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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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MS Drug RPC1063 Discovered at TSRI Is Safe and Effective in Phase II Study
Brazil 2014 worldcup week POST
RPC1063
(S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile ……..any error report amcrasto@gmail.com
COMPD IS I-S
X=-OH AND Y = CN ………any error report amcrasto@gmail.com
(S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile
Receptos, Inc. INNOVATOR
WO 2011060389
THIS IS COMPD RPC1063 as above.ignore rest
RPC1063 is a novel, differentiated sphingosine 1-phosphate 1 receptor (S1P1) selective modulator exhibiting picomolar potency that is effective in rodent models of both multiple sclerosis (MS) and inflammatory bowel disease (IBD), and possesses an excellent safety profile in non-clinical toxicology studies. Receptos has completed a Phase 1 study with RPC1063 which tested single ascending doses, multiple ascending doses and dose titration regimens in healthy volunteers. The Phase 1 results confirmed optimal pharmacokinetic, pharmacodynamic and safety features, which provide supportive data for the differentiation strategy for RPC1063 as a potential best-in-class second generation S1P1 receptor modulator.
A Phase 2/3 study has been initiated to study RPC1063 in the indication of relapsing multiple sclerosis (RMS). RPC01-201, designed to demonstrate the clinical efficacy of RPC1063 in patients suffering from RMS, is a Phase 2/3 placebo-controlled (Phase 2) and active comparator-controlled (Phase 3) trial, and is the first of two planned pivotal studies for RPC1063 in RMS. Receptos anticipates initiating a second Phase 2 study with RPC1063 in ulcerative colitis in 2012.
A compound discovered and synthesized in The Scripps Research Institute (TSRI) labs of Professors Hugh Rosen and Edward Roberts has provided positive results for safety and efficacy in Phase 2 clinical trials for relapsing multiple sclerosis, according to Receptos, the biopharmaceutical company developing the drug for approval by the US Food and Drug Administration.
“The Rosen and Roberts laboratories are very gratified to see these direct improvements in the lives of patients and families dealing with this debilitating illness,” said Rosen. “These data support our labs’ approach at TSRI—that discovery of fundamental mechanisms in chemical biology provides the foundation for intelligent intervention in disease processes. Meeting the needs of patients and their families is our high calling in biomedical science.”
The drug candidate, RPC1063, was first discovered at TSRI from work in the National Institutes of Health (NIH) Molecular Libraries Initiative. The randomized, double-blind Phase 2 study assessed the efficacy, safety and tolerability of two orally administered doses of RPC1063 against placebo in 258 patients with relapsing multiple sclerosis across 77 sites in 13 countries. There was a highly statistically significant 86 percent reduction in MRI measures of disease activity.
A Phase 3 trial—a randomized, double-blind study involving 1,200 patients with relapsing multiple sclerosis—was launched in December 2013.
On June 9th, 2014 Receptos announced that a portion of its Phase 2 results in relapsing multiple sclerosis (RMS) met the primary endpoint of reducing MRI brain lesion activity. News of being a potential best in class profile has caused RCPT shares to shoot up 50% in a matter of two days. Detailed results of the RADIANCE trial are expected to be presented in coming months.
The MS market is valued at around $16B, but faces competition from existing products (below). Positioning a successful therapy will prove to be difficult even if FDA approval is attained. With Phase 3 initiation just announced, RPC1063 is years away from the market.
Given the competitive landscape and Receptos’ top line results, the company may be seen as a potential takeover target by the investing community. For example, Teva’s Copaxone lost US market exclusivity May 2014 and has patents expiring in May 2015 in most of the rest of the world. As a result of generics, Teva expects to take a $550M hit during 2014. A therapy such as RPC1063 could minimize these losses in the upcoming future.
SYNTHESIS
http://www.google.com/patents/WO2011060389A1?cl=en
Scheme 1:
Reagents: (i) Zn(CN)2, Pd(PPh3)4, NMP; (ii) RuCl(p-cymene)[(R,R)-Ts-DPEN], HC02H- TEA complex; (iii) NH2OH*HCl, Na2C03 or TEA, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.
Scheme 2:
Reagents: (i) DPPA, DBU, toluene; (ii) PG = protecting group e.g. Boc: Pd/C, H2, Boc20, TEA, MeOH; (iii) NH2OH*HCl, NaHC03, EtOH; (iv) HOBt, EDC, benzoic acid, DMF (v) deprotection e.g. 4M HC1 in dioxane; (vi) (a) R’-LG or R”-LG, where LG represents a leaving group, K2C03, CH3CN; (b) R’-C02H or R2-C02H, HOBt, EDC, DMF or Rl-COCl or R2-COCl, TEA, DCM; (c) R -S02C1 or R3-S02C1, TEA, DCM (d) R2-CHO, HOAc, NaB¾ or NaCNBH3 or Na(OAc)3BH, MeOH; (e) R1– OCOC1 or R2-OCOCl, DIEA, DMF; (f) HN(R5R5), CDI, TEA, DCM; (g) ¾NS02NH2, Δ, dioxane; (h) dimethyloxirane, Δ, EtOH; (vii) (a) If R’ or R” = H, then reactions (vi)(a-d) can be performed; (b) If R’ or R” contains an ester then (i) hydrolysis NaOH, EtOH or (ii) reduction NaBFL,, MeOH can be performed; (c) If R’ or R” contains an acid then couplings HN(R5R5), HOBt, EDC, DMF can be performed; (d) If R’ or R” contains an appropriate activated alkene then Michael additions HN(R5R5), DMF can be performed.
The (R)-enantiomer was prepared in the same manner outlined in Scheme 2 starting from (5)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile.
Scheme 3:
Reagents: (i) Sodium borohydride, ethanol, silica gel; (ii) PG = protecting group e.g. TBDMS chloride, imidazole; (iii) 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi( 1,3,2- dioxaborolane), PdCl2(dppf).CH2Cl2, potassium acetate, dioxane.
Scheme 4:
Reagents: (i) Zn(CN)2, Pd(PPh3)4, NMP; (ii) For racemic material: Sodium borohydride, ethanol, silica gel; For (/?)-indanol: 0S)-(-)-2-methyl-CBS- oxazaborolidine, BH3-DMS, toluene; For (5)-indanol: (R)-(+)-2-methyl-CBS- oxazaborolidine, BH3-DMS, toluene; (iii) NH2OH*HCl, Na2C03 or TEA, EtOH.
Scheme 5:
Reagents: (i) Oxalylchloride, DCM; (ii) Ethanolamine, Et3N, DCM; (iii) SOCl2, DCM, KOH, MeOH (iv) N-Bromosuccinimide, azoisobutyronitrile, DCM; (v) Protected (e.g. TBDMS) 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3-dihydro- lH-inden-l-ol, K2C03, Pd(PPh3)4, DME, H20; (vi) deprotection e.g. TBAF, THF; (vii) SOCl2, DCM; (viii) R’-NH2 or R”-NH2, DLPEA, DMA.
Scheme 6:
W
Reagents: (i) (R)-2-methylpropane-2-sulfinamide, Ti(OEt)4, toluene; (ii) NaB¾, THF; (iii) 4N HC1 in dioxane, MeOH; (iv) Boc20, TEA, DCM; (v) 4,4,4′,4′,5,5,5′,5′- octamethyl-2,2′-bi(l,3,2-dioxaborolane), PdCl2(dppf).CH2Cl2> potassium acetate, dioxane; (vi) 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile, K2C03, Pd(PPh3)4, DME, H20; (vii) 4N HC1 in dioxane; (viii) (a) R’-LG or R”-LG, where LG represents a leaving group, K2C03, CH3CN; (b) R1-C02H or R2-C02H, HOBt, EDC, DMF or R’-COCl or R2-COCl, TEA, DCM; (c) R’-SOaCl or R3-S02C1, TEA, DCM (d) R2– CHO, HOAc, NaB¾ or NaCNBH3 or Na(OAc)3BH, MeOH; (e) R’-OCOCl or R2– OCOC1, DIEA, DMF; (f) HN(R5R5), CDI, TEA, DCM; (g) H2NS02NH2, Δ, dioxane; (h) dimethyloxirane, Δ, EtOH; (ix) (a) If R’ or R” = H, then reactions (viii)(a-d) can be performed; (b) If R’ or R” contains an ester then (i) hydrolysis NaOH, EtOH or (ii) reduction NaBFLt, MeOH can be performed; (c) If R’ or R” contains an acid then couplings HN(R5R5), HOBt, EDC, DMF can be performed; (d) If R’ or R” contains an appropriate activated alkene then Michael additions HN(R5R5), DMF can be performed. [0255] The (5)-enantiomer can be prepared using (5)-2-methylpropane-2-sulfinamide in step (i).
[0256] Scheme 7:
Reagents: (i) HOBt, EDC, 2-(3,4-diethoxyphenyl)acetic acid, DMF; (ii) S0C12, DCM; (iii) R’-NH2, DIPEA, DMA.
[0257] Scheme 8:
Reagents: (i) Zn(CN)2, Pd(PPh3)4, NMP; (ii) (R)-2-methylpropane-2-sulfinamide, Ti(OEt)4, toluene; (iii) NaB¾, THF; (iv) 4M HC1 in dioxane, MeOH; (v) PG = protecting group e.g. Boc20, TEA, DCM; (vi) NH2OH*HCl, TEA, EtOH; (vii) R’- halide, NaH, DMF.
Reagents: (i) (a) HOBt, EDC, 2-(3,4-diethoxyphenyl)acetic acid, DMF (b) deprotection e.g. 4N HCl in dioxane; (ii) (a) R’-LG, where LG represents a leaving group, K2C03, CH3CN; (b) if R’ contains an ester then (a) followed by NaOH, EtOH; (c) R’-C02H, HOBt, EDC, DMF or R’-COCl, TEA, DCM; (d) R’-S02C1, TEA, DCM (e) R’-CHO, HOAc, NaBFL or NaCNBH3 or Na(OAc)3BH, MeOH.
[0259] The (5)-enantiomer can be prepared using protected (/?)-l-amino-N-hydroxy-2,3 dihydro-lH-indene-4-carboximidamide in step (i).
Scheme 10:
Reagents: (i) HOBt, EDC, 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid, DMF; (ii) 2N HCL in ether, DCM.
[0261] Scheme 11:
Reagents: (i) PG = protecting group e.g. Boc20, DMAP, ACN; (ii) NH2OH*HCl, Na2C03, EtOH; (iii) HOBt, EDC, benzoic acid, DMF; (iv) deprotection e.g. 4N HCl in dioxane.
Scheme 12:
Reagents: (i) NH2OH*HCl, Na2C03, EtOH; (ii) HOBt, EDC, benzoic acid, DMF. [0263] Scheme 13:
Reagents: (i) NH2OH*HCl, Na2C03, EtOH; (ii) HOBt, EDC, 3-cyano-4- isopropoxybenzoic acid, DMF.
[0264] Scheme 14:
Reagents: (i) PG= protecting group e.g. tert-butylchlorodimethylsilane, TEA, DCM; (ii) Zn(CN)2, Pd(PPh3)4, NMP; (iii) NH2OH*HCl, Na2C03, EtOH; (iv) HOBt, EDC, benzoic acid, DMF.
Selected compounds and their corresponding analytical data is shown in Table 1, where the LCMS data was collected using Method 2 (see General Methods). The enantiomeric purity was determined for key intermediates and selected final compounds and is presumed from the synthesis for the remaining compounds. TABLE 1
see compd 2
TABLE 2
Experimental Procedures
[0266] 5-oxo-5, 6, 7, 8-tetrahydronaphthalene-l-carbonitrile (INT-1)
[0267] To a stirred solution of 5-bromo-3,4-dihydronaphthalen-l(2H)-one (9.95g, 44.2 mmol) in NMP (50 mL) was added Zn(CN)2 (10.38 g, 88.4 mmol). The mixture was degassed twice by bubbling N2 through the solution for 30 min then evacuated. Pd(Ph3)4 (0.5g, 0.44 mmol) was added and the mixture was heated to 110°C under N2. After 5h, the mixture was cooled to room temperature and poured onto ice (600 mL), using water (300 mL) to complete the transfer. After the ice had melted, the solution was filtered and the resulting solid was collected, suspended in DCM, and filtered again. The solid was collected, washed with water, and purified by column chromatography (EA/ hex) to provide 6.9 g (91%) of 5-oxo-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-1 as a white solid. LCMS- ESI (m/z) calculated for CnH9NO: 171.2; found 172.1 [M+H]+, tR = 2.95 min. Ή NMR (400 MHz, CDCI3) 6 8.26 (dd, J = 7.9, 1.4 Hz, 1H), 7.82 (dd, J = 7.6, 1.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 3.20 (t, J = 6.1 Hz, 2H), 2.72 (dd, J = 7.2, 6.1 Hz, 2H), 2.30 – 2.17 (m, 2H). I3C NMR (101 MHz, CDC13) δ 196.22, 147.39, 137.18, 133.39, 131.59, 127.19, 116.93, 112.94, 38.48, 28.05, 22.28.
[0268] (R)-5-hydroxy-5, 6, 7, 8-tetrahydronaphthalene-l -carbonitrile (INT-2)
[0269] To a stirred solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-1 (3.0 g, 17.5 mmol) in 5:1 HC02:NEt3 (24 mL) was added RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.13 g, 0.26 mmol). The mixture was stirred at 30°C for 15 h then partitioned between EA and H20. The combined organic layers were dried over Na2S04 and chromatographed (EA/ hex) to provide 2.99 g (99%) of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l -carbonitrile INT-2 as a white solid. LCMS-ESI (m/z) calculated for CnHnNO: 173.2; found 174.1 [M+H]+, 156.1 [Μ-Ν¾]+, tR = 2.60 min. Ή NMR (400 MHz, CDC13) δ 7.71 (d, J = 7.8 Hz, 1H), 7.54 (dt, J = 8.7, 4.4 Hz, 1H), 7.34 – 7.26 (m,lH), 4.85 – 4.71 (m, 2H), 3.48 (s, 1H), 3.13 – 2.96 (m, lH), 2.90 (ddd, J = 17.7, 7.8, 5.6 Hz, 1H), 2.15 – 1.95 (m, 2H), 1.97 – 1.76 (m, 2H). Chiral HPLC: (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile was eluted with 5% IPA / hexane: 99.1% ee, tR = 15.3 min.
[0270] (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT-3 was prepared in an analogous fashion using INT-1 and RuCl(p-cymene)[(S,S)-Ts-DPEN]. Chiral HPLC: 99.4% ee, tR for the (S)-enantiomer = 17.99 min.
[0271] General Procedure 1. Preparation of Amide Oximes
[0272] To (R)- or (S)-cyanides (1 eq) in EtOH (0.56 M) was added hydroxylamine hydrochloride (3 eq) and either NaHC03 or TEA (3 eq) and the reaction mixture heated at 85°C for 1-2 h. The organic soluble amide oximes were isolated by removal of the solvent and partitioning between water and DCM. The water soluble amide oximes were chromatographed or used directly in the cyclization. Pure amide oximes can be obtained by recrystallization from alcoholic solvents.
[0273] (R)-N,5-dihydroxy-5,6, 7,8-tetrahydronaphthalene-l-carboximidamide (INT-4)
[0274] Prepared using General Procedure 1. To a stirring solution of (R)-5-hydroxy-5 ,6,7,8- tetrahydronaphthalene-l-carbonitrile INT-2 (79.1 mg, 0.46 mmol) in EtOH (2 mL) was added hydroxylamine hydrochloride (34.9 mg, 0.50 mmol) and sodium bicarbonate (42.2 mg, 0.50 mmol). The mixture was heated at 70°C for 18 h. The product was purified by chromatography (MeOHV DCM) to provide 27.3 mg (29%) (R)-N,5-dihydroxy-5,6,7,8- tetrahydronaphthalene-l-carboximidamide INT-4 as a white solid. LCMS-ESI (m/z) calculated for CuHnNO: 173.2; found 174.1 [M+H]+, 156.1 [M-NH ]+, tR = 2.60 min.(S)- N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-l-carboximidamide ENT-5 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-l-carbonitrile INT -3.
[0275] General Procedure 2. Cyclization to Oxadiazole Amines
[0276] A solution of the appropriate acid (1 eq), HOBt (1.3 eq), and EDC (1.3 eq) in DMF
(0.08 M in acid) was stirred at room temperature under an atmosphere of N2. After the complete formation of the HOBt- acid complex (1-3 h), the (R)- or (S)-amide oxime (1.1 eq) was added to the mixture. After complete formation of the coupled intermediate (ca. 0.5- 2 h), the mixture was heated to 75-95°C until the cyclization was complete (8-12 h). The reaction mixture was diluted with saturated NaHC03 and extracted with EA. The combined organic extracts were dried, concentrated, and could be purified by chromatography (EA/hexanes), preparative HPLC or recrystallization.
[0277] (R)-5-(3-(5-hydroxy-5, 6, 7,8-tetrahydronaphthalen-l-yl)-l,2,4-oxadiazol-5-yl)-2- isopropoxybenzonitnle (Compound 1)
[0278] Prepared using General Procedure 2. To a stirring solution of 3-cyano-4- isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy- 5,6,7, 8-tetrahydronaphthalene-l-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90°C for 15 h. The mixture was diluted with EA and washed with NaHC03. The combined organic layers were dried, concentrated, chromatographed (EA/ hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l- yl)-l,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m z) calculated for C22H21N303: 375.4; found 376.1 [M+H]+, tR = 3.73 min. 1H NMR (400 MHz, CDC13) δ 8.42 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 8.9, 2.2 Hz, 1H), 7.97 (dd, J = 7.7, 1.3 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 1H), 4.91 – 4.83 (m, 1H), 4.79 (dq, J = 12.0, 6.0 Hz, 1H), 3.20 (dt, J = 17.8, 5.4 Hz, 1H), 3.01 (dt, J = 13.3, 6.4 Hz, lH), 2.13 – 1.81 (m, 4H), 1.79 (d, J = 7.2 Hz, 1H), 1.47 (d, J = 5.6 Hz, 6H). 13C NMR (101 MHz, CDC13) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl)-l,2,4-oxadiazol-5-yl)- 2-isopropoxybenzonitrile was eluted with 10% IPA / hexane: 99.4% ee, tR = 40.85 min.
[0279] (S)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-l-yl) -l,2,4-oxadiazol-5-yl) -2- isopropoxybenzonitrile 2 was prepared in an analogous fashion from (S)-5-hydroxy-5,6,7,8- tetrahydronaphthalene-l-carbonitrile INT-5. Chiral HPLC: 99.1% ee, tR for the (S)- enantiomer = 38.19 min.
DRUG APPROVAL PROCESS IN EUROPE
DRUG APPROVAL PROCESS IN EUROPE
A regulatory process by which a person/organization/sponsor/innovator gets authorization to launch a drug in the market, is known as drug approval process. In general, a drug approval process comprises of various stages: application to conduct clinical trials, conducting clinical trials, application to marketing authorization of drug and post-marketing studies. Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of the drugs. This article will focus the similarities and differences in drug approval process of various regulatory bodies. IntroductionIn the present scenario, countries have different regulatory requirements for approval of a new drug. The single regulatory approach for marketing authorization application (MAA) of a new drug product applicable to various countries (on the basis of single dossier) is utmost difficult. Therefore, the knowledge of exact and detailed regulatory requirements for… |
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Nonracemic Synthesis of GK−GKRP Disruptor AMG-3969
Hi Folks, it was a busier week than normal and I finally got a chance to work on a post. There is no witty title here, either. I couldn’t think of one. I wanted to find something with some structures to draw because I haven’t posted anything of that nature in a while. I originally thought I found a process development paper in JOC, but I was in error. I decided to post about it anyways, because it hits on some points that process chemists will identify with.
The post can be found in J. Org. Chem. 2014, 79, 3684−3687, doi: 10.1021/jo500336e. Lead author is Matthew P. Bourbeau and colleagues at Amgen. The paper is about the rework of an API synthesis. The original synthesis was used to produce material but when your final product is racemic and being separated using SFC or SMB chromatography at the final step, it…
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Flu and other viral infections could be stopped by boosting natural protein
Boosting a naturally occurring protein may help the body to detect and fend off certain viral infections on its own.
The discovery could lead to new, more effective treatments for many dangerous viruses – such as hepatitis C and influenza.
In a new study published in the journal Immunity, researchers from the University of Pittsburgh Cancer Institute (UPCI) detailed their investigation into the protein oligoadenylate synthetases-like, or OASL. They revealed that by amplifying OASL in human cells, they were able to effectively inhibit viral replication.
According to the researchers, OASL is a key component of the body’s innate immune system, a subsystem of the overall immune system that allow our cells to intrinsically defend against pathogens.
“It was initially thought the [adaptive] immune system is all we have to protect against invasion – the one that makes antibodies and cells that can essentially destroy infected…
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Antibodies from the desert as guides to diseased cells
With help of proteins, nanoparticles can be produced, which bind specifically to cancer cells, thus making it possible to detect tumours. Credit: CBNI, UCD
Nanoparticles are considered a promising approach in detecting and fighting tumour cells. The method has, however, often failed because the human immune system recognizes and rejects them before they can fulfil their function. Researchers at Helmholtz-Zentrum Dresden-Rossendorf and at University College Dublin have developed nanoparticles that bypass the body’s defence system and find the diseased cells. This procedure uses fragments from an antibody that only occurs in camels and llamas.
The use of nanoparticles in cancer research is considered as a promising approach in detecting and fighting tumour cells. The method has, however, often failed because the human immune system recognizes the particles as foreign objects and rejects them before they can fulfil their function. Researchers at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) and at University College…
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Cleaning Validation
Cleaning Validation
Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in the pharmaceutical industry. The focus of cleaning validation is those cleaned surfaces that, if inadequately cleaned, could potentially contaminate the product subsequently manufactured in that same equipment.
This primarily covers product contact surfaces in the cleaned equipment. Cleaning validation is not performed only to satisfy regulatory authorities. The safety of patients is the primary objective, and product contamination presents serious liability issues for any pharmaceutical manufacturer or contract organization.
The history behind cleaning validation
The unhygienic conditions in Chicago’s meat- packing plants revealed in Upton Sinclair’s novel, “The Jungle”, allowed the government investigators and congress to enact the meat inspection law and the Pure Food and Drugs Act in 1906, the law forbade adulteration, misbranding adulteration, misbranding of foods, drinks, and drugs.
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BI-836845 a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.
BI-836845
Human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2
| IGF pathway modulator (iv, cancer), Boehringer Ingelheim; |
Phase 2 Clinical
Anticancer protein kinase inhibitor; Anticancer monoclonal antibody
WO-2008155387
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim is developing BI-836845, a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.
In April 2011, a phase I trial was initiated in the UK . In October 2011, another phase I trial was initiated in Taiwan. In February 2014, recruitment was ongoing. At that time, the trial was expected to be completed in March 2015 In June 2014, the drug was listed as being in phase I development for solid tumors in Japan and for breast cancer
In May 2014, an open-label, randomized, parallel-assigned, phase II trial (NCT02123823; 1280.4; 2013-001110-15) to evaluate the safety and efficacy of BI-836845 and everolimus in combination with exemestane in women with breast cancer (expected n = 198) was planned to be initiated in Belgium, France and the Netherlands. At that time, the trial was expected to complete in December 2017
In June 2014, an open-label, single-group assigned, phase I trial (NCT02145741; 1280.15) to evaluate BI-836845 in Japanese patients (expected n = 18) with advanced solid tumors was planned to be initiated in Japan. At that time, the trial was expected to complete in June 2015
In March 2011, a non-randomized, open-label, phase I study (NCT01317420; 1280.2; 2010-021714-29) was planned to begin later that month in patients with solid tumors (expected n = 70) in the UK, to assess the safety, efficacy, pharmacokinetics, pharmacodynamics and pharmacogenomics of BI-836845. The study began in April 2011; at that time, completion was expected in March 2013 .
In June 2012, preclinical data were presented at the 48th ASCO meeting in Chicago, IL. In the study, the combination of BI-836845 plus rapamycin was more effective than single agent therapy at inhibiting Ewing’s sarcoma cell proliferation in vitro and in a nude mouse xenograft model .
In November 2011, preclinical data were presented at the 23rd AACR-NCI-EORTC International Conference in San Francisco, CA. BI-836845 potently inhibited proliferation of the multiple myeloma cell line LP-1 with an EC50 of 0.4 nM.
BI-836845 is a human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2 (insulin growth factor-2). Phase II clinical trials are ongoing at Boehringer Ingelheim for the treatment of patients with breast cancer, and phase I clinical trials are ongoing with patients with advanced solid tumors.
Insulin-like growth factor-1 (IGF-1; a 70 amino-acid polypeptide) and insulin-like growth factor-2 (IGF-2; a 67 amino-acid polypeptide) are 7.5-kD soluble factors present in serum that can potently stimulate the growth of many mammalian cells (reviewed by Pollack et al., 2004). Although IGFs can be detectable in a number of tissues the main source of circulating IGFs is the liver which secretes the IGFs and IGF binding proteins (IGFBPs) in response to a complex signaling pathway that is initiated in the pituitary gland and transduced via growth hormone. On secretion into the bloodstream the IGFs form complexes with the IGFBPs which not only protects them from proteolytic degradation in the serum en route to their target tissues but also prevents their association with the IGF receptors. In addition to this endocrine source of IGFs they are also known to be secreted in an autocrine or paracrine manner in target tissues themselves. This is known to occur during normal fetal development where the IGFs play a key role in the growth of tissues, bone and organs. It is also seen in many cancer tissues where there is thought to be paracrine signaling between tumour cells and stromal cells or autocrine IGF production by the tumour cells themselves (reviewed by LeRoith D, 2003).
30 May 2014
MEDIA ALERT
ASCO 2014: Boehringer Ingelheim to present latest oncology research, including overall survival results
• Highly anticipated new overall survival data for Giotrif® (afatinib*) to be presented on June 2nd (3:00 – 6:00 PM, E Hall D2 [Abstract #8004 scheduled for 4:00 – 4:12 PM])
• 7 total abstracts accepted for Giotrif® (afatinib*), nintedanib** and BI 836845**: 1 for oral presentation and 6 posters
| BI 836845 (IGF ligand antibody)** | ||
| A Phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers | Chia-Chi Lin, Kwang-Yu Chang, Dennis Chin-Lun Huang, Vicky Marriott, Ludy van Beijsterveldt, Li-Tzong Chen, Ann-Lii Cheng | Sunday, June 1 8:00 – 11:45 AM S Hall A2 (Abstract #2617 Poster #80) |
| Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumours | Rihawi K, Ong M, Michalarea V, Bent L, Buschke S4, Bogenrieder T, Anthoney A, de Bono J, Twelves CJ | Sunday, June 1 8:00 – 11:45 AM S Hall A2 (Abstract #2622 Poster #85) |
The activity of the IGFs is thought to be regulated by a complex and relatively poorly understood interaction involving seven different IGFBPs and other serum proteins. Activation of the IGFs involves their release from this ternary complex after proteolytic release of the serum binding protein and IGFBPs, this is thought to occur in close proximity to cell surfaces where the IGFs are then free to bind to their receptors and transduce intracellular signals that ultimately leads to cellular proliferation and the inhibition of apoptosis. IGF-1 and IGF-2 are able to bind to the IGF-1 receptor (IGF-1R) expressed on many normal tissues, which functionally is a 460 kD heterotetramer consisting of a dimerised alpha- and beta-subunit, with similar affinities (Rubin et al., 1995). IGF-2 can also bind to the IGF-2 receptor (also know as the mannose-6-phosphate receptor) which does not have any known signaling function, rather it is thought to act as a sink for IGF-2 and prevent it from binding and signaling through the IGF-1R. In this respect the IGF-2R has been demonstrated to be a tumour suppressor protein. The IGF-1R is structurally similar to the insulin receptor which exists in two forms, IR-A and IR-B, which differ by an alternatively spliced 12 amino acid exon deletion in the extracellular domain of IR-A. IR-B is the predominant IR isoform expressed in most normal adult tissues where it acts to mediate the effects of insulin on metabolism. IR-A on the other hand is known to be highly expressed in developing fetal tissues but not in adult normal tissues. Recent studies have also shown that IR-A, but not IR-B, is highly expressed in some cancers. The exon deletion in IR-A has no impact on insulin binding but does cause a small conformational change that allows IGF-2 to bind with much higher affinity than for IR-B (Frasca et al., 1999; Pandini et al., 2002). Thus, because of it’s expression in cancer tissues and increase propensity for IGF-2 binding, IR-A may be as important as IGF1-R in mediating the mitogenic effects of IGF-2 in cancer.
Binding of the IGFs to IGF-1R triggers a complex intracellular signaling cascade which results in activation of proteins that stimulate growth and inhibit apoptosis (reviewed by Pollack et al., 2004). In terms of growth, upregulated translation is induced by the activation of p70 S6 kinase, which in turn phosphorylates the S6 ribosomal protein (Dufner and Thomas, 1999). Thus, IGF-stimulated cell growth can be measured by the rapid increase in phosphorylated S6 ribosomal protein.
Unlike the EGFR and Her2neu receptors there is no known amplification of the IGF1-R or IR-A receptors in cancers indicating that receptor activation is controlled by the presence of active ligand. There is a very large body of scientific, epidemiological and clinical literature implicating a role for the IGFs in the development, progression and metastasis of many different cancer types (reviewed by Jerome et al., 2003; and Pollack et al., 2004).
For example, in colorectal cancer the expression of IGF-2 mRNA and protein is elevated in clinical colorectal tumour specimens compared with adjacent normal tissue (Freier et al., 1999; Li et al., 2004). There is also a positive correlation of elevated IGF serum levels with proliferating cell index in patients with colorectal neoplasia (Zhao et al., 2005). In addition, elevated circulating levels of IGF-2 correlate with an increased risk of developing colorectal cancers and adenomas (Renehan et al., 2000a) and b); Hassan et al., 2000). Loss of parental imprinting (LOI) of the IGF-2 gene, an epigenetic alteration that results in elevated IGF-2 expression, is a heritable molecular trait that has recently been identified in patients with colorectal and other tumour types. Loss of IGF-2 imprinting has been shown to be associated with a five-fold risk of colorectal neoplasia (Cui et al., 2003; Cruz-Correa et al., 2004) and adenomas (Woodson et al., 2004). Antibodies targeting the alpha-subunit of the IGF-1R which block IGF binding and internalize the receptor have been shown to delay the growth of the xenografted colon cancer-derived cell lines such as COLO 205 (Burtrum et al., 2003).
Elevated levels of IGFs are associated with a poor prognosis in human pulmonary adenocarcinomas (Takanami et al., 1996) and IGFs are expressed and secreted by many SCLC— and NSCLC-derived cell lines (Quinn et al., 1996). Transgenic over-expression of IGF-2 induces spontaneous lung tumours in a murine model (Moorhead et al., 2003). In terms of hepatocellular carcinoma (HCC), human clinical specimens and animal models of HCC express higher levels of IGF mRNA and protein than corresponding normal tissues and this has been correlated with increased tumour growth (Wang et al., 2003; Ng et al., 1998). IGF-2 has also been shown to be a serological marker of HCC with elevated levels in the serum of HCC patients compared with controls (Tsai et al., 2005). An orthotopic xenograft tumour model of HCC was established using Hep 3B cells, and used to demonstrate that inhibition of IGF-2 expression using a methylated oligonucleotide enhances survival (Yao et al., 2003a) and b).
Many childhood solid tumours such as Ewing sarcoma and rhabdomyosarcoma appear to be particularly dependent on the IGF signaling pathway for their growth (Scotlandi et al., 1996). LOI of the IGF-2 gene has been implicated as a primary genetic event in the development for embryonal rhabdomyosarcoma (Fukuzawa et al., 1999). Autocrine IGF signaling is also thought to strongly influence the growth of Ewing sarcoma in cases where the type-1 EWS-FLI1 chimeric transcription factor is expressed through a chromosomal translocation resulting in elevated expression of target genes including the IGF ligands and IGF-1R, and reduced expression of IGFBP-3. Antibodies and small molecule compounds targeting the IGF-1R have been shown to reduce the growth of xenografted pediatric solid tumour derived cell lines (Kolb et al., 2008; Manara et al., 2007).
Using IGF ligand-specific antibodies it has been demonstrated that the growth of human prostate cancer cells in adult human bone implanted into SCID mice can be inhibited (Goya et al., 2004). In addition, it was demonstrated that the same IGF ligand antibodies could block the paracrine supply of IGF and suppress the liver metastasis of human colorectal cancer cells in a murine xenograft system (Miyamoto et al., 2005).
There is also considerable evidence suggesting that the IGF signaling system reduces the sensitivity of cancers to chemotherapeutic agents and radiation. One of the earliest findings in this respect was the demonstration that IGF-1R knock-out mouse embryos are refractory to transformation by viruses, oncogenes and over-expressed growth factor receptors (Sell et al., 1993; Sell et al., 1994) and that over-expression of IGF-1R protects cells from UV irradiation and gamma radiation-induced apoptosis (Kulik et al., 1997). Furthermore, using liver tumour cell lines that secrete large amounts of IGF-2, it was found that neutralization of IGF-2 significantly increased response to chemotherapeutic agents such as cisplatin and etoposide in vitro, especially at lower, cytostatic doses, suggesting that IGF-2 can reduce the susceptibility to chemotherapeutic agents (Lund et al., 2004). Consistent with these findings it has been demonstrated that antibodies targeting the IGF-1R increase the susceptibility of tumour xenografts to growth inhibition by chemotherapeutic drugs and radiation (Goetsch et al., 2005).
A number of antibodies that show cross-reactive binding to human IGF-1 and human IGF-2 have been reported. Antibody sm1. was raised against human IGF-1 and shows 40% cross-reactivity to human IGF-2 and was shown to inhibit the proliferation of a mouse fibroblast cell line BALB/c3T3 which was stimulated with 20 ng/ml human IGF-1 (Russell et al., 1984). In a study designed to functionally epitope map IGF-1 by raising monoclonal antibodies to whole IGF-1 protein and portions of the protein a number of antibodies where identified that cross reacted with IGF-2 (Manes et al., 1997). The percent cross-reactivity with IGF-2 ranged from 0 to 800% and several antibodies were identified which were equally IGF-1 and IGF-2 reactive. KM1486 is a rat monoclonal antibody that cross-reacts with human IGF-1 and IGF-2 and it was demonstrated that KM1486 can inhibit growth of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice (Goya et al., 2004). In addition, it was demonstrated that KM1486 suppresses the liver metastasis of human colorectal cancers (Miyamoto et al., 2005). KM1486 has also been described in WO 03/093317, JP 2003-310275, WO 2005/018671, WO 2005/028515, and WO 2005/027970.
For the treatment of human disease an antibody with a fully human sequence is highly desirable in order to minimize the risk of generating a human anti-antibody reaction and neutralizing antibodies that will rapidly eliminate the administered antibody from the body and thereby reduce the therapeutic effect. As such, and given the roles of IGF-1 and IGF-2 dependent signaling in the development and progression of cancers it would be desirable to obtain high affinity fully human antibodies that co-neutralise the mitogenic effects of both ligands.
In addition, to maximize the therapeutic potential of such an antibody, it is important to have a suitably long terminal half life (T1/2). Prior to terminal half life determination in human subjects, the most accurate estimation of an antibody’s human terminal half life can be obtained from administration to non-human primates such as cynomolgus monkeys. For example, bevacizumab, a registered humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used for the treatment of several human cancers, has a terminal half-life in cynomolgus monkeys of 8.57±0.38 days (Lin et al., 1999), which translates to a terminal half life in humans of approximately 20 days allowing for a single administration once every two weeks (Lu et al., 2008).
It was a further object of the invention to obtain an antibody that does not affect binding of insulin to its receptor.
The clinical development of therapeutic agents is supported by pharmacodynamic biomarkers of drug activity. Clinical studies with antibodies targeting the IGF-1R have demonstrated that an increase in total serum IGF-1 levels may be a useful pharmacodynamic marker for these agents (Pollack et al., 2007). The reason for the increase in total serum IGF-1 levels is likely due to a feedback mechanism involving pituitary growth hormone (GH) secretion which releases both IGF-1 and IGFBPs from the liver. Indeed, in humans it has been demonstrated that free or bioactive IGF-1, which represents only around 1% of total IGF-1 levels, determines the feedback response (Chen et al., 2005). The inventors thus sought to confirm whether total serum IGF-1 levels are also a useful pharmacodynamic marker for the activity of a therapeutic anti-IGF antibody. In this case it would be desirable for such antibody to be cross-reactive with IGFs from a suitable animal species, e.g. mouse or rat, such that a pharmacodynamic effect can already be tested pre-clinically.
Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.
Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.
In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.
Fig.1 Production of MAb
| Adam, P.J.; Friedbichler, K.; Hofmann, M.H.; Bogenrieder, T.; Borges, E.; Adolf, G.R. BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation 48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 3092 |
| Lin, C.-C.; Chang, K.-Y.; Huang, D.C.; Marriott, V.; Van Beijsterveldt, L.; Chen, L.-T.; Cheng, A.-L. A phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers 50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2617 |
Adam, P.J.; Ostermann, E.; Lamche, H.R.; Hofmann, M.H.; Kroez, M.; Borges, E.; Adolf, G.R.
Pharmacodynamic properties and anti-tumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody
AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (November 12-16, San Francisco) 2011, Abst A208
| Rihawi, K.; Ong, M.; Michalarea, V.; et al. Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumors 50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2622 |
cGMPs for Active Pharmaceutical Ingredient (API) and Excipient Production
Polyphenols and Alzheimers
“Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of AD is the accumulation of plaques in the brain of AD patients. The plaques predominantly consist of aggregates of amyloid-beta (Abeta), a peptide of 39-42 amino acids generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein.” (Finder & Glockshuber)
Stefani & Rigacci review the evidence for polyphenols and their ability to reduce amyloid aggregation. Natural polyphenols are emerging as an increasingly attractive treatment for amyloid disease prevention and therapy. Evidence suggests that they can inhibit the production of amyloidogenic peptides, increase antioxidant enzyme activity and reduce inflammation. The researchers suggest that we should now be describing them as potentially multitargeting drugs.
Potential sources of polyphenols are found in, amongst others, vegetables, fruit and green tea.
Design, construction and start-up of a pilot plant for active pharmaceutical ingredients
- Linde-KCA-Dresden built a pilot plant 16 times the size of the laboratory apparatus for Novo Nordisk A/S
- The building layouts show different areas for the pilot plant, the utility systems and the technical rooms with hazardous and non-hazardous proof conditions (top). The engineering documents include
The construction of a pilot plant constitutes an important milestone in the development cycle of a new active pharmaceutical ingredient. Pilot plants are used to gain the technological experience needed for the scale-up process and are required for producing sufficient quantities of the active pharmaceutical ingredient for clinical trials and other types of tests. As a result, even these testing facilities must comply with GMP regulations.
http://www.cpp-net.com/pharma/-/article/5829537/15910929/Challenging+task/
New Drug Approvals 