Home » Articles posted by DR ANTHONY MELVIN CRASTO Ph.D (Page 435)
Author Archives: DR ANTHONY MELVIN CRASTO Ph.D
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HEREFlag and hits
ORGANIC SPECTROSCOPY
SUBSCRIBE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
Recent Comments
 | shivkr2 on SPSR Excellence Award 2025 – S… |
 | Bonkasaurus on Infigratinib phosphate |
 | PALOVAROTENE | ORGAN… on Palovarotene |
| Pfizer just purchase… on Temanogrel | |
| Pfizer To Cash In On… on Temanogrel |
Gilead Initiates Phase 3 Clinical Program for Tenofovir Alafenamide,TAF a Novel Low-Dose Prodrug for the Treatment of HIV
Tenofovir Alafenamide
(S)-Isopropyl 2-(((S)-((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(phenoxy)phosphoryl)amino)propanoate
| cas no | 379270-37-8 |
|---|---|
http://www.ama-assn.org/resources/doc/usan/tenofovir-alafenamide.pdf
Gilead Sciences, Inc.on January 24, 2013 announced the initiation of the first of two Phase 3 clinical trials (Study 104) evaluating a single tablet regimen containing tenofovir alafenamide (TAF) for the treatment of HIV-1 infection in treatment-naïve adults. TAF is a novel prodrug of tenofovir, the active agent in Viread® (tenofovir disoproxil fumarate). The Phase 3 studies will examine a once-daily single tablet regimen of TAF 10 mg/elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg compared to Gilead’s Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) among patients new to HIV therapy. The second Phase 3 study (Study 111) will be initiated later this quarter.
We are pleased to move TAF into Phase 3 clinical research,” said Norbert Bischofberger, PhD, Executive Vice President, Research and Development and Chief Scientific Officer, Gilead Sciences. “We believe that TAF’s smaller milligram size has the potential to offer safety and tolerability advantages over existing therapies, and may enable the creation of new single tablet regimens for HIV.”
In October 2012, Gilead announced topline results from a Phase 2 study comparing the TAF/elvitegravir/cobicistat/emtricitabine single tablet regimen to Stribild. The study found that the TAF-based regimen met its primary objective based on the proportion of patients with HIV RNA (viral load) levels < 50 copies/mL at 24 weeks of therapy. In addition, statistically significant differences in bone and renal safety were observed between the two arms in favor of the TAF-containing regimen. Both the type and frequency of laboratory abnormalities and adverse events were otherwise comparable between study arms. Full results from the Phase 2 study will be presented at an upcoming medical conference.
Stribild was approved by the U.S. Food and Drug Administration (FDA) in August 2012 and is Gilead’s third single tablet regimen for HIV. A marketing application for Stribild is currently pending in Europe.
Tenofovir alafenamide fumarate (TAF), or GS 7340, is a nucleotide reverse transcriptase inhibitor and a novel prodrug of tenofovir. It is under development by Gilead Sciences for use in the treatment of HIV infection. Closely related to the commonly used reverse-transcriptase inhibitor tenofovir disoproxil fumarate (Viread), TAF has greater antiviral activity and better distribution into lymphoid tissues than that agent.[1][2] Gilead has announced a phase 3 clinical trial evaluating a single-tablet regimen combining GS-7340 with cobicistat, emtricitabine and elvitegravir[3] and plans to coformulate the drug with cobicistat, emtricitabine and the protease inhibitor darunavir.[4][5][6] In a 48 week study comparing Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate toelvitegravir/cobicistat/emtricitabine/GS 7340, the results showed the prodrug to be non inferior to the established agent, but at much lower dosages and with lower incidence of adverse side effects such as impaired kidney function.[7]
References
- Eisenberg, E. J.; He, G. X.; Lee, W. A. (2001). “Metabolism of Gs-7340, A Novel Phenyl Monophosphoramidate Intracellular Prodrug of Pmpa, in Blood”. Nucleosides, Nucleotides and Nucleic Acids 20 (4–7): 1091–1098. doi:10.1081/NCN-100002496.PMID 11562963. edit
- M Markowitz, A Zolopa, et al. GS-7340 Demonstrates Greater Declines in HIV-1 RNA than Tenofovir Disoproxil Fumarate During 14 Days of Monotherapy in HIV-1 Infected Subjects. 18th Conference on Retroviruses and Opportunistic Infections 2 Mar 2011. Paper # 152LB
- “Gilead Initiates Phase 3 Clinical Program for Tenofovir Alafenamide” (Press release). Gilead. January 2013.
- McQueen, Courtney (16 Nov 2011). “Gilead And Tibotec To Develop Single-Pill Protease Inhibitor-Based Combination Regimen”. The AIDS Beacon.
- GS 7340 Packs Greater HIV Punch, Potentially Better Safety, Versus Viread Horn, Tim. 15 Mar 2012. AIDSmeds.com
- Pharmacokinetics of a Novel EVG/COBI/FTC/GS-7340 Single Tablet Regimen. 13th International Workshop on Clinical Pharmacology of HIV Therapy. Barcelona, Spain. April 16-18, 2012.
- Once-Daily Tenofovir Prodrug Combo Pill as Effective as Stribild. AIDSmeds.com 1 Nov 2012.
CytRx Receives Recommendation from Data Safety Monitoring Committee to Complete Global Phase 2b Clinical Trial with Tamibarotene as First-Line Treatment for Non-Small-Cell Lung Cancer
4-[(1,1,4,4-tetramethyltetralin-6-yl)carbamoyl]benzoic acid, cas no 94497-51-5
“Tamibarotene is an orally available, rationally designed, synthetic retinoid compound that is 10-times more potent than all-trans retinoic acid (ATRA) and was designed to avoid several side effects of ATRA”
Tamibarotene, also called retinobenzoic acid, is orally active, synthetic retinoid, developed to overcome all-trans retinoic acid (ATRA) resistance, with potentialantineoplastic activity.
Y. Hamada, I. Yamada, M. Uenaka, T. Sakata, U.S. Patent 5,214,202 (1993).
- “Tamibarotene: AM 80, retinobenzoic acid, Tamibaro”. Drugs in R&D 5 (6): 359–62. 2004. PMID 15563242.
January 31, 2013
CytRx Corporation(NASDAQ: CYTR), a biopharmaceutical research and development company specializing in oncology, announced that the Data Safety Monitoring Committee overseeing the Company’s global Phase 2b clinical trial with tamibarotene in combination with chemotherapeutical agents as a first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC) has recommended conducting the clinical trial through completion. Enrollment of at least 140 evaluable patients is expected in the first quarter of 2013.
“Tamibarotene is an orally available, rationally designed, synthetic retinoid compound that is 10-times more potent than all-trans retinoic acid (ATRA) and was designed to avoid several side effects of ATRA”
“The Committee’s recommendation indicates that no significant safety issues have been seen with tamibarotene in the international Phase 2b clinical trial as we near enrollment completion with tamibarotene’s use in combination with potent chemotherapy agents in patients with advanced NSCLC,” said CytRx CEO Steven A. Kriegsman. “We are one step closer to completing this important clinical trial and further assessing tamibarotene in a potential multibillion dollar market, which is a major priority for our Company and our shareholders.”
Subjects with stage IIIb or IV NSCLS who have not received prior non-adjuvant chemotherapy are being enrolled in the blinded, randomized clinical trial at sites in the U.S., Bulgaria, India, Mexico, Russia and Ukraine. Trial patients are treated with paclitaxel plus carboplatin and either tamibarotene or placebo. The primary objective of this trial is to determine the objective response rate (complete and partial responses) and progression-free survival. Secondarily, the trial will evaluate overall survival and quality-of-life in this population, among other measures. The Data Safety Monitoring Committee is an independent group of oncologists and biostatisticians who monitor the safety and efficacy of the Phase 2b trial.
“Tamibarotene is an orally available, rationally designed, synthetic retinoid compound that is 10-times more potent than all-trans retinoic acid (ATRA) and was designed to avoid several side effects of ATRA,” said Daniel Levitt, MD, Ph.D., CytRx’s Executive Vice President and Chief Medical Officer. “This event is significant due to favorable results from a single-center clinical trial in patients with advanced NSCLC that compared treatment with ATRA added to a regimen of paclitaxel plus cisplatin to a regimen of paclitaxel plus cisplatin alone. Patients who received the regimen with ATRA showed improved response rates of 55.8% versus 25.4%, increased progression-free survival of 8.9 months versus 6.0 months, and a 14-month median extension of life.”
CytRx holds the North American and European rights to certain tamibarotene intellectual property for the treatment of NSCLC, and retains an option to expand its licenses for the use of tamibarotene in other fields in oncology.
New oral anticancer drug, TS-1 (S-1)
New oral anticancer drug, TS-1 (S-1)
http://www.ncbi.nlm.nih.gov/pubmed/11432358
novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively
components, an oral fluoropyrimidine agent, tegafur (FT);
a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT;
and
an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract
TS-1 and (TS-), the gastric cancer (oral anti-cancer agent that is used, for example, an anti-cancer agent is a kind of), is classified as an antimetabolite.
Product names, TS- , the common name tegafur, gimeracil, oteracil potassium in, manufacturing, vendors are Taiho Pharmaceutical Co., Ltd
Tegafur (tegafur, international generic name ) is a cancer to thechemotherapy used in the fluorouracil of prodrug is. Tegafur-uracil ( UFTcomponents of). Tegafur is metabolized fluorouracil shows anti-cancer activity
5-fluoro-1-(tetrahydrofuran-2-yl) pyrimidine-2, four (1 H , three H )-dione
Wednesday, 30 January 2013
ASCO GU – Another Breakthrough in Pancreatic Cancer – TS-1 superior to Gemcitabine in improving overall survival in patients with resected Pancreatic Cancer
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
- GA101 is the first glycoengineered, type II anti-CD20 mAb.
Roche’s Phase III leukemia drug Obinutuzumab (GA101) yields positive results
Obinutuzumab (GA101)
| Formula | C6512H10060N1712O2020S44 |
|---|
GA101 is the first glycoengineered, type II anti-CD20 monoclonal antibody (mAb) that has been designed for increased antibody-dependent cellular cytotoxicity (ADCC) and Direct CellDeath.1 This agent is being investigated in collaboration with Biogen Idec.
Swiss pharmaceutical company Roche has announced that its early Phase III trial of Leukemia drug obinutuzumab (GA101) demonstrated significantly improved progression-free survival in people with chronic lymphocytic leukemia (CLL).
The positive results yield from stage 1 of a three-arm study called CLL11, designed to investigate the efficacy and safety profile of obinutuzumab (GA101) plus chlorambucil, a chemotherapy, compared with chlorambucil alone in people with previously untreated chronic lymphocytic leukemia (CLL).
This phase of the study met its primary endpoint and an improvement in progression-free survival was achieved; obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared to chlorambucil alone.
Roche chief medical officer and global product development head Hal Barron said; “the improvement in progression-free survival seen with GA101 is encouraging for people with CLL, a chronic illness of older people for which new treatment options are needed.”
“GA101 demonstrates our ongoing commitment to the research and development of new medicines for this disease.”
Obinutuzumab is Roche’s most advanced drug in development for the treatment of hematological malignancies.
It has been specifically designed as the first glycoengineered, type 2 anti-CD20 monoclonal antibody in development for B cell malignancies.
Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]
References
- Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
- Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab,American Medical Association.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
-
obinutuzumab isMonoclonal antibody Type Whole antibody Source Humanized (from mouse) Target CD20
Health Canada Approves ADCETRIS® (Brentuximab Vedotin) for the Treatment of Relapsed or Refractory Hodgkin Lymphoma (HL) and Systemic Anaplastic Large Cell Lymphoma (sALCL)
Structure of brentuximab vedotin
Brentuximab vedotin on track for BLA filing with FDA during first half of 2011. [© Sebastian Kaulitzki – Fotolia.com]
Brentuximab is a human antibody. The antibody portion of Brentuximab vedotin has the sequence of two copies of:
>Brentuximab vedotin - heavy chain QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKY NEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSAAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY SLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQG NVFSCSVMHEALHNHYTQKSLSLSPG >Brentuximab vedotin - light chain DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLES GIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
February 01, 2013
Seattle Genetics, Inc. today announced that Health Canada has issued a Notice of Compliance with conditions (NOC/c), authorizing marketing of ADCETRIS for two lymphoma indications: (1) the treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two multi-agent chemotherapy regimens in patients who are not ASCT candidates, and (2) the treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one multi-agent chemotherapy regimen. The indications for ADCETRIS were authorized based on promising response rates demonstrated in single-arm trials. No data demonstrate increased survival with ADCETRIS.
“they are focused on making ADCETRIS available globally to all eligible patients with relapsed HL and sALCL. The approval of ADCETRIS in Canada, as well as the recent approval in the European Union, are important milestones to accomplish this goal,” said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. “Now that Health Canada has approved ADCETRIS, we are committed to working closely with public and private insurers to secure reimbursement coverage for patients in Canada.”
“The approval of ADCETRIS in Canada marks a significant milestone for patients with relapsed HL or sALCL who have had few new treatment options in several decades,” Joseph M. Connors, M.D., FRCPC, Clinical Director, Center for Lymphoid Cancer at BC Cancer Agency in Vancouver, Canada.
Health Canada grants NOC/c, a form of market approval, on the basis of promising evidence of clinical effectiveness, for products intended for the treatment of serious, life-threatening or severely debilitating illnesses that meet a serious unmet medical need or demonstrate a significant improvement in the benefit/risk profile over existing therapies. Conditions associated with market authorization under the NOC/c policy include a requirement that Seattle Genetics conduct clinical trials designed to confirm the anticipated clinical benefit of ADCETRIS in these patients. Two confirmatory phase III clinical trials evaluating ADCETRIS in the front-line treatment setting of HL and mature T-cell lymphoma (MTCL), including sALCL, are currently underway and enrolling patients.
ADCETRIS (brentuximab vedotin) was issued marketing authorization under the NOC/c policy based on results from a single-arm, phase II pivotal trial in HL patients with relapsed or refractory disease following an ASCT and a single-arm, phase II pivotal trial in relapsed or refractory sALCL patients. ADCETRIS is administered in hospitals through IV infusion over 30 minutes every three weeks and patients who achieve stable disease or better should receive a minimum of 8 cycles and up to a maximum of 16 cycles (approximately one year).
ADCETRIS is the first in a new class of antibody-drug conjugates (ADCs) to be approved in Canada. Using Seattle Genetics’ proprietary technology, the ADC consists of a monoclonal antibody directed to an antigen called CD30. The monoclonal antibody is connected to a cell-killing agent by a linker system that is designed to be stable in the bloodstream but to release the cell-killing agent into CD30-expressing cells, resulting in target cell death. The CD30 antigen is known to be expressed on the Reed-Sternberg cells of HL and on sALCL, an aggressive type of T-cell non-Hodgkin lymphoma.
“Health Canada’s approval of ADCETRIS is the first step in getting patients access to this important therapy,” said Sue Robson, Executive Director of Lymphoma Foundation Canada. “The Lymphoma Foundation is committed to working with Canada provincial governments to ensure that appropriate patients have access to this new therapy.”
About Lymphoma
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma and non-Hodgkin lymphoma. Hodgkin lymphoma is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30. Systemic ALCL is an aggressive type of T-cell non-Hodgkin lymphoma that also expresses CD30.
Brentuximab vedotin (INN, codenamed SGN-35 and previously cAC10-vcMMAE) is an antibody-drug conjugate approved to treat anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma. The U.S. Food and Drug Administration granted the agent an accelerated approval on August 19, 2011 for use against these two diseases.[1] It is marketed as Adcetris.[2]
The compound consists of the chimeric monoclonal antibody brentuximab (which targets the cell-membrane protein CD30) linked to three to five units of the antimitotic agent monomethyl auristatin E (MMAE, reflected by the ‘vedotin’ in the drug’s name). The antibody portion of the drug attaches to CD30 on the surface of malignant cells, delivering MMAE which is responsible for the anti-tumour activity.[3][4] Hence it is an antibody-drug conjugate.
In a 2010 clinical trial,[5] 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission.[6] Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumors shrinkage.[7]
On 28 February 2011 a Biologics License Application (BLA) was submitted to the U.S. Food and Drug Administration (FDA) for the use of brentuximab vedotin in relapsed or refractory Hodgkin’s lymphoma and relapsed or refractory systemic anaplastic large cell lymphoma.[8] Both indications were approved by the FDA in Aug 2011.[9]
For these same indications brentuximab vedotin received a conditional Marketing authorization from the European Medicines Agency in october 2012.[10]
- FDA: Brentuximab Vedotin
- Seattle Genetics to Present Brentuximab Vedotin and SGN-75 Clinical Data at the American Society of Clinical Oncology Annual Meeting
- Seattle Genetics: Brentuximab vedotin (SGN-35)
- Francisco, Joseph A; et al. (2003). “cAC10-vcMMAE, an anti-CD30–monomethyl auristatin E conjugate with potent and selective antitumor activity”. Blood 102 (4): 1458–1465. doi:10.1182/blood-2003-01-0039. PMID 12714494.
- ClinicalTrials.gov NCT00848926 A Pivotal Open-Label Trial of SGN-35 for Hodgkin Lymphoma
- “Seattle Genetics and Millennium Report Positive Data from Pivotal Trial of Brentuximab Vedotin (SGN-35) in Relapsed or Refractory Hodgkin Lymphoma at ASH Annual Meeting”. Dec 2010.
- “Is Seattle Genetics the Next Big Thing?”. 2 Dec 2010.
- “Seattle Genetics Submits BLA to FDA for Brentuximab Vedotin in Relapsed or Refractory Hodgkin Lymphoma and Systemic ALCL”. 28 Feb 2011.
- Genetic Engineering & Biotechnology News: Seattle Genetics’ Antibody-Drug Conjugate Receives FDA Okay to Treat Lymphomas
- http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002455/WC500135004.pdf
FDA Approves Ravicti (glycerol phenylbutyrate)for the Chronic Management of Some Urea Cycle Disorders
FDA Approves Ravicti (glycerol phenylbutyrate)for the Chronic Management of Some Urea Cycle Disorders
Ravicti is marketed by Hyperion Therapeutics, based in South San Francisco, Calif.
February 1, 2013 — The U.S. Food and Drug Administration today approved Ravicti (glycerol phenylbutyrate) for the chronic management of some urea cycle disorders (UCDs) in patients ages 2 years and older.
UCDs are genetic disorders that involve deficiencies of specific enzymes involved in the urea cycle, a series of biochemical steps normally required to remove ammonia from the blood. When protein is absorbed and broken down by the body, it produces nitrogen as a waste product. The urea cycle removes nitrogen from the blood and converts it to urea, which is removed from the body through urine. In people with UCDs, nitrogen accumulates and remains in the body as ammonia, which can travel to the brain and cause brain damage, coma or death.
Ravicti, a liquid taken three times a day with meals, helps dispose of ammonia in the body. It is intended for patients whose UCD cannot be managed by a protein-restricted diet or amino acid supplements alone. Ravicti must be used with a protein-restricted diet and, in some cases, dietary supplements.
“Ravicti provides another treatment for chronic management of urea cycle disorders, a group of life-threatening conditions,” said Donna Griebel, M.D., director of the Division of Gastrointestinal and Inborn Errors Products in the FDA’s Center for Drug Evaluation and Research. “The approval of this new therapeutic option demonstrates FDA’s commitment to providing treatments for patients suffering from rare diseases.”
Ravicti was reviewed under the agency’s fast track program, designed to facilitate the development and expedite the review of drugs to treat serious diseases, fill unmet medical needs, and get important new drugs to patients earlier. Ravicti also was granted orphan product designation because it is intended to treat a rare disease.
Glycerol phenylbutyrate (HPN-100) is a pro-drug of phenylbutryrate and a pre-pro-drug of phenylacetic acid (PAA), the active moiety of Buphenyl, the only therapy currently FDA-approved as adjunctive therapy for the chronic management of patients with the most prevalent urea cycle disorders — carbamylphosphate synthetase, ornithine transcarbamylase, and argininosuccinic acid synthetase. HPN-100, which is dosed orally in liquid form, provides an alternative pathway to the urea cycle for the disposal of waste nitrogen through the renal excretion of phenylacetylglutamine, which is formed from PAA and glutamine.
伯舒替尼 Bosutinib
Bosutinib Monohydrate (伯舒替尼)
(Bosulif®)
Approved sept4 2012 by FDA
PMDA SEPT26 2014
EMA MAR 27 2013
A kinase inhibitor indicated for the treatment of adult patients with Ph+ chronic myelogenous leukemia (CML).
WYETH INNOVATOR
PFIZER DEVELOPER
SKI-606; SK-606
CAS No.380843-75-4 (Free form)
CAS 918639-08-4(Bosutinib Monohydrate)
Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is atyrosine kinase inhibitor undergoing research for use in the treatment of cancer. [1] [2]Originally synthesized by Wyeth, it is being developed by Pfizer.
。
Some commercial stocks of bosutinib (from sources other than the Pfizer material used for clinical trials) have recently been found to have the incorrect chemical structure, calling the biological results obtained with them into doubt.[3]
Bosutinib received US FDA approval on September 5, 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+)chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.[4][5][6]
Article
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) on January 17, 2013, adopts a positive opinion, recommending a conditional marketing authhorization for Pfizer’s orphan drug Bosulif (Bosutinib) for Chronic Leukemia (CML). Bosutinib receives orphan designation from the European Commission (EC) on August 4, 2010, for CML.
Pfizer receives FDA approval on September 4, 2012, for orphan drug Bosulif (Bosutinib) for CML. Pfizer receives on February 24, 2009, FDA Orphan Drug Designation (ODD) for Bosutinib for CML.
Per a September 2012 article in FierceBioTech.com, a Pfizer spokesperson says that “the drug will cost less than $8,200/month”/patient in the US. In other words, treatment will cost approximately $98,400/patient/year. Also per FierceBiotech,“Bosulif is the 3rd new medicine from Pfizer Oncology’s pipeline to be approved by the FDA in just 13 months ….”.
ARTICLE
Pfizer’s response to compound fraud spotlights quality issues
read ………http://www.rsc.org/chemistryworld/2015/12/pfizer-bogus-bosutinib-isomer-fraud-leukaemia-drug
Synthesis
Confirmation of Bosutinib Structure; Demonstration of Controls To Ensure Product Quality
Nonbranded/unauthorized vendors had been manufacturing/selling what they described as bosutinib, while the material supplied was actually an isomer of bosutinib. This raised concerns within the worldwide research community around the established control strategies for bosutinib. This manuscript summarizes that the appropriate testing was in place to ensure product quality, along with additional experimentation that was performed to confirm that testing (methods) can differentiate the potential isomeric compounds. Testing includes the use of IR for identity confirmation of raw materials, material characterization by NMR, single crystal X-ray to confirm structure, and evaluation of several potential isomers by HPLC, melting point, and IR, thus demonstrating the control strategy needed to ensure the product controls.
REFERENCES
- Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, Ahmed S, Redaelli S, Piazza R, Magistroni V, Andreoni F, Scapozza L, Formelli F, Gambacorti-Passerini C. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006 Dec 1;66(23):11314-22. Epub 2006 Nov 17.
- Vultur A, Buettner R, Kowolik C, et al. (May 2008). “SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells”.Mol. Cancer Ther. 7 (5): 1185–94. doi:10.1158/1535-7163.MCT-08-0126.PMC 2794837. PMID 18483306.
- Derek Lowe, In The Pipeline (blog), “Bosutinib: Don’t Believe the Label!”
- Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24.
- Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicus L, Malhotra H, Powell C, Gogat K, Countouriotis AM, Gambacorti-Passerini C. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial. J Clin Oncol. 2012 Sep 4. [Epub ahead of print]
- “Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia”. 05 Sep 2012.
-
P Bowles et al, Org. Process Res. Dev., 2015, DOI: 10.1021/acs.oprd.5b00244
8 N M Levinson and S G Boxer, PLoS One, 2012, 7, e29828 (DOI: 10.1371/journal.pone.0029828)
9 N Beeharry et al, Cell Cycle, 2014, 13, 2172 (DOI: 10.4161/cc.29214)
update…………….
file:///C:/Users/Inspiron/Downloads/molecules-15-04261%20(1).pdf
Synthesis of Bosutinib from 3-Methoxy-4-hydroxybenzoic Acid
Jun 11, 2010 – Abstract: This paper reports a novel synthesis of bosutinib starting from … C-NMR, MS and the purities of all the compounds were determined …
4-(2,4-Dichloro-5-methoxyphenylamino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline- 3-carbonitrile (10). A mixture of 7-(3-chloropropoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-6-methoxyquinoline-3-carbonitrile (9, 0.328 g, 0.7 mmol) and sodium iodide (0.11 g, 0.70 mmol) in N-methylpiperazine (4 mL) was heated at 80 ºC for 12 h. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography, eluting with 30% methanol in dichloromethane. The fractions containing product were collected and concentrated in vacuo. Diethyl ether was added to the residue, and the light pink solid was collected by filtration (0.28 g, 75% yield, 98.7% HPLC purity): m.p. 116–120 ºC;
1H-NMR (DMSO-d6): 1.92–1.97 (m, 2H), 2.15 (s, 3H), 2.32–2.46 (m, 10H), 3.84 (s, 3H), 3.93 (s, 3H), 4.19 (t, J = 6.3 Hz, 2H), 7.31 (br s, 2H), 7.43 (s, 1H), 7.64 (s, 1H), 8.52 (s, 1H), 9.51 (s, 1H);
13C-NMR (CDCl3): 25.96, 45.68, 52.67, 52.67, 54.24, 54.72, 54.72, 56.01, 60.71, 66.87, 89.10, 101.66, 101.66, 109.12, 113.95, 117.17, 122.99, 122.99, 128.27, 137.88, 146.15, 148.13, 148.51, 149.50, 150.43, 153.03;
MS (ES) m/z 530.2, 532.2 (M+1).
…………………..
Structural and spectroscopic analysis of the kinase inhibitor …
files.figshare.com/337292/Figure_S2.doc
by NM Levinson – Cited by 39 – Related articles
NMR spectroscopy on bosutinib and the bosutinib isomer. As described in the main text, the 1H NMR spectra of the compounds we purchased from LC Labs and …
Figure S2. NMR experiments on bosutinib and the bosutinib isomer. A) The structure of bosutinib and a putative structure for the bosutinib isomer are shown. The blue numbers on the bosutinib structure represent the five aromatic proton-carbon pairs. The numbers on the aniline ring of the bosutinib isomer are 13C chemical shifts. B) NMR spectra. In the top left panel, 1H-13C HSQC spectra of bosutinib and the bosutinib isomer are shown. The thick black lines connect the peaks that arise from the equivalent proton-carbon pairs in the two compounds. The thin gray lines are intended to guide the eye to the corresponding peaks in the 1-dimensional spectra. The peaks for the five aromatic proton-carbon pairs in authentic bosutinib are indicated with large blue numbers. These putative assignments are based on 13C chemical shift predictions. The bottom panel shows the 1H NMR spectra of both compounds. The peak located at 7.34 ppm in the bosutinib isomer sample, which integrates to 2, is indicated. The colored numbers directly next to the peaks are the peak integrations. The panel on the upper right shows the aromatic region of the 13C NMR spectrum of the bosutinib isomer. The peak located at 123 ppm, which displays an integrated intensity of 2, is indicated.
//////////////Clc1c(OC)cc(c(c1)Cl)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
Health Canada approves Forest Laboratories Bystolic
Health Canada approves Forest Laboratories Bystolic
The chemical name for the active ingredient in BYSTOLIC (nebivolol) tablets is (1RS,1’RS)-1,1′-[(2RS,2’SR)bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]-2,2′-iminodiethanol hydrochloride. Nebivolol is a racemate composed of d-Nebivolol and l-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and [RSSS]nebivolol, respectively. Nebivolol’s molecular formula is (C22H25F2NO4•HCl) with the following structural formula:
 |
SRRR – or d-nebivolol hydrochloride
RSSS – or l-nebivolol hydrochloride
MW: 441.90 g/mol
Nebivolol hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, and methylbenzene.
BYSTOLIC as tablets for oral administration contains nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol base. In addition, BYSTOLIC contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake, FD&C Blue #2 Lake, FD&C Yellow #6 Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate.
Class: beta-Adrenergic Blocking Agents
Chemical Name: (1RS,1′RS)-1,1′-[(2RS,2′SR)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]- 2,2′-iminodiethanol hydrochloride
Molecular Formula: C22H25F2NO4•HCl
CAS Number: 152520-56-4
Brands: Bystolic
Health Canada has issued a notice of compliance for Forest Laboratories Canada’s hypertension therapy, Bystolic (nebivolol) tablets.
The company anticipates making the hypertension medication, that is to be administered once a day, available to patients across Canada in the second quarter of 2013.
Forest Laboratories corporate development and strategic planning senior vice president David Solomon said, “We are pleased that Health Canada has granted approval for BYSTOLIC. This is an important milestone for Forest, as it is the first product approved for our newly established Canadian subsidiary.”
Nebivolol is a beta adrenergic receptor blocking agent which is metabolized by various routes such as glucuronidation and hydroxylation by CYP2D6.
Possible factors that allow Bystolic to act as antihypertensive agent include decreased heart rate, decreased myocardial contractility, diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppression of renin activity and vasodilation and decreased peripheral vascular resistance.
Jetrea(TM) receives positive CHMP opinion
Jetrea(TM) receives positive CHMP opinion
Ocriplasmin is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kD a produced by recombinant DNA technology in a Pichia pastoris expression system.
JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.5 mg ocriplasmin in 0.2 mL solution for intravitreal injection after dilution.
Each vial contains 0.5 mg ocriplasmin (active) and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for pH adjustment) and water for injection. The pH of the solution is 3.1.
Jetrea(TM) (ocriplasmin),
USFDA Approves Octaplas
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm336009.htm
FRI 18 JAN
Octaplas is presented as a solution for infusion containing 45 – 70 mg/mL human plasmaproteins.
New Drug Approvals 
