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Alipogene tiparvovec (Glybera®; AMT-011, AAV1-LPLS447X) is an adeno-associated virus serotype 1-based gene therapy for adult patients with familial lipoprotein lipase (LPL) deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. It is administered as a one-time series of intramuscular injections in the legs. LPLD, a rare autosomal recessive disorder, results in hyperchylomicronaemia and severe hypertriglyceridaemia, which in turn, are associated with an increased risk of clinical complications, the most debilitating of which is recurrent severe and potentially life-threatening pancreatitis. In clinical studies (n = 27 patients), one-time administration of alipogene tiparvovec was associated with significant reductions in plasma triglyceride levels during the 12 or 14 week study period post administration. Although triglyceride levels returned to pre-treatment levels within 16-26 weeks after administration, patients had sustained improvements in postprandial chylomicron metabolism, with sustained expression of functional copies of the LPLS477X gene and of biologically active LPL in skeletal muscle. Moreover, after up to 6 years' follow-up post administration, there were clinically relevant reductions in the incidence of documented pancreatitis and acute abdominal pain events consistent with pancreatitis. Alipogene tiparvovec was generally well tolerated, with most adverse events being localized, transient, mild to moderate injection-site reactions. This article reviews the pharmacology of alipogene tiparvovec and its efficacy and safety in adults with LPLD. © 2014 Springer International Publishing Switzerland.


Poole R.M.,Springer
Drugs | Year: 2014

Belinostat [Beleodaq® (US)], a small-molecule hydroxamate-type inhibitor of class I, II and IV histone deacetylase (HDAC) enzymes, has been developed by TopoTarget and Spectrum Pharmaceuticals for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat has received its first global approval as monotherapy for this indication in the US, under the Food and Drug Administration's accelerated approval program. This article summarizes the milestones in the development of belinostat leading to this first approval for the treatment of PTCL. © 2014 Springer International Publishing Switzerland.


Poole R.M.,Springer
Drugs | Year: 2014

Pembrolizumab [Keytruda® (US)], a humanized monoclonal antibody against the programmed death receptor-1 (PD-1) protein, has been developed by Merck & Co for the treatment of cancer. Pembrolizumab has received its first global approval for the treatment of advanced, unresectable or metastatic malignant melanoma in the US, for use in patients with disease progression after prior treatment with ipilimumab and, for BRAF V600 mutation-positive patients, a BRAF inhibitor. It is the first anti-PD-1 therapy to receive regulatory approval in the US, and is currently under regulatory review in the EU. This article summarizes the milestones in the development of pembrolizumab leading to this first approval for the treatment of malignant melanoma. © 2014 Springer International Publishing Switzerland.


Garnock-Jones K.P.,Springer
Drugs | Year: 2014

Ripasudil hydrochloride hydrate (Glanatec® ophthalmic solution 0.4 %; hereafter referred to as ripasudil) is a small-molecule, Rho-associated kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compound, which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogues (which increase uveoscleral outflow) and β blockers (which reduce aqueous production). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarises the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension. © 2014 Springer International Publishing Switzerland.


Keating G.M.,Springer
Drugs | Year: 2014

The humanized monoclonal antibody bevacizumab (Avastin®) has been available in the EU since 2005. Results of phase III trials demonstrate that adding intravenous bevacizumab to antineoplastic agents improves progression-free survival and/or overall survival in patients with advanced cancer, including when used as first- or second-line therapy in metastatic colorectal cancer, as first-line therapy in advanced nonsquamous non-small cell lung cancer, as first-line therapy in metastatic renal cell carcinoma, as first-line therapy in metastatic breast cancer, and as first-line therapy in epithelial ovarian, fallopian tube or primary peritoneal cancer or in recurrent, platinum-sensitive or platinum-resistant disease. Results of these studies are supported by the findings of routine oncology practice studies conducted in real-world settings. The tolerability profile of bevacizumab is well defined and adverse events associated with its use (e.g. hypertension, proteinuria, haemorrhage, wound healing complications, arterial thromboembolism, gastrointestinal perforation) are generally manageable. In conclusion, bevacizumab remains an important option for use in patients with advanced cancer. © 2014 Springer International Publishing Switzerland.


Deeks E.D.,Springer
Drugs | Year: 2015

Olaparib (Lynparza™) is an oral, small molecule, poly (ADP-ribose) polymerase inhibitor being developed by AstraZeneca for the treatment of solid tumours. The primary indication that olaparib is being developed for is BRCA mutation-positive ovarian cancer. A capsule formulation of the drug has received approval for use in this setting in the EU and USA, and a tablet formulation is in global phase III trials (including in the USA, EU, Australia, Brazil, Canada, China, Israel, Japan, Russia and South Korea). In addition, phase III trials in breast, gastric and pancreatic cancer are underway/planned, and phase I/II investigation is being conducted in other malignancies, including prostate cancer, non-small cell lung cancer, Ewing's sarcoma and advanced cancer. This article summarizes the milestones in the development of olaparib leading to this first approval for ovarian cancer. © 2015 Springer International Publishing Switzerland.


The single-tablet regimen of the hepatitis C virus (HCV) NS5A inhibitor ledipasvir and the HCV NS5B polymerase inhibitor sofosbuvir (ledipasvir/sofosbuvir; Harvoni®) was recently approved in the US and the EU. The phase III ION trials included treatment-naive (ION-1 and -3) or treatment-experienced (ION-2) patients with chronic HCV genotype 1 infection (≈20 % of patients in ION-1 and -2 had cirrhosis, whereas no patient in ION-3 had cirrhosis). A sustained virological response 12 weeks' post-treatment (SVR12) was seen in 99 % of treatment-naive patients receiving ledipasvir/sofosbuvir for 12 weeks in ION-1, with no additional benefit conferred by the addition of ribavirin or extending the treatment duration to 24 weeks. Moreover, in ION-3, an 8-week regimen achieved an SVR12 rate of 94 % overall and 97 % in the subgroup of patients with a baseline HCV RNA level of <6 million IU/mL. SVR12 rates of 94 and 99 % were seen in treatment-experienced patients who received ledipasvir/sofosbuvir for 12 and 24 weeks in ION-2. Data also support the use of ledipasvir/sofosbuvir in chronic HCV genotype 4 infection, in HCV and HIV co-infection and, in combination with ribavirin, in patients with chronic HCV genotype 1 or 4 infection who have decompensated cirrhosis or are liver transplant recipients and in chronic HCV genotype 3 infection. Oral ledipasvir/sofosbuvir was generally well tolerated. In conclusion, ledipasvir/sofosbuvir is an important new single-tablet regimen that represents a significant advance in the treatment of chronic hepatitis C. © 2015 Springer International Publishing Switzerland.


Patent
Springer | Date: 2016-07-20

An orthesis with a foot part and a lower leg part connected with the foot part is characterised in that the foot part comprises an outer shell connected with the lower leg part as well as an insole (1) arranged inside the outer shell and forming a negative shape of a sole of a foot. A method for producing such an orthesis includes at least the following method steps:


McCormack P.L.,Springer
Drugs | Year: 2015

Nintedanib (Ofev(®)) is an orally available, small, multiple receptor tyrosine kinase inhibitor developed by Boehringer Ingelheim for the treatment of idiopathic pulmonary fibrosis (IPF) and cancer. Nintedanib received its first global approval in the US in October 2014 for the treatment of IPF. Nintedanib has received a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use for the treatment of IPF, and for the second-line treatment in combination with docetaxel of locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology. Phase 3 development programmes are also underway for colorectal cancer and ovarian cancer. Phase 2 investigation is being conducted for a variety of other solid tumours, including hepatocellular carcinoma, mesothelioma, prostate cancer, glioblastoma, renal cell carcinoma and endometrial cancer. This article summarizes the milestones in the development of nintedanib leading to this first approval for IPF.


Garnock-Jones K.P.,Springer
Drugs | Year: 2015

Novartis has developed oral and intravenous formulations of panobinostat (Farydak®), a histone deacetylase (HDAC) inhibitor, for the treatment of cancer. HDACs have important roles in maintaining chromatin structure and in regulating gene expression, including that of tumour suppressor genes, and thus represent valid targets in the search for cancer therapeutics. Oral panobinostat is approved in the US, as combination therapy with bortezomib and dexamethasone in patients with recurrent multiple myeloma who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory agent. Regulatory submissions have been made for the use of combination therapy with panobinostat in patients with recurrent multiple myeloma in the EU and Japan. Panobinostat is in various stages of clinical development worldwide for a range of haematological and solid tumours. This article summarizes the milestones in the development of panobinostat leading to this first approval for multiple myeloma. © 2015 Springer International Publishing Switzerland.

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