Ark Therapeutics Ltd

Kuopio, Finland

Ark Therapeutics Ltd

Kuopio, Finland

Time filter

Source Type

Westphal M.,University of Hamburg | Yla-Herttuala S.,University of Eastern Finland | Yla-Herttuala S.,Kuopio University Hospital | Martin J.,University College London | And 6 more authors.
The Lancet Oncology | Year: 2013

Background: Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. Methods: For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18-70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1×1012 viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. Findings: Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283-373) than in the control group (268 days, 210-313; hazard ratio [HR] 1·53, 95% CI 1·13-2·07; p=0·006). In a subgroup of patients with non-methylated MGMT, the HR was 1·72 (95% CI 1·15-2·56; p=0·008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369-574 for the experimental group vs 452 days, 95% CI 437-558 for the control group; HR 1·18, 95% CI 0·86-1·61, p=0·31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3-4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). Interpretation: Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. Funding: Ark Therapeutics Ltd. © 2013 Elsevier Ltd.


Kaikkonen M.U.,University of Eastern Finland | Kaikkonen M.U.,Ark Therapeutics Ltd | Maatta A.I.,University of Eastern Finland | Yla-Herttuala S.,University of Eastern Finland | And 2 more authors.
Molecular Therapy | Year: 2010

One of the major obstacles in the use of baculovirus vectors for in vivo gene transfer is the virus inactivation by serum complement. In this study, we investigated the effect of decay-accelerating factor (DAF), factor H (FH)-like protein-1 (FHL-1), C4b-binding protein (C4BP), and membrane cofactor protein (MCP) on protection of baculovirus vectors from the complement-mediated inactivation. Complement regulatory proteins were displayed on baculovirus surface as fusions to membrane anchor of the vesicular stomatitis virus-G (VSV-G) protein. This strategy resulted in abundant expression of recombinant proteins on the viral envelope while viral titers comparable to control virus were reached. The surface-modified vectors exhibited complement resistance in vitro, DAF showing the highest level of protection. Intraportal delivery of DAF-displaying baculovirus resulted in increased survival and enhanced gene expression in immunocompetent mice. Mice receiving DAF-displaying baculovirus also exhibited lower level of liver inflammation as evidenced by aspartate aminotransferase (AST). In line with this, macrophages treated with DAF baculovirus produced lower levels of inflammatory cytokines IL-1Β, IL-6, and IL-12p40 compared to control virus. These results suggest that DAF-display can protect the vector against complement inactivation but also reduce complement-mediated inflammation injury. In conclusion, complement shielded baculovirus vectors represent attractive tools for effective in vivo gene delivery. © The American Society of Gene & Cell Therapy.


Mehta V.,University College London | Abi-Nader K.N.,University College London | Peebles D.M.,University College London | Benjamin E.,University College London | And 9 more authors.
Gene Therapy | Year: 2012

Increasing uterine artery blood flow (UABF) may benefit fetal growth restriction where impaired uteroplacental perfusion prevails. Based on previous short-term results, we examined the long-term effects of adenovirus vector-mediated overexpression of vascular endothelial growth factor-A 165 (VEGF-A165) in the uterine artery (UtA). Transit-time flow probes were implanted around both UtAs of mid-gestation pregnant sheep (n=11) to measure UABF. A carotid artery catheter was inserted to measure maternal or fetal hemodynamics. Baseline UABF was measured over 3 days, before injection of adenovirus vector (5 × 1011 particles) encoding the VEGF-A165 gene (Ad.VEGF-A165) into one UtA and a reporter Β-galactosidase gene (Ad.LacZ) contralaterally. UABF was then measured daily until term. At 4 weeks post injection, the increase in UABF was significantly higher in Ad.VEGF-A165 compared with Ad.LacZ-transduced UtAs (36.53% vs 20.08%, P=0.02). There was no significant effect on maternal and fetal blood pressure. Organ bath studies showed significantly lesser vasoconstriction (Emax 154.1 vs 184.7, P<0.001), whereas immunohistochemistry demonstrated a significantly increased number of adventitial blood vessels (140 vs 91, n=26, P<0.05) following Ad.VEGF-A 165 transduction. Local overexpression of VEGF-A165 in the UtAs of pregnant mid-gestation sheep leads to a sustained long-term increase in UABF, which may be explained by neovascularization and altered vascular reactivity. © 2012 Macmillan Publishers Limited. All rights reserved.


Seyedarabi A.,University College London | Cheng L.,Ark Therapeutics Ltd. | Cheng L.,University College London | Zachary I.,University College London | Djordjevic S.,University College London
PLoS ONE | Year: 2013

We report a method for production of soluble heparin binding domain (HBD) of human vascular endothelial growth factor VEGF-A165. Recombinant VEGF-A165-HBD that contains four disulphide bridges was expressed in specialised E. coli SHuffle cells and its activity has been confirmed through interactions with neuropilin and heparin. The ability to produce significant quantities of a soluble active form of VEGF-A165-HBD will enable further studies addressing the role of VEGF-A in essential processes such as angiogenesis, vasculogenesis and vascular permeability. © 2013 Seyedarabi et al.


Musthafa H.-S.N.,University of Eastern Finland | Dragneva G.,University of Eastern Finland | Lottonen L.,University of Eastern Finland | Merentie M.,University of Eastern Finland | And 6 more authors.
Magnetic Resonance in Medicine | Year: 2013

Longitudinal relaxation time in the rotating frame (T1 ρ) was measured using continuous wave irradiation in normal and infarcted mouse myocardium in vivo. Significant increase in T1 ρ was found after 7 days of infarction when compared with reference myocardium or in myocardium before infarction. Cine MRI and histology were performed to verify the severity of infarction. The time course of T 1ρ in the infarct fits better with granulation and scar tissue formation than necrosis and edema. The results of the study show that T1ρ could potentially be a noninvasive quantitative marker for tissue remodeling after ischemic damage. © 2012 Wiley Periodicals, Inc.


Patent
Ark Therapeutics Ltd. | Date: 2013-05-01

An agent comprises a vector having a functional gene, a prodrug which can be converted into a cytotoxic agent by an expression product of the gene, and another cytotoxic agent, as a combined preparation for simultaneous, sequential or separate use in the therapy of cancer or of a disease characterised by an impaired mismatch repair (MMR) pathway, wherein the dosage regimen comprises beginning another cytotoxic agent therapy no later than 7 days after the prodrug therapy has finished.


Patent
Ark Therapeutics Ltd. | Date: 2012-01-18

An agent comprises a vector having a functional gene, a prodrug which can be converted into a cytotoxic agent by an expression product of the gene, and another cytotoxic agent, as a combined preparation for simultaneous, sequential or separate use in the therapy of cancer or of a disease characterised by an impaired mismatch repair (MMR) pathway, wherein the dosage regimen comprises beginning the another cytotoxic agent therapy no later than 7 days after the prodrug therapy has finished.


Trademark
Ark Therapeutics Ltd | Date: 2010-01-26

Diagnostic protein preparations for use in science, scientific diagnostics and industry; diagnostic preparations of genes for use in science, scientific diagnostics and industry. Pharmaceutical preparations for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumours, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; pharmaceutical preparations for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; pharmaceutical preparations to promote or suppress angiogenesis and enhance blood flow; pharmaceutical preparations for increasing the efficiency of muscle cell energy production; therapeutic agents for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumours, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; therapeutic agents for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; therapeutic agents to promote or suppress angiogenesis and enhance blood flow; therapeutic agents for increasing the efficiency of muscle cell energy production; diagnostic preparations for medical purposes; protein preparations for clinical or medical laboratory use, namely for targeting therapeutic agents to specific sites; medical dressings; surgical dressings; burn dressings; wound dressings; absorbent wound and burn dressings in the nature of pads; foot and hand dressings for medical purposes; fluid handling foot and hand dressings for medical purposes; preparations of genes for therapeutics purposes namely for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumours, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; preparations of genes for therapeutic purposes namely for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; preparations of genes for therapeutic purposes namely to promote or suppress angiogenesis and enhance blood flow; preparations of genes for therapeutic purposes namely for increasing the efficiency of muscle cell energy production. Boots and gloves for orthopaedic and medical purposes; boots and gloves for medical purposes with the ability to handle wound fluid; boots and gloves for medical use and absorbent filters, liners and inserts for use therewith; filters, soles and absorbent inserts for socks, boots and gloves for medical purposes, namely, for the treatment of wounds and burns; foot and hand dressings for medical purposes, namely, for the treatment of wounds and burns; parts and fittings for all the aforesaid goods. Scientific, medical and clinical research, all in the field of the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumours, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting, prevention of stenosis, increasing the efficiency of muscle cell energy production and promoting or suppressing angiogenesis and enhancing blood flow; scientific, medical and clinical research for the discovery, design, creation, development and testing in the field of pharmaceutical preparations and therapeutically active substances; scientific, medical and clinical research in the field of gene therapy; scientific, medical and clinical research for the discovery, design, creation, development and testing in the field of pharmaceutical preparations and therapeutically active substances for use in the field of gene therapy; advisory services relating to the aforesaid services; scientific, medical and clinical research in the field of genes and genetics; medical and scientific research, namely, conducting gene therapy trials; provision of information relating to the above.


Trademark
Ark Therapeutics Ltd | Date: 2010-11-08

PHARMACEUTICAL PREPARATIONS AND THERAPEUTIC AGENTS FOR TREATING MUSCLE WASTING; PHARMACEUTICAL PREPARATIONS AND THERAPEUTIC AGENTS FOR TREATING CANCER AND MUSCLE WASTING IN CANCER; PHARMACEUTICAL PREPARATIONS AND THERAPEUTIC AGENTS FOR TREATING LIPODYSTROPYY AND OTHER METABOLIC CONDITIONS ASSOCIATED WITH THE USE OF ANTI-HIV THERAPY; PHARMACEUTICAL PREPARATIONS AND THERAPEUTIC AGENTS FOR INCREASING THE EFFICIENCY OF MUSCLE CELL ENERGY PRODUCTION.


Trademark
Ark Therapeutics Ltd | Date: 2012-08-07

Diagnostic protein preparations for use in science, scientific diagnostics, medical laboratory use and research; diagnostic preparations of genes for use in science, scientific diagnostics, medical laboratory use and research. Diagnostic protein preparations for medical use; diagnostic preparations of genes for medical use; pharmaceutical preparations for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumors, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; pharmaceutical preparations for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; pharmaceutical preparations to promote or suppress angiogenesis and enhance blood flow; pharmaceutical preparations for increasing the efficiency of muscle cell energy production; therapeutic agents for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumors, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; therapeutic agents for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; therapeutic agents to promote or suppress angiogenesis and enhance blood flow; therapeutic agents for increasing the efficiency of muscle cell energy production; diagnostic preparations for medical purposes; protein preparations for clinical or medical laboratory use, namely, for targeting therapeutic agents to specific sites; medical dressings; surgical dressings; burn dressings; wound dressings; absorbent wound and burn dressings in the nature of pads; foot and hand dressings for medical purposes; fluid handling foot and hand dressings for medical purposes; preparations of genes for therapeutic purposes, namely, for the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumors, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting; preparations of genes for therapeutic purposes, namely, for the prevention of stenosis, namely, stenosis caused by intimal hyperplasia following surgical procedures; preparations of genes for therapeutic purposes, namely, to promote or suppress angiogenesis and enhance blood flow; preparations of genes for therapeutic purposes, namely, for increasing the efficiency of muscle cell energy production; foot and hand dressings for medical purposes, namely, for the treatment of wounds and burns; none of the above including dietary and nutritional supplements. Boots and gloves for orthopaedic and medical purposes; parts of boots and gloves for orthopedic and medical purposes, namely, heels, soles and inserts; boots and gloves for medical purposes with the ability to handle wound fluid; boots and gloves for medical use and absorbent filters, liners and inserts for use therewith; filters, soles and absorbent inserts for boots and gloves for medical purposes, namely, for the treatment of wounds and burns; biodegradable collagen collar delivery devices for delivering therapeutic agents and gene therapy products to specific sites. Scientific, medical and clinical research, all in the field of the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumors, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting, prevention of stenosis, increasing the efficiency of muscle cell energy production and promoting or suppressing angiogenesis and enhancing blood flow; providing scientific, medical and clinical research information, all in the field of the treatment of wounds, burns, vascular and circulatory system related diseases, cancer, malignant glioma and other malignant brain tumors, macular degeneration, lipodystrophy and other metabolic conditions associated with the use of anti-HIV therapy, cachexia and muscle wasting, prevention of stenosis, increasing the efficiency of muscle cell energy production and promoting or suppressing angiogenesis and enhancing blood flow; scientific, medical and clinical research for the discovery, design, creation, development and testing in the field of pharmaceutical preparations and therapeutically active substances; scientific, medical and clinical research in the field of gene therapy; scientific, medical and clinical research for the discovery, design, creation, development and testing in the field of pharmaceutical preparations and therapeutically active substances for use in the field of gene therapy; scientific, medical and clinical research in the field of genes and genetics; medical and scientific research, namely, conducting gene therapy trials; none of the above in the dietary or nutritional supplement field.

Loading Ark Therapeutics Ltd collaborators
Loading Ark Therapeutics Ltd collaborators