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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Hope for Hepatitis Drug, entecavir
Entecavir
A straightforward synthesis of an antiviral drug, entecavir, to treat hepatitis B has industrial scale-up potential
New Route to Anticancer Agent Quinocarcin
Quinocarcin,
Antibiotic DC 52, DC 52, CHEBI:554143, CID158486, LS-80981, 3,6-Imino-1H-2-oxa-11c-azanaphth(1,2,3-cd)azulene-5-carboxylic acid, 2a,3,4,5,6,6a,7,11b-octahydro-11-methoxy-12-methyl-, (2a-alpha,3-alpha,5-alpha,6-alpha,6a-alpha,11b-alpha)-, (-)-, 84573-33-1
Synthesis of quinocarcin through a convergent strategy based on Sonogashira coupling and gold(I)-catalyzed hydroamination
Takeda’s Ixazomib, Multiple Myeloma Drug
CAS#: 1201902-80-8
Synonym: Ixazomib; MLN-9708.
IUPAC/Chemical name:
4-(carboxymethyl)-2-((R)-1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid
UPDATES AT THE BOTTOM OF PAGE
CAMBRIDGE, Mass., May 23, 2013 – Takeda Pharmaceutical Company Limited (TSE:4502) today announced the initiation of an international phase 3 clinical trial evaluating once a week MLN9708 in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma who are not candidates for transplant. The multi-center study with MLN9708, an investigational, oral proteasome inhibitor, will be conducted in Europe and North America.———————-READ MORE AT
http://www.pharmalive.com/takeda-begins-phase-iii-trial-of-multiple-myeloma-drug
Description of Ixazomib: ixazomib is an orally bioavailable second generation proteasome inhibitor (PI) with potential antineoplastic activity. Ixazomib inhibits the activity of the proteasome, blocking the targeted proteolysis normally performed by the proteasome, which results in an accumulation of unwanted or misfolded proteins; disruption of various cell signaling pathways may follow, resulting in the induction of apoptosis. Compared to first generation PIs, second generation PIs may have an improved pharmacokinetic profile with increased potency and less toxicity. Proteasomes are large protease complexes that degrade unneeded or damaged proteins that have been ubiquinated
MLN9708 is an investigational proteasome inhibitor that, compared with bortezomib, has improved pharmacokinetics, pharmacodynamics, and antitumor activity in preclinical studies. MLN9708 rapidly hydrolyzes to MLN2238, the biologically active form. MLN9708 has a shorter proteasome dissociation half-life and improved pharmacokinetics, pharmacodynamics, and antitumor activity compared with bortezomib.MLN9708 has a larger blood volume distribution at steady state, and analysis of 20S proteasome inhibition and markers of the unfolded protein response confirmed that MLN9708 has greater pharmacodynamic effects in tissues than bortezomib. MLN9708 showed activity in both solid tumor and hematologic preclinical xenograft models, and we found a correlation between greater pharmacodynamic responses and improved antitumor activity. Moreover, antitumor activity was shown via multiple dosing routes, including oral gavage. Taken together, these data support the clinical development of MLN9708 for both hematologic and solid tumor indications. (source: Cancer Res. 2010 Mar 1;70(5):1970-80. Epub 2010 Feb 16.).
| References |
1: Mullard A. Next-generation proteasome blockers promise safer cancer therapy. Nat Med. 2012 Jan 6;18(1):7. doi: 10.1038/nm0112-7a. PubMed PMID: 22227650.
2: Anderson KC. The 39th David A. Karnofsky Lecture: bench-to-bedside translation of targeted therapies in multiple myeloma. J Clin Oncol. 2012 Feb 1;30(4):445-52. Epub 2012 Jan 3. PubMed PMID: 22215754.
3: Appel A. Drugs: More shots on target. Nature. 2011 Dec 14;480(7377):S40-2. doi: 10.1038/480S40a. PubMed PMID: 22169800.
4: Lee EC, Fitzgerald M, Bannerman B, Donelan J, Bano K, Terkelsen J, Bradley DP, Subakan O, Silva MD, Liu R, Pickard M, Li Z, Tayber O, Li P, Hales P, Carsillo M, Neppalli VT, Berger AJ, Kupperman E, Manfredi M, Bolen JB, Van Ness B, Janz S. Antitumor activity of the investigational proteasome inhibitor MLN9708 in mouse models of B-cell and plasma cell malignancies. Clin Cancer Res. 2011 Dec 1;17(23):7313-23. Epub 2011 Sep 8. PubMed PMID: 21903769.
5: Chauhan D, Tian Z, Zhou B, Kuhn D, Orlowski R, Raje N, Richardson P, Anderson KC. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 2011 Aug 15;17(16):5311-21. doi: 10.1158/1078-0432.CCR-11-0476. Epub 2011 Jun 30. PubMed PMID: 21724551; PubMed Central PMCID: PMC3156932.
6: Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, Yu J, Yang Y, Hales P, Bruzzese F, Liu J, Blank J, Garcia K, Tsu C, Dick L, Fleming P, Yu L, Manfredi M, Rolfe M, Bolen J. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010 Mar 1;70(5):1970-80. Epub 2010 Feb 16. Erratum in: Cancer Res. 2010 May 1;70(9):3853. Hales, Paul [added]. PubMed PMID: 20160034.
7: Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today. 2010 Mar;15(5-6):243-9. Epub 2010 Jan 29. Review. PubMed PMID: 20116451.8: Marblestone JG. Ubiquitin Drug Discovery & Diagnostics 2009 – First Annual Conference. IDrugs. 2009 Dec;12(12):750-3. PubMed PMID: 19943215.
http://www.cancernetwork.com/conference-reports/ash2012/content/article/10165/2119611
Nasopharyngeal cancer is a sub-type of head and neck cancer that arises from the epithelial cells that cover the surface and line the nasopharynx. The incidence of nasopharyngeal cancer has been reported at approximately 0.5 to 2 new cases per year per 100,000 in Europe and the USA. Rottey et ah, Curr. Opin. Oncol., 23(3): 254-258 (201 1). There are three subtypes of nasopharyngeal cancer recognized in the World Health Organization (WHO) classification: (i) Type 1 – squamous cell carcinoma, typically found in the older adult population; (ii) Type 2 non-keratinizing carcinoma; and (iii) Type 3 – undifferentiated carcinoma. Treatment for nasopharyngeal cancer often involves radiotherapy and/or chemotherapy. There remains a continuing need for new and improved treatments for patients with nasopharyngeal cancer. There remains a further need to identify nasopharyngeal patients most likely to benefit from treatment with a proteasome inhibitor.
Proteasome inhibition represents an important new strategy in cancer treatment. King et al. , Science 274: 1652-1659 ( 1996), describes an essential role for the ubiquitin-proteasome pathway in regulating cell cycle, neoplastic growth and metastasis. The authors teach that a number of key regulatory proteins, including cyclins, and the cyclin-dependent kinases p21 and p27K,P ! , are temporally degraded during the cell cycle by the ubiquitin-proteasome pathway. The ordered degradation of these proteins is required for the cell to progress through the cell cycle and to undergo mitosis.
The proteasome inhibitor VELCADE© (bortezomib; N-2-pyrazinecarbonyl-L -phenylalanine -L- leucineboronic acid) is the first proteasome inhibitor to achieve regulatory approval. Mitsiades et ai, Current Drug Targets, 7: 1341 (2006), reviews the clinical studies leading to the approval of bortezomib for the treatment of multiple myeloma patients who have received at least one prior therapy. Fisher et ai , J. Clin. Oncol, 30:4867, describes an international multi-center Phase II study confirming the activity of bortezomib in patients with relapsed or refractory mantle cell lymphoma. Ishii et al, Anti-Cancer Agents in Medicinal Chemistry, 7:359 (2007), and Roccaro et al., Curr. Pharm. Biotech., 7: 1341 (2006), discuss a number of molecular mechanisms that may contribute to the antitumor activities of bortezomib. The proteasome inhibitor MLN9708 [2,2′-{2-[(lR)- l -( {[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3- methylbutyl]-5-oxo-l,3,2-dioxaborolane-4,4-diyl}diacetic acid] is currently undergoing clinical evaluation for hematological and solid cancers. MLN9708 is a citrate ester which rapidly hydrolyzes to the active form [(lR)-l -({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]boronic acid (MLN2238) on exposure to aqueous solution or plasma. MLN9708 has demonstrated anti-tumor activity in a range of hematological and solid tumor xenograft models (Kupperman et al. (2010) Cancer Res. 70: 1970- 1980),
Summary
The invention relates to the discovery that patients with nasopharyngeal cancer respond to treatment with MLN9708. In one aspect, the invention relates to the discovery of the increased expression of Nuclear Factor Kappa-B RelA 65,000 dalton subunit (NFKB p65) in biological samples comprising cells obtained from patients with nasopharyngeal cancer and responsive to MLN9708.
Accordingly, the invention features treating nasopharyngeal cancer patients withMLN9708 if a sample from the patient demonstrates an elevated expression of NFKB p65.
PATENT
or a pharmaceutically acceptable salt or a pharmaceutical composition or a boronic acid anhydride thereof.
[048| The compound of formula (II), [( l R)-l -( } [(2,5-dichlorobenzoyl)amino]acetyl} amino)-3- methylbutyljboronic acid (MLN2238) is disclosed in Olhava and Danca, U .S. Patent No. 7,442,830, herein incorporated by reference in its entirety. [049] In some other embodiments, Z and Z together form a moiety derived from a compound having at least two hydroxyl groups separated by at least two connecting atoms in a chain or ring, said chain or ring comprising carbon atoms and, optionally, a heteroatom or heteroatoms which can be N, S, or O, wherein the atom attached to boron in each case is an oxygen atom.
In certain embodiments, wherein the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid, the compound of formula (I) is characterized by formula (III-A) or (III-B):
(III-B), or a mixture thereof or a pharmaceutical composition thereof.
[054] In certain embodiments, wherein the alpha-hydroxy carboxylic acid or beta-hydroxy carboxylic acid is citric acid, the compound of formula (I) is characterized by formula (III-A):
or a pharmaceutical composition thereof.
[055] The compound of formula (III-A), 2,2′- {2-[( l i?)- l -( { [(2,5-dichlorobenzoyl)amino]acetyl } amino)- 3-methylbutyl]-5-oxo- l ,3,2-dioxaborolane-4,4-diyl} diacetic acid (MLN9708) is disclosed in Elliott et al. , WO 09/ 154737, herein incorporated by reference in its entirety
PATENT
http://www.google.com/patents/WO2009154737A1?cl=en
Example 1: Synthesis of 4-(/?,S)-(carboxymethyl)-2-( (R)-I -(2-(2,5- dichlorobenzamido)acetamido)-3-methylbutyl)-6-oxo-l,3,2-dioxaborinane-4- carboxylic acid (1-1)
Step l: 2,5-r(dichlorobenzoyI)aminolacetic acid
[0310] To a mixture of NaOH (12 g, 300 mmol) and glycine (18 g, 239 mmol) in water (120 mL) was added dropwise over 45 min a solution of 2,5-dichlorobenzoyl chloride (10 g, 48 mmol) in THF (15 mL) keeping the internal temperature below about 25 0C. After 1 h, the mixture was acidified with 2.0 M HCl (125 mL) keeping the internal temperature below about 5 0C. The resulting precipitate was collected by vacuum filtration. The crude product was recrystallized from water to give 2,5-[(dichlorobenzoyl)amino]acetic acid as a white, crystalline solid (6.1 g, 52%). mp 173.3 0C. 1H NMR (300 MHz, DMSOd6, δ): 12.72 (bs, IH), 8.89 (t, J = 6.0 Hz, IH), 7.54 (m, 2H), 7.48 (m, IH), 3.93 (d, J = 6.0 Hz). 13C NMR (75 MHz, DMSO-Ci6, δ): 41.6, 129.3, 129.6, 131.4, 132.2, 138.2, 171.4, 165.9. MS (ni/z): [M+H] calculated for C9H8Cl2NO3, 248.0; found, 248.0; [M+Na] calculated for C9H7Cl2NNaO3, 270.0; found 270.2.
2,5-[(dichlorobenzoyl)amino]acetic acid was also be prepared via the following procedure: To a mixture of glycine (21.5 g, 286 mmol) in water (437 mL), was added 2.0 M NaOH (130 mL) and the resulting solution was cooled to 0 0C. A solution of 2,5-dichlorobenzoyl chloride (50.0 g, 239 mmol) in THF (75 mL) was added dropwise at such a rate that the internal temperature was maintained at 0 ± 1 0C. During the addition, the pH was controlled at 11.0 ± 0.2 using a pH controller titrated with 2.0 M NaOH. After complete addition, the mixture was stirred at 0 ± 1 0C for an additional 2 h. The mixture was then acidified with 2.0 M HCl (176 mL) to a final pH of 2.5. The resulting precipitate was collected by filtration, washed with cold water (125 mL), and dried at 45 0C in a vacuum oven to afford 2,5-[(dichlorobenzoyl)amino]acetic acid as a white solid (57.6 g, 97.3%). Step 2: 2,5-dichloro-N-f2-(( (lR’)-3-niethyl-l-r(3aS,4S.6S.7aR)-3a,5,5-trimethylhexahvdro-
4,6-methano-l,3,2-benzodioxaborol-2-yllbutyl }amino)-2-oxoethvπbenzamide
To a solution of 2,5-[(dichlorobenzoyl)amino]acetic acid (6.10 g, 24.6 mmol) and TBTU (8.34 g, 26.0 mmol) in DMF (40 mL) with an internal temperature below about 5 0C was added (IR)- 3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-l,3,2-benodioxaborol-2- yl]butan-l-amine»TFA (9.35 g, 24.7 mmol). DIPEA (13 mL, 75 mmol) was then added dropwise over 2 h keeping the internal temperature below about 5 0C. After 40 min, the mixture was diluted with EtOAc (90 mL), washed with 5% NaCl (150 mL), twice with 10% NaCl (2 x 40 mL), once with 2% K2CO3 (1 x 40 mL), once with 1% H3PO4 (1 x 40 mL), and once with 10% NaCl (1 x 40 mL). The resulting organic layer was concentrated to a thick oil, diluted with heptane (40 mL) and evaporated to yield 2,5-dichloro-N-[2-({ (lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methano-l ,3,2-benzodioxaborol-2-yl]butyl }amino)-2-oxoethyl]benzamide as a white solid which was used in the next step without purification.
Step 3: N,N\N’Wboroxin-2A6-triyltrisir(lR)-3-methylbutane-l J-diyllimino(2-oxoethane- 2,l-diyl)^ ^tris(2,5-dichlorobenzamide)
To a solution of 2,5-dichloro-N-[2-({(lR)-3-methyl-l-[(3aS,4S,6S,7aR)-3a,5,5- trimethylhexahydro-4,6-methano-l,3,2-benzodioxaborol-2-yl]butyl }amino)-2-oxoethyl]benzamide (12.2 g, 24.6 mmol) in methanol/hexane (1 :1) (250 mL) were added IN HCl (30 mL, 30 mmol) and (2-methylpropyl)boronic acid (6.5 g, 64 mmol). The reaction mixture was allowed to stir overnight. The phases were separated and the methanol layer was washed twice with additional heptane (2 x 55 mL). The resulting organic layer was concentrated to about 10 mL and partitioned between 2.0M NaOH (30 mL) and DCM (25 mL). The DCM layer was washed once with additional 2.0M NaOH (5 mL). The basic aqueous layers were then combined, washed twice with DCM (2 x 25 mL) and acidified with IM HCl (60 mL). The resulting mixture was diluted with DCM (40 mL), the layers were separated, and the resulting aqueous layer was washed three times with DCM (3 x 10 mL). The combined DCM extracts were dried over MgSO4 (25 g) and evaporated to a thick oil. The product was precipitated with heptane (50 mL) and collected by filtration to yield N,N’,N”-{boroxin-2,4,6- -riyltris[[(lR)-3-methylbutane-l,l-diyl]imino(2-oxoethane-2,l-diyl)] }tris(2,5-dichlorobenzamide) as a white solid (6.6 g, 74%). 1H NMR (300 MHz, DMSO-Cl6, δ): 8.93 (t, J – 6.0 Hz, IH), 8.68 (bs, IH), 7.63 (m, IH), 7.52 (m, 2H), 4.00 (d, J = 6.0 Hz, 2H), 2.62 (m, IH), 1.59 (m, IH), 1.33 (m, IH), 1.24 (m, IH), 0.81 (d, / = 5.9 Hz, 6H). 13C NMR (125 MHz, DMSO-Cl6, δ): 23.2, 25.8, 40.1, 40.7, 43.0, 129.0, 130.0, 131.0, 137.5, 165.0, 172.5. MS (m/z) in CH3CN: [M+H] calculated for C42H52B3Cl6N6O9, 1027.2; found, 1027.3; [M+Na] calculated for C42H51B3Cl6N6NaO9, 1049.2; found 1049.5.
Step 4: 4-(/?.S)-(carboxymethyl)-2-((/?)-l-(2-(2,5-dichlorobenzamido)acetamido)-3- methylbutyl)-6-oxo-l,3,2-dioxaborinane-4-carboxylic acid (1-1)
Form 1: To a solution of citric acid (2.75 g, 14.3 mmol) in EtOAc (85 mL) with an internal temperature of about 74 0C was added N,N’,N”-{boroxin-2,4,6-triyltris[[(lR)-3-methylbutane-l,l- diyl]imino(2-oxoethane-2,l-diyl)] }tris(2,5-dichlorobenzamide) (5.00 g, 4.87 mmol) as a solid. The solution was cooled uncontrolled until the internal temperature was about 25 0C and the mixture was stirred overnight. The resulting precipitate was collected by filtration to yield 2,2′-{2-[(lR)-l-({ [(2,5- dichlorobenzoyl)amino]acetyl }amino)-3-methylbutyl]-5-oxo-l,3,2-dioxaborolane-4,4-diyl}diacetic acid Form 1 as a crystalline solid (6.65 g, 88 %). 1H NMR (500 MHz, DMSOd6, δ 110 0C): 10.08 (s, IH), 8.69 (s, IH), 7.61 (s, IH), 7.52 (d, J = 1.3 Hz, 2H), 4.26 (d, J = 5.5 Hz, 2H), 2.70 (q, J = 14.5 Hz, 4H), 2.70 (bs, IH), 1.72 (sept, J – 6.5 Hz, IH), 1.42 (ddd, J = 5.2 Hz, J = 8.6 Hz, J = 13.9 Hz, IH), 1.28 (ddd, J = 5.3, J = 9.4 Hz, J = 14.3 Hz, IH), 0.91 (dd, J = 3.3 Hz, J = 6.6 Hz, 6H). MS (m/z) in CH3CN: [M+Na] calculated for C20H23BCl2N2NaO9, 539.1; found, 539.1.
Ixazomib citrate [USAN]
1,3,2-Dioxaborolane-4,4-diacetic acid, 2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo- [ACD/Index Name]
1,3,2-Dioxaborolane-4,4-diacetic acid,2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-
1239908-20-3 [RN]
2,2′-{2-[(1R)-1-{[N-(2,5-Dichlorbenzoyl)glycyl]amino}-3-methylbutyl]-5-oxo-1,3,2-dioxaborolan-4,4-diyl}diessigsäure [German] [ACD/IUPAC Name]
2,2′-{2-[(1R)-1-{[N-(2,5-dichlorobenzoyl)glycyl]amino}-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid [ACD/IUPAC Name]
2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diacetic acid
2-[4-(carboxymethyl)-2-[(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methyl-butyl]-5-oxo-1,3,2-dioxaborolan-4-yl]acetic acid
Acide 2,2′-{2-[(1R)-1-{[N-(2,5-dichlorobenzoyl)glycyl]amino}-3-méthylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacétique [French] [ACD/IUPAC Name]
MLN9708
UPDATES………..
Ixazomib (trade name Ninlaro) is a drug for the treatment of multiple myeloma, developed by Takeda Pharma. It acts as aproteasome inhibitor and has orphan drug status in the US. In November 2015, the U.S. Food and Drug Administration approved ixazomib for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma after at least one prior therapy.[2]
Mechanism
Ixazomib is a peptide analogue that reversibly inhibits the protein proteasome subunit beta type-5 (PSMB5), which is part of the 20Sproteasome complex.[3]
Chemistry
Ixazomib citrate—a prodrug for ixazomib
U.S. FDA Approves Takeda’s NINLARO® (ixazomib), the First and Only Oral Proteasome Inhibitor to Treat Multiple Myeloma
NINLARO Provides a New Option for Patients Living with Multiple Myeloma Who Have Received at Least One Prior Therapy
Cambridge, Mass. and Osaka, Japan, November 20, 2015 – Takeda Pharmaceutical Company Limited (TSE: 4502) today announced that the U.S. Food and Drug Administration (FDA) has approved NINLARO®(ixazomib) capsules, the first and only oral proteasome inhibitor, indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is a once-weekly pill. More information is available at www.NINLARO.com.
Takeda submitted a New Drug Application for NINLARO to the FDA in July 2015, and in September NINLARO was granted Priority Review status with a PDUFA date of March 10, 2016, reflecting the profound and continuing unmet need for new treatments for multiple myeloma, a devastating, relapsing and incurable rare cancer.
“With the approval of NINLARO, we can now offer patients a once-weekly oral proteasome inhibitor as part of a highly active triplet therapy,” said Paul Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center Institute Physician at Dana-Farber Cancer Institute, and investigator for TOURMALINE-MM1, the pivotal Phase 3 trial on which today’s approval is based. “We, as investigators of the TOURMALINE-MM1 trial, felt it was vital to conduct a comprehensive ‘real world’ evaluation of this combination that included some of the most common patient types in the relapsed/refractory multiple myeloma setting, such as older patients, patients with moderate renal impairment, light chain disease, and high risk cytogenetics. Further, we treated patients until disease progression to determine the sustainability of NINLARO in treating their relapsed/refractory disease. The TOURMALINE-MM1 data demonstrate convincingly that oral NINLARO-based triplet treatment is effective at extending progression-free survival, over and above the clinical benefit seen with lenalidomide and dexamethasone, with a tolerable safety profile.”
“We introduced the first proteasome inhibitor for multiple myeloma, VELCADE, into clinical research approximately 20 years ago. Since that time, we’ve significantly advanced scientific understanding of this rare cancer, culminating in the introduction of NINLARO,” said Andy Plump, M.D., Ph.D, Takeda Chief Medical and Scientific Officer. “NINLARO is an entirely new molecule that offers the efficacy of this proteasome inhibitor in a convenient once-weekly pill with a tolerable safety profile. Takeda is delighted to bring this significant innovation to multiple myeloma patients today, and we continue to examine the potential of NINLARO through a robust clinical development program.”
Dr. Brian Durie, Chairman of the International Myeloma Foundation, said, “The IMF is pleased by the approval of ixazomib. This opens the door for a fully oral proteasome inhibitor-based triplet combination therapy. Having worked in multiple myeloma for decades, I’ve seen notable progress, yet significant unmet needs remain. With today’s approval, we now have another attractive option for many patients living with multiple myeloma.”
The FDA approval of NINLARO is based on results from the TOURMALINE-MM1 Phase 3 clinical trial, the first double-blind, placebo-controlled trial with a proteasome inhibitor. TOURMALINE-MM1 is the first of five ongoing Phase 3 clinical trials with study results available. The TOURMALINE program has enrolled approximately 3,000 patients to date in 40 countries. Data from the NINLARO Phase 3 TOURMALINE-MM1 pivotal trial will be presented at the upcoming 57th Annual Meeting of the American Society of Hematology on December 7, 2015.
“The approval of ixazomib offers a much-needed additional option in the multiple myeloma treatment landscape. It is developments such as these that help us to better understand the disease and provide continued hope for patients,” said Kathy Giusti, Founder and Executive Chairman of the Multiple Myeloma Research Foundation (MMRF). “A cancer diagnosis today is different from what it was just a few years ago and it’s exciting to see continued progress. As a patient, I understand the urgent need for advancing research through partnerships that bring new treatment options, as we’ve done with Takeda.”
“NINLARO is a first-of-its-kind innovation that is supported by a global development program, unprecedented for us at Takeda Oncology, and we would like to express our immense appreciation for all patients involved for their incredible strength and invaluable participation. The introduction of NINLARO marks an important step forward, as its efficacy and safety profile – coupled with its completely oral administration – potentially can reduce some logistical burdens, and help enable patients to reap the full benefits of this sustainable therapy,” explained Christophe Bianchi, M.D., President, Takeda Oncology. “As part of our unwavering 20-year commitment, Takeda will continue to pursue advances for these patients, and we look forward to introducing and expanding access to NINLARO in other markets around the world.”
About the TOURMALINE-MM1 Trial
TOURMALINE-MM1 is an international, randomized, double-blind, placebo-controlled clinical trial of 722 patients, designed to evaluate NINLARO plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone in adult patients with relapsed and/or refractory multiple myeloma. Results showed NINLARO is effective in extending Progression Free Survival (PFS) and has a manageable safety profile. The trial achieved its primary endpoint and demonstrated a clinically meaningful and statistically significant prolongation in PFS at this analysis, which showed that patients treated in the NINLARO arm lived without their disease worsening for a significantly longer time compared to patients in the control arm. Patients continue to be treated to progression in this trial and will be evaluated for long term outcomes.
In the TOURMALINE-MM1 trial, the most common adverse reactions (≥20%) in patients receiving NINLARO included diarrhea, constipation, thrombocytopenia, peripheral neuropathy, nausea, peripheral edema, vomiting and back pain. Serious adverse reactions reported in ≥2% patients included thrombocytopenia (2%) and diarrhea (2%).
Efficacy and safety data were reviewed by an Independent Data Monitoring Committee (IDMC), who recommended the study be continued in blinded fashion to allow further maturation of long term outcomes, including overall survival (OS) and long-term safety.
About NINLARO (ixazomib) capsules
NINLARO (ixazomib) is the first and only oral proteasome inhibitor indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. NINLARO is administered orally, once-weekly on days 1, 8, and 15 of a 28-day treatment cycle. NINLARO is currently under review by the European Medicines Agency (EMA) and was granted an accelerated assessment by the Committee for Medicinal Products for Human Use (CHMP). NINLARO also received Breakthrough Therapy status by the U.S. FDA for relapsed or refractory systemic light-chain (AL) amyloidosis, a related ultra orphan disease, in 2014.
The TOURMALINE clinical development program further reinforces Takeda’s ongoing commitment to developing innovative therapies for people living with multiple myeloma worldwide and the healthcare professionals who treat them. Five global Phase 3 trials are ongoing:
- TOURMALINE-MM1, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma
- TOURMALINE-MM2, investigating ixazomib vs. placebo, in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma
- TOURMALINE-MM3, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma following induction therapy and autologous stem cell transplant (ASCT)
- TOURMALINE-MM4, investigating ixazomib vs. placebo as maintenance therapy in patients with newly diagnosed multiple myeloma who have not undergone ASCT
- TOURMALINE-AL1, investigating ixazomib plus dexamethasone vs. physician choice of selected regimens in patients with relapsed or refractory AL amyloidosis
In addition to the TOURMALINE program, a large number of investigator initiated studies are evaluating ixazomib for patients globally.
For additional information on the ongoing Phase 3 studies please visit www.clinicaltrials.gov. To learn more about NINLARO, please visit www.NINLARO.com or call 1-844-N1POINT (1-844-617-6468).
References
- “Ninlaro (ixazomib) Capsules, for Oral Use. Full Prescribing Information” (PDF). NINLARO (ixazomib) For Healthcare Professionals. Takeda Pharmaceutical Company Limited Cambridge, MA 02139. Retrieved 21 November 2015.
- “FDA Okays Ixazomib, Another Multiple Myeloma Drug”. November 20, 2015.
- KEGG: Ixazomib
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
N2-(2,5-Dichlorobenzoyl)-N-[(1R)-1-(dihydroxyboryl)-3-methylbutyl]glycinamide
|
|
| Clinical data | |
| Trade names | Ninlaro |
| AHFS/Drugs.com | entry |
| Legal status |
|
| Routes of administration |
Oral |
| Pharmacokinetic data | |
| Bioavailability | 58%[1] |
| Protein binding | 99% |
| Metabolism | hepatic, CYP3A4 (42%),CYP1A2 (26%) and others |
| Biological half-life | 9.5 days |
| Excretion | urine (62%), feces (22%) |
| Identifiers | |
| CAS Number | 1072833-77-2 |
| ATC code | L01XX50 |
| PubChem | CID 25183872 |
| ChemSpider | 25027391 |
| UNII | 71050168A2 |
| KEGG | D10130 |
| ChEBI | CHEBI:90942  |
| Synonyms | MLN2238 |
| Chemical data | |
| Formula | C14H19BCl2N2O4 |
| Molar mass | 361.03 g·mol−1 |
//////////
see….http://apisynthesisint.blogspot.in/2016/02/takedas-ixazomib-multiple-myeloma-drug.html
Transverse myletis, one in a million ailment, will give self support to any one
Today when this blog has taken 10,000 views across 100 countries in 2 months, I take this opportunity to update any one needing information on transverse myletis, one in a million ailment, which I am going through myself , will give self support to any one approaching on mail, person or phone
IT CAN BE CONQUERED
amcrasto@gmail.com
call me in India, +91 9323115463
DETAILS
Paralysis head to toe, from DEC 2007 TILL TODAY MAR 2013. poor recovery, hands ok , head ok and miraculously all organs ok, diabetic and medical attention needed for that
on a wheel chair
bowel zero, all sensation zero below neck
plus points
motivation unmatched, sleep 5 hrs, office work 7 hrs, computer or ipad 6 hrs
special care
control blood thickness, avoid vein thrombosis, stretch limbs physically using help,try more exercises on bed, avoid fever, try antibiotics quickly in iv format, keep tight control on diabetes if any
divine
sixth sense extraordinary, knowledge grasp 1000 times more, motivation high to live and focussed on living only, no much desires except childrens happiness. television, news , sports are hobbies
TLC388 (Lipotecan®) Taiwan Liposome Company Hepatic cancer drug candidate gets fast track approval status from SFDA
TLC388 (Lipotecan®) structure can be figured out from a link below of a poster
http://www.tlcbio.com/files/news/2011111701580783.pdf
IT IS A CAMPOTHECIN ANALOGUE
The str can be concluded from above picture from a poster by TLC BIO
TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors.
Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients.
http://mct.aacrjournals.org/cgi/content/meeting_abstract/10/11_MeetingAbstracts/A89
http://clinicaltrials.gov/show/NCT00747474
MAR19 2013
China SFDA has granted fast track approval status to Taiwan Liposome company hepatic cancer drug Lipotecan, shortening the review period. The drug will enter Phase 2 clinical trials in China in the second half of this year. Lipotecan has been granted orphan drug status by US FDA and EU EMEA for the treatment of hepatocellular carcinoma (HCC)
Nexavar is the standard of care in first line advanced liver cancer patients. Lipotecan as a second-line treatment allows patients who have failed prior treatment with Nexavar to maintain a six month course of the disease without progressing
The FDA has opened the inside track to Novartis’ experimental lung cancer drug, LDK378, which gained “Breakthrough Therapy” designation
The FDA has opened the inside track to Novartis’ experimental lung cancer drug, which gained “Breakthrough Therapy” designation that speeds the development and review schedules for new treatments. The Swiss drug giant plans to file for approval the drug, now in mid-stage clinical trials, in early 2014. Since clinical development began in 2011, the program has advanced with lightning speed compared with those that take 10 years or so to trial before submitted for approval.
While there are no guarantees of an FDA approval for Novartis’ compound, code-named LDK378, the “breakthrough” tag provides an early nod to the potential of the candidate to improve treatment for patients with metastatic non-small cell lung cancer with anaplastic lymphoma kinase (ALK) mutations.
The “breakthrough” designation is also important because Novartis’ compound and others with the coveted status have a shot to be approved by the FDA without completing all three phases of clinical trials typically required before an approval decision.
Novartis’ LDK378 joined the “breakthrough” club after showing an 80% response rate in patients studied in Phase I trial of 88 subjects with advanced cases of ALK-positive NSCLC. The company has already begun a pair of Phase II studies of the compound for patients with the same kind of ALK-positive cancers, which account for about 3% to 8% of cases of NSCLC. And plans call for kicking off Phase III development of the new drug later this year.
“LDK378 is a strong example of our research approach, which focuses on identifying the underlying cause of disease pathways,” said Alessandro Riva, Novartis’ global head of oncology development, in a statement. “This Breakthrough Therapy designation will allow us to collaborate more closely with the FDA and potentially to expedite the availability of an important new treatment option for patients with ALK+ NSCLC.”
ThromboGenics NV, European Commission has approved JETREA® (ocriplasmin) in the European Union
Leuven, March 15, 2013
ThromboGenics NV an integrated biopharmaceutical company focused on developing and commercializing innovative ophthalmic medicines, today announces that the European Commission has approved JETREA® (ocriplasmin) in the European Union. JETREA® is approved for the treatment of vitreomacular traction (VMT), including when associated with macular hole of diameter less than or equal to 400 microns. The EU approval triggers a €45 million milestone payment to ThromboGenics from its partner Alcon. The first sale of JETREA® in the EU by Alcon will trigger a further €45 million milestone payment to ThromboGenics.
Alcon, a division of Novartis, acquired the rights to commercialize JETREA® outside the United States in March 2012. ThromboGenics retains the right to commercialize the drug in the US. ThromboGenics launched JETREA® in the US in mid-January 2013 where it is approved for the treatment of patients with symptomatic vitreomacular adhesion (VMA).
Ocriplasmin (trade name Jetrea) is a recombinant protease with activity against fibronectin and laminin, components of the vitreoretinal interface. It is used for treatment of symptomatic vitreomacular adhesion, for which it received FDA approval on 17 October 2012. It works by dissolving the proteins that link the vitreous to the macula, resulting in posterior detachment of the vitreous from the retina.[1]
Intravenous formulation of Melphalan, which is in a Phase III trial for use as a conditioning treatment prior to autologous stem cell transplant for patients with multiple myeloma
Mephalan
15 march 2013
Spectrum Pharmaceuticals has licensed an investigational multiple myeloma drug from Ligand Pharmaceuticals in a deal that could be worth over $50 million.
The treatment in question is an intravenous formulation of melphalan, which is in a Phase III trial for use as a conditioning treatment prior to autologous stem cell transplant for patients with multiple myeloma. Spectrum is assuming the responsibility for the trial and hopes to file Captisol-enabled melphalan in the first half of 2014.
The Captisol technology used to reformulate melphalan allows for longer administration durations and slower infusion rates. It has been used with six US Food and Frug Administration-approved products, including Onyx Pharmaceuticals’ multiple myeloma drug Kyprolis (carfilzomib )and Pfizer’s antifungal Vfend (voriconazole).
Melphalan hydrochloride (trade name Alkeran) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.
An alkylating agent adds an alkyl group (CnH2n+1) to DNA. It attaches the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring.
Otherwise known as L-Phenylalanine Mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine.
Uses
It is used to treat multiple myeloma[1] and ovarian cancer, and occasionally malignant melanoma.
The agent was first investigated as a possible drug for use in melanoma. It was not found to be effective, but has been found to be effective in the treatment of myeloma.
Oral or intravenous; dosing varies by purpose and route of administration as well as patient weight.
Melphalan Prescribing Information: Alkeran[2]
Melphalan Patient Information: MedlinePlus[3]
Melphalan Material Safety Data Sheet (MSDS): Sequoia Research Products[4]
- Facon T, Mary JY, Hulin C, et al. (October 2007). “Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial”. Lancet 370 (9594): 1209–18. doi:10.1016/S0140-6736(07)61537-2. PMID 17920916.
- celgene.com
- nlm.nih.gov
- seqchem.com
Sinovac Reports Preliminary Top-Line Results from Phase III Clinical Trial for EV71 Vaccine Candidate Against Hand, Foot and Mouth Disease
BEIJING, March 14, 2013
Sinovac Biotech Ltd. a leading provider of vaccines in China, announced today preliminary top-line data from its Phase III clinical trial assessing the efficacy, immunogenicity and safety of the Company’s proprietary Enterovirus 71 (“EV71”) vaccine against hand, foot and mouth disease (“HFMD”).
The primary objective of the study was to evaluate the efficacy of the EV71 vaccine in the prevention of HFMD caused by EV71 in infants of 6 to 35 months old. The preliminary Phase III data showed that Sinovac’s EV71 vaccine was 95.4% (95% CI: 87.5%, 98.3%) efficacious against HFMD caused by EV71.
The Phase III trial showed good immunogenicity and safety for Sinovac’s EV71 vaccine. The overall incidence of serious adverse events in this trial was 2.2% among the EV71 candidate vaccine recipients and 2.6% among those receiving a control vaccine during the fourteen months observation period. The difference in rates of serious adverse events (“SAEs”) is not statistically significant. Most of the SAEs were considered unlikely to be vaccine-related.
The double-blinded, randomized, placebo controlled Phase III clinical trial was conducted at three sites across China’s Jiangsu province. Approximately 10,000 healthy infants completed the two dose vaccination schedule (at 0 and 28 days) in the first quarter of 2012, prior to the HFMD epidemic season in China, followed by active monitoring period.
In parallel, Sinovac conducted another clinical study that was comprised of 1,400 volunteers and designed to evaluate the consistency of three consecutive lots of EV71 vaccine manufactured by the Company. The trial was conducted in children from 6 month to 5 years old. After receiving the vaccine, the ratios of neutralizing antibody GMTs on the 56th day of any two groups were calculated and the 95% confidence intervals of the ratios are all between 0.67 and1.5, which indicates the immunogenicity of the three vaccine lots is equivalent. The study results showed consistent immune response for all three lots and a good safety profile. With immunogenicity equivalent across the three consecutive lots, the results showed Sinovac’s vaccine production process and quality are stable.
In March 2008, an EV71 outbreak in Fuyang City of China’s Anhui Province caused 23 fatalities, and attracted significant attention from the government and medical communities. In May 2008, the PRC Ministry of Health identified EV71 as a Class C infectious disease according to prevention and control regulations. EV71 outbreaks have increased over the last five years, with over 1 million cases identified and 500 to 900 reported fatalities each year.
Dr. Weidong Yin , Chairman, President and CEO of Sinovac, commented, “We are excited to report an over 95% efficacy rate from the Phase III trial on our proprietary EV71 vaccine candidate. The conclusion of this trial marks an important milestone in the development of our proprietary vaccine. Hand, foot, and mouth disease continues to represent a significant unmet public health need and economic burden in China, as well as several other Asian countries. Our EV71 vaccine is poised to provide an effective solution to prevent hand, food and mouth disease caused by EV71, a much needed resource given the current limited prevention and EV71 specific treatment methods. At Sinovac, we are committed to our stated mission to develop and supply vaccines to eliminate human diseases.”
Professor Hua Wang, Lead Principal Investigator, stated, “The Phase III study for Sinovac’s EV71 vaccine candidate met its primary objective. The trial results demonstrated that the vaccine is not only safe, but shows significant efficacy in subjects.”
The Company’s next step is to finalize the clinical report, which will become an important part of documents to be filed with the PRC State Food and Drug Administration (“SFDA”) for the application of new drug certificate, GMP certification, and the production license in order to commence the commercial production of the vaccine. In parallel, Sinovac’s dedicated EV71 vaccine manufacturing facility has been completed and is ready for the GMP inspection by SFDA.
Sinovac obtained clinical research approval for its proprietary EV71 vaccine candidate from the SFDA in December 2010, and completed Phase I and II clinical trials in 2011. The preliminary results of the Phase I and Phase II studies confirmed that Sinovac’s vaccine candidate has good safety and immunogenicity profile.
About Sinovac
Sinovac Biotech Ltd. is a China-based biopharmaceutical company that focuses on research, development, manufacturing and commercialization of vaccines that protect against human infectious diseases including hepatitis A and B, seasonal influenza, H5N1 pandemic influenza and mumps, as well as animal rabies vaccine. In 2009, Sinovac was the first company worldwide to receive approval for its H1N1 influenza vaccine, Panflu.1, and has manufactured it for the Chinese Central Government, pursuant to the government-stockpiling program. The Company is also the only supplier of the H5N1 pandemic influenza vaccine to the government-stockpiling program. Sinovac is developing a number of new pipeline vaccines including vaccines for enterovirus 71 (against hand, foot, and mouth disease), pneumococcal conjugate, pneumococcal polysaccharides, varicella and rubella. Sinovac sells its vaccines mainly in China and exports selected vaccines to Mongolia, Nepal, and the Philippines.
A sensor-adaptor mechanism for enterovirus uncoating from structures of EV71
Xiangxi Wang, Wei Peng, Jingshan Ren, Zhongyu Hu, Jiwei Xu, Zhiyong Lou, Xumei Li, Weidong Yin, Xinliang Shen, Claudine Porta, Thomas S Walter, Gwyndaf Evans, Danny Axford, Robin Owen, David J Rowlands, Junzhi Wang*, David I Stuart*, Elizabeth E Fry* & Zihe Rao*
Enterovirus 71 1 (EV71) is a major agent of hand, foot and mouth disease in children that can cause severe central nervous system disease and death. No vaccine or antiviral therapy is available. High-resolution structural analysis of the mature virus and natural empty particles shows that the mature virus is structurally similar to other enteroviruses. In contrast, the empty particles are markedly expanded and resemble elusive enterovirus-uncoating intermediates not previously characterized in atomic detail. Hydrophobic pockets in the EV71 1 capsid are collapsed in this expanded particle, providing a detailed explanation of the mechanism for receptor-binding triggered virus uncoating. These structures provide a model for enterovirus uncoating in which the VP1 1 GH loop acts as an adaptor-sensor for cellular receptor attachment, converting heterologous inputs to a generic uncoating mechanism, highlighting new opportunities for therapeutic intervention. [ Nat Struct Mol Biol. 2012 Mar 4. doi: 10.1038/nsmb.2255. Epub ahead of print. PMID: 22388738 ][ PDF ]
New Drug Approvals