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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Glaxo, Theravance Asthma Drug Elvar Ellipta OK’d in Japan
umeclidinium
vilanterol
ELVAR™ ELLIPTA™ Gains Approval in Japan for the Treatment of Asthma
LONDON, UNITED KINGDOM and SOUTH SAN FRANCISCO, CA–(Marketwired – Sep 20, 2013) – GlaxoSmithKline plc (LSE: GSK) (NYSE: GSK) and Theravance, Inc. (NASDAQ: THRX) today announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved RELVAR™ ELLIPTA™ for the treatment of bronchial asthma (in cases where concurrent use of inhaled corticosteroid and long-acting inhaled beta2 agonist is required). Relvar Ellipta is not indicated for the treatment of chronic obstructive pulmonary disease (COPD) in Japan.
Relvar is a combination of the inhaled corticosteroid (ICS), fluticasone furoate “FF”, and the long-acting beta2 agonist (LABA), vilanterol “VI”. The MHLW has approved two doses of FF/VI – 100/25 mcg and 200/25 mcg. Both strengths will be administered once-daily using the Ellipta, a new dry powder inhaler (DPI).
Anoro Ellipta is the proposed proprietary name for UMEC/VI, a combination of two investigational bronchodilator molecules — GSK573719 or umeclidinium bromide (UMEC), a long-acting muscarinic antagonist (LAMA) and vilanterol (VI), a long-acting beta2 agonist (LABA), administered using the Ellipta inhaler.
The FDA Advisory Committee also voted that the safety of the investigational medicine has been adequately demonstrated at the 62.5/25mcg dose for the proposed indication (10 yes, 3 no), and the efficacy data provided substantial evidence of a clinically meaningful benefit for UMEC/VI 62.5/25mcg once daily for the long-term, maintenance treatment of airflow obstruction in COPD (13 yes, 0 no).
Patrick Vallance, GSK’s President of Pharmaceuticals R&D, said: “Today’s recommendation is good news and a reflection of our commitment to giving an alternative treatment option for patients living with COPD — a disease that affects millions of Americans. If approved, Anoro Ellipta will be the first, once-daily dual bronchodilator available in the US, marking another significant milestone for GSK’s portfolio of medicines to treat respiratory disease. We will continue to work with the FDA as they complete their review.”
“We are pleased with the Advisory Committee’s support of UMEC/VI,” said Rick E Winningham, Chief Executive Officer of Theravance. “This is a transformative year for Theravance and today’s positive recommendation brings the second major respiratory medicine in our GSK collaboration closer to approval and becoming an important therapeutic option for COPD patients.”
In December 2012, a New Drug Application (NDA) was submitted to the FDA for the use of UMEC/VI administered by the Ellipta™ inhaler for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. UMEC/VI is not proposed for the relief of acute bronchospasm or for the treatment of asthma in any of the regulatory applications.
The FDA Advisory Committee provides non-binding recommendations for consideration by the FDA, with the final decision on approval made by the FDA. The Prescription Drug User Fee Act (PDUFA) goal date for UMEC/VI is 18 December 2013.
UMEC/VI is an investigational medicine and is not currently approved anywhere in the world.
Safety Information
Across the four pivotal COPD studies for UMEC/VI, the most frequently reported adverse events across all treatment arms, including placebo, were headache, nasopharyngitis, cough, upper respiratory tract infection, and back pain. COPD exacerbation was the most common serious adverse event reported. In addition, in the four pivotal COPD studies, a small imbalance was observed in cardiac ischemia which was not observed in the long term safety study.
The UMEC/VI clinical development programme involved over 6,000 COPD patients.
About COPD
Chronic obstructive pulmonary disease (COPD) is a term referring to two lung diseases, chronic bronchitis and emphysema, that are characterized by obstruction to airflow that interferes with normal breathing. COPD is the third most common cause of death in the US and The National Heart, Lung and Blood Institute (NHLBI) estimates that nearly 15 million US adults have COPD and another 12 million are undiagnosed or developing COPD(1).
According to the NHLI, long-term exposure to lung irritants that damage the lungs and the airways are usually the cause of COPD and in the United States, the most common irritant that causes COPD is cigarette smoke. Breathing in second hand smoke, air pollution, or chemical fumes or dust from the environment or workplace also can contribute to COPD. Most people who have COPD are at least 40 years old when symptoms begin.
EC Approves Second Sanofi MS Drug
Wed, 09/18/2013 – 9:50am
Source: Genzyme
http://www.dddmag.com/news/2013/09/ec-approves-second-sanofi-ms-drug
Sanofi and its subsidiary Genzyme announced that the European Commission has granted marketing authorization for Lemtrada. This follows the Aug. 30 approval of Aubagio. The company intends to begin launching both products in the EU soon.
Alemtuzumab (marketed as Campath, MabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantation, kidney transplantation and Islet cell transplantation.
Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.
Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canadafor the same indication, and additionally for CLL patients who have not had any previous therapies.
It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise. Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.
A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.
US FDA grants breakthrough therapy designation to Boehringer Ingelheim’s volasertib to treat patients with AML
Volasertib
755038-65-4
CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide
CODE DESIGNATION BI 6727
| Ingelheim, Germany Thursday, September 19, 2013, 16:00 Hrs [IST] |
|
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation to Boehringer Ingelheim’s volasertib, a selective and potent polo-like kinase (Plk) inhibitor, for the treatment of patients with acute myeloid leukaemia (AML), a type of blood cancer. |
http://www.pharmabiz.com/NewsDetails.aspx?aid=77733&sid=2
Volasertib (also known as BI 6727) is a small molecule inhibitor of the PLK1 (polo-like kinase 1) protein being developed byBoehringer Ingelheim for use as an anti-cancer agent. Volasertib is the second in a novel class of drugs called dihydropteridinone derivatives.[1]
Mechanism of action
Volasertib is a novel small-molecule targeted therapy that blocks cell division by competitively binding to the ATP-binding pocket of the PLK1 protein. PLK1 proteins are found in the nuclei of all dividing cells and control multiple stages of the cell cycle and cell division.[2] [3] [4] The levels of the PLK1 protein are tightly controlled and are raised in normal cells that are dividing. Raised levels of the PLK1 protein are also found in many cancers including; breast, non-small cell lung, colorectal, prostate, pancreatic, papillary thyroid, ovarian, head and neck and Non-Hodgkin’s Lymphoma.[5] [3] [6] [4] [7] [8] Raised levels of PLK1 increase the probability of improper segregation of chromosomes which is a critical stage in the development of many cancers. Raised levels of PLK1 have been associated with a poorer prognosis and overall survival in some cancers[4][9] [10] In addition to its role in cell division, there is evidence that PLK1 also interacts with components of other pathways involved in cancer development including the K-Ras oncogene and the retinoblastoma and p53 tumour suppressors[11] These observations have led to PLK1 being recognised as an important target in the treatment of cancer.
Volasertib can be taken either orally or via intravenous infusion, once circulating in the blood stream it is distributed throughout the body, crosses the cell membrane and enters the nucleus of cells where it binds to its target; PLK1. Volasertib inhibits PLK1 preventing its roles in the cell-cycle and cell division which leads to cell arrest and programmed cell death.[2] Volasertib binds to and inhibits PLK1 at nanomolar doses however, it has also been shown to inhibit other PLK family members; PLK2 and PLK3 at higher; micromolar doses. The roles of PLK2 and PLK3 are less well understood; however they are known to be active during the cell cycle and cell division.[12]
Volasertib inhibits PLK1 in both cancer and normal cells; however it only causes irreversible inhibition and cell death in cancer cells, because inhibition of PLK1 in cancer cells arrests the cell cycle at a different point to normal, non-cancer cells. In cancer cells PLK1 inhibition results in G2/M cell cycle arrest followed by programmed cell death, however, in normal cells inhibition of PLK1 only causes temporary, reversible G1 and G2 arrest without programmed cell death.[13] This specificity for cancer cells improves the efficacy of the drug and minimizes the drug related toxicity.
Clinical uses
Volasertib is currently undergoing investigation in phase 1 and 2 trials and has yet to be licensed by the FDA. Volasertib may be effective in several malignancies evidenced by the fact that its target PLK1 is overexpressed in up to 80% of malignancies, where it has been associated with a poorer treatment outcome and reduced overall survival.[1][4][9]Further phase 1 and 2 trials are active, investigating the effects of Volasertib both as a single agent and in combination with other agents in solid tumours and haematological malignancies including; ovarian cancer, urothelial cancer and acute myeloid leukaemia.[14]
Studies
Preclinical studies on volasertib have demonstrated that it is highly effective at binding to and blocking PLK1 function and causing programmed cell death in colon and non-small cell lung cancer cells both in vitro and in vivo. Volasertib can also cause cell death in cancer cells that have are no longer sensitive to existing anti-mitotic drugs such as vinca alkaloids and taxanes.[13] This suggests that volasertib may be effective when used as a second line treatment in patients who have developed resistance to vinca alkaloid and taxane chemotherapeutics.
A first in man trial of volasertib in 65 patients with solid cancers reported that the drug is safe to administer to patients and is stable in the bloodstream. This study also reported favourable anti-cancer activity of the drug; three patients achieved a partial response, 48% of patients achieved stable disease and 6 patients achieved progression free survival of greater than 6 months.[15] A further phase 1 trial of volasertib in combination with cytarabine in patients with relapsed / refractory acute myeloid leukaemiareported that 5 of 28 patients underwent a complete response, 2 achieved a partial response and a further 6 patients no worsening of their disease.[16]
- Schoffski, P. (2009). “Polo-like kinase (PLK) inhibitors in preclinical and early clinical development in oncology”. Oncologist 14 (6): 559–70. ISSN (Electronic) 1083-7159 (Linking) 1549-490X (Electronic) 1083-7159 (Linking).
- Barr, F. A.; H. H. Sillje, E. A. Nigg (2004). “Polo-like kinases and the orchestration of cell division”. Nat Rev Mol Cell Biol 5 (6): 429–40. ISSN (Print) 1471-0072 (Linking) 1471-0072 (Print) 1471-0072 (Linking).
- Garland, L. L.; C. Taylor, D. L. Pilkington, J. L. Cohen, D. D. Von Hoff (2006). “A phase I pharmacokinetic study of HMN-214, a novel oral stilbene derivative with polo-like kinase-1-interacting properties, in patients with advanced solid tumors”. Clin Cancer Res 12 (17): 5182–9. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
- Santamaria, A.; R. Neef, U. Eberspacher, K. Eis, M. Husemann, D. Mumberg, S. Prechtl, V. Schulze, G. Siemeister, L. Wortmann, F. A. Barr, E. A. Nigg (2007). “Use of the novel Plk1 inhibitor ZK-thiazolidinone to elucidate functions of Plk1 in early and late stages of mitosis”. Mol Biol Cell 18 (10): 4024–36. ISSN (Print) 1059-1524 (Linking) 1059-1524 (Print) 1059-1524 (Linking).
- Fisher, R.A.H.; D.K. Ferris (2002). “The functions of Polo-like kinases and their relevance to human disease.”. Curr Med Chem 2: 125–134.
- Holtrich, U.; G. Wolf, A. Brauninger, T. Karn, B. Bohme, H. Rubsamen-Waigmann, K. Strebhardt (1994). “Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors”. Proc Natl Acad Sci U S A 91 (5): 1736–40. doi:10.1073/pnas.91.5.1736. ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 43238. PMID 8127874.
- Steegmaier, M.; M. Hoffmann, A. Baum, P. Lenart, M. Petronczki, M. Krssak, U. Gurtler, P. Garin-Chesa, S. Lieb, J. Quant, M. Grauert, G. R. Adolf, N. Kraut, J. M. Peters, W. J. Rettig (2007). “BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo”. Curr Biol 17 (4): 316–22. doi:10.1016/j.cub.2006.12.037. ISSN (Print) 0960-9822 (Linking) 0960-9822 (Print) 0960-9822 (Linking). PMID 17291758.
- Winkles, J. A.; G. F. Alberts (2005). “Differential regulation of polo-like kinase 1, 2, 3, and 4 gene expression in mammalian cells and tissues”. Oncogene 24 (2): 260–6.doi:10.1038/sj.onc.1208219. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640841.
- Eckerdt, F.; J. Yuan, K. Strebhardt (2005). “Polo-like kinases and oncogenesis”. Oncogene 24 (2): 267–76. doi:10.1038/sj.onc.1208273. ISSN (Print) 0950-9232 (Linking) 0950-9232 (Print) 0950-9232 (Linking). PMID 15640842.
- Weichert, W.; A. Ullrich, M. Schmidt, V. Gekeler, A. Noske, S. Niesporek, A. C. Buckendahl, M. Dietel, C. Denkert (2006). “Expression patterns of polo-like kinase 1 in human gastric cancer”. Cancer Sci 97 (4): 271–6. ISSN (Print) 1347-9032 (Linking) 1347-9032 (Print) 1347-9032 (Linking).
- Liu, X.; R. L. Erikson (2003). “Polo-like kinase (Plk)1 depletion induces apoptosis in cancer cells”. Proc Natl Acad Sci U S A 100 (10): 5789–94. doi:10.1073/pnas.1031523100.ISSN (Print) 0027-8424 (Linking) 0027-8424 (Print) 0027-8424 (Linking). PMC 156279. PMID 12732729.
- Schmit, T. L.; N. Ahmad (2007). “Regulation of mitosis via mitotic kinases: new opportunities for cancer management”. Mol Cancer Ther 6 (7): 1920–31. ISSN (Print) 1535-7163 (Linking) 1535-7163 (Print) 1535-7163 (Linking).
- Rudolph, D.; M. Steegmaier, M. Hoffmann, M. Grauert, A. Baum, J. Quant, C. Haslinger, P. Garin-Chesa, G. R. Adolf (2009). “BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity”. Clin Cancer Res 15 (9): 3094–102. ISSN (Print) 1078-0432 (Linking) 1078-0432 (Print) 1078-0432 (Linking).
- ClinicalTrials.gov (2011). “Clinical Trials.gov Search of: Volasertib”. Missing or empty
|url=(help) - Gil, T.; P. Schöffski, A. Awada, H. Dumez, S. Bartholomeus, J. Selleslach, M. Taton, H. Fritsch, P. Glomb, Munzert G.M. (2010). “Final analysis of a phase I single dose-escalation study of the novel polo-like kinase 1 inhibitor BI 6727 in patients with advanced solid tumors”. J Clin Oncol 28.
- Bug, G.; R. F. Schlenk, C. Müller-Tidow, M. Lübbert, A. Krämer, F. Fleischer, T. Taube, O. G. Ottmann, H. Doehner (2010). “Phase I/II Study of BI 6727 (volasertib), An Intravenous Polo-Like Kinase-1 (Plk1) Inhibitor, In Patients with Acute Myeloid Leukemia (AML): Results of the Dose Finding for BI 6727 In Combination with Low-Dose Cytarabine”. 52nd ASH Annual Meeting and Exposition. Orange County Convention Centre, Florida: American Society of Haematology.
VOLASERTIB TRIHYDROCHLORIDE
CHEMICAL NAMES
1. Benzamide, N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-
ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-
methoxy-, hydrochloride (1:3)
2. N-{trans-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl}-4-{[(7R)-7-ethyl-5-methyl-8-
(1-methylethyl)-6-oxo-5,6,7,8-tetrahydropteridin-2-yl]amino}-3-methoxybenzamide
trihydrochloride
MOLECULAR FORMULA C34H50N8O3 . 3 HCl
MOLECULAR WEIGHT 728.2
SPONSOR Boehringer Ingelheim Pharmaceuticals, Inc.
CODE DESIGNATION BI 6727 CL3
CAS REGISTRY NUMBER 946161-17-7
Volasertib is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1), a key regulator of cell-cycle progression. Volasertib is a dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for combination therapy of advanced and/or metastatic solid tumours.
Volasertib (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,
This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.
U.S. 8,188,086
Several dihydropteridione derivatives effectively prevent cell proliferation. G. Linz and co-inventors report a comprehensive method for preparing pharmacologically active crystalline and anhydrous forms of compound 1 (Figure 1) that are suitable for drug formulations.
The inventors list several criteria for the properties of 1 and its manufacturing procedure:
- favorable bulk characteristics such as drying times, filterability, solubility in biologically acceptable solvents, and thermal stability;
- purity of the pharmaceutical composition;
- low hygroscopicity;
- no or low tendency toward polymorphism; and
- scalability to a convenient commercial process.
They describe their finding that the tri-HCl salt of 1 satisfies these criteria as “surprising”.
Free base 1 is prepared by condensing cyclopropylmethylpiperazine derivative 2 with pteridinone 3 in the presence of p-toluenesulfonic acid (TsOH), as shown in Figure 1. After the reaction is complete, the crude free base 1 is recovered as a viscous oil. It is then treated with HCl in an organic solvent to form 1·3HCl, isolated in 91% yield. Alternatively, the free base is not isolated; instead, concd HCl is added to the reaction mixture, followed by acetone. The crude salt is recovered in 92% yield.
The salt is purified by crystallization from refluxing EtOH, adding water, and cooling to precipitate the crystals. The inventors do not report the purity of this or any other reaction product.
The inventors obtained a hydrated form of the tri-HCl salt by dissolving the free base in EtOH at room temperature, followed by adding concd HCl and cooling to 2 °C. An anhydrous form can be recovered by drying the hydrate at 130 °C. The solubility of the hydrated salt in aqueous and organic media is reported, as are X-ray diffraction data for the hydrated form. The hydrated salt has good solid-state stability.
The patent also contains the syntheses of reactants 2 and 3 (Figures 2 and 3). The preparation of 2 begins with the formation of amide 7. Acid 4 is treated with SOCl2–DMF to form acid chloride 5; the crude product is added to a suspension of chiral difunctionalized cyclohexane 6 in THF and aq K2CO3 to produce 7. The crude product is recovered in 98% yield and oxidized to 8 with RuCl3 and N-methylmorpholine N-oxide (NMMO) in 91% yield.
Amide 8 reacts with cyclopropylmethylpiperazine 9 in the presence of methanesulfonic acid (MsOH). The solvent is evaporated, and the reaction mixture is treated with NaBH4. After further workup, product 10 is isolated in 46% yield. The nitro group is then hydrogenated over Raney Ni to give 2 in 90% yield. An alternative method for preparing10 is also described.
To prepare 3, readily available amino acid 11 is esterified and alkylated to form 12. In a multistep, one-pot procedure, 11 is first treated with HC(OMe)3 and SOCl2. Further reaction with NaBH(OAc)3, acetone, and NH4OH produces 12 as its HCl salt in 90% yield. The salt is treated with aq NaOH to form the free base, which reacts with pyrimidine 13 in the presence of NaHCO3 to form 14 in 79% isolated yield.
The pteridinone system is formed by hydrogenating 14 over a Pt/C catalyst in the presence of V(acac)3. Precursor 15 is recovered in 90% yield and methylated with (MeO)2CO and K2CO3 to give 3 in 82% isolated yield.
The inventors succeeded in developing a route for making a crystalline salt that is suitable for preparing pharmaceutical formulations. The many synthetic steps, however, use a large number of solvents that are frequently evaporated to dryness. [This observation implies that the processes have a significant environmental burden. —Ed.] (Boehringer Ingelheim International [Ingelheim am Rhein, Germany]. US Patent U.S. 8,188,086,
FDA accepts new drug application for investigational compound Epanova for the treatment of severe hypertriglyceridaemia
LONDON, Sept. 18, 2013 – AstraZeneca today announced that the US Food and Drug Administration (FDA) has accepted for review a New Drug Application (NDA) for EpanovaTM, an investigational compound for the treatment for patients with severe hypertriglyceridaemia (triglyceride levels greater than or equal to 500mg/dL). The NDA submission for Epanova was filed by Omthera Pharmaceuticals, now a wholly-owned subsidiary of AstraZeneca, as a 505(b)(1) application in July 2013. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA is 5 May 2014.http://www.pharmalive.com/fda-accepts-astrazeneca-nda-for-epanova
Forigerimod, (Rigerimod) also known as Lupuzor, CEP-3345 for treatment of systemic lupus erythematosus (SLE)
FORIGERIMOD
CHEMICAL NAMES
1. L-Tyrosine, L-arginyl-L-isoleucyl-L-histidyl-L-methionyl-L-valyl-L-tyrosyl-L-seryl-L-lysyl-L-arginyl-O-phosphono-L-serylglycyl-L-lysyl-L-prolyl-L-arginylglycyl-L-tyrosyl-L-alanyl-L-phenylalanyl-L-isoleucyl-L-α-glutamyl-
2. O3,140-phosphono(human U1 small nuclear ribonucleoprotein 70 kDa (snRNP70))-(131-151)-peptide
MOLECULAR FORMULA C117H181N34O32PS
MOLECULAR WEIGHT 2639
TRADEMARK Lupuzor
SPONSOR Cephalon, Inc.
CODE DESIGNATION IPP 201101
CAS REGISTRY NUMBER 497156-60-2
STRUCTURAL FORMULA
stucture, http://www.ama-assn.org/ama1/pub/upload/mm/365/forigerimod.pdf
-
Forigerimod nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/forigerimod.pdfSTATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN. FORIGERIMOD.
…………………………………………………………………………………………………………..
FORIGERIMOD ACETATE
CAS REGISTRY NUMBER 1160237-55-7 of acetate
http://www.ama-assn.org/resources/doc/usan/forigerimod-acetate.pdf
-
Forigerimod acetate nonproprietary drug name
http://www.ama-assn.org/resources/doc/usan/forigerimod-acetate.pdfSTATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL. USAN. FORIGERIMOD ACETATE
str is
FORIGERIMOD ACETATE
Forigerimod, also known as Lupuzor or CEP-33457, (SyB L-1001) is a CD4 T-cell modulator being investigated for the treatment of systemic lupus erythematosus (SLE). In the Phase II trials, Lupuzor was administered subcutaneously at a dose of 200 mcg once a month for 3 months. The Phase III study is anticipated to be complete in September 2012 and will measure the proportion of patients achieving a combined clinical response using the SLE responder index.
Positive final Lupuzor trial results. Marketwire. www.marketwire.com/press-release/Positive-Final-Lupuzor-Trial-Results-AIM-IMM-1176375.htm. Published November 19, 2009. Accessed June 18, 2011.
Rigerimod (IPP-201101, Lupuzor) is a polypeptide corresponding to the sequence 131-151 of the 70k snRNP protein with a serine phosphorylated in position 140.[1]
It gave encouraging results in a phase IIb trial for severe lupus.[1] Another phase IIb trial has started recruiting in the US.[2]
References
Lupuzor™ is a potential treatment for lupus, currently given the approval by the US FDA to start Phase III with a Special Protocol Assessment (SPA) and Fast Track designation. ImmuPharma holds all worldwide rights in this lead compound.
Background
Lupus (or Systemic Lupus Erythematosus) is a chronic, potentially life-threatening autoimmune disease. An estimated 1.4 million people are diagnosed in the 7 major world markets (the USA, Japan, Germany, France, Spain, the UK and Italy). Lupus is an inflammatory disease, which attacks multiple organs such as the skin, joints, kidneys, blood cells, heart and lungs. There is currently no cure.
The development of ImmuPharma’s Lupuzor™
ImmuPharma’s compound Lupuzor™ (previously known as IPP-201101 and also referred to as rigerimod or P140) has a novel mechanism of action aimed at modulating the body’s immune system so it does not attack healthy cells, without causing adverse side effects. It has the potential to halt the progression of the disease in a substantial proportion of patients.
Lupuzor™ has successfully completed Phase I, Phase IIa and Phase IIb studies and has now been given the approval by the US FDA to enter Phase III, the final testing phase.
The latest highlights of Lupuzor’s™ development as a treatment for lupus include:
- An ‘End of Phase 2’ meeting package with ImmuPharma’s Phase IIb data was submitted to the FDA and the FDA responded to all the questions
- The Investigational Medicinal Product Dossier (IMPD) submitted via the Voluntary Harmonized Procedure (VHP) in the EU was approved
- The Scientific Advice meeting with the European Medicines Evaluation Agency (EMEA) was held; the recommendations were very similar to those in the FDA’s ‘End Of Phase 2’ responses. Recommendations were incorporated into the Phase III pivotal programme
- The Japanese equivalent authorities (PMDA) have agreed to the initiation of clinical trials in Japan
- The FDA has granted Lupuzor™ the approval to start Phase III with a Special Protocol Assessment (SPA)
- The FDA has granted Lupuzor™ Fast Track designation
How Lupuzor™ works in the treatment of lupus
Lupuzor™ is a drug that specifically modulates the immune system of lupus patients by modifying the behaviour of some of the key cells involved in the pathogenesis of the disease. The clinical profile of lupus patients is generally assessed by standardised scales such as SLEDAI (SLE Disease Activity Index): the lower the score, the better the condition of the patient. During this Phase II study, the SLEDAI scores were assessed on multiple occasions even though the study was not designed or powered to demonstrate clinical benefit as the primary endpoint due to the short treatment period.
| forigerimod | IPP-201101 | oligopeptide | therapeutic | nucleolin |
| forigerimod acetate | CEP-33457, P-140, IPP-201101 | oligopeptide (salt) | therapeutic | nucleolin |
GLENMARK- ELOVERA , for dry skin disorders
Compositions:
Elovera extract 10% cream, Vitamin E 0.5%
Category–Locally Acting Skin Preparations
Description
* Aqueeze adequate amount of elovera moisturizing body wash onto wet hands or wet loran and work into a creamy lather. apply it all ovr the body, keep for some time and then rinse with water.
| Products Name : | Elovera Moisturizing Body Wash 150ml – (Glenmark) |
Elovera Cream, manufacture by Glenmark pharmaceuticals limited , is cream enriched with vitamin E and Aloe Vera. It’s a very special cream specially for treating scars and other minor pimple spots on the face.
reviews from net
My skin is very much oily hence I get these ugly Pimples very profoundly. On top of it i have the habit of bursting out the puss from these pimples. I always play it with my hands and as a result forms some very ugly scars on my face which are visible from distant away.Though I am bit dark with my completion ,even then It’s clearly visible and my mother scolds me like hell for bursting the pimples out.Honestly I just can’t stop my hands reaching out for them no matter how busy I am so Finally has to resort to some ointments to reduce the visibility of the scars.
I did try few popular products but were of no use basically. The spots didn’t get reduced but instead effected the completion of my face.Finally my mother came to my rescue. She had hear about this Elovera Cream from some one and bought home one for me.Initially i was a bit skeptic but finally I thought of trying it. For the first few days it had no effect what-so-ever , but slowly it started clearing the skin blemishes. My skin started showing it’s effects and the scars became less visible. Not only does it clear the scars but it helped me to fight the ugly pimples as well.
My face became much more glowing and healthy and i use the cream regularly even now.It’s really a magical product and should try it for clearing the blemishes and other skin problem.
EMA approves biosimilar Somatropin from Biopartners Gmbh
![OMNITROPE® (somatropin [rDNA origin] injection) Structural Formula Illustration](https://i0.wp.com/images.rxlist.com/images/rxlist/omnitrope1.gif)
SOMATROPIN
The European Medicine agency has approved a biosimilar somatropin from Biopartners GMBH. Somatropin biopartner would be the third biosimilar version of somatropin the European market. Other players selling somatropin inlcude Sandoz and Roche. Sandoz sells under the brand Omnitrope, while Roche which is the innovator of somatropin sells it under the brand name NutropinAq.
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DETAILS OF OMNITROPE
Omnitrope® (somatropin-[rDNA] origin) is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). Omnitrope® is synthesized in a strain of. Escherichia coli that has been modified by the addition of the gene for human growth hormone. Omnitrope® Cartridge is a clear, colorless, sterile solution for subcutaneous injection. Omnitrope® for Injection is a lyophilized powder that is reconstituted for subcutaneous injection.
Figure 1: Schematic amino acid sequence of human growth hormone including the disulfide bonds
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Each Omnitrope® Cartridge or vial contains the following (see Table 4):
Table 4. Contents of Omnitrope® Cartridges and Vial
| Product | Cartridge 5 mg/1.5 mL | Cartridge 10 mg/1.5 mL | For Injection 5.8 mg/vial |
| Component | |||
| Somatropin | 5 mg | 10 mg | 5.8 mg |
| Disodium hydrogen phosphate heptahydrate | 1.3 mg | 1.70 mg | 2.09 mg |
| Sodium dihydrogen phosphate dihydrate | 1.6 mg | 1.35 mg | 0.56 mg |
| Poloxamer 188 | 3.0 mg | 3.0 mg | – |
| Mannitol | 52.5 mg | – | – |
| Glycine | – | 27.75 mg | 27.6 mg |
| Benzyl alcohol | 13.5 mg | – | – |
| Phenol | – | 4.50 mg | – |
| Water for Injection | to make 1.5 mL | to make 1.5 mL | – |
| Diluent (vials only) | Bacteriostatic Water for Injection | ||
| Water for injection | to make 1.14 mL | ||
| Benzyl alcohol | 17 mg | ||
Genzyme’s multiple sclerosis treatment approved by European Commission
Alemtuzumab
Sanofi and its subsidiary Genzyme have been given marketing approval by the European Commission for Lemtrada (alemtuzumab), a treatment for multiple sclerosis. read all at
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Genzyme’s multiple sclerosis treatment approved by European Commission
Generic versions of high cholesterol drug Lovaza can be developed, rules judge
LOVAZA, a lipid-regulating agent, is supplied as a liquid-filled gel capsule for oral administration. Each 1-gram capsule of LOVAZA (omega-3-acid ethyl esters) contains at least 900 mg of the ethyl esters of omega-3 fatty acids. These are predominantly a combination of ethyl esters of eicosapentaenoic acid (EPA – approximately 465 mg) and docosahexaenoic acid (DHA – approximately 375 mg).
The structural formula of EPA ethyl ester is:
The empirical formula of EPA ethyl ester is C22H34O2, and the molecular weight of EPA ethyl ester is 330.51.
The structural formula of DHA ethyl ester is:
The empirical formula of DHA ethyl ester is C24H36O2, and the molecular weight of DHA ethyl ester is 356.55.
LOVAZA capsules also contain the following inactive ingredients: 4 mg α-tocopherol (in a carrier of partially hydrogenated vegetable oils including soybean oil), and gelatin, glycerol, and purified water (components of the capsule shell).
Lovaza
A US appeals court ruled on this week that drug companies can develop generic versions of fish oil-derived, high-cholesterol drug Lovaza.
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Lovaza is a brand name prescription drug. The capsule sold by GlaxoSmithKline but developed by Reliant Pharmaceuticals, contains esterified fish oils and is approved by the U.S. Food and Drug Administration to lower very high triglyceride levels. It is metabolized intoOmega-3 fatty acids. It is a dietary supplement that has been purified, chemically altered, branded, and been put through the approval process of the U.S. Food and Drug Administration (FDA); in these respects it is considered a pharmaceutical. Due to the esterification process during manufacturing there is no risk of contamination[citation needed] by methyl mercury, arsenic,[1] or other pollutants that are often seen in the world’s oceans. Each 1-gram capsule is 38% DHA, 47% EPA, and 17% other fish oils in the form of the ethyl ester.
Lovaza is named Omacor in Europe (and this name was once used in the US).[2]
Effectiveness
Lovaza is approved in the U.S. for treatment of patients with very high triglycerides (hypertriglyceridemia).[3]
In the European markets and other major markets outside the US Lovaza is known as Omacor, and is indicated for:
- Hypertriglyceridemia. Used as monotherapy, or in combination with a statin for patients with mixed dyslipidemia.
- Secondary prevention after myocardial infarction (heart attack)
in addition to other standard therapy (e.g. statins, antiplatelets medicinal products, beta-blockers, and ACE-I).
Lovaza has been demonstrated to reduce triglycerides in patients with high or very high triglycerides. [3]
Lovaza has also been demonstrated to reduce VLDL-cholesterol and non-HDL-cholesterol, and increase HDL-cholesterol. But, it can raise LDL-cholesterol up to 45%.[4] The LDL raising activity correlates with a reduction in ApoB levels, though. Lovaza, through the stimulation of Lipoprotein Lipase, seems to stimulate the production of less atherogenic LDL species. In some patients, it can elevatealanine transaminase levels, so liver enzymes should be checked, periodically.[4]
Effects on significant patient outcomes such as acute myocardial infarction, stroke, cardiovascular and all-cause mortality have been studied in patients who have suffered a myocardial infarction (this is in the US; however, data from GISSI-P showed a combined end-point of all-cause death, non-fatal MI, and non-fatal stroke was significantly reduced by 15%). Lovaza has not been shown to lower the rates of all cause mortality and cardiovascular mortality, or the combination of mortality and non-fatal cardiovascular events.[3]
GlaxoSmithKline‘s patent expired in September 2012. Generic versions may be made available at that time. Other DHA/EPA products containing similar amounts of Omega-3 fatty acids are currently sold over the counter in the United States as dietary supplements.
Competitors
In July 2012, Amarin Corporation received U.S. FDA marketing approval for Vascepa, also referred to as AMR-101.[5] Vascepa will undoubtedly become a major competitor for Lovaza.[6] In clinicial trials, Vascepa was shown to lower triglycerides; while Lovaza also lowers the triglyceride concentration, Vascepa also lowers LDL-C; Lovaza does not. Lovaza was approved to treat people with very high triglyceride levels (>500 mg/dl), Vascepa is also approved for this market; however the company has also demonstrated that the drug can impact levels in people with high triglyceride (> 200 mg/dl and < 500 mg/dl) levels and will file an sNDA for this indication late in 2012.[7]
In 2011, Ariix started selling an almost identical FDA-Certified Omega3 Ethyl Ester 1000 mg capsule ‘OmegaQ’ fish oil through direct marketing and online auto-ship at a discounted price, creating another major competitor for Lovaza and Amarin’s Vascepa. One capsule contains 295 mg EPA, and 235 mg DHA, but it is unique in that it is combined with 20 mg of the coenzyme CoQ-10, with reported ‘anti-aging’ effects on the cell’s telomeres, which are still under study.
Forms of Lovaza
Lovaza is available as 1-gram soft-gelatin capsules.[8]
Active Ingredient: Omega-3-acid ethyl esters
Inactive Ingredients: Gelatin, glycerol, purified water, alpha-tocopherol (in soybean oil)
References
- NIFES (Nasjonalt institutt for ernærings- og sjømatforskning – Norwegian National Institute for Nutrition and Seafood Research)
- University of Utah Pharmacy Services (August 15, 2007) “Omega-3-acid Ethyl Esters Brand Name Changed from Omacor to Lovaza”
- GSK Information for Medical Professionals
- Pharmacy & Therapeutics (May, 2008) “Omega-3-acid Ethyl Esters (Lovaza) For Severe Hypertriglyceridemia”
- “Amarin Prescription Fish-Oil Pill Approved – TheStreet”. Retrieved 26 July 2012.
- “http://www.reuters.com/article/2012/07/26/us-amarin-fda-vascepa-idUSBRE86P1SX20120726”. Reuters. 26 July 2012. Retrieved 27 July 2012.
- “Amarin’s AMR101 Phase 3 ANCHOR Trial Meets all Primary and Secondary Endpoints with Statistically Significant Reductions in Triglycerides at Both 4 Gram and 2 Gram Doses and Statistically Significant Decrease in LDL-C (NASDAQ:AMRN)”. Amarin. 18 April 2011. Retrieved 26 July 2012.
- http://www.rxwiki.com/lovaza
