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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Lurasidone hydrochloride, Jubilant Generics Ltd, WO 2016059649, New patent
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Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent
An improved process for the preparation of lurasidone hydrochloride
Jubilant Life Sciences Ltd
WO 2016059649
JUBILANT GENERICS LIMITED (FORMERLY JUBILANT LIFE SCIENCES DIVISION) [IN/IN]; Plot 1A, Sector 16 A, NOIDA Uttar Pradesh 201301 (IN)
MISHRA, Vaibhav; (IN).
DUBEY, Shailendr; (IN).
SINGH, Kumber; (IN).
CHOUDHARY, Alka Srivastava; (IN).
VIR, Dharam; (IN)
Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.
Improved process for preparing lurasidone or its hydrochloride, substantially free of residual solvent, useful for treating schizopherenia and bipolar disorder. Also claims novel intermediate of lurasidone eg ((R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone) and its preparation method.
In April 2016, Newport Premium™ reported that Jubilant Life Sciences was capable of producing commercial quantities of lurasidone and lists the drug as a molecule available under research and development on the company’s website.
This is the first patenting to be seen from Jubilant Life Sciences that focuses on lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma and EU licensee Takeda, for treating schizophrenia.
May 2, 2014
Neeraj Agrawal: Took charge of API business for Jubilant Life Sciences at the age of 31
Position: CEO Generics, Jubilant Life Sciences
Education: IIIM-C, MBA, 1998; IIT, Bombay, Electrical Engg., 1995.
Previous Jobs: Associate-Business Strategy, Operations Improvement, McKinsey & Co.
Claim to Fame: Took charge of the API business for Jubilant when he was just 31-years-old
Management mantra: It revolves around trust, freedom and teams. I like my team to think and act like an entrepreneur – assess business risks and rewards suitably and then take decisions.
Lurasidone and its pharmaceutically acceptable salts like lurasidone hydrochloride is chemically, (3a ?,45,7 ?,7a5)-2-{ (1 ?,2 ?)-2-[4-(l,2-benzisothiazol-3-yl)piperazin-lyl-methyl] cyclohexylmethyl }hexahydro-4,7-methano-2H-isoindole- 1 ,3 -dione hydrochloride and has the structure represented by the Formula (I):
Formula-I
Lurasidone hydrochloride is marketed in the United States under the trade name Latuda®. Lurasidone and its pharmaceutically acceptable salts as well as process for their preparation was first disclosed in US patent no. 5,532,372. The patent discloses the preparation of lurasidone hydrochloride using racemic trans 1,2-cyclohexane dicarboxylic acid. Racemic trans 1,2-cyclohexane dicarboxylic acid on reduction with lithium aluminium hydride in THF at reflux temperature forms l,2-bis(hydroxymethyl)cyclohexane which is converted into racemic iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane by reaction with methane sulfonyl halide. l-(l,2-benzisothiazol-3-yl)piperazine on reaction with trans-l, 2-b (methanesulfonyloxymethyl)cyclohexane in the presence of sodium carbonate and acetonitrile forms iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in the presence of potassium carbonate, dibenzo-18-crown-6-ether and xylene on refluxing forms racemic lurasidone free base. The compound is obtained by column chromatography and then treated the resulting lurasidone free base with IPA.HCl in acetone to obtain racemic lurasidone hydrochloride. Resolution of racemic lurasidone hydrochloride is carried out using tartaric acid as resolving agent. The process involves use of lithium aluminium hydride which is highly pyrophoric reagent and is not to utilize the same on commercial scale due to its handling problems associated with its reactivity. Also, the use of the column chromatography for purification is not viable on commercial scale. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production. Carrying out the resolution in the last stages is difficult due to the presence of six chiral centres in lurasidone and is also not suitable for an industrial scale preparation as it affects the overall yield and cost of the manufacturing process.
Chinese patent application no. CN102731512 discloses a process for preparation of lurasidone which comprises reaction of racemic irans-l,2-bis(methanesulfonyloxymethyl) cyclohexane and l-(l,2-benzisothiazol-3-yl)piperazine in toluene in the presence of sodium carbonate or potassium carbonate having particle size less than 200 micron and tetrabutyl ammonium bromide to give the intermediate /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazinemethanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in toluene using potassium carbonate having particle size less than 200 micron forms racemic lurasidone free base. The racemic free base is converted into racemic hydrochloride salt using acetone and cone, hydrochloric acid. Racemic lurasidone hydrochloride is resolved by following the method disclosed in US patent no. 5,532,372. The process involves resolution of product in the last stage which is not commercially viable as it affects the overall yield and cost of the manufacturing process.
Japanese patent no. JP4219696 discloses the resolution of trans 1,2-cycloheaxne dicarboxylic acid using (lS,2R)-(+)-norephedrine or (lR,2S)-(-)norephedrine to provide (R,R)-trans 1 ,2-cyclohexanedicarboxylic acid. The (R,R)-iran,sl,2-cyclohexane dicarboxylic acid obtained was esterified with ethanol and the obtained ester compound was reduced with vitride to provide (R,R)-l,2-bis(hydroxymethyl)cyclohexane followed by treatment with methane sulfonyl chloride to form (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane. The process requires large quantity of reducing agent viz., for reducing one lg of compound about 5g of reducing agent is required which is not conducive for industrial production.
Chinese patent application no. CN 102952001 discloses a process for the preparation of (lR,2R)cyclohexane-l,2-dimethanol by the reduction of (lR,2R)cyclohexane-l,2-
dicarboxylic acid using sodium borohydride or potassium borohydride and boron triflouoride diethyl ether in THF or diethyl ether as solvent. Boron triflouoride diethyl ether is used in large quantity and quite expensive which makes the process commercially unviable.
International publications no. WO 2012/131606 and WO 2014/037886 disclose a process for preparation of lurasidone which involves separating the racemic transl,2-cyclohexane dicarboxylic acid into its (R,R) trans and (S,S) trans isomers and then using the desired trans (R,R) isomer for the preparation of lurasidone hydrochloride using the chemistry disclosed in US patent no. 5,532,372 for preparation of racemic lurasidone hydrochloride. In these publications diisobutyl aluminium hydride (DIBAL) is used as the reducing agent for the preparation of (1R,2R) cyclohexane 1,2-dimethanol from (1R,2R) cyclohexane 1,2-dicarboxylic acid which is quite expensive. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production.
Some of the prior art processes disclose the process for the preparation of lurasidone hydrochloride from l,2-(lR,2R)-bis-(methanesulfonyloxymethyl)cyclohexane using different solvents and bases.
US patent no. 8,853,395 discloses a process for the preparation of lurasidone in which condensation of iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benz isothiazol-3-yl)piperazine and condensation of /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide is carried out using organic bases with a ρ¾ higher than 10 such as l,4-diazabicycloundec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diaza bicyclo[2.2.2] -octane (DABCO). These organic bases are comparatively expensive.
Indian patent application no. IN 2306/MUM/2014 and Chinese patent applications no. CN 102863437 and CN 103864774 disclose the use of dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), dimethyl acetamide (DMA) and N-methyl pyrrolidine (NMP) for the condensation of iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)] piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide to form lurasidone. These solvents have high boiling point so not preferred at commercial scale.
Some of the prior art processes are related to reduction of impurities or quality improvement of lurasidone hydrochloride.
International publication no. WO2011/136383 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by increasing the quantity of l-(l,2-benzisothiazol-3-yl)piperazine instead of sodium carbonate or potassium carbonate as base in the reaction mixture. Increasing the amount of l-(l,2-benzisothiazol-3-yl)piperazine causes an increase in cost of production and removal of excess compound makes the process less commercially viable.
International publication no. WO2011/136384 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by using dibasic potassium phosphate with a small amount of water as a base instead of sodium carbonate. Use of dibasic potassium phosphate as a base causes an increase in cost of production as dibasic potassium phosphate is expensive.
International publication no. WO2013/014665 discloses various processes for the preparation of lurasidone hydrochloride. In general the process is shown below:
Formula-(I)
In this process iran5-(lR,2R)-2-(aminomethyl)cyclohexyl)methanol of Formula (B) is first reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula (A) to form (3aR,4S,7R,7aS)-2-(((lR,2R)-2-(hydroxymethyl)cyclohexyl)methyl)hexahydro-lH-4,7-methanoisoindole-l,3(2H)-dione of Formula (C) which on reaction with methane sulphonyl chloride followed by reaction with l-(l,2-benzisothiazol-3-yl)piperazine of Formula (D) forms lurasidone free base which was converted into lurasidone hydrochloride using acetone and cone, hydrochloric acid.
Some of the prior art processes disclose various combinations of hydrogen chloride and solvent for the preparation of lurasidone hydrochloride from lurasidone free base.
US 7,605,260 discloses use of acetone and aqueous HC1 having strength 1.8-14.4 % for preparing lurasidone hydrochloride. The yield of lurasidone hydrochloride is relatively low (85%) by this method. If the acid concentration during the salt formation is more than 5.0% then acetone quantity as the residual solvent in the reaction product is found to be greater than 0.5% in our hands which is above the ICH limits. If acid concentration during the salt formation is less than 1.8%, then yield is reduced drastically to 65%. Therefore, this method has limitations on the large-scale industrial production.
Chinese patent application no. CN102746289A discloses the process for the preparation of lurasidone hydrochloride by adding a mixture of acetone and aqueous HC1 to a solution of lurasidone free base in acetone. On reproducing this process in laboratory, it was observed that the XRPD of the product obtained does not match with XRPD of lurasidone hydrochloride.
Indian patent application IN 777/MUM/2013 discloses use of IPA, water and 35% Aqueous HC1 for the preparation of lurasidone hydrochloride. The IPA content in the product was found to be more than 5000ppm.
The methods described in the prior art are not suitable for large scale commercial production as the residual solvent is out of the ICH limits and thus the product obtained can’t be used as a drug. In order to keep the residual solvent(s) within ICH limits, repeated crystallization/purification are required which results in reduced yield and make the process quite expensive.
The prior art discloses various processes for the preparation of lurasidone hydrochloride and its intermediates. However, there still remains a need for alternative process for the preparation of lurasidone and its pharmaceutically acceptable salts substantially free of residual solvent(s) which can be used as a drug.
According to another embodiment of the present invention, novel process for the preparation of the compound of Formula (III), their isomers and pharmaceutically acceptable salts thereof, comprises condensing 1,2-cyclohexane dicarboxylic acid of Formula (II), their isomers with carbonyl diimidazole, optionally in a solvent.
(IV) 
Formula (III)
NaBH4 RT /H20
Formula (VII)
Scheme-1:
Example-1
Synthesis of trans(R,R)-l,2-cyclo exane dicarboxylic acid
A round bottom flask was charged with methanol (500 mL), IPA (500 mL) and trans (racemic)-l,2-cyclohexane dicarboxylic acid (100 g). In this reaction mass (R)-l-phenylethyl amine (74 mL) was added over a period of 30 minutes and stirred for 2-3 hrs at 30-40 °C. The solid obtained was filtered, washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure to obtain crude salt of iran5(R,R)-l,2-cyclohexane dicarboxylic acid. The obtained salt was stirred in a solution of methanol (500 mL) and IPA (500 mL) at 65-70 °C for 2-3 hours, cooled to room temperature and filtered. The solid was washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure. The solid thus obtained was dissolved in about 2N hydrochloric acid and extracted two times with ethyl acetate (1000 mL+200 mL). Organic layers were combined and washed with brine solution (100 mL). Ethyl acetate was distilled off under vacuum at 50-55 °C and cyclohexane was added to the residue. The solid separated out was filtered and washed with cyclohexane and dried under vacuum at 45-50 °C for 8-10 hours. Yield = 29.4 g
Example-2
Synthesis of ((R,R)-cyclohexane-L2-diyl)bis((lH-imidazol-l-yl)methanone)
To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) is added and stirred for one hour at 25-30 °C . To the said solution of (R,R)2-(((lH-imidazole-lcarbonyl)oxy)carbonyl)cyclohexanecarboxylic acetic anhydride lH-imidazole (25.0 g) in THF (250 mL) is stirred for one hour at 45-50 °C. The compound obtained is isolated and is characterized by mass and NMR.
[m z = 272.75; 1H-NMR: 8.24 (s, 2H), 7.72 (d, 2H); 7.50 (d, 2H), 3.5 (m, 2H), 2.26-1.50 (m, 8H)]
Example-3
Synthesis of tra»,s(R,R)-l,2- bis(hydroxymethyl)cyclohexane
To a solution of ((R,R)-cyclohexane-l,2-diyl)bis((lH-imidazol-l-yl)methanone) (25 g) in THF (250 mL), sodium borohydride (22.0 g) followed by water (44.0 mL) are added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) are added, stirred and layers separated. The organic layer is washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass
dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) are added, stirred and layers obtained are separated. The dichloromethane is distilled off completely from organic layer at 40 °C to obtain oily mass (15.5 g).
Example-4
One pot process for synthesis of trans(R,R)-l,2- bis(hydroxymethyl)cyclohexane from trans(R,R)-l,2-cyclo exane dicarboxylic acid
To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) was added and stirred for one hour at 25-30 °C. To the intermediate obtained sodium borohydride (22.0 g) and water (44.0 mL) were added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) were added, stirred and layers separated. The aqueous layer was washed with dichloromethane (250 mL). The organic layer was washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) were added, stirred and layers obtained were separated. The dichloromethane was distilled off completely at 40 °C to obtain oily mass (15.5 g).
Example-5
Synthesis of m¾ns(R,R)- 2-bis(methanesulfonylmethyl) cyclohexane
To a suspension of irafts(R,R)-l,2-bis(hydroxymethyl)cyclohexane (15.0g) in dichloro methane (300 mL), triethyl amine (43.7 mL) followed by methane sulphonyl chloride (17.8 mL) were added over a period of 30-45 minutes. Reaction mass was stirred for 2-3 hrs. Reaction was monitored by HPLC (RI detector). After the completion of reaction, water was added, stirred and layers separated. The organic layer was washed with 10% sodium bicarbonate solution (150 mL) followed by water (150 mL). The dichloromethane was distilled off from organic layer under vacuum at 40-55 °C to give an oily mass. Methanol (30 mL) was added to the oily mass and strip off under vacuum at 40°C, added methanol (150 mL) and stirred for 1 h at 10-15°C and the solid obtained was filtered, washed with methanol (15 mL) and dried under vacuum to get the product (15.8g).
Example-6
Synthesis of ?ran (R,R)-3aJ(¾-octahvdroisoindolium-2-spiro- -r4-(L2-benzoisothiazole-3-yl)l piperazine methanesulfonate:
To a suspension of iran5(R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (15 g) in acetonitrile (150 mL) l-(l,2-benzisothiazol-3-yl)piperazine (10.95g) and sodium carbonate (7.8 g) were added, heated and stirred for 20 hrs at reflux temperature. Reaction was monitored by HPLC. After the completion of reaction, mass was cooled to 40-45 °C, filtered and washed with acetonitrile (20 mL). The acetonitrile was distilled off under vacuum at 45-50 °C. To the residue acetone (100 mL) was added, stirred for 1 hour, filtered, washed with acetone (10 mL), dried at 50-55°C for 6-8 hours to get the product (12.5 g).
Example-7
Synthesis of Lurasidone
To a suspension of iran5(R,R)-3<3,7(3-octahydroisoindolium-2-spiro- -[4-(l,2-benzo isothiazole-3-yl)]piperazinemethanesulfonate (10 g) in toluene (150 mL), bicycle[2.2.1] heptane-2-exo-3-exo-dicarboximide (5.9 g) and potassium carbonate (4.8 g) were added, heated to 110° C and stirred for 8-10 hours. Reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 20-30 °C, filtered and washed with toluene (10 mL). The toluene was distilled off at 55-60°C. To the residue IPA (100 mL) was added and stirred for 1-2 hours at room temperature. Lurasidone free base obtained was filtered and washed with IPA (10 mL). The solid was suck dried for 30 minutes to obtain lurasidone.
Example-8
Synthesis of Lurasidone hydrochloride
To lurasidone base (5g), acetone (75mL) and water (10 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (lOmL) and stirred for 1-2 hours, reflux temperature. The clear solution obtained was stirred for 30 min and then 5ml IPA.HCl (10%) was added. The reaction mixture was stirred at reflux temperature for 30 min, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 60°C for 8 hours.
Acetone: 542 ppm; IPA= 38ppm; Yield=93%
Example-9
Synthesis of Lurasidone hydrochloride
To lurasidone base (5g), acetone (75mL) and water (5 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (5mL) and stirred for about 1-2 hours. The reaction mixture was stirred for 30 min. at 55-60°C, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 70-80°C for 8 hours.
Jubilant Generics Limited
Chairman & Managing Director
Jubilant Bhartia Group Shyam, together with his brother Hari, is founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India. The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorks Limited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.Shyam, holds a bachelors’ degree in commerce from St. Xavier’s College, Calcutta University, and is a qualified cost and works accountant & a fellow member of the Institute of Cost and Works Accountants of India (ICWAI).Shyam has been associated with various institutions and has served as Member of Board of Governors, Indian Institute of Technology (IIT), Mumbai, and Indian Institute of Management (IIM), Ahmedabad. Shyam has also served as a Member of the Executive Committee of Federation of Indian Chamber of Commerce & Industry (FICCI) & Confederation of Indian Industry (CII) and was also a member of Task Force on Chemicals appointed by the Government of IndiaShyam’s immense contributions have been recognized by various awards. CHEMEXCIL has conferred Lifetime Achievement Award 2010-11 to him. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-covetedErnst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Shyam serves on the Board of several Public and Private and Foreign companies likes of Chambal Fertilizers and Chemicals Ltd, Putney Inc., CFCL Technologies Limited (Cayman Islands), Tower Promoters, BT Telecom India Pvt Ltd., American Orient Capital Partners India Pvt Ltd, IMACID, Morocco, Safe Food Corporation, etc. He was also a Director on the Board of Air India.Shyam is a regular participant at the World Economic Forum Annual Meeting in Davos and a member of the Chemical Governors Council of the World Economic Forum.Shyam is married to Shobhana, Former Member of Parliament & Chairperson, The Hindustan Times Media Ltd. They have two sons- Priyavrat and Shamit.
ISO Certification
ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 certified
Code of Conduct
Code Of Conduct for Directors and Senior ManagementThis Code of Conduct highlights the standards of conduct expected from the Company’s Directors and Senior Management so as to align these with the Company’s Vision, Promise and Values.Jubilant Life Sciences Ltd. (Jubilant) has a well formulated Vision which drives the business and has the promise of Caring, Sharing, Growing to all the stakeholders–We will, with utmost care for the environment, continue to enhance value for our customers by providing innovative products and economically efficient solutions and for our shareholders through sales growth, cost effectiveness and wise investment of resources.
Director’s Desk
Co-Chairman & Managing Director
Jubilant Bhartia Group
Hari, together with his brother Shyam, is co-founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India.The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorksLimited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.A Chemical Engineering Graduate from the prestigious Indian Institute of Technology (IIT), Delhi, Hari was conferred the Distinguished Alumni award by his alma mater in 2000. He has been associated in various capacities with the IIT system and with the Ministry of Human Resource Development, Government of India.Hari is a past President of the Confederation of Indian Industry (CII) & a member of several educational, scientific and technological programmes of the Government of India. He is currently the Chairman of the Board of Governors of the Indian Institute of Management (IIM), Raipur and Member of the International Advisory Board of McGill University, Canada.Hari is the Co-Chairman of India-Canada CEO’s Forum appointed by the Prime Minister of India. He is also a member of CEO’s Forum for India-USA, India-France and India-Sri Lanka and Joint Task Force for India-Myanmar & India-UAE. He is a regular participant at the World Economic Forum Annual Meeting in Davos and is a member of the World Economic Forum’s International Business Council and the Health Governors.Hari’s immense contributions have been recognized by various awards. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-coveted Ernst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Hari serves on the board of several public and private companies like TV 18 Broadcast Ltd., Shriram Pistons & Rings Ltd., Export Credit Guarantee Corporation of India Ltd., BT Telecom India Pvt. Ltd & India Brand Equity Foundation.Hari is married to Kavita, a leading Fashion Designer and Retailer. They have a daughter, Aashti and a son, Arjun.
Executive Leadership Team
Shyam S Bhartia
Chairman
Hari S Bhartia
Co-Chairman & Managing Director
Shyamsundar Bang
Executive Director –Manufacturing & Supply Chain
R Sankaraiah
Executive Director – Finance
Pramod Yadav
Co-CEO
Life Science Ingredients
Rajesh Srivastava
Co-CEO
Life Science Ingredients
G. P. Singh
Fine Chemicals and CRAMS
CEO – Jubilant Pharma
Chandan Singh
President – Life Science Chemicals
Martyn Coombs
President – Jubilant DraxImage
Bryan Downey
President – Allergy Business
T. S. Parmar
President – India Branded Pharmaceuticals
Dr. Ashutosh Agarwal
Chief Scientific Officer –Chemicals and Life Science Ingredients
Ajay Khanna
Chief – Strategic & Public Affairs
///////Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent
Albutrepenonacog alfa
Albutrepenonacog alfa
recombinant factor IX
(Idelvion®)Approved, 2016-03-04 USFDA
A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.
Research Code CSL-654
| Type | Recombinant coagulation factor |  |
| Source | Human | |
| Molecular Formula | C5077H7846N1367O1588S67 | |
| Molecular Weight | ~125000 |
Other Names
- Albutrepenonacog alfa
Protein Sequence
Sequence Length: 1018modified (modifications unspecified)
- Originator CSL Behring
- Class Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins
- Mechanism of Action Blood coagulation factor replacements; Factor X stimulants
- Orphan Drug Status Yes – Haemophilia B
- Marketed Haemophilia B
Most Recent Events
- 21 Mar 2016 Launched for Haemophilia B (In adolescents, In children, In adults) in USA (IV) – First global launch
- 07 Mar 2016 Preregistration for Haemophilia B in Australia (IV) before March 2016
- 04 Mar 2016 Registered for Haemophilia B (In children, In adolescents, In adults) in USA (IV)
| Latest Stage of Development | Approved |
| Standard Indication | Hemophilia |
| Indication Details | Treat and prevent bleeding episodes in hemophilia B patients; Treat hemophilia B |
| Regulatory Designation | U.S. – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); EU – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); Switzerland – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients) |
-
BNF Category:Antifibrinolytic drugs and haemostatics (02.11)
Pharmacology: Albutrepenonacog alfa is a recombinant factor IX (rIX-FP) albumin fusion protein, designed to exhibit an extended half-life. Factor IX has a short half-life which necessitates multiple injections. Epidemiology: Haemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein. It has a prevalence of around 1 in 50,000 live births in the UK and is more common in males. In 2012-13, there were 476 hospital admissions in England due to haemophilia B, accounting for 508 finished consultant episodes and 125 bed days. Indication: Haemophilia B
Albutrepenonacog alfa was approved by the U.S. Food and Drug Administration (FDA) on March 4, 2016. It was developed and marketed as Idelvion® by CSL Behring.
Albutrepenonacog alfa is a recombinant albumin-human coagulation factor IX (FIX) fusion protein, which replaces the missing FIX needed for effective hemostasis. It is indicated for the treatment and prevention of bleeding in children and adults with hemophilia B.
Idelvion® is available as injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1000 IU or 2000 IU of albutrepenonacog alfa in single-use vials. In control and prevention of bleeding episodes and perioperative management, the required dosage is determined using the following formulas: Required Dose (IU) = Body Weight (kg) x Desired Factor IX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)). In routine prophylaxis, the recommended dose is 25-40 IU/kg (for patients ≥12 years of age) or 40-55 IU/kg (for patients <12 years of age) every 7 days.
On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product IDELVION, intended for treatment and prophylaxis of bleeding in patients with Haemophilia B. IDELVION was designated as an orphan medicinal producton 04 February 2010. The applicant for this medicinal product is CSL Behring GmbH.
IDELVION will be available as 250 IU, 500 IU, 1000 IU and 2000 IU Powder and solvent for solution for injection. The active substance of IDELVION is albutrepenonacog alfa, an antihaemorrhagic, blood coagulation factor IX, (ATC code: B02BD04). It works as replacement therapy and temporarily increases plasma levels of factor IX, helping to prevent and control bleeding.
The benefits with IDELVION are its ability to stop the bleeding when given on demand and prevent bleeding when used as routine prophylaxis or for surgical procedures. The most common side effects are injection site reaction and headache.
The full indication is: “the treatment and prophylaxis of bleeding in patients with Haemophilia B (congenital factor IX deficiency)”. Idelvion can be used in all age groups. It is proposed that IDELVION be prescribed by physicians experienced in the treatment of haemophilia B.
Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
| Name | Idelvion |
|---|---|
| INN or common name | albutrepenonacog alfa |
| Therapeutic area | Hemophilia B |
| Active substance | albutrepenonacog alfa |
| Date opinion adopted | 25/02/2016 |
| Company name | CSL Behring GmbH |
| Status | Positive |
| Application type | Initial authorisation |
//////Albutrepenonacog alfa, CSL-654, Idelvion; Recombinant factor IX – CSL Behring, Recombinant factor IX fusion protein linked with human albumin, rFIX-FP – CSL Behring; rIX-FP, Orphan Drug Status, Haemophilia B, recombinant factor IX , FDA 2016
update
Human medicines European public assessment report (EPAR): Idelvion, albutrepenonacog alfa, Hemophilia B, 11/05/2016,  , 9, Authorised |
Asfotase alfa
> Asfotase Alfa Sequence LVPEKEKDPKYWRDQAQETLKYALELQKLNTNVAKNVIMFLGDGMGVSTVTAARILKGQL HHNPGEETRLEMDKFPFVALSKTYNTNAQVPDSAGTATAYLCGVKANEGTVGVSAATERS RCNTTQGNEVTSILRWAKDAGKSVGIVTTTRVNHATPSAAYAHSADRDWYSDNEMPPEAL SQGCKDIAYQLMHNIRDIDVIMGGGRKYMYPKNKTDVEYESDEKARGTRLDGLDLVDTWK SFKPRYKHSHFIWNRTELLTLDPHNVDYLLGLFEPGDMQYELNRNNVTDPSLSEMVVVAI QILRKNPKGFFLLVEGGRIDHGHHEGKAKQALHEAVEMDRAIGQAGSLTSSEDTLTVVTA DHSHVFTFGGYTPRGNSIFGLAPMLSDTDKKPFTAILYGNGPGYKVVGGERENVSMVDYA HNNYQAQSAVPLRHETHGGEDVAVFSKGPMAHLLHGVHEQNYVPHVMAYAACIGANLGHC APASSLKDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEV KFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKDIDDDD DDDDDD
Asfotase alfa
Indicated for the treatment of patients with perinatal/infantile and juvenile onset hypophosphatasia (HPP).
(Strensiq®)Approved
A mineralized tissue targeted fusion protein used to treat hypophosphatasia.
Research Code ALXN-1215; ENB-0040; sALP-FcD-10
CAS No.1174277-80-5
| 180000.0
C7108H11008N1968O2206S56 |
| Company | Alexion Pharmaceuticals Inc. |
| Description | Fusion protein incorporating the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP; ALPL) and a bone-targeting peptide |
| Molecular Target | |
| Mechanism of Action | Enzyme replacement therapy |
| Therapeutic Modality | Biologic: Fusion protein |
| Latest Stage of Development | Approved |
| Standard Indication | Metabolic (unspecified) |
| Indication Details | Treat hypophosphatasia (HPP); Treat hypophosphatasia (HPP) in children; Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age; Treat perinatal, infantile and juvenile-onset hypophosphatasia (HPP) |
| Regulatory Designation | U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in children); U.S. – Breakthrough Therapy (Treat hypophosphatasia (HPP) in patients whose first signs or symptoms occurred prior to 18 years of age); U.S. – Fast Track (Treat hypophosphatasia (HPP)); U.S. – Orphan Drug (Treat hypophosphatasia (HPP)); U.S. – Priority Review (Treat hypophosphatasia (HPP) in children); EU – Accelerated Assessment (Treat hypophosphatasia (HPP)); EU – Accelerated Assessment (Treat hypophosphatasia (HPP) in children); EU – Orphan Drug (Treat hypophosphatasia (HPP)); Japan – Orphan Drug (Treat hypophosphatasia (HPP)); Australia – Orphan Drug (Treat hypophosphatasia (HPP) |
Asfotase Alfa is a first-in-class bone-targeted enzyme replacement therapy designed to address the underlying cause of hypophosphatasia (HPP)—deficient alkaline phosphatase (ALP). Hypophosphatasia is almost always fatal when severe skeletal disease is obvious at birth. By replacing deficient ALP, treatment with Asfotase Alfa aims to improve the elevated enzyme substrate levels and improve the body’s ability to mineralize bone, thereby preventing serious skeletal and systemic patient morbidity and premature death. Asfotase alfa was first approved by Pharmaceuticals and Medicals Devices Agency of Japan (PMDA) on July 3, 2015, then approved by the European Medicine Agency (EMA) on August 28, 2015, and was approved by the U.S. Food and Drug Administration (FDA) on October 23, 2015. Asfotase Alfa is marketed under the brand name Strensiq® by Alexion Pharmaceuticals, Inc. The annual average price of Asfotase Alfa treatment is $285,000.
Hypophosphatasia (HPP) is a rare inheritable disease that results from loss-of-function mutations in the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Therapeutic options for treating the underlying pathophysiology of the disease have been lacking, with the mainstay of treatment being management of symptoms and supportive care. HPP is associated with significant morbidity and mortality in paediatric patients, with mortality rates as high as 100 % in perinatal-onset HPP and 50 % in infantile-onset HPP. Subcutaneous asfotase alfa (Strensiq(®)), a first-in-class bone-targeted human recombinant TNSALP replacement therapy, is approved in the EU for long-term therapy in patients with paediatric-onset HPP to treat bone manifestations of the disease. In noncomparative clinical trials in infants and children with paediatric-onset HPP, asfotase alfa rapidly improved radiographically-assessed rickets severity scores at 24 weeks (primary timepoint) as reflected in improvements in bone mineralization, with these benefits sustained after more than 3 years of treatment. Furthermore, patients typically experienced improvements in respiratory function, gross motor function, fine motor function, cognitive development, muscle strength (normalization) and ability to perform activities of daily living, and catch-up height-gain. In life-threatening perinatal and infantile HPP, asfotase alfa also improved overall survival. Asfotase alfa was generally well tolerated in clinical trials, with relatively few patients discontinuing treatment and most treatment-related adverse events being of mild to moderate intensity. Thus, subcutaneous asfotase alfa is a valuable emerging therapy for the treatment of bone manifestations in patients with paediatric-onset HPP.
October 23, 2015
Release
Today, the U.S. Food and Drug Administration approved Strensiq (asfotase alfa) as the first approved treatment for perinatal, infantile and juvenile-onset hypophosphatasia (HPP).
HPP is a rare, genetic, progressive, metabolic disease in which patients experience devastating effects on multiple systems of the body, leading to severe disability and life-threatening complications. It is characterized by defective bone mineralization that can lead to rickets and softening of the bones that result in skeletal abnormalities. It can also cause complications such as profound muscle weakness with loss of mobility, seizures, pain, respiratory failure and premature death. Severe forms of HPP affect an estimated one in 100,000 newborns, but milder cases, such as those that appear in childhood or adulthood, may occur more frequently.
“For the first time, the HPP community will have access to an approved therapy for this rare disease,” said Amy G. Egan, M.D., M.P.H., deputy director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Strensiq’s approval is an example of how the Breakthrough Therapy Designation program can bring new and needed treatments to people with rare diseases.”
Strensiq received a breakthrough therapy designation as it is the first and only treatment for perinatal, infantile and juvenile-onset HPP. The Breakthrough Therapy Designation program encourages the FDA to work collaboratively with sponsors, by providing timely advice and interactive communications, to help expedite the development and review of important new drugs for serious or life-threatening conditions. In addition to designation as a breakthrough therapy, the FDA granted Strensiq orphan drug designation because it treats a disease affecting fewer than 200,000 patients in the United States.
Orphan drug designation provides financial incentives, like clinical trial tax credits, user fee waivers, and eligibility for market exclusivity to promote rare disease drug development. Strensiq was also granted priority review, which is granted to drug applications that show a significant improvement in safety or effectiveness in the treatment of a serious condition. In addition, the manufacturer of Strensiq was granted a rare pediatric disease priority review voucher – a provision intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. Development of this drug was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and/or effectiveness of products for use in rare diseases or conditions.
Strensiq is administered via injection three or six times per week. Strensiq works by replacing the enzyme (known as tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone, which has been shown to improve patient outcomes.
The safety and efficacy of Strensiq were established in 99 patients with perinatal (disease occurs in utero and is evident at birth), infantile- or juvenile-onset HPP who received treatment for up to 6.5 years during four prospective, open-label studies. Study results showed that patients with perinatal- and infantile-onset HPP treated with Strensiq had improved overall survival and survival without the need for a ventilator (ventilator-free survival). Ninety-seven percent of treated patients were alive at one year of age compared to 42 percent of control patients selected from a natural history study group. Similarly, the ventilator-free survival rate at one year of age was 85 percent for treated patients compared to less than 50 percent for the natural history control patients.
Patients with juvenile-onset HPP treated with Strensiq showed improvements in growth and bone health compared to control patients selected from a natural history database. All treated patients had improvement in low weight or short stature or maintained normal height and weight. In comparison, approximately 20 percent of control patients had growth delays over time, with shifts in height or weight from the normal range for children their age to heights and weights well below normal for age. Juvenile-onset patients also showed improvements in bone mineralization, as measured on a scale that evaluates the severity of rickets and other HPP-related skeletal abnormalities based on x-ray images. All treated patients demonstrated substantial healing of rickets on x-rays while some natural history control patients showed increasing signs of rickets over time.
The most common side effects in patients treated with Strensiq include injection site reactions, hypersensitivity reactions (such as difficulty breathing, nausea, dizziness and fever), lipodystrophy (a loss of fat tissue resulting in an indentation in the skin or a thickening of fat tissue resulting in a lump under the skin) at the injection site, and ectopic calcifications of the eyes and kidney.
Strensiq is manufactured by Alexion Pharmaceuticals Inc., based in Cheshire, Connecticut.
| Patent Number | Pediatric Extension | Approved | Expires (estimated) | |
|---|---|---|---|---|
| US7763712 | No | 2004-04-21 | 2026-07-15 |
STRENSIQ is a formulation of asfotase alfa, which is a soluble glycoproteincomposed of two identical polypeptide chains. Each chain contains 726amino acids with a theoretical mass of 161 kDa. Each chain consists of the catalytic domain of human tissue non-specific alkaline phosphatase (TNSALP), the human immunoglobulin G1 Fc domain and a deca-aspartatepeptide used as a bone targeting domain. The two polypeptide chains are covalently linked by two disulfide bonds.
STRENSIQ is a tissue nonspecific alkaline phosphatase produced byrecombinant DNA technology in a Chinese hamster ovary cell line. TNSALP is a metallo-enzyme that catalyzes the hydrolysis of phosphomonoesters with release of inorganic phosphate and alcohol. Asfotase alfa has a specific activity of 620 to 1250 units/mg. One activity unit is defined as the amount of asfotase alfa required to form 1 μmol of p-nitrophenol from pNPP per minute at 37°C.
STRENSIQ (asfotase alfa) is a sterile, preservative-free, nonpyrogenic, clear, slightly opalescent or opalescent, colorless to slightly yellow, with few small translucent or white particles, aqueous solution for subcutaneous administration. STRENSIQ is supplied in glass single-use vials containing asfotase alfa; dibasic sodium phosphate, heptahydrate; monobasic sodium phosphate, monohydrate; and sodium chloride at a pH between 7.2 and 7.6. Table 5 describes the content of STRENSIQ vial presentations.
Table 5: Content of STRENSIQ Vial Presentations
| INGREDIENT | QUANTITY PER VIAL | |||
| ASFOTASE ALFA | 18 MG/0.45 ML | 28 MG/0.7 ML | 40 MG/ML | 80 MG/0.8 ML |
| Dibasic sodium phosphate, heptahydrate | 2.48 mg | 3.85 mg | 5.5 mg | 4.4 mg |
| Monobasic sodium phosphate, monohydrate | 0.28 mg | 0.43 mg | 0.62 mg | 0.5 mg |
| Sodium chloride | 3.94 mg | 6.13 mg | 8.76 mg | 7.01 mg |
REFERNCES
- Whyte MP: Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment. Nat Rev Endocrinol. 2016 Apr;12(4):233-46. doi: 10.1038/nrendo.2016.14. Epub 2016 Feb 19. [PubMed:26893260 ]
- Whyte MP, Rockman-Greenberg C, Ozono K, Riese R, Moseley S, Melian A, Thompson DD, Bishop N, Hofmann C: Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia. J Clin Endocrinol Metab. 2016 Jan;101(1):334-42. doi: 10.1210/jc.2015-3462. Epub 2015 Nov 3. [PubMed:26529632 ]
- Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millan JL, Skrinar AM, Crine P, Landy H: Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173. [PubMed:22397652 ]
//////Asfotase alfa, Strensiq, treat hypophosphatasia, ALXN-1215, ENB-0040, sALP-FcD-10, FDA 2015
Idarucizumab
Idarucizumab
(Praxbind®) Approved
An antidote for rapid reversal of dabigatran-induced anticoagulation indicated for emergency surgery (urgent procedures) and life-threatening or uncontrolled bleeding in patients treated with dabigatran.
BI-655075
CAS No.1362509-93-0
Other Names
- BI 655075
- Idarucizumab
- Praxbind
Protein Sequence
Sequence Length: 444, 225, 219multichain; modified (modifications unspecified)
Idarucizumab, sold under the brand name Praxbind, is a monoclonal antibody designed for the reversal of anticoagulant effects ofdabigatran.[1][2]
This drug was developed by Boehringer Ingelheim Pharmaceuticals. A large study sponsored by the manufacturer found that idarucizumab effectively reversed anticoagulation by dabigatran within minutes.[3] It was FDA approved in October 2015.[4] In the United States the wholesale cost is $3500 US.[5]
References
- Statement On A Nonproprietary Name Adopted By The USAN Council – Idarucizumab, American Medical Association.
- World Health Organization (2013). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 109” (PDF). WHO Drug Information 27 (2).
- Pollack, Charles V.; Reilly, Paul A.; Eikelboom, John; Glund, Stephan; Verhamme, Peter; Bernstein, Richard A.; Dubiel, Robert; Huisman, Menno V.; Hylek, Elaine M. (2015-08-06).“Idarucizumab for Dabigatran Reversal”. The New England Journal of Medicine 373 (6): 511–520. doi:10.1056/NEJMoa1502000. ISSN 1533-4406. PMID 26095746.
- “Press Announcements – FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa”. http://www.fda.gov. Retrieved 2015-10-17.
- Elia, Joe. “Dabigatran-Reversal Agent Price Set”. Retrieved 20 October 2015.
| Monoclonal antibody | |
|---|---|
| Type | Fab fragment |
| Source | Humanized (from mouse) |
| Target | Dabigatran |
| Clinical data | |
| Trade names | Praxbind |
| Identifiers | |
| CAS Number | 1362509-93-0 |
| ATC code | V03AB37 (WHO) |
| IUPHAR/BPS | 8298 |
| ChemSpider | none |
| Chemical data | |
| Formula | C2131H3299N555O671S11 |
| Molar mass | 47.8 kg/mol |
/////Idarucizumab
Daratumumab
Daratumumab
(Darzalex®)Approved
An anti-CD38 monoclonal antibody used to treat multiple myeloma.
Research Code HuMax-CD-38; HuMaxCD-38
CAS No.
Daratumumab (HuMax®-CD38)
Daratumumab (Darzalex) is an anti-cancer drug. It binds to CD38.[1] Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.[2]
Clinical trials
Encouraging preliminary results were reported in June 2012 from a Phase 1/2 clinical trial in relapsed multiple myeloma patients.[3]Updated trial results presented in December 2012 indicate daratumumab is continuing to show promising single-agent anti-myeloma activity.[4] A 2015 study compared monotherapy 8 and 16mg/kg at monthly to weekly intervals.[5]
In November 2015, the U.S. Food and Drug Administration approved daratumumab for treatement of multiple myeloma.[6]
Interference with blood compatibility testing
Daratumumab can also bind to CD38 present on red blood cells and interfere with antibody testing. Patients will show a panreactive antibody panel, including a positive auto-control. Treatment of the antibody panel cells with dithiothreitol (DTT) and repeating testing will effectively negate the binding of daratumumab to CD38 on the RBC surface; however, DTT also inactivates/destroys many antigens on the RBC surface by disrupting disulfide bonds. Fortunately, the only antigen system affected that is associated with common, clinically significant antibodies is Kell, making K-negative RBCs a reasonable alternative when urgent transfusion is indicated.[7]
Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis, and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.
Daratumumab is approved in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.
In May 2013, daratumumab received Fast Track Designation and Breakthrough Therapy Designation from the US FDA for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy including a PI and an immunomodulatory agent or who are double refractory to a PI and an immunomodulatory agent. Breakthrough Therapy Designation is a program intended to expedite the development and review of drugs to treat serious or life-threatening diseases in cases where preliminary clinical evidence shows that the drug may provide substantial improvements over available therapy. Daratumumab has also received Orphan Drug Designation from the US FDA and the EMA for the treatment of multiple myeloma.
Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin’s lymphoma.
Genmab announced a global license and development agreement for daratumumab with Janssen Biotech, Inc. in August 2012. The agreement became effective in September 2012.
DARZALEX® (daratumumab) Approved by U.S. FDA: First Human Anti-CD38 Monoclonal Antibody Available for the Treatment of Multiple Myeloma
First-in-class immunotherapy approved for multiple myeloma patients who have received three or more prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double refractory to a PI and immunomodulatory agent
HORSHAM, PA, November 16, 2015 – Janssen Biotech, Inc., a Janssen Pharmaceutical Company of Johnson & Johnson, announced today the U.S. Food and Drug Administration (FDA) has approved DARZALEX® (daratumumab) injection for intravenous infusion for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3 Refractory cancer occurs when a patient’s disease is resistant to treatment or in the case of multiple myeloma, the disease progresses within 60 days of their last therapy.4,5 Relapsed cancer means the disease has returned after a period of initial, partial or complete remission.6
DARZALEX is the first human anti-CD38 monoclonal antibody (mAb) approved anywhere in the world. CD38 is a surface protein that is expressed by most, if not all, multiple myeloma cells.7 DARZALEX is believed to induce tumor cell death through multiple immune-mediated mechanisms of action,8,9 in addition to apoptosis, in which a series of molecular steps in a cell lead to its death.10 Its approval comes just two months after the Biologics License Application (BLA) was accepted for Priority Review by the FDA in September 2015.11 DARZALEX received Breakthrough Therapy Designation from the FDA for this indication in May 2013.12
“Multiple myeloma is a highly complex disease and remains incurable, with almost all patients relapsing or becoming resistant to therapy,” said DARZALEX clinical trial investigator Paul G. Richardson, M.D., Clinical Program Leader and Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute. “With DARZALEX, we have a promising new immunotherapy, which has shown pronounced efficacy as a single agent with an acceptable adverse event profile. This is especially important for treating these heavily pre-treated patients in whom all of the major classes of currently available medicines have failed.”
The pivotal open-label Phase 2 MMY2002 (SIRIUS) study showed treatment with single-agent DARZALEX resulted in an overall response rate (ORR) of 29.2 percent (95% CI; 20.8, 38.9) in patients who received a median of five prior lines of therapy, including a PI and an immunomodulatory agent.1
Stringent complete response (sCR) was reported in 2.8 percent of patients, very good partial response (VGPR) was reported in 9.4 percent of patients, and partial response (PR) was reported in 17 percent of patients.1 These efficacy results were based on ORR as determined by the Independent Review Committee assessment using IMWG (International Myeloma Working Group) criteria and the range for median duration of response.
For responders, the median duration of response was 7.4 months (range 1.2-13.1+ months).1 At baseline, 97 percent of patients were refractory to their last line of therapy, 95 percent were refractory to both a PI and an immunomodulatory agent, and 77 percent were refractory to alkylating agents.1 Additional efficacy data from the Phase 1/2 GEN501 monotherapy study – published in The New England Journal of Medicine in August 2015 – also support this approval.1
“The responses we saw in clinical trials that led to today’s approval were striking, especially considering that these patients received a median of five prior lines of therapy,” said MMY2002 investigator Sagar Lonial, M.D., Chief Medical Officer, Winship Cancer Institute of Emory University and Professor and Executive Vice Chair, Department of Hematology and Medical Oncology, Emory University School of Medicine. “It appears the mechanism of action for daratumumab (DARZALEX) may play an important role in its single-agent activity among this group of advanced-stage multiple myeloma patients.”
“Living with multiple myeloma is challenging, both physically and emotionally, especially as the disease progresses and treatment options become more limited,” said Debby Graff, a patient enrolled in a clinical trial at Dana-Farber Cancer Institute. “I am encouraged by emerging treatments for multiple myeloma, and I have a new outlook on my path forward.”
“While there have been considerable improvements over the past decade in the treatment of people living with multiple myeloma, these patients face a long, hard road – especially those whose disease has relapsed or is no longer responding to current therapies,” said Walter M. Capone, President and Chief Executive Officer of the Multiple Myeloma Research Foundation (MMRF). “With the approval of daratumumab, a new antibody option targeting CD38, along with ongoing work to advance the development of novel classes of therapies by both Janssen and MMRF, we are ushering in a new era of myeloma therapy focused on individualized treatment approaches for patients with significant unmet needs.”
“Our focus is developing transformational medicines for people living with hard-to-treat cancers, such as multiple myeloma,” said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen. “The rapid development and approval of DARZALEX – the first human anti-CD38 monoclonal antibody – is a great example of this commitment and our ongoing work in developing immunotherapies. We will continue to study this compound as both a mono- and a combination therapy to understand its full clinical benefit for patients across the treatment continuum in multiple myeloma and other tumor types.”
The warnings and precautions for DARZALEX include infusion reactions, interference with serological testing and interference with determination of complete response (see Important Safety Information).1 The most frequently reported adverse reactions (incidence ≥20%) were: fatigue, nausea, back pain, pyrexia, cough and upper respiratory tract infection.1
In data from three pooled clinical studies including a total of 156 patients, four percent of patients discontinued treatment due to adverse reactions.1 Infusion reactions were reported in approximately half of all patients treated with DARZALEX.1 Common (≥5 percent) symptoms of infusion reactions included nasal congestion, chills, cough, allergic rhinitis, throat irritation, dyspnea (shortness of breath) and nausea.1 Severe infusion reactions, including bronchospasm, dyspnea, hypoxia and hypertension (<2 percent each).1
The recommended dose of DARZALEX is 16 mg/kg body weight administered as an intravenous infusion.1 The dosing schedule begins with weekly administration (weeks 1-8) and reduces in frequency over time to every two weeks (weeks 9-24) and ultimately every four weeks (week 25 onwards until disease progression).1
In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive license to develop, manufacture and commercialize DARZALEX.13 Janssen is currently the global sponsor of all but one clinical study. DARZALEX will be commercialized in the U.S. by Janssen Biotech, Inc.
About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that occurs when malignant plasma cells grow uncontrollably in the bone marrow.2,3 Multiple myeloma is the third most common blood cancer in the U.S., following only leukemia and lymphoma.14 Approximately 26,850 new patients will be diagnosed with multiple myeloma, and approximately 11,240 people will die from the disease in the U.S. in 2015.15 Globally, it is estimated that 124,225 people will be diagnosed, and 87,084 will die from the disease in 2015.16,17 While some patients with multiple myeloma have no symptoms at all, most patients are diagnosed due to symptoms which can include bone problems, low blood counts, calcium elevation, kidney problems or infections.18 Patients who relapse after treatment with standard therapies (including PIs or immunomodulatory agents) typically have poor prognoses and few remaining options.3
Access to DARZALEX® (daratumumab) Injection, for Intravenous Infusion
DARZALEX (daratumumab) injection for intravenous infusion will be available for distribution in the U.S. within two weeks following FDA approval. Janssen Biotech offers comprehensive access and support information, resources and services to assist U.S. patients in gaining access to DARZALEX through the Janssen CarePath Program. For more information, health care providers or patients can contact: 1-844-55DARZA (1-844-553-2792). Information will also be available at www.DARZALEX.com. Dedicated case coordinators are available to work with both healthcare providers and patients.
Patients with private or commercial insurance may be eligible for the Janssen CarePath Savings Program for DARZALEX. Information on the enrollment process will be available online at www.darzalex.com/access-and-cost-support#affordability.
About DARZALEX® (daratumumab) Injection, for Intravenous Infusion
DARZALEX® (daratumumab) injection for intravenous infusion is indicated for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. DARZALEX is the first human anti-CD38 monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. DARZALEX is believed to induce tumor cell death through apoptosis, in which a series of molecular steps in a cell lead to its death1,10 and multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).1,8 More information will be available atwww.DARZALEX.com.
References
- World Health Organization (2009). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 101” (PDF). WHO Drug Information 23 (2).
- “‘Janssen Biotech Announces Global License and Development Agreement for Investigational Anti-Cancer Agent Daratumumab'”. Janssen Biotech. Retrieved 2013-01-31.
- “ASCO: Drug Shows Promise in Myeloma”. MedPage Today.
- “‘Daratumumab Continues To Show Promise For Relapsed/Refractory Myeloma Patients (ASH 2012)'”. The Myeloma Beacon. Retrieved 2013-01-31.
- Lokhorst, Henk M.; Plesner, Torben; Laubach, Jacob P.; Nahi, Hareth; Gimsing, Peter; Hansson, Markus; Minnema, Monique C.; Lassen, Ulrik; Krejcik, Jakub (2015-09-24). “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma”. The New England Journal of Medicine 373 (13): 1207–1219. doi:10.1056/NEJMoa1506348. ISSN 1533-4406. PMID 26308596.
- http://www.medscape.com/viewarticle/854548?nlid=91686_3663&src=wnl_edit_newsal&uac=78316PX&impID=890536&faf=1
- Chapuy, CI; Nicholson, RT; Aguad, MD; Chapuy, B; Laubach, JP; Richardson, PG; Doshi, P; Kaufman, RM (June 2015). “Resolving the daratumumab interference with blood compatibility testing.”. Transfusion 55 (6 Pt 2): 1545–54. PMID 25764134.
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Human |
| Target | CD38 |
| Legal status | |
| Legal status |
|
| Identifiers | |
| CAS Number | 945721-28-8  |
| ATC code | none |
| ChemSpider | none |
| UNII | 4Z63YK6E0E  |
| Chemical data | |
| Formula | C6466H9996N1724O2010S42 |
| Molar mass | 145,391.67 g·mol−1 |
////Daratumumab
Reslizumab
Reslizumab
(Cinqair®) Approved Active, FDA 2016-03-23
An interleukin-5 (IL-5) antagonist used to treat severe asthma.
CAS 241473-69-8
Research Code CDP-835; CEP-38072; CTx-55700; SCH-5570; SCH-55700; TRFK-5,
Anti-interleukin-5 monoclonal antibody – Celltech/Schering-Plough
Reslizumab was approved by the U.S. Food and Drug Administration (FDA) on March 23, 2016. It was developed and marketed as Cinqair® by Teva.
Reslizumab is an interleukin-5 antagonist, which binds to human IL-5 and prevents it from binding to the IL-5 receptor, thereby reducing eosinophilic inflammation. It is indicated for the maintenance treatment of patients with severe asthma in patients aged 18 years and older.
Cinqair® is available as injection for intravenous infusion, containing 100 mg of reslizumab in 10 mL solution in single-use vials. The recommended dose is 3 mg/kg once every four weeks.
- Originator Celltech R&D; Schering-Plough
- Developer Celltech R&D; Teva Pharmaceutical Industries
- Class Antiasthmatics; Monoclonal antibodies
- Mechanism of Action Interleukin 5 receptor antagonists
- Orphan Drug Status Yes – Oesophagitis
- 23 Mar 2016 Registered for Asthma in USA (IV) – First global approval
- 04 Mar 2016 Pooled efficacy data from two phase III trials in Asthma presented at the 2016 Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2016)
- 10 Dec 2015 Preregistration for Asthma in Canada (IV)
Reslizumab (trade name Cinqair) is a humanized monoclonal antibody intended for the treatment of eosinophil-meditated inflammations of the airways, skin and gastrointestinal tract.[1] The FDA approved reslizumab for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older on March 23, 2016. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.[2]
Teva Announces FDA Acceptance of the Biologics License Application for Reslizumab
Investigational Biologic for the Treatment of Inadequately Controlled Asthma in Patients with Elevated Blood Eosinophils Accepted for Review
JERUSALEM–(BUSINESS WIRE)–Jun. 15, 2015– Teva Pharmaceutical Industries Ltd., (NYSE: TEVA) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the Biologics License Application (BLA) for reslizumab, the company’s investigational humanized monoclonal antibody (mAb) which targets interleukin-5 (IL-5), for the treatment of inadequately controlled asthma in adult and adolescent patients with elevated blood eosinophils, despite an inhaled corticosteroid (ICS)-based regimen.
“Despite currently available medicines, uncontrolled asthma remains a serious problem for patients, physicians and healthcare systems, highlighting the need for targeted new treatment options,” said Dr. Michael Hayden, President of Global R&D and Chief Scientific Officer at Teva Pharmaceutical Industries Ltd. “The reslizumab BLA filing acceptance represents a significant milestone for Teva as we work toward serving a specific asthma patient population that is defined by elevated blood eosinophil levels and inadequately controlled symptoms despite standard of care therapy. In clinical trials, patients treated with reslizumab showed significant reductions in the rate of asthma exacerbations and significant improvement in lung function. If approved, we believe reslizumab will serve as an important new targeted treatment option to achieve better asthma control for patients with eosinophil-mediated disease.”
The BLA for reslizumab includes data from Teva’s Phase III BREATH clinical trial program. The program consisted of four separate placebo-controlled Phase III trials involving more than 1,700 adult and adolescent asthma patients with elevated blood eosinophils, whose symptoms were inadequately controlled with inhaled corticosteroid-based therapies. Results from these studies demonstrated that reslizumab, in comparison to placebo, reduced asthma exacerbation rates by at least half and provided significant improvement in lung function and other secondary measures of asthma control when added to an existing ICS-based therapy. Common adverse events in the reslizumab treatment group were comparable to placebo and included worsening of asthma, nasopharyngitis, upper respiratory infections, sinusitis, influenza and headache. Two anaphylactic reactions were reported and resolved following medical treatment at the study site.
Results from the reslizumab BREATH program were recently presented at the American Thoracic Society 2015 Annual Meeting and the American Academy of Allergy, Asthma and Immunology 2015 Annual Meeting, in addition to being published in The Lancet Respiratory Medicine. The BLA for reslizumab has been accepted for filing by the FDA for standard review, with FDA Regulatory Action expected in March 2016.
About Reslizumab
Reslizumab is an investigational humanized monoclonal antibody which targets interleukin-5 (IL-5). IL-5 is a key cytokine involved in the maturation, recruitment, and activation of eosinophils, which are inflammatory white blood cells implicated in a number of diseases, such as asthma. Elevated levels of blood eosinophils are a risk factor for future asthma exacerbations. Reslizumab binds circulating IL-5 thereby preventing IL-5 from binding to its receptor.
About Asthma
Asthma is a chronic (long term) disease usually characterized by airway inflammation and narrowing of the airways, which can vary over time. Asthma may cause recurring periods of wheezing (a whistling sound when you breathe), chest tightness, shortness of breath and coughing that often occurs at night or early in the morning. Without appropriate treatment, asthma symptoms may become more severe and result in an asthma attack, which can lead to hospitalization and even death.
About Eosinophils
Eosinophils are a type of white blood cell that are present at elevated levels in the lungs and blood of many asthmatics. Evidence shows that eosinophils play an active role in the pathogenesis of the disease. IL-5 has been shown to play a crucial role in maturation, growth and activation of eosinophils. Increased levels of eosinophils in the sputum and blood have been shown to correlate with severity and frequency of asthma exacerbations.
About Teva
Teva Pharmaceutical Industries Ltd. (NYSE and TASE: TEVA) is a leading global pharmaceutical company that delivers high-quality, patient-centric healthcare solutions to millions of patients every day. Headquartered in Israel, Teva is the world’s largest generic medicines producer, leveraging its portfolio of more than 1,000 molecules to produce a wide range of generic products in nearly every therapeutic area. In specialty medicines, Teva has a world-leading position in innovative treatments for disorders of the central nervous system, including pain, as well as a strong portfolio of respiratory products. Teva integrates its generics and specialty capabilities in its global research and development division to create new ways of addressing unmet patient needs by combining drug development capabilities with devices, services and technologies. Teva’s net revenues in 2014 amounted to $20.3 billion. For more information, visit www.tevapharm.com.
The U.S. Food and Drug Administration today approved Cinqair (reslizumab) for use with other asthma medicines for the maintenance treatment of severe asthma in patients aged 18 years and older. Cinqair is approved for patients who have a history of severe asthma attacks (exacerbations) despite receiving their current asthma medicines.
Asthma is a chronic disease that causes inflammation in the airways of the lungs. During an asthma attack, airways become narrow making it hard to breathe. Severe asthma attacks can lead to asthma-related hospitalizations because these attacks can be serious and even life-threatening. According to the Centers for Disease Control and Prevention, as of 2013, more than 22 million people in the U.S. have asthma, and there are more than 400,000 asthma-related hospitalizations each year.
“Health care providers and their patients with severe asthma now have another treatment option to consider when the disease is not well controlled by their current asthma therapies,” said Badrul Chowdhury, M.D., Ph.D., director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’s Center for Drug Evaluation and Research.
Cinqair is administered once every four weeks via intravenous infusion by a health care professional in a clinical setting prepared to manage anaphylaxis. Cinqair is a humanized interleukin-5 antagonist monoclonal antibody produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Cinqair reduces severe asthma attacks by reducing the levels of blood eosinophils, a type of white blood cell that contributes to the development of asthma.
The safety and efficacy of Cinqair were established in four double-blind, randomized, placebo‑controlled trials in patients with severe asthma on currently available therapies. Cinqair or a placebo was administered to patients every four weeks as an add-on asthma treatment. Compared with placebo, patients with severe asthma receiving Cinqair had fewer asthma attacks, and a longer time to the first attack. In addition, treatment with Cinqair resulted in a significant improvement in lung function, as measured by the volume of air exhaled by patients in one second.
Cinqair can cause serious side effects including allergic (hypersensitivity) reactions. These reactions can be life-threatening. The most common side effects in clinical trials for Cinqair included anaphylaxis, cancer, and muscle pain.
Cinqair is made by Teva Pharmaceuticals in Frazer, Pennsylvania.
References
- 1Walsh, GM (2009). “Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions”. Current opinion in molecular therapeutics 11 (3): 329–36. PMID 19479666.
- 2http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491980.htm
- http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491980.htm
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (from rat) |
| Target | IL-5 |
| Clinical data | |
| Trade names | Cinquil |
| Identifiers | |
| ATC code | R03DX08 (WHO) |
| ChemSpider | none |
/////////CDP-835, CEP-38072, CTx-55700, SCH-5570, SCH-55700, TRFK-5, Reslizumab, Cinqair®, teva, interleukin-5 (IL-5) antagonist, severe asthma, FDA 2016, Orphan Drug StatuS
Istradefylline
Istradefylline, KW-6002
(Nouriast®) Approved
A selective adenosine A2A receptor antagonist used to treat Parkinson’s disease.
KW-6002
CAS No. 155270-99-8
Istradefylline; 155270-99-8; KW-6002; KW 6002; 8-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methyl-purine-2,6 -dione; (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione;
| Molecular Formula: | C20H24N4O4 |
|---|---|
| Molecular Weight: | 384.42896 g/mol |
Istradefylline (KW-6002) is a selective antagonist at the A2A receptor. It has been found to be useful in the treatment of Parkinson’s disease.[1] Istradefylline reduces dyskinesia resulting from long-term treatment with classical antiparkinson drugs such as levodopa. Istradefylline is an analog of caffeine.
Kyowa Hakko Kirin is developing istradefylline, a selective adenosine A2A receptor antagonist, for the once-daily oral treatment of Parkinson’s disease (PD). Adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain; the degeneration or abnormality observed in PD is believed to occur in the basal ganglia, which is recognized to play a significant role in motor control.
Commercially available dopamine replacement therapies effectively treat the early motor symptoms of PD; however, these agents are associated with development of motor complications, limiting usefulness in late stages of the disease. Istradefylline is proposed to possess a clearly distinct action site from existing agents which act on dopamine metabolism or dopamine receptors. Kyowa Hakko Kirin has received approval for istradefylline in the adjunctive treatment of PD in Japan. A New Drug Application was filed in the USA, but the FDA issued a non-approvable letter in February 2008.
PATENT
US5484920A
http://www.google.co.in/patents/US5484920
PAPER
http://www.sciencedirect.com/science/article/pii/S0960894X13003983
Scheme 1.
Synthesis of KW 6002 (2). Reagents and conditions: (i) acetic anhydride, 80 °C, 2 h, 83%; (ii) sodium nitrite, 50% acetic acid, 60 °C, 15 min, 86%; (iii) sodium dithionite, NH4OH solution (12.5% (w/v)), 60 °C, 30 min, 98%; (iv) SOCl2, toluene, 75 °C, 2 h, 97%; (v) pyridine, DCM, rt, 16 h, 66%; (vi) HMDS, cat. (NH4)2SO4, CH3CN, 160 °C, microwave, 5 h, 100% followed by (vii) MeI, K2CO3, DMF, rt, 2 h, 75%.
Synthesis
(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-1H-purine-2,6(3H,7H)-dione (2)3
- J. Hockemeyer; J. C. Burbiel; C. E. Müller, J. Org. Chem. 2004, 69, 3308.
(E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-1H-purine-2,6(3H,7H)-dione (1.11 g, 3.00 mmol) was taken up in dimethylformamide (15 mL) and potassium carbonate (828 mg, 6.00 mmol). To the milky white mixture was added iodomethane (468 µL, 7.50 mmol) and it was allowed to stir at room temperature for 2 h. The mixture was then filtered and washed with water (100 mL), leaving the title compound 2 as a pale yellow solid which was dried in the oven at 110 °C (863 mg, 75%), mp: 192 °C (lit.3 191 °C). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 15.7 Hz, 1H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 15.7 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.12 – 4.04 (m, 5H), 3.95 (s, 3H), 3.93 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 155.0 (C), 150.8 (C), 150.4 (C), 150.3 (C), 149.2 (C), 148.2 (C), 138.1 (CH), 128.6 (C), 121.2 (CH), 111.2 (CH), 109.5 (CH), 109.3 (CH), 108.0 (C), 55.98 (CH3), 55.97 (CH3), 38.4 (CH2), 36.3 (CH2), 31.5 (CH3), 13.43 (CH3), 13.39 (CH3). LCMS: m/z (ESI 20 V) 385.2 (MH+, 100).
PATENT
http://www.google.com/patents/CN103254194A?cl=en
Specific synthetic route is as follows:
the above reaction is a synthetic Parkinson’s disease clinical drug KW-6002 against a yield of 83%.
Example 26 (a new synthetic method for anti-Parkinson’s disease in clinical drug KW-6002):
In addition to use in place of 3,4-dimethoxy-styryl boronic acid (0.4mmol, i.e., in formula IV, R5 is 3,4_-dimethoxy-styryl) benzene boronic acid in Example 23 and 1,3 – two-ethyl-8-phenylthio-9-methyl-xanthine (0.4mmol, i.e., Formula I, R1 is methyl, R2 and R3 are ethyl, R4 is a phenyl group) in place of Example 23 in 1 , 3,9-trimethyl xanthine -8- phenylthio, the remaining steps in Example 23 to give a white solid, yield 83%, mp = 101~103 ° C I1H NMR (⑶CI3, 600MHz): δ 7.71 (d, J = 15.6Hz, 1H), 7.17 (dd, J = 8.2,1.9Hz, 1H), 7.07 (d, J = L 9Hz, 1H), 6
• 88 (d, J = 8.2Hz, 1H), 6.74 (d, J = 15.8Hz, 1H), 4.19 (q, J = 7Hz, 2H), 4.07 (q, J = 7Hz, 2H), 4.03 (s , 3H), 3.93 (s, 3H), 3.90 (s, 3H), 1.36 (t, J = 7Hz, 3H), 1.23 (t, J = 7Hz, 3H); 13C NMR (150MHz, CDCl3): 155.1, 150.8,150.4,150.2,149.2,148.2,138.2,128.6,121.2, 111.2,109.5,109.3,108.0,56.0,55.9,38.4,36.3,31.5,13.4,13.4; HRMS: calcd for C20H25N4O4 (M + H) +385.187
6, Found385.1879. It indicates that the white solid was 8- (3,4-dimethoxy-styryl) structural formula shown KW-6002 (E) -1,3_ diethyl-7-methylxanthine.
In contrast, KW-6002 is a new drug to treat Parkinson’s disease developed by Kyowa Hakko in Japan, Japan and the United States is currently the second phase of clinical trials. Literature (. J.Hockemeyer, JCBurbiel andC.E.Muller, J.0rg.Chem, 2004,69,3308) through the following synthetic route:
The synthetic route requires five steps, with a total yield of 33%, and there is the use of environmentally unfriendly halogenated solvent methylene chloride, the reaction requires high pressure high temperature (170~180 ° C) and other shortcomings. By comparison, the present invention starting from 8- phenylthio xanthine coupling reaction catalyzed by palladium simple, a yield of 83% was synthesized KW6002, it is currently the most efficient synthesis route KW-6002’s. In particular, the multi-step synthesis route to avoid the complex operation of the reactor, but under relatively mild conditions (60 ° C) conduct, simple operation, suitable for scale synthesis.
PATENT
http://www.google.com/patents/CN104744464A?cl=en
itraconazole theophylline (Istradefylline, KW6002), the chemical name 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl -7 – methyl-purine-2,6-dione, CAS number: 155270-99-8, structural formula shown below.
itraconazole Theophylline is a selective adenosine A2a receptor antagonist, by changing the activity of neurons in Parkinson’s disease patients to improve motor function, for the treatment of Parkinson’s disease and Parkinson’s disease improve early dyskinesia.
The invention and JPH0940652A European Patent 0,590,919 discloses a method for preparing itraconazole and theophylline. WO 2004/099207 published good solubility stability of a particle size of less than 50 micrometers 8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3- diethyl-7-methyl-purine-2,6-dione crystallites.
Example 1 Preparation of theophylline itraconazole Example
ships equipped with a mechanical stirrer, a thermometer, a 2L 4-neck flask was added 30g8 – [(E) -2- (3, 4- dimethoxyphenyl) ethenyl] -1,3-diethyl- -7- hydrogen – purine-2,6-dione (Intermediate A), 400mL N, N- dimethylformamide and 15g of potassium carbonate, and 25g of methyl iodide and heated to 80 ° C after the reaction was stirred 8h, added 200mL water, cooled to room temperature, and stirring was continued crystallization 2h. The resulting suspension was suction filtered, washed with water after the cake was 800mL sash, 50 ° C under blast drying 24h, 32g give a pale yellow solid, for each polymorph of itraconazole theophylline preparation example the following examples.
References
- Peter A. LeWitt, MD, M. Guttman, James W. Tetrud, MD, Paul J. Tuite, MD, Akihisa Mori, PhD, Philip Chaikin, PharmD, MD, Neil M. Sussman, MD (2008). “Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces off time in Parkinson’s disease: A double-blind, randomized, multicenter clinical trial (6002-US-005)”. Annals of Neurology 63 (3): 295–302. doi:10.1002/ana.21315. PMID 18306243.
Reference：1. EP0590919A1.
2. US5484920A.
3. US5543415A.
4. J. Org. Chem. 2004, 69, 3308-3318.
5. Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352.
6. Bioorgan. Med. Chem. 2003, 11, 1299-1310.
7. Bioorg. Med. Chem. Lett. 2013, 23, 3427-3433.
8. Chinese Journal of Pharmaceuticals 2010, 41, 241-243.
9. JP0940652A.
10. Org. Biomo. Chem. 2010, 8, 4155-4157.
1. Chem. Commun. 2012, 48, 2864-2866.
2. CN103254194A.
| CN104744464A * | Nov 15, 2013 | Jul 1, 2015 | 南京华威医药科技开发有限公司 | Istradefylline crystal forms |
-
Istradefylline Systematic (IUPAC) name 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dioneIdentifiers CAS Number 155270-99-8 ATC code none PubChem CID 5311037 IUPHAR/BPS 5608 ChemSpider 4470574 UNII 2GZ0LIK7T4 KEGG D04641 ChEMBL CHEMBL431770 Chemical data Formula C20H24N4O4 Molar mass 384.429 g/mol
//////Istradefylline, KW-6002, Nouriast®, Approved, A selective adenosine A2A receptor antagonist, Parkinson’s disease,
O=C2N(c1nc(n(c1C(=O)N2CC)C)\C=C\c3ccc(OC)c(OC)c3)CC
Blinatumomab
Blinatumomab, AMG-103, MEDI-538, MT-103,
(Blincyto®) Approved
A bispecific CD19-directed CD3 T-cell engager used to treat philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
Other Names
1: PN: WO2005052004 SEQID: 1 claimed protein
cas 853426-35-4
Blinatumomab (trade name Blincyto, previously known as AMG103) is a biopharmaceutical drug used as a second-line treatmentfor Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructedmonoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells.[1] In December 2014 it was approved by the US Food and Drug Administration under the accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.[2][3] When it launched, blinatumomab was priced at $178,000 per year in the United States; only about 1,000 people were eligible to take the drug, based on its label.[4]
Medical use
Blinatumomab is used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory Bcell precursor acute lymphoblastic leukemia.[2]
Mechanism of action
Blinatumomab linking a T cell to a malignant B cell.
Blinatumomab enables a patient’s T cells to recognize malignant B cells. A molecule of blinatumomab combines two binding sites: aCD3 site for T cells and a CD19 site for the target B cells. CD3 is part of the T cell receptor. The drug works by linking these two cell types and activating the T cell to exert cytotoxic activity on the target cell.[5] CD3 and CD19 are expressed in both pediatric and adult patients, making blinatumomab a potential therapeutic option for both pediatric and adult populations.[6]
History
The drug was developed by a German-American company Micromet, Inc. in cooperation with Lonza; Micromet was later purchased byAmgen, which has furthered the drug’s clinical trials. In July 2014, the FDA granted breakthrough therapy status to blinatumomab for the treatment of acute lymphoblastic leukemia (ALL).[7] In October 2014, Amgen’s Biologics License Application for blinatumomab was granted priority review designation by the FDA, thus establishing a deadline of May 19, 2015 for completion of the FDA review process.[8]
On December 3, 2014, the drug was approved for use in the United States to treat Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia under the FDA‘s accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval.[2][9]
Cost
When blinatumomab was approved, Amgen announced that the price for the drug would be $178,000 per year, which made it the most expensive cancer drug on the market. Merck’s pembrolizumab was priced at $150,000 per year when it launched; unlike that drug and others, only about 1,000 people can be given the drug, based on its label.[4]
Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan-Kettering Cancer Center, has calculated that according to “value-based pricing,” assuming that the value of a year of life is $120,000 with a 15% “toxicity discount,” the market price of blinaumomab should be $12,612 a month, compared to the market price of $64,260 a month. A representative of Amgen said, “The price of Blincyto reflects the significant clinical, economic and humanistic value of the product to patients and the health-care system. The price also reflects the complexity of developing, manufacturing and reliably supplying innovative biologic medicines.”[10]
Patent
WO 2010052013
http://www.google.co.in/patents/WO2010052013A1?cl=en
Examples:
1. CD19xCD3 bispecific single chain antibody
The generation, expression and cytotoxic activity of the CD19xCD3 bispecific single chain antibody has been described in WO 99/54440. The corresponding amino and nucleic acid sequences of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 1 and 2, respectively. The VH and VL regions of the CD3 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs. 7 to 10, respectively, whereas the VH and VL regions of the CD19 binding domain of the CD19xCD3 bispecific single chain antibody are shown in SEQ ID NOs 3 to 6, respectively.
PATENT
http://www.google.com.ar/patents/WO2010052014A1?cl=en
PATENT
WO 2015006749
http://www.google.com/patents/WO2015006749A2?cl=un
PATENT
CN 104861067
http://www.google.com/patents/CN104861067A?cl=zh
| WO1998008875A1 * | 18 Aug 1997 | 5 Mar 1998 | Viva Diagnostika Diagnostische Produkte Gmbh | Novel combination preparations and their use in immunodiagnosis and immunotherapy |
| WO1999054440A1 | 21 Apr 1999 | 28 Oct 1999 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | CD19xCD3 SPECIFIC POLYPEPTIDES AND USES THEREOF |
| WO2004106381A1 | 26 May 2004 | 9 Dec 2004 | Micromet Ag | Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders |
| WO2007068354A1 | 29 Nov 2006 | 21 Jun 2007 | Micromet Ag | Means and methods for the treatment of tumorous diseases |
References
- “blinatumomab” (PDF). United States Adopted Names Council » Adopted Names.American Medical Association. 2008. N08/16.(registration required)
- Blinatumomab label Updated 12/2014
- Food and Drug Administration December 3, 2014 FDA Press release: Blinatumomab
- Tracy Staton for FiercePharmaMarketing. December 18, 2014 Amgen slaps record-breaking $178K price on rare leukemia drug Blincyto
- Mølhøj, M; Crommer, S; Brischwein, K; Rau, D; Sriskandarajah, M; Hoffmann, P; Kufer, P; Hofmeister, R; Baeuerle, PA (March 2007). “CD19-/CD3-bispecific antibody of the BiTE class is far superior to tandem diabody with respect to redirected tumor cell lysis”.Molecular Immunology 44 (8): 1935–43. doi:10.1016/j.molimm.2006.09.032.PMID 17083975.
- Amgen (30 October 2012). Background Information for the Pediatric Subcommittee of the Oncologic Drugs Advisory Committee Meeting 04 December 2012 (PDF) (PDF). Food and Drug Administration. Blinatumomab (AMG 103).
- “Amgen Receives FDA Breakthrough Therapy Designation For Investigational BiTE® Antibody Blinatumomab In Acute Lymphoblastic Leukemia” (Press release). Amgen. 1 July 2014.
- “Amgen’s BiTE® Immunotherapy Blinatumomab Receives FDA Priority Review Designation In Acute Lymphoblastic Leukemia” (Press release). Amgen. 9 October 2014.
- “Business: Antibody advance”. Seven Days. Nature (paper) 516 (7530): 149. 11 December 2014. doi:10.1038/516148a.
- Peter Loftus (June 18, 2015). “How Much Should Cancer Drugs Cost? Memorial Sloan Kettering doctors create pricing calculator that weighs factors such as side effects, extra years of life”. The Wall Street Journal. Retrieved 22 June 2015.
| Monoclonal antibody | |
|---|---|
| Type | Bi-specific T-cell engager |
| Source | Mouse |
| Target | CD19, CD3 |
| Clinical data | |
| Trade names | Blincyto |
| Pregnancy category |
|
| Routes of administration |
intravenous |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | 100% (IV) |
| Metabolism | degradation into small peptides and amino acids |
| Biological half-life | 2.11 hours |
| Excretion | urine (negligible) |
| Identifiers | |
| CAS Number | 853426-35-4 |
| ATC code | L01XC19 (WHO) |
| ChemSpider | none |
| UNII | 4FR53SIF3A |
| Chemical data | |
| Formula | C2367H3577N649O772S19 |
| Molar mass | 54.1 kDa |
///////
Lobeglitazone Sulfate
Lobeglitazone Sulfate, CKD-501
(Duvie®) Approved
Chong Kun Dang (Originator)
A dual PPARα and PPARγ agonist used to treat type 2 diabetes.
Trade Name：Duvie®MOA：Dual PPARα and PPARγ agonistIndication：Type 2 diabetes
CAS No. 607723-33-1(FREE)
763108-62-9(Lobeglitazone Sulfate)
2,4-Thiazolidinedione, 5-((4-(2-((6-(4-methoxyphenoxy)-4- pyrimidinyl)methylamino)ethoxy)phenyl)methyl)-, sulfate (1:1);
Lobeglitazone (trade name Duvie, Chong Kun Dang) is an antidiabetic drug in the thiazolidinedione class of drugs. As an agonistfor both PPARα and PPARγ, it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin.[3]
Lobeglitazone sulfate was approved by the Ministry of Food and Drug Safety (Korea) on July 4, 2013. It was developed and marketed as Duvie® by Chong Kun Dang Corporation.
Lobeglitazone is an agonist for both PPARα and PPARγ, and it works as an insulin sensitizer by binding to the PPAR receptors in fat cells and making the cells more responsive to insulin. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.
Duvie® is available as tablet for oral use, containing 0.5 mg of free Lobeglitazone. The recommended dose is 0.5 mg once daily.
Lobeglitazone which was reported in our previous works belongs to the class of potent PPARα/γ dual agonists (PPARα EC50: 0.02 μM, PPARγ EC50: 0.018 μM, rosiglitazone; PPARα EC50: >10 μM, PPARγ EC50: 0.02 μM, pioglitazone PPARα EC50: >10 μM, PPARγ EC50: 0.30 μM). Lobeglitazone has excellent pharmacokinetic properties and was shown to have more efficacious in vivo effects in KKAy mice than rosiglitazone and pioglitazone.17 Due to its outstanding pharmacokinetic profile, lobeglitazone was chosen as a promising antidiabetes drug candidate.
Medical uses
Lobeglitazone is used to assist regulation of blood glucose level of diabetes mellitus type 2 patients. It can be used alone or in combination with metformin.[4]
Lobeglitazone was approved by the Ministry of Food and Drug Safety (Korea) in 2013, and the postmarketing surveillance is on progress until 2019.[4][5]
SYNTHESIS
PAPER
Org. Process Res. Dev. 2007, 11, 190-199.
Process Development and Scale-Up of PPAR α/γ Dual Agonist Lobeglitazone Sulfate (CKD-501)
http://pubs.acs.org/doi/abs/10.1021/op060087u
A scaleable synthetic route to the potent PPARα/γ dual agonistic agent, lobeglitazone (1), used for the treatment of type-2 diabetes was developed. The synthetic pathway comprises an effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (6), from the commercially available 4,6-dichloropyrimidine (3) without the isolation of pyrimidinyl phenoxy ether (4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione (10), using Hantzsch dihydropyridine ester (HEH) with silica gel as an acid catalyst. The sulfate salt form of lobeglitazone was selected as a candidate compound for further preclinical and clinical study. More than 2 kg of lobeglitazone sulfate (CKD-501, 2) was prepared in 98.5% purity after the GMP batch. Overall yield of 2 was improved to 52% from 17% of the original medicinal chemistry route.
Silica gel TLC Rf = 0.35 (detection: iodine char chamber, ninhydrin solution, developing solvents: CH2Cl2/MeOH, 20:1); mp 111.4 °C; IR (KBr) ν 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1; 1H NMR (400 MHz, CDCl3) δ 3.09 (m, 4H), 3.29 (m, 1H), 3.76 (s, 3H), 3.97 (m, 2H), 4.14 (m, 2H), 4.86 (m, 1H), 6.06 (bs, 1H), 6.86 (m, 2H), 7.00 (m, 2H), 7.13 (m, 4H), 8.30 (s, 1H), 11.99 (s, NH); 13C NMR (100 MHz, CDCl3) δ 37.1, 38.2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5; MS (ESI)m/z (M + 1) 481.5; Anal. Calcd for C24H26N4O9S2: C, 49.82; H, 4.53; N, 9.68; S, 11.08. Found: C, 49.85; H, 4.57; N, 9.75; S, 11.15.
PATENT
References
- Lee JH, Noh CK, Yim CS, Jeong YS, Ahn SH, Lee W, Kim DD, Chung SJ. (2015). “Kinetics of the Absorption, Distribution, Metabolism, and Excretion of Lobeglitazone, a Novel Activator of Peroxisome Proliferator-Activated Receptor Gamma in Rats.”.Journal of Pharmaceutical sciences 104 (9): 3049–3059.doi:10.1002/jps.24378. PMID 25648999.
- Kim JW, Kim JR, Yi S, Shin KH, Shin HS, Yoon SH, Cho JY, Kim DH, Shin SG, Jang IJ, Yu KS. (2011). “Tolerability and pharmacokinetics of lobeglitazone (CKD-501), a peroxisome proliferator-activated receptor-γ agonist: a single- and multiple-dose, double-blind, randomized control study in healthy male Korean subjects.”. Clinical therapeutics 33 (11): 1819–1830.doi:10.1016/j.clinthera.2011.09.023. PMID 22047812.
- Lee JH, Woo YA, Hwang IC, Kim CY, Kim DD, Shim CK, Chung SJ. (2009). “Quantification of CKD-501, lobeglitazone, in rat plasma using a liquid-chromatography/tandem mass spectrometry method and its applications to pharmacokinetic studies.”. Journal of Pharmaceutical and Biomedical Analysis 50 (5): 872–877.doi:10.1016/j.jpba.2009.06.003. PMID 19577404.
- “MFDS permission information of Duvie Tablet 0.5mg”(Release of Information). Ministry of Food and Drug Safety. Retrieved2014-10-23.
- “국내개발 20번째 신약‘듀비에정’허가(20th new drug developed in Korea ‘Duvie Tablet’ was approved)”. Chong Kun Dang press release. 2013-07-04. Retrieved 2014-10-23.
 |
|
| Systematic (IUPAC) name | |
|---|---|
|
5-[(4-[2-([6-(4-Methoxyphenoxy)pyrimidin-4-yl]-methylamino)ethoxy]phenyl)methyl]-1,3-thiazolidine-2,4-dione
|
|
| Clinical data | |
| Trade names | Duvie |
| Routes of administration |
Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Protein binding | >99%[1] |
| Metabolism | liver (CYP2C9, 2C19, and 1A2)[1] |
| Biological half-life | 7.8–9.8 hours[2] |
| Identifiers | |
| CAS Number | 607723-33-1 |
| PubChem | CID 9826451 |
| DrugBank | DB09198 |
| ChemSpider | 8002194 |
| Synonyms | CKD-501 |
| Chemical data | |
| Formula | C24H24N4O5S |
| Molar mass | 480.53616 g/mol |
///Lobeglitazone Sulfate, CKD-501, Duvie®, Approved KOREA, Chong Kun Dang, A dual PPARα and PPARγ agonist , type 2 diabetes.
CN(CCOC1=CC=C(C=C1)CC2C(=O)NC(=O)S2)C3=CC(=NC=N3)OC4=CC=C(C=C4)OC.OS(=O)(=O)O
Kiran Mazumdar Shaw Conferred with ‘The Global Leadership in Engineering 2016’ Award by USC
http://societyofwomenengineers.swe.org/awards/individual-awards/4153-global-leadership
The Global Leadership Award honors a person with at least fifteen (15) years professional experience who has worked in and led an internationally based engineering, scientific or technology-based business or organization, and in doing so, serves as a role model to women engineers and technologists worldwide. A maximum of three (3) awards may be presented annually.
“This award is a recognition of Biocon’s significant role in harnessing the potential of Biotechnology to provide affordable access to highly complex bio-pharmaceuticals like Insulins and monoclonal antibodies for the benefit of patients the world over.” – Kiran Mazumdar-Shaw
//////Kiran Mazumdar Shaw, ‘The Global Leadership in Engineering 2016’ , Award by USC
New Drug Approvals 
