Axcentua Pharmaceuticals AB

Alle, Sweden

Axcentua Pharmaceuticals AB

Alle, Sweden

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Lohr J.-M.,Center for Digestive Diseases | Lohr J.-M.,Karolinska Institutet | Omazic B.,Center for Allogenic Stem Cell Transplantation | Kartalis N.,Karolinska Institutet | And 2 more authors.
Pancreatology | Year: 2016

Background: AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-naïve patients with inoperable pancreatic carcinoma. Patients and methods: AXP107-11 was given orally in escalating doses (400 mg-1600 mg daily) in combination with standard gemcitabine treatment (1000 mg/m2/week) for the first seven of eight weeks and thereafter for a maximum of four × four-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated. Results: Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1 μM. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up. Conclusion: Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients. © 2016 IAP and EPC.


Grant
Agency: European Commission | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.1-6 | Award Amount: 4.23M | Year: 2011

Pancreatic cancer is one of the most lethal human cancers with a five-year survival rate of less than 5%. Late presentation and a high level of resistance to chemotherapeutic drugs are among the major reasons for this dismal prognosis. The presence of the highest degree of desmoplasia among all solid tumours and the fact that chronic inflammatory pancreatic disease is associated with an increased risk for pancreatic cancer indicate, that the tumour microenvironment is of particular importance for carcinogenesis in the pancreas. The long-term objective of this proposal is to increase survival of pancreatic cancer patients by exploring the contribution of the tumour microenvironment to the failure of presently available oncological treatments. For this purpose the clinical observation will be reverse-translated into innovative in-vitro and mouse models closely mimicking the human disease. This will allow a profound study of the mechanistic basis of treatment failure by deciphering the complex network between components of the microenvironment and cancer cells leading to increased resistance to chemotherapy and infiltrative growth along adjacent lymphatic and neural structures as well as metastatic spread. Identification of cancer (stem) cell-autonomous as well as stromal-derived mediators of invasion and chemoresistance will lead to novel drug targets to overcome the current therapeutic dilemma. The consortium has been specifically designed to include all required levels of expertise: 1) surgical and medical oncology groups conducting the largest clinical trials for pancreatic cancer in Europe, 2) expert pancreatic pathologists, 3) basic scientists focused on the study of carcinogenesis and tumour microenvironment interactions in the pancreas, 4) molecular oncology groups that have developed genetically engineered mouse models faithfully recapitulating human pancreatic cancer, as well as 5) pharmaceutical industry specialised on drug development.


PubMed | Karolinska Institutet, Center for Allogenic Stem Cell Transplantation, Karolinska University Hospital and Axcentua Pharmaceuticals AB
Type: Journal Article | Journal: Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] | Year: 2016

AXP107-11 is a novel, multi-component crystalline form of the naturally occurring compound genistein. AXP107-11 has improved physiochemical properties and oral bioavailability compared to the natural form of genistein, and it is possible that combining AXP107-11 with chemotherapy may increase the effect and reduce chemoresistance. The purpose of this dose escalation phase Ib study was to assess the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of AXP107-11 in combination with gemcitabine in treatment-nave patients with inoperable pancreatic carcinoma.AXP107-11 was given orally in escalating doses (400mg-1600mg daily) in combination with standard gemcitabine treatment (1000mg/m(2)/week) for the first seven of eight weeks and thereafter for a maximum of fourfour-week treatment cycles. PK, safety, MTD and efficacy of AXP107-11 in combination with gemcitabine were evaluated.Sixteen patients were enrolled and received AXP107-11. The maximum concentration in serum of unconjugated (free) genistein was 1M. Neither dose-limiting toxicities (DLTs) nor signs of hematological or non-hematological toxicities related to AXP107-11 were observed over a period ranging from 0.7 to 13.2 months. The median overall survival time was 4.9 months (range 1.5-19.5 months). Seven patients (44%) survived longer than six months and 19% were alive at the one-year follow-up.Treatment of pancreatic cancer patients with AXP107-11 in combination with gemcitabine resulted in a favorable PK-profile with high serum levels without signs of either hematological or non-hematological toxicity. Accordingly, we suggest further studies with AXP107-11 in pancreatic cancer patients.


Mork L.-M.,Karolinska Institutet | Rehnmark S.,KaroBio AB | Rehnmark S.,Axcentua Pharmaceuticals AB | Davoodpour P.,Karolinska Institutet | And 8 more authors.
PLoS ONE | Year: 2013

Background: Thyroid hormones (TH) regulate cholesterol metabolism but their use as lipid-lowering drugs is restricted due to negative cardiac effects. TH mimetic compounds modulating TH receptor β (THRβ) have been designed as potential drugs, reducing serum cholesterol levels while avoiding apparent deleterious cardiac effects. Objective: Using ApoE deficient mice, we examined whether KB3495, a TH mimetic compound, reduces atherosclerosis and if there is a synergistic effect with atorvastatin. The effect of KB3495 was investigated after 10 and 25 weeks. Results: KB3495 treatment reduced atherosclerotic plaque formation in aorta and decreased the cholesteryl ester (CE) content by 57%. Treatment with KB3495 was also associated with a reduction of macrophage content in the atherosclerotic plaques and reduced serum levels of IL-1β, TNFalpha, IL-6, Interferon γ, MCP-1 and M-CSF. Serum lipoprotein analysis showed no change in total cholesterol levels in ApoB-containing lipoproteins. KB3495 alone increased fecal BA excretion by 90%. The excretion of neutral sterols increased in all groups, with the largest increase in the combination group (350%). After 25 weeks, the animals treated with KB3495 showed 50% lower CE levels in the skin and even further reductions were observed in the combination group where the CE levels were reduced by almost 95% as compared to controls. Conclusion: KB3495 treatment reduced atherosclerosis independently of total cholesterol levels in ApoB-containing lipoproteins likely by stimulation of sterol excretion from the body and by inhibition of the inflammatory response. © 2013 Mörk et al.


Grant
Agency: European Commission | Branch: FP7 | Program: MC-IAPP | Phase: PEOPLE-2007-3-1-IAPP | Award Amount: 1.66M | Year: 2008

SME RECEPTOR is a transfer of knowledge programme which will bring top scientists from industry and academia together to address key questions in nuclear receptor research. The programme of research, which is implemented through the two way exchange of researchers between three leading research organisations and three specialist innovative SMEs, will develop methodology to tackle one of the most pressing medical challenges in Europe characterization of the nuclear receptor role and the development of drugs targeting the complex symptoms characterized by the metabolic syndrome. SME RECEPTOR will exploit new opportunities for drug design provided by advances in bioinformatics and transgenic technology. This will enhance the understanding of basis mechanisms underlying nuclear receptor actions and their translation into the physiological regulation of diseases. Since cardiovascular toxicity is a major factor involved in both early and late drug failure, SME RECEPTOR will primarily focus on the development of early screening methods for cardiovascular toxicity, as well as to expand the knowledge of the governing molecular mechanisms. A key factor is the ability to translate the knowledge generated within this exchange programme into more advanced and efficient development of novel pharmaceuticals within the industry. The project will generate a group of scientists with unique knowledge and international expertise in nuclear receptor biology as well as nuclear receptor targeting pharmaceuticals. The mutually beneficial two way transfer of knowledge between industry and academia will provide a career boost to the researchers who will acquire leading new knowledge, complementary training and a detailed understanding of the research culture in their opposite sector. The project will further promote industry-academic networking, creating a strategic long-lasting industry-academia partnership.


Longati P.,Karolinska Institutet | Jia X.,Karolinska Institutet | Eimer J.,Karolinska Institutet | Wagman A.,Karolinska Institutet | And 6 more authors.
BMC Cancer | Year: 2013

Background: Pancreatic ductal adenocarcinoma (PDAC) is the fourth most common cause of cancer related death. It is lethal in nearly all patients, due to an almost complete chemoresistance. Most if not all drugs that pass preclinical tests successfully, fail miserably in the patient. This raises the question whether traditional 2D cell culture is the correct tool for drug screening. The objective of this study is to develop a simple, high-throughput 3D model of human PDAC cell lines, and to explore mechanisms underlying the transition from 2D to 3D that might be responsible for chemoresistance. Methods: Several established human PDAC and a KPC mouse cell lines were tested, whereby Panc-1 was studied in more detail. 3D spheroid formation was facilitated with methylcellulose. Spheroids were studied morphologically, electron microscopically and by qRT-PCR for selected matrix genes, related factors and miRNA. Metabolic studies were performed, and a panel of novel drugs was tested against gemcitabine. Results: Comparing 3D to 2D cell culture, matrix proteins were significantly increased as were lumican, SNED1, DARP32, and miR-146a. Cell metabolism in 3D was shifted towards glycolysis. All drugs tested were less effective in 3D, except for allicin, MT100 and AX, which demonstrated effect. Conclusions: We developed a high-throughput 3D cell culture drug screening system for pancreatic cancer, which displays a strongly increased chemoresistance. Features associated to the 3D cell model are increased expression of matrix proteins and miRNA as well as stromal markers such as PPP1R1B and SNED1. This is supporting the concept of cell adhesion mediated drug resistance. © 2013 Longati et al.; licensee BioMed Central Ltd.


Kannisto K.,Karolinska Institutet | Rehnmark S.,Axcentua Pharmaceuticals AB | Slatis K.,Karolinska Institutet | Webb P.,Houston Methodist Research Institute | And 4 more authors.
Atherosclerosis | Year: 2014

Thyroid hormone reduces plasma cholesterol and increases expression of low-density lipoprotein receptor (LDL-R) in liver, an effect mediated by thyroid receptor β (TRβ). The selective TRβ modulator GC-1 also enhances several steps in reverse cholesterol transport and can decrease serum cholesterol independently of LDL-R. To test whether GC-1 reduces atherosclerosis and to determine which mechanisms are active, we treated ApoE deficient mice with atherogenic diet±GC-1. GC-1 reduced cholesteryl esters in aorta after 20 weeks. Serum free and esterified cholesterol were reduced after 1 and 10 weeks, but not 20 weeks. Hepatic bile acid synthesis and LDL-R expression was elevated after 1, 10 and 20 weeks, without changes in hepatic de novo cholesterol synthesis. GC-1 increased faecal neutral sterols and reduced serum campesterol after 1 week, indicating reduced intestinal cholesterol absorption. After 20 weeks, GC-1 increased faecal bile acids, but not faecal neutral sterols. Hepatic scavenger receptor B1 (SR-B1) expression was decreased by GC-1. We conclude that GC-1 delays the onset of atherosclerosis in ApoE deficient mice. Since ApoE is needed for hepatic cholesterol reabsorption by LDL-R, this supports the idea that GC-1 reduces serum cholesterol independently of LDL-R by increasing hepatic bile acid synthesis. GC-1 lipid-lowering effects in ApoE deficient mice may also be partly due to reduced intestinal cholesterol absorption. Since reductions in serum cholesterol are reversed at longer times, these GC-1 dependent effects may not be enough for sustained cholesterol reduction in long term treatments. © 2014 Published by Elsevier Ireland Ltd.


PubMed | Karolinska Institutet, Houston Methodist Research Institute and Axcentua Pharmaceuticals AB
Type: Journal Article | Journal: Atherosclerosis | Year: 2014

Thyroid hormone reduces plasma cholesterol and increases expression of low-density lipoprotein receptor (LDL-R) in liver, an effect mediated by thyroid receptor (TR). The selective TR modulator GC-1 also enhances several steps in reverse cholesterol transport and can decrease serum cholesterol independently of LDL-R. To test whether GC-1 reduces atherosclerosis and to determine which mechanisms are active, we treated ApoE deficient mice with atherogenic diet GC-1. GC-1 reduced cholesteryl esters in aorta after 20 weeks. Serum free and esterified cholesterol were reduced after 1 and 10 weeks, but not 20 weeks. Hepatic bile acid synthesis and LDL-R expression was elevated after 1, 10 and 20 weeks, without changes in hepatic de novo cholesterol synthesis. GC-1 increased faecal neutral sterols and reduced serum campesterol after 1 week, indicating reduced intestinal cholesterol absorption. After 20 weeks, GC-1 increased faecal bile acids, but not faecal neutral sterols. Hepatic scavenger receptor B1 (SR-B1) expression was decreased by GC-1. We conclude that GC-1 delays the onset of atherosclerosis in ApoE deficient mice. Since ApoE is needed for hepatic cholesterol reabsorption by LDL-R, this supports the idea that GC-1 reduces serum cholesterol independently of LDL-R by increasing hepatic bile acid synthesis. GC-1 lipid-lowering effects in ApoE deficient mice may also be partly due to reduced intestinal cholesterol absorption. Since reductions in serum cholesterol are reversed at longer times, these GC-1 dependent effects may not be enough for sustained cholesterol reduction in long term treatments.


Patent
Axcentua Pharmaceuticals Ab | Date: 2015-04-20

The disclosure relates to new crystalline forms of genistein. The disclosed crystalline forms include crystalline genistein sodium salt dihydrate; crystalline genistein potassium salt dihydrate; crystalline genistein calcium salt; crystalline genistein magnesium salt; crystalline genistein L-lysine salt; crystalline genistein N-methylglucamine salt; crystalline genistein N-ethylglucamine salt; crystalline genistein diethylamine salt; and crystalline genistein monohydrate. The disclosure also relates to the novel genistein salts represented by these crystalline forms. Therapeutic compositions containing at least one of these crystalline forms of genistein and/or a genistein salt and a pharmaceutically acceptable carrier are described. The disclosure also relates to methods of treating cancer comprising the step of administering to a patient in need thereof a therapeutically effective amount of a therapeutic composition containing the compounds of the disclosure, of a crystalline form of genistein, or of a genistein salt.

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