts: the National Cancer Institute (USA), the Netherland’s Cancer Institute, and Righospitalet (Copenhagen, Denmark). TopoTarget has been working with the Division of Cancer Treatment and Diagnosis at NCI since 2001 to develop new anti-cancer agents. Currently, NCI is handling the clinical development of TopoTarget’s HDAC inhibitor Belinostat (PXD101). NCI’s efforts are focused on determining the molecular basis of Belinostat’s anti-cancer activity and the drug’s viability in combination drug therapy. The Netherlands Cancer Institute provides TopoTarget access to the extensive research conducted by the Division of Carcinogenesis, which uses advanced techniques in functional genomics to identify novel genes with roles in carcinogenesis. May 2003 saw the establishment of a five-year research collaboration agreement between TopoTarget and Copenhagen’s Rigshospitalet to test the drug Topotect for effectiveness against brain metastases. Such relationships allow TopoTarget to advance its products through clinical development where its immediate resources are insufficient for the task.
Products
TopoTarget has a large amount of drugs that are currently in clinical trials or being licensed to other companies. The drugs include Belinostat, Savicol, Baceca, Avugane, APO866, TopotectA, Zemab, APO010, HSP90Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
Inhibitors, APO200.
Savene
Savene (aka Totect) is TopoTarget's single marketed drug as of the end of 2008., pg. 14 The generic name for Savene is dexrazoxaneDexrazoxane
Dexrazoxane hydrochloride is a cardioprotective agent.-Uses:...
. Savene was developed by TopoTarget and authorized to be put on the market in July 2007 by the European Commission
European Commission
The European Commission is the executive body of the European Union. The body is responsible for proposing legislation, implementing decisions, upholding the Union's treaties and the general day-to-day running of the Union....
for the treatment of anthracycline extravasation. Savene, developed by TopoTarget is used for the treatment of anthracycline extravasation, a rare complication to chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
. Anthracycline extravasation is defined as the unintentional installation or leakage into the perivascular or subcutaneous spaces during administration. Savene works by inhibiting DNA topoisomerase II, which is the target of anthracycline chemotherapy. The drug binds to DNA topoisomerase II at a different step in the catalytic cycle than anthracyclines, which locks the enzyme in a conformational form that is no longer affected by anthracyclines. The drug is delivered as a ready-to-use kit containing both Savene powder and Savene diluents., ppg. 12–13;
Belinostat
see Gallery below for structureBelinostat (aka PXD101), pg. 15 is TopoTarget’s lead product that is currently in late-stage clinical development for the treatment of hematological malignancies and solid tumors
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
. Belinostat works through a new mechanism of action to restore cell control which has been shut down by cancer, as a histone deacetylase inhibitor
Histone deacetylase inhibitor
Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...
(HDACi). TopoTarget expects to launch an initial regulatory study using Belinostat as monotherapy to treat peripheral T-cell lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
(PTCL) by the beginning of 2009. In October 2007 preliminary results were released from the Phase II clinical trial of intravenous belinostat in combination with carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
and paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
for relapsed ovarian cancer
Ovarian cancer
Ovarian cancer is a cancerous growth arising from the ovary. Symptoms are frequently very subtle early on and may include: bloating, pelvic pain, difficulty eating and frequent urination, and are easily confused with other illnesses....
. Final results in late 2009 of a phase II trial for T cell lymphoma were encouraging.
Belinostat has been granted orphan drug
Orphan drug
An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...
and fast track
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
designation by the FDA. Belinostat is in a phase II pivotal trial with NDA
New drug application
The New Drug Application is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration approve a new pharmaceutical for sale and marketing...
submission planned for 2011H2.
Savicol
Savicol, formerly known as PEAC (Pulse Enhanced ACetylation), is an anti-cancer drug candidate that treats familial adenomatous polyposisFamilial adenomatous polyposis
Familial adenomatous polyposis is an inherited condition in which numerous polyps form mainly in the epithelium of the large intestine. While these polyps start out benign, malignant transformation into colon cancer occurs when not treated....
(FAP). Savicol delivers valproic acid
Valproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
as a proprietary, which builds up on a specific pharmacokinetic release pattern that is projected to inhibit certain HDAC enzymes in a more efficient manner. Savicol has been entered into Phase II studies by TopoTarget for the treatment of colorectal polyps in FAP patients. Orphan drug status has been granted to Savicol in both the United States and in Europe.
Baceca
Baceca comprises a topical formulation of valproic acidValproic acid
Valproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
(VPA) for the treatment of hyperproliferative skin diseases, including basal cell carcinoma
Basal cell carcinoma
Basal-cell carcinoma is the most common type of skin cancer. It rarely metastasizes or kills. However, because it can cause significant destruction and disfigurement by invading surrounding tissues, it is still considered malignant. Statistically, approximately 3 out of 10 Caucasians may develop a...
and pre-cancerous actinic keratosis
Actinic keratosis
Actinic keratosis is a premalignant condition of thick, scaly, or crusty patches of skin. It is more common in fair-skinned people. It is associated with those who are frequently exposed to the sun, as it is usually accompanied by solar damage...
. VPA primarily targets HDAC class I enzymes that are involved in cell proliferation and tumorigenesis. Baceca is currently in Phase II clinical trials.
Avugane
Avugane is a novel proprietary formulation of the HDACi VPA that has the potential to be used as a topical treatment of inflammatory skin diseases including common acneAcne
Acne is a general term used for acneiform eruptions. It is usually used as a synonym for acne vulgaris, but may also refer to:*Acne aestivalis*Acne conglobata*Acne cosmetica*Acne fulminans*Acne keloidalis nuchae*Acne mechanica...
. Randomized Phase II clinical studies were performed with Avugane in April 2006 and further studies have been conducted since then to investigate the clinical utility of the drug. If the results are successful, TopoTarget may consider conduction trials on other diseases including psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...
.
TopotectA
TopotectA is a topoisomerase II inhibitor for the treatment of brain metastases. This drug is based on the same compound as Savene (dexrazoxaneDexrazoxane
Dexrazoxane hydrochloride is a cardioprotective agent.-Uses:...
) and is currently involved in Phase I clinical trials for the treatment of brain metastases, which are a common secondary condition to patients that have lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
and breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Zemab
Zemab comprises an antibodyAntibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
-toxin for the treatment of specific types of cancers in the form of a protein product., pg 20 The recombinant protein product targets the ErbB2/HER2 receptor, which is overexpressed in 30% of breast cancer
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and is often a marker of a more aggressive disease. This receptor is also believed to be involved in certain other cancers, including head and neck cancers. The next clinical studies of Zemab were expected to be initiated by the start of 2009. but no clinical trials were registered.
APO010
APO010, also known as mega-FasLigand is a recombinant fusion protein. This protein was derived from the pro-apoptotic human Fas ligand (FasL) protein. APO010 causes cell death of cancerous cells through a mechanism of targeting Fas receptorFas receptor
The FAS receptor also known as apoptosis antigen 1 , cluster of differentiation 95 or tumor necrosis factor receptor superfamily member 6 is a protein that in humans is encoded by the TNFRSF6 gene....
s on the surface of cancer cells inducing cell apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. A Phase I study is currently being conducted with APO010 on patients with untreatable, advanced or refractory solid tumors.
APO866
APO866, a drug that inhibits the growth of human tumors, is a potent and specific inhibitor of a key enzyme that is involved in the synthesis of NADNAD
NAD may refer to:* No abnormality detected, a medical status description* No apparent distress, a status description in childbirth* NAD Electronics, a Canadian audio equipment manufacturer...
, called NMPRT
Nicotinamide phosphoribosyltransferase
Nicotinamide phosphoribosyltransferase also known as pre-B-cell colony-enhancing factor 1 or visfatin is an enzyme that in humans is encoded by the PBEF1 gene...
. The worldwide development and marketing rights to APO866 were acquired from Astellas in October 2005. APO866 is a drug that provides a new therapeutic approach to cancer with the potential of acting as both a monotherapy and in combination with other chemotherapeutic agents or radiotherapy. TopoTarget has opened three separate clinical studies of APO866. The clinical studies are (1) to assess APO866 as a treatment of advanced melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, (2) to assess APO866 as a treatment of cutaneous T-cell lymphoma and (3) to assess APO866 as a treatment of refractory or relapsed B-chronic lymphocytic leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
APO200
APO200 is a therapeutic recombinant protein that is developed from the ectodysplasin A-1 (EDA1EDA (gene)
Ectodysplasin-A is a protein that in humans is encoded by the EDA gene.-Further reading:...
) gene. This product is used to treat a rare human genetic disease linked with mutations in the EDA1 gene. The disease reduces a patient’s ability to sweat
SWEAT
SWEAT is an OLN/TSN show hosted by Julie Zwillich that aired in 2003-2004.Each of the 13 half-hour episodes of SWEAT features a different outdoor sport: kayaking, mountain biking, ice hockey, beach volleyball, soccer, windsurfing, rowing, Ultimate, triathlon, wakeboarding, snowboarding, telemark...
and increases hypersensitivity to heat, aberrant dentition
Dentition
Dentition pertains to the development of teeth and their arrangement in the mouth. In particular, the characteristic arrangement, kind, and number of teeth in a given species at a given age...
, hairlessness, and dry skin. Completed pre-clinical development has shown the potential of APO200 in animal models of X-Linked Hypohidrotic Ectodermal Dysplasia (XLHED). APO200 gained orphan drug status from the FDA in February 2006. TopoTarget plans to sell this project to another company or to out-license it.
HSP90 Inhibitors
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
) small molecule inhibitors have been developed by TopoTarget, with several compounds showing high potency in several cancer cell lines, particularly those cell lines which over-express HER2 receptors. This project is still in pre-clinical trials and TopoTarget is in the process of out-licensing the product or looking for companies to collaborate with on the project.
Research
TopoTarget has several drugs in preclinical development. A current target is Heat Shock Protein 90 (HSP90). HSP90 is key in protein folding and maturation. TopoTarget is currently looking for small molecule drugs that inhibit HSP90 function to induce apoptosis. Current molecules have shown great promise and are undergoing optimization and evaluation in order to obtain a patent. TopoTarget is also studying the mechanism of action behind the mTORMammalian target of rapamycin
The mammalian target of rapamycin also known as mechanistic target of rapamycin or FK506 binding protein 12-rapamycin associated protein 1 is a protein which in humans is encoded by the FRAP1 gene...
(mammalian target of rapamycin) pathway to understand targets for anti-tumor drugs. Currently they are looking to find a lead compound in order to continue these studies. TopoTarget is also looking into more drugs that interrupt HDAC activity, not only for cancer therapy, but for diseases like malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
and CNS disorders.
Financial Outlook
For 2008, the company foresees a pre-tax loss of around DKK 175-195 million due to higher research and development costs as well as an increase in international collaboration.Collaborative works
N.B. — full text not freely available online
- "Positive SPA Reply From The FDA For TopoTarget's Pivotal Trial With Belinostat In PTCL." Medical News Today. 8 Sept. 2008. MediLexicon International Ltd. 23 Nov. 2008
- Targeting the cancer chaperone HSP90. Jennifer R. Smith and Paul Workman. Drug Discovery Today: Therapeutic Strategies. Volume 4, Issue 4, Winter 2007, Pages 219-227
- Thougaard AV, Grauslund M, Jensen PB, Bjorkling F, Hasinoff BB, Tjørnelund J, Sehested M, Jensen LH. Evaluation of the topoisomerase II-inactive bisdioxopiperazine ICRF-161 as a protectant against doxorubicin-induced cardiomyopathy.Toxicology. 2008 Oct 25.
- Tumber A, Collins LS, Petersen KD, Thougaard A, Christiansen SJ, Dejligbjerg M, Jensen PB, Sehested M, Ritchie JW. The histone deacetylase inhibitor PXD101 synergises with 5-fluorouracil to inhibit colon cancer cell growth in vitro and in vivo. Cancer Chemother Pharmacol. 2007 Jul;60(2):275-83.