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Niche play, alliances hold promise for Biocon
DR KIRAN SHAW MAXUMDAR
MD BIOCON
Niche play, alliances hold promise for Biocon
While biosimilar opportunity in the regulated markets is likely to play out in the medium term, its existing biopharma and branded portfolio will ensure growth in the short term
Niche play, alliances hold promise for Biocon
Business Standard
Innovator sales for these two drugs are pegged at $10 billion which is slightly over half of the worldwide insulin market of $19 billion.On the monoclonal antibody front, the company is in phase III for the cancer drug Trastuzumab which has a market …
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HIV/AIDS vaccine passes Phase 1 clinical trial in humans
HIV/AIDS vaccine passes Phase 1 clinical trial in humans
DVICE
While other HIV/AIDS vaccines that haven’t used killed whole viruses (relying instead on targeting specific components of HIV) have failed in Phase 3 trials, Sumagen is optimistic about their drug because other successful vaccines (including polio …read all at
http://www.dvice.com/2013-9-4/hivaids-vaccine-passes-phase-1-clinical-trial-humans
European Approval for Glaxos Tafinlar
European Approval for Glaxos Tafinlar
Zacks.com
GlaxoSmithKline (GSK – Analyst Report) recently announced that its melanoma drug, Tafinlar, has been cleared by the European Commission (EC). Tafinlar is indicated as a monotherapy for treating adults suffering from unresectable or metastatic melanoma with a BRAF V600 mutation
The approval came on the basis of encouraging data from several multi-center global trials including the phase III BREAK-3 study. We remind investors that … Currently approved melanoma drugs include Zelboraf and Yervoy. Glaxo carries a Zacks Rank #3 …http://www.zacks.com/stock/news/108341/european-approval-for-glaxos-tafinlar
Cytokinetics: Clinical Investigators’ Opinions On ATOMIC-AHF Trial Results
omecamtiv mecarbil
Cytokinetics, Inc. (CYTK): Cytokinetics: Clinical Investigators’ Opinions On …
Seeking Alpha
Pending the results of the ongoing COSMIC-HF trial in 1H, 2014, I believe that the ATOMIC-AHF results support moving omecamtiv mecarbil into Phase III. With success in the Phase III, omecamtiv mecarbil would likely be a several billion drug. I regard …http://seekingalpha.com/article/1672892-cytokinetics-clinical-investigators-opinions-on-atomic-ahf-trial-results?source=google_news
Omecamtiv mecarbil (INN), previously codenamed CK-1827452, is a cardiac specific myosin activator. It is clinically tested for its role in the treatment of left ventricular systolic heart failure.[1] Systolic heart failure is characterised as a decreased cardiac output (<40% ejection fraction), due to decreased stroke volume, resulting in the inability to meet the metabolic demands of the body.[2] The loss of contraction is caused by a reduced number of effective actin-myosin cross bridges in the left ventricular myocytes. One possible underlying mechanism is altered signal transduction that interferes with excitation-contraction coupling.[3] A decreased cardiac output causes peripheral hypotension and activation of the sympathetic nervous system.[2] This in turn stimulates the cardiac myocytes excessively, eventually leading to left ventricular hypertrophy, characteristic of chronic heart failure. Some symptoms of systolic heart failure are fatigue, peripheral oedema, dyspnoea, exercise intolerance and breathlessness.[2] Current inotropic drug therapies such as dobutamine, are palliative and not a cure. They also cause many adverse effects including arrhythmias related to increased myocardical oxygen consumption, desensitization of adrenergic receptors and altering intracellular calcium levels.[4] Thus systolic heart failure is considered malignant, however the novel mechanism of Omecamtiv Mecarbil is a hopeful long-term resolution.
Mechanism of action
Cardiac myocytes contract through a cross-bridge cycle between the myofilaments, actin and myosin. Chemical energy in the form of ATP is converted into mechanical energy which allows myosin to strongly bind to actin and produce a power stroke resulting in sarcomere shortening/contraction.[3] Omecamtiv Mecarbil specifically targets and activates myocardial ATPase and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same.[5] It also increases the rate of phosphate release from myosin, thereby accelerating the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state.[1] The overall result of Omecamtiv Mecarbil is an increase in left ventricular systolic ejection time, sarcomere shortening and stroke volume, while the systolic pressure remains the same.[5] This causes a decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels.[4][6] Thus Omecamtiv Mecarbil improves systolic function by increasing the systolic ejection duration/stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.[5]
Clinical trials
Experimental studies on rats and dogs, proved the efficacy and mechanism of action of Omecamtiv Mecarbil.[4] Current clinical studies on humans have shown there is a direct linear relationship between dose and systolic ejection time.[1][7][8] The dose-dependent effects persisted throughout the entire trial, suggesting that desensitization does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time.[1] Thus due to the unique cardiac myosin activation mechanism, Omecamtiv Mecarbil could safely improve cardiac function within tolerated doses. Omecamtiv Mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It drastically improves cardiac performance in the short term, however the hopeful long term effects of reduced mortality have yet to be studied.[2][1]
- ^ a b c d e Teerlink, JR (2009). “A novel approach to improve cardiac performance: cardiac myosin activators”. Heart Fail Rev 14 (4): 289–298. doi:10.1007/s10741-009-9135-0. ISSN 1382-4147.
- ^ a b c d Dyke D, Koelling T (2008). “Heart failure due to left ventricular systolic dysfunction”. In Eagle KA, Baliga RR. Practical Cardiology. Philadelphia: Lippincott Williams & Wilkins. pp. 246–285. ISBN 978-0-7817-7294-5.
- ^ a b Bers, DM (Jan 2002). “Cardiac excitation-contraction coupling”. Nature 415 (6868): 198–205. doi:10.1038/415198a. PMID 11805843.
- ^ a b c Shen YT, Malik FI, Zhao X, Depre C, Dhar SK, Abarzúa P, Morgans DJ, Vatner SF (Jul 2010). “Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure”. Circ Heart Fail 3 (4): 522–7. doi:10.1161/CIRCHEARTFAILURE.109.930321. PMID 20498236.
- ^ a b c Malik F, Teerlink J, Escandon R, Clake C, Wolff A (2006). “The Selective Cardiac Myosin Activator, CK-1827452, a Calcium-Independent Inotrope, Increases Left Ventricular Systolic Function by Increasing Ejection Time Rather than the Velocity of Contraction”. Circulation 114 (18 Suppl): 441.
- ^ Teerlink JR, Metra M, Zacà V, Sabbah HN, Cotter G, Gheorghiade M, Cas LD (Dec 2009). “Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond”. Heart Fail Rev 14 (4): 243–53. doi:10.1007/s10741-009-9153-y. PMID 19876734.
- ^ Teerlink JR, Clarke CP, Saikali KG, Lee JH, Chen MM, Escandon RD, Elliott L, Bee R, Habibzadeh MR, Goldman JH, Schiller NB, Malik FI, Wolff AA (Aug 2011). “Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.”. Lancet 378 (9792): 667–75. doi:10.1016/S0140-6736(11)61219-1. PMID 21856480.
- ^ Cleland JG, Teerlink JR, Senior R, Nifontov EM, Mc Murray JJ, Lang CC, Tsyrlin VA, Greenberg BH, Mayet J, Francis DP, Shaburishvili T, Monaghan M, Saltzberg M, Neyses L, Wasserman SM, Lee JH, Saikali KG, Clarke CP, Goldman JH, Wolff AA, Malik FI (Aug 2011). “The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial”. Lancet 378 (9792): 676–83. doi:10.1016/S0140-6736(11)61126-4. PMID 21856481.
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Prof. Dr. Rafael Boritzer
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we are marketers of non-branded recombinant proteins with a primary mission of high quality, low priced material for encouraging biopharma research and development outside of North America. We try to integrate our supply services with education of our clients’ with industry videos and information.
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Cytokines
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Diet Pill Dilemma: Why Is FDA Approving Drugs When Europe Isn’t?
We’ve all dreamt of popping a pill to help us safely lose weight, or at least eat that chocolate cake without guilt. But alas, even though the Food and Drug Administration has approved two new diet drugs in recent months, that dream probably isn’t any closer to reality.
In the current issue of the BMJ (formerly the British Medical Journal), Sidney Wolfe, founder of the advocacy group Public Citizen, slams the FDA for approving the drugs – lorcaserin (US brand name Belviq) and topiramate (called Qsymia). The FDA’s European counterpart rejected both of them because of heart risks that turned up during preliminary trials.
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http://commonhealth.wbur.org/2013/08/diet-pill-dilemma-why-is-fda-approving-drugs-when-europe-isnt
A Return to Health
One Woman’s Ayurvedic Experience
by Jodi Boone
Over a cup of tea, she told me how they found her tumour. Mira, a middle-aged woman with large blue eyes and a gentle smile, holds a Ph.D. in Organizational Development and works as an administrator for the Swedish Army.
She explained how the stress and long hours of her work had culminated in 25 kilos of extra weight and high blood pressure. “For 20 years, I didn’t have time for myself – no time for exercise and no energy to shop or cook meals at home,” Mira said. Devoted to her studies in her 20’s and later to her career, Mira acknowledged that her trip to India in 2010 was the first time in her life she’d taken to focus on her health.
“I’d never been to India before, and I’d never heard of Ayurveda,” said Mira. One evening, as she searched…
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Fruit Lowers the Risk of Diabetes
The press is all over a recent study done at the Harvard school of public health that was published in the British Medical Journal last week. The study showed that those that ate fruit had a lower risk of diabetes. Specifically they singled out blueberries for a 25% reduction in risk. Grapes offered 11%, apples 5%, prunes 11%, pears 7%. This was not a randomized trial so there are a lot of uncontrolled variables but that being said they did look at 187,382 patients so that sample size does give this study a lot of weight. It also brings further support to a recommendation I have been giving to my diabetic or pre-diabetic patients for years, become a vegan and forget about the ADA (American Diabetes Association) diet.
A study done in 2006 published in Diabetes Care compared patients on a Vegan diet to patients on the ADA diet. The Vegan diet patients…
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New Drug Shows Promise for Type 2 Diabetes
TUESDAY Sept. 3, 2013 — An injectable drug that mimics the action of a little-known hormone may hold promise for patients with type 2 diabetes.
The experimental drug, called LY, is a copy of a hormone called fibroblast growth factor 21 (FGF21), and researchers report that it seems to help protect against obesity and may boost the action of insulin.
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http://www.drugs.com/news/new-shows-promise-type-2-diabetes-47140.html
FGF21
http://alfin2600.blogspot.in/2012/10/fgf21-learning-to-live-longer-from.html
Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species
Type II diabetes is the most prevalent form of diabetes. The disease is caused by insulin resistance and pancreatic β cell failure, which results in decreased glucose-stimulated insulin secretion. Fibroblast growth factor (FGF) 21, a member of the FGF family, has been identified as a metabolic regulator and is preferentially expressed in the liver and adipose tissue and exerts its biological activities through the cell surface receptor composed of FGFR1c and β-Klotho on target cells such as liver and adipose tissues (WO0136640, and WO0118172).
The receptor complex is thought to trigger cytoplasmic signaling and to up-regulate the GLUT1 expression through the Ras/MAP kinase pathway.
Its abilities to provide sustained glucose and lipid control, and improve insulin sensitivity and β-cell function, without causing any apparent adverse effects in preclinical settings, have made FGF21 an attractive therapeutic agent for type-2 diabetes and associated metabolic disorders.
There have been a number of efforts towards developing therapies based on FGF21. WO2006065582, WO2006028714, WO2006028595, and WO2005061712 relate to muteins of FGF21, comprising individual amino-acid substitutions. WO2006078463 is directed towards a method of treating cardiovascular disease using FGF21. WO2005072769 relates to methods of treating diabetes using combinations of FGF21 and thiazolidinedione. WO03059270 relates to methods of reducing the mortality of critically ill patients comprising administering FGF21. WO03011213 relates to a method of treating diabetes and obesity comprising administering FGF21.
However, many of these proposed therapies suffer from the problem that FGF21 has an in-vivo half-life of between 1.5 and 2 hrs in humans. Some attempts have been made to overcome this drawback. WO2005091944, WO2006050247 and WO2008121563 disclose FGF21 molecules linked to PEG via lysine or cysteine residues, glycosyl groups and non-natural amino acid residues, respectively. WO2005113606 describes FGF21 molecules recombinantly fused via their C-terminus to albumin and immunoglobulin molecules using polyglycine linkers.
However, developing protein conjugates into useful, cost-effective pharmaceuticals presents a number of significant and oftentimes competing challenges: a balance must be struck between in vivo efficacy, in vivo half-life, stability for in vitro storage, and ease and efficiency of manufacture, including conjugation efficiency and specificity. In general, it is an imperative that the conjugation process does not eliminate or significantly reduce the desired biological action of the protein in question.
The protein-protein interactions required for function may require multiple regions of the protein to act in concert, and perturbing any of these with the nearby presence of a conjugate may interfere with the active site(s), or cause sufficient alterations to the tertiary structure so as to reduce active-site function. Unless the conjugation is through the N′ or C′ terminus, internal mutations to facilitate the linkage may be required. These mutations can have unpredictable effects on protein structure and function. There therefore continues to be a need for alternative FGF21-based therapeutics.
The reference to any art in this specification is not, and should not be taken as, an acknowledgement of any form or suggestion that the referenced art forms part of the common general knowledge.
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 