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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Merck KGaA has entered a collaboration with China-based biotech BeiGene to research a new treatment for cancer.
Merck KGaA has entered a collaboration with China-based biotech BeiGene to research a new treatment for cancer.
The compound, currently known as BeiGene-283, BGB-283 , is a second-generation BRAF inhibitor and is expected to enter clinical development in 2014.
It is designed to work by hindering the action of the BRAF protein, which is thought to play a part in the promotion of cancer cell growth and has been found to be mutated in some cancer patients.
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http://www.pmlive.com/pharma_news/merck_kgaa_to_research_cancer_drug_with_chinese_biotech_480521
A positive genotoxicity result can throw the fate of a promising drug candidate—in which a firm has invested significant time and money—into doubt
A positive genotoxicity result can throw the fate of a promising drug candidate-in which a firm has invested significant time and money-into doubt. The statistical improbability and challenges of bringing a drug to market become paramount.
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BY WORLD DRUG TRACKER
Automating Lead Optimization
This diagram illustrates the methods used to determine solubility as a compound advances toward further clinical study, and the increasing reach of automation and informatics systems. Initially, screens are run in silico on a library after hits are determined through a high-throughput screen; then various kinetic solubility assays are used to determine the compound’s potency at various concentrations. Two rounds of kinetic solubility assays determine gross and broad solubility (mmol/L) and finite solubility (less than 20 µmol/L) before the compound is advanced into thermodynamic solubility assays. Figure modified from Petereit A, Saal C. What is the Solubility of My Compound? Assessing Solubility for Pharmaceutical Research and Development Compounds. Am Pharm Rev. 2011; 14
The drug discovery business is changing rapidly. More pharmaceutical companies are working with smaller biotech firms to create early-stage compounds, and thus need quicker and standardized solutions to early-stage development problems.
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by
WORLD DRUGTRACKER
Gilead Announces U.S. FDA Priority Review Designation for Sofosbuvir for the Treatment of Hepatitis C
Sofosbuvir
Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no
Jun. 7, 2013– Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted priority review to the company’s New Drug Application (NDA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The FDA grants priority review status to drug candidates that may offer major advances in treatment over existing options. Gilead filed the NDA for sofosbuvir on April 8, 2013, and FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of December 8, 2013.
The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.
Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.[2]
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.[3]
Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.
Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[6]
Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[7][8]
Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir (formerly GS-5885), and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[9]Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.
- Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
- “PSI-7977″. Gilead Sciences.
- Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
- Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
- Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
- http://www.gilead.com/pr_1757156
- AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
- Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
- CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
Eating Broccoli Reduces Risk of Cardiovascular Disease, Promotes Heart Health
by Elizabeth Renter , MY SCIENCE ACADEMY
It’s not good enough to know that vegetables like broccoli are healthful; we need to know specifically what sort of benefits they deliver, how they deliver those benefits and how we can make the most of them.
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Japanese drugmaker Kyowa Hakko Kirin (TYO: 4151) say that it launched its novel Parkinson’s disease drug Nouriast (istradefylline) in Japan on May 30.
Istradefylline (KW-6002), 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione, is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.
1–
- Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.
Nouriast, which is the world’s first anti-parkinsonian agent of a first-in-class adenosine A2A receptor antagonist, was listed on the National Health Insurance Drug Price List on May 24, 2013 after the manufacturing and marketing approval in Japan on March 25, the company noted. In clinical trials in Japan, Nouriast improved wearing-off phenomena and was well tolerated in Parkinson’s disease patients
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Otsuka Pharmaceutical Submits New Drug Application in Japan for Tolvaptan for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)
TOLVAPTAN
may 30 2013
- Tolvaptan was discovered by Otsuka in Japan, and its primary results from a global clinical trial involving 1,400 ADPKD patients from 15 countries, which demonstrated a statistically significant reduction in the rate of total kidney volume, were published in New England Journal of Medicine in 2012. It is also currently under a fast track review in the US, following our announcement of FDA accepting to review the application in April 2013.
- ADPKD is a hereditary and often physically and mentally burdensome disease characterized by the development of multiple cysts in the kidneys. ADPKD is often associated with pain, hypertension, decreased kidney function and ultimately, kidney failure that may result in hemodialysis or kidney transplantation.
- There are estimated to be approximately 31,000 ADPKD patients in Japan, and the diagnosed prevalence is estimated to be between 1:1000 and 1:4000 globally.
(Tokyo, Japan, May 30, 2013) – Otsuka Pharmaceutical Co., Ltd. Today announced it filed an application with the Pharmaceutical and Medical Devices Agency in Japan (PMDA) to market its novel compound tolvaptan for the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phase III clinical trial results that form the basis of the regulatory filing were published in the New England Journal of Medicine in November 2012. The MHLW has designated tolvaptan as an Orphan Drug.http://www.otsuka.co.jp/en/release/2013/0603_02.html
Tolvaptan (INN), also known as OPC-41061, is a selective, competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated withcongestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone(SIADH). Tolvaptan was approved by the U.S. Food and Drug Administration (FDA) on May 19, 2009, and is sold by Otsuka Pharmaceutical Co. under the trade name Samsca and in India is manufactured & sold by MSN laboratories Ltd. under the trade name Tolvat & Tolsama.
Tolvaptan is also in fast-track clinical trials[2] for polycystic kidney disease. In a 2004 trial, tolvaptan, when administered with traditional diuretics, was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia(decreased blood levels of potassium) and without having an adverse effect on kidney function.[3] In a recently published trial (TEMPO 3:4 ClinicalTrials.gov number, NCT00428948) the study met its primary and secondary end points. Tolvaptan, when given at an average dose of 95 mg per day over a 3-year period, slowed the usual increase in kidney volume by 50% compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001) and reduced the decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001)[4]
Chemical synthesis:[5] 
- Shoaf S, Elizari M, Wang Z, et al. (2005). “Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias”. J Cardiovasc Pharmacol Ther 10 (3): 165–71. doi:10.1177/107424840501000304. PMID 16211205.
- Otsuka Maryland Research Institute, Inc.
- Gheorghiade M, Gattis W, O’Connor C, et al. (2004). “Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial”. JAMA 291 (16): 1963–71. doi:10.1001/jama.291.16.1963. PMID 15113814.
- (2012) Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease
- Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.; Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.; et al.; Bioor. Med. Chem. 1999, 7, 1743.
- http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm350185.htm?source=govdelivery
- Gheorghiade M, Niazi I, Ouyang J et al. (2003). “Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial”. Circulation 107 (21): 2690–6. doi:10.1161/01.CIR.0000070422.41439.04.PMID 12742979.
FDA panel urges looser restrictions on diabetes drug Avandia
june 6 2013,
The controversial diabetes drug Avandia will get a second look from federal regulators this week, nearly two years after its use was severely restricted because of a link to heart problems.
The U.S. Food and Drug Administration has convened a panel of experts to consider an independent review by Duke University researchers of Avandia’s original clinical trial. The expert panel will conclude its sessions on Thursday, and could decide to alter or even lift the tight restrictions now in place regarding the medication’s use.
The Duke scientists did uncover some previously unreported cases of heart complications and deaths, but concluded that these cases did not significantly raise the overall risk of heart disease and the conclusions of the original trial still hold.
The FDA’s reconsideration of Avandia’s safety has prompted stinging criticism from the drug’s detractors, who say the agency is trying to save face following a very public embarrassment over the drug.
“This is a drug that has essentially been off the market in almost the entire world for the last three years. It has been banned in most countries, and is available in the United States under such strict requirements that only 3,000 patients now take it,” said Dr. Steven Nissen, the Cleveland Clinic cardiologist who first led the charge against Avandia. “It’s really about the FDA wanting to clean up its image, not about whether the drug is actually safe or unsafe.”
The FDA has defended its decision to review the Duke re-analysis of the original trial, which was conducted by the drug’s maker, GlaxoSmithKline, under the name Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD).
“Given the public interest in Avandia, the extensive history of the product and the continued uncertainty of risk, the FDA is holding the advisory committee meeting to have a transparent, public discussion of the results of the RECORD readjudication,” FDA spokesperson Morgan Liscinsky said.
Avandia quickly became a blockbuster diabetes drug following its release in 1999, with sales topping $3 billion in 2006.
OXYTOCIN , THE LOVE MOLECULE
OXYTOCIN
1-({(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-(4-hydroxybenzoyl)-13-[(1S)-1-methylpropyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosan-4-yl}carbonyl)-L-prolyl-L-leucylglycinamide
Oxytocin is a mammalian neurohypophysial hormone that acts primarily as a neuromodulator in the brain.
Oxytocin plays roles in sexual reproduction, in particular during and after childbirth. It is released in large amounts after distension of the cervix and uterus during labor, facilitating birth, maternal bonding, and, after stimulation of the nipples, breastfeeding. Both childbirth and milk ejection result from positive feedback mechanisms.
Recent studies have begun to investigate oxytocin’s role in various behaviors, including orgasm, social recognition, pair bonding, anxiety, and maternal behaviors. For this reason, it is sometimes referred to as the “love hormone”. There is some evidence that oxytocin promotes ethnocentric behavior, incorporating the trust and empathy of in-groups with their suspicion and rejection of outsiders. Furthermore, genetic differences in the oxytocin receptor gene (OXTR) have been associated with maladaptive social traits such as aggressive behaviour.
Oxytocin , sometimes known as the “love molecule” or the “trust molecule” plays an important role in many processes. These include uterine contractions during childbirth, sexual arousal, lactation, puberty, orgasm, facial recognition, trust, memory formation and pair bonding.
Oxytocin is a cyclic peptide hormone with just nine amino acids in sequence (CYIQNCPLG) that also acts as a neurotransmitter in the brain where it is produced in the hypothalamus. It was the first ever polypeptide hormone to be sequenced and synthesized biochemically, work for which the American biochemist Vincent du Vigneaud was awarded the 1955 Nobel Prize in Chemistry.
Together with the neuropeptide argipressin (arginine vasopressin), it is believed to influence social cognition and behaviour. First shown in mice, recent studies have shown that also in humans simply sniffing a spray containing oxytocin increases a person’s level of trust in others.
References
- Lee, H.J., Macbeth, A.H., Pagani, J.H. and Young, W.S. (2009) Oxytocin: the great facilitator of life. Prog. Neurobiol. (Amsterdam, Neth.) 88, 127–151.
- du Vigneaud, V., Ressler, C., Swan, J.M., Roberts, C.W., Katsoyannis, P.G. and Gordon, S. (1953) The synthesis of an octapeptide amide with the hormonal activity of oxytocin. J. Am. Chem. Soc. 75, 4879–4880..
- Kosfeld, M., Heinrichs, M., Zak, P.J., Fischbacher, U. and Fehr, E. (2005) Oxytocin increases trust in humans. Nature 435, 673–676.
Oxytocin (ball-and-stick) bound to its carrier protein neurophysin (ribbons) based on: “Crystal structure of the neurophysin-oxytocin complex” Rose, J.P., Wu, C.K., Hsiao, C.D., Breslow, E., Wang, B.C. (1996) Nat.Struct.Biol. 3: 163-169
Avanir said the FDA agreed to a faster development process for its experimental drug AVP-786 and will allow the company to use some data from studies of Nuedexta in its applications for AVP-786
6/may/2013
Avanir Pharmaceuticals Inc. announced that the Food and Drug Administration will allow it to speed research on a newer version of its drug Nuedexta.
Avanir said the FDA agreed to a faster development process for its experimental drug AVP-786 and will allow the company to use some data from studies of Nuedexta in its applications for AVP-786.
Avanir plans to start human clinical trials of the drug after it completes some limited preclinical testing. The company said the FDA’s decision could reduce the cost of developing the drug and allow it to win marketing approval sooner.
Nuedexta is a treatment for pseudobulbar affect, a condition that involves involuntary emotional outbursts like laughing or crying. It is associated with brain disease or injury. Net revenue from the drug more than doubled to $31.4 million over the first six months of the company’s current fiscal year. That was almost all of the Aliso Viejo, Calif., company’s revenue.
Nuedexta was approved in February 2011. The drug combines two ingredients: dextromethorphan, a common ingredient in cough and cold medicines that can suppress coughing, and quinidine, which is used to treat abnormal heart rhythms.
Avanir is also studying Nuedexta as a treatment for diabetic nerve pain, agitation in patients with Alzheimer’s disease, central nerve pain in multiple sclerosis, and levodopa-induced dyskinesia in Parkinson’s disease. Dyskinesias are involuntary movements tied to most treatments used to manage Parkinson’s.
Canaccord Genuity analyst Ritu Baral said Avanir considers AVP-786 to be a safer version of Nuedexta because it contains less quinidine. The drug also has stronger patent protection and is patent protected until 2030, a few years longer than Nuedexta.
In a telephone interview, Baral said the FDA’s decision could speed approval of AVP-786 by two to four years. She said Avanir may start late-stage testing of the drug in the second half of 2014 depending on the results of current studies of Nuedexta.
New Drug Approvals