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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Golodirsen, ゴロジルセン;


VYONDYS 53 (golodirsen) Structural Formula - Illustration

Golodirsen

  • RNA, [P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(G-m5U-m5U-G-C-C-m5U-C-C-G-G-m5U-m5U-C-m5U-G-A-A-G-G-m5U-G-m5U-m5U-C), 5′-[P-[4-[[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]carbonyl]-1-piperazinyl]-N,N-dimethylphosphonamidate]
  • Nucleic Acid Sequence
  • Sequence Length: 25
Formula
C305H481N138O112P25
CAS
1422959-91-8
Mol weight
8647.2841
  • Exon 53: NG-12-0163
  • Golodirsen
  • SRP 4053

Nucleic Acid Sequence

Sequence Length: 252 a 6 c 8 g 9 umodified

FDA APPROVED, Vyondys 53, 019/12/12

Antisense oligonucleotide

ゴロジルセン;

Duchenne muscular dystrophy (DMD variant amenable to exon 53 skipping)

Image result for Golodirsen

VYONDYS 53 (golodirsen) injection is a sterile, aqueous, preservative-free, concentrated solution for dilution prior to intravenous administration. VYONDYS 53 is a clear to slightly opalescent, colorless liquid. VYONDYS 53 is supplied in single-dose vials containing 100 mg golodirsen (50 mg/mL). VYONDYS 53 is formulated as an isotonic phosphate buffered saline solution with an osmolality of 260 to 320 mOSM and a pH of 7.5. Each milliliter of VYONDYS 53 contains: 50 mg golodirsen; 0.2 mg potassium chloride; 0.2 mg potassium phosphate monobasic; 8 mg sodium chloride; and 1.14 mg sodium phosphate dibasic, anhydrous, in water for injection. The product may contain hydrochloric acid or sodium hydroxide to adjust pH.

Golodirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Golodirsen contains 25 linked subunits. The sequence of bases from the 5′ end to 3′ end is GTTGCCTCCGGTTCTGAAGGTGTTC. The molecular formula of golodirsen is C305H481N138O112P25 and the molecular weight is 8647.28 daltons. The structure of golodirsen is:

VYONDYS 53 (golodirsen) Structural Formula - Illustration
Side Effects & Drug Interactions

SIDE EFFECTS

  • Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the VYONDYS 53 clinical development program, 58 patients received at least one intravenous dose of VYONDYS 53, ranging between 4 mg/kg (0.13 times the recommended dosage) and 30 mg/kg (the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 to 13 years. Most (86%) patients were Caucasian.

VYONDYS 53 was studied in 2 double-blind, placebo-controlled studies.

In Study 1 Part 1, patients were randomized to receive once-weekly intravenous infusions of VYONDYS 53 (n=8) in four increasing dose levels from 4 mg/kg to 30 mg/kg or placebo (n=4), for at least 2 weeks at each level. All patients who participated in Study 1 Part 1 (n=12) were continued into Study 1 Part 2, an open-label extension, during which they received VYONDYS 53 at a dose of 30 mg/kg IV once weekly [see Clinical Studies].

In Study 2, patients received VYONDYS 53 (n=33) 30 mg/kg or placebo (n=17) IV once weekly for up to 96 weeks, after which all patients received VYONDYS 53 at a dose of 30 mg/kg.

Adverse reactions observed in at least 20% of treated patients in the placebo-controlled sections of Studies 1 and 2 are shown in Table 1.

Table 1: Adverse Reactions That Occurred in At Least 20% of VYONDYS 53-Treated Patients and at a Rate Greaterthan Placebo in Studies 1 and 2

Adverse Reaction VYONDYS 53
(N = 41) %
Placebo
(N = 21) %
Headache 41 10
Pyrexia 41 14
Fall 29 19
Abdominal pain 27 10
Nasopharyngitis 27 14
Cough 27 19
Vomiting 27 19
Nausea 20 10

Other adverse reactions that occurred at a frequency greater than 5% of VYONDYS 53-treated patients and at a greater frequency than placebo were: administration site pain, back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, tachycardia, catheter site related reaction, constipation, and fracture.

Hypersensitivity reactions have occurred in patients treated with VYONDYS 53 [see WARNINGS AND PRECAUTIONS].

Antisense technology provides a means for modulating the expression of one or more specific gene products, including alternative splice products, and is uniquely useful in a number of therapeutic, diagnostic, and research applications. The principle behind antisense technology is that an antisense compound, e.g., an oligonucleotide, which hybridizes to a target nucleic acid, modulates gene expression activities such as transcription, splicing or translation through any one of a number of antisense mechanisms. The sequence specificity of antisense compounds makes them attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in disease.

Duchenne muscular dystrophy (DMD) is caused by a defect in the expression of the protein dystrophin. The gene encoding the protein contains 79 exons spread out over more than 2 million nucleotides of DNA. Any exonic mutation that changes the reading frame of the exon, or introduces a stop codon, or is characterized by removal of an entire out of frame exon or exons, or duplications of one or more exons, has the potential to disrupt production of functional dystrophin, resulting in DMD.

Recent clinical trials testing the safety and efficacy of splice switching

oligonucleotides (SSOs) for the treatment of DMD are based on SSO technology to induce alternative splicing of pre-mRNAs by steric blockade of the spliceosome (Cirak et al., 2Q\ \; Goemans et al., 2011; Kinali et al., 2009; van Deutekom et al., 2007). However, despite these successes, the pharmacological options available for treating DMD are limited. Golodirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 53 of the human dystrophin gene in patients with DMD who are amendable to exon 53 skipping to restore the read frame and produce a functional shorter form of the dystrophin protein.

Although significant progress has been made in the field of antisense technology, there remains a need in the art for methods of preparing phosphorodiamidate morpholino oligomers with improved antisense or antigene performance.

PATENT

https://patents.google.com/patent/WO2017205880A1/en

Provided herein are processes for preparing phosphorodiamidate morpholino oligomers (PMOs). The synthetic processes described herein allow for a scaled-up PMO synthesis while maintaining overall yield and purity of a synthesized PMO.

Accordingly, in one aspect, provided herein is a process for preparing an oligomeric compound of Formula A):

Figure imgf000003_0001

(A).

In certain embodiments, provided herein is a process for preparing an oligomeric compound of Formula (G):

Figure imgf000004_0001

In yet another embodiment, the oligomeric compound of the disclosure including, for example, some embodiments of an oligomeric compound of Formula (G), is an oligomeric compound of Formula (XII):

Figure imgf000005_0001

(XII).

For clarity, the structural formulas including, for example, oligomeric compound of Formula (C) and Golodirsen depicted by Formula (XII), are a continuous structural formula from 5′ to 3′, and, for the convenience of depicting the entire formula in a compact form in the above structural formulas, Applicants have included various illustration breaks labeled “BREAK A” and “BREAK B.” As would be understood by the skilled artisan, for example, each indication of “BREAK A” shows a continuation of the illustration of the structural formula at these points. The skilled artisan understands that the same is true for each instance of “BREAK B” in the structural formulas above including Golodirsen. None of the illustration breaks, however, are intended to indicate, nor would the skilled artisan understand them to mean, an actual discontinuation of the structural formulas above including

Example 1: NCP2 Anchor Synthesis

1. Preparation of Meth l 4-Fluoro-3-Nitrobenzoate (1)

Figure imgf000103_0002

To a 100L flask was charged 12.7kg of 4-fluoro-3-nitrobenzoic acid was added 40kg of methanol and 2.82kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0° C. Crystals formed at 38° C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100L flask was washed and filter cake was washed with 10kg of methanol that had been cooled to 0° C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695kg methyl 4-fluoro-3-nitrobenzoate (100% yield; HPLC 99%).

2. Preparation of 3-Nitro-4-(2-oxopropyl)benzoic Acid

A. (Z)-Methyl 4-(3 -Hydroxy- l-Methoxy-l-Oxobut-2-en-2-yl)-3-Nitrobenzoate (2)

Figure imgf000104_0001

To a 100L flask was charged 3.98kg of methyl 4-fluoro-3-nitrobenzoate (1) from the previous step 9.8kg DMF, 2.81kg methyl acetoacetate. The mixture was stirred and cooled to 0° C. To this was added 3.66kg DBU over about 4 hours while the temperature was maintained at or below 5° C. The mixture was stirred an additional 1 hour. To the reaction flask was added a solution of 8.15kg of citric acid in 37.5kg of purified water while the reaction temperature was maintained at or below 15° C. After the addition, the reaction mixture was stirred an addition 30 minutes then filtered under nitrogen. The wet filter cake was returned to the 100L flask along with 14.8kg of purified water. The slurry was stirred for 10 minutes then filtered. The wet cake was again returned to the 100L flask, slurried with 14.8kg of purified water for 10 minutes, and filtered to crude (Z)-methyl 4-(3 -hydroxy- 1 – methoxy-l-oxobut-2-en-2-yl)-3-nitrobenzoate.

B. 3-Nitro-4-(2-oxopropyl)benzoic Acid

Figure imgf000105_0001

2 3

The crude (Z)-m ethyl 4-(3 -hydroxy- 1-methoxy-l -ox obut-2-en-2-yl)-3-nitrobenzoate was charged to a 100L reaction flask under nitrogen. To this was added 14.2kg 1,4-dioxane and the stirred. To the mixture was added a solution of 16.655kg concentrated HC1 and 13.33kg purified water (6M HC1) over 2 hours while the temperature of the reaction mixture was maintained below 15° C. When the addition was complete, the reaction mixture was heated at reflux (80° C) for 24 hours, cooled to room temperature, and filtered under nitrogen. The solid filter cake was triturated with 14.8kg of purified water, filtered, triturated again with 14.8kg of purified water, and filtered. The solid was returned to the 100L flask with 39.9kg of DCM and refluxed with stirring for 1 hour. 1.5kg of purified water was added to dissolve the remaining solids. The bottom organic layer was split to a pre-warmed 72L flask, then returned to a clean dry 100L flask. The solution was cooled to 0° C, held for 1 hour, then filtered. The solid filter cake was washed twice each with a solution of 9.8kg DCM and 5kg heptane, then dried on the funnel. The solid was transferred to trays and dried to a constant weight of 1.855kg 3-Nitro-4-(2-oxopropyl)benzoic Acid. Overall yield 42% from compound 1. HPLC 99.45%.

3. Preparation of N-Tritylpiperazine Succinate (NTP)

Figure imgf000105_0002

To a 72L jacketed flask was charged under nitrogen 1.805kg triphenylmethyl chloride and 8.3kg of toluene (TPC solution). The mixture was stirred until the solids dissolved. To a 100L jacketed reaction flask was added under nitrogen 5.61kg piperazine, 19.9kg toluene, and 3.72kg methanol. The mixture was stirred and cooled to 0° C. To this was slowly added in portions the TPC solution over 4 hours while the reaction temperature was maintained at or below 10° C. The mixture was stirred for 1.5 hours at 10° C, then allowed to warm to 14° C. 32.6kg of purified water was charged to the 72L flask, then transferred to the 100L flask while the internal batch temperature was maintained at 20+/-50 C. The layers were allowed to split and the bottom aqueous layer was separated and stored. The organic layer was extracted three times with 32kg of purified water each, and the aqueous layers were separated and combined with the stored aqueous solution.

The remaining organic layer was cooled to 18° C and a solution of 847g of succinic acid in 10.87kg of purified water was added slowly in portions to the organic layer. The mixture was stirred for 1.75 hours at 20+/-50 C. The mixture was filtered, and the solids were washed with 2kg TBME and 2kg of acetone then dried on the funnel. The filter cake was triturated twice with 5.7kg each of acetone and filtered and washed with 1kg of acetone between triturations. The solid was dried on the funnel, then transferred to trays and dried in a vacuum oven at room temperature to a constant weight of 2.32kg of NTP. Yield 80%. 4. Preparation of (4-(2-Hydroxypropyl)-3-NitrophenyI)(4-Tritylpiperazin-l-yl)Methanone A. Preparation of l-(2-Nitro-4(4-Tritylpiperazine-l-Carbonyl)Phenyl)Propan-2-one

Figure imgf000106_0001

3 4

To a 100L jacketed flask was charged under nitrogen 2kg of 3-Nitro-4-(2- oxopropyl)benzoic Acid (3), 18.3 kg DCM, 1.845kg N-(3-dimethylaminopropyl)-N’- ethylcarbodiimide hydrochloride (EDC.HC1). The solution was stirred until a homogenous mixture was formed. 3.048kg of NTP was added over 30 minutes at room temperature and stirred for 8 hours. 5.44kg of purified water was added to the reaction mixture and stirred for 30 minutes. The layers were allowed to separate and the bottom organic layer containing the product was drained and stored. The aqueous layer was extracted twice with 5.65kg of DCM. The combined organic layers were washed with a solution of 1.08kg sodium chloride in 4.08kg purified water. The organic layers were dried over 1.068kg of sodium sulfate and filtered. The sodium sulfate was washed with 1.3kg of DCM. The combined organic layers were slurried with 252g of silica gel and filtered through a filter funnel containing a bed of 252g of silica gel. The silica gel bed was washed with 2kg of DCM. The combined organic layers were evaporated on a rotovap. 4.8kg of THF was added to the residue and then evaporated on the rotovap until 2.5 volumes of the crude l-(2-nitro-4(4-tritylpiperazine-l- carbonyl)phenyl)propan-2-one in THF was reached.

B. Preparation of (4-(2-Hydroxypropyl)-3-NitrophenyI)(4-Tritylpiperazin-l- yl)Methano

Figure imgf000107_0001

To a 100L jacketed flask was charged under nitrogen 3600g of 4 from the previous step and 9800g THF. The stirred solution was cooled to <5° C. The solution was diluted with 11525g ethanol and 194g of sodium borohydride was added over about 2 hours at <5° C. The reaction mixture was stirred an additional 2 hours at <5° C. The reaction was quenched with a solution of about 1.1kg ammonium chloride in about 3kg of water by slow addition to maintain the temperature at <10° C. The reaction mixture was stirred an additional 30 minutes, filtered to remove inorganics, and recharged to a 100L jacketed flask and extracted with 23kg of DCM. The organic layer was separated and the aqueous was twice more extracted with 4.7kg of DCM each. The combined organic layers were washed with a solution of about 800g of sodium chloride in about 3kg of water, then dried over 2.7kg of sodium sulfate. The suspension was filtered and the filter cake was washed with 2kg of DCM. The combined filtrates were concentrated to 2.0 volumes, diluted with about 360g of ethyl acetate, and evaporated. The crude product was loaded onto a silica gel column of 4kg of silica packed with DCM under nitrogen and eluted with 2.3kg ethyl acetate in 7.2kg of DCM. The combined fractions were evaporated and the residue was taken up in 11.7kg of toluene. The toluene solution was filtered and the filter cake was washed twice with 2kg of toluene each. The filter cake was dried to a constant weight of 2.275kg of compound 5 (46% yield from compound 3) HPLC 96.99%. 5. Preparation of 2,5-Dioxopyrrolidin-l-yl(l-(2-Nitro-4-(4-triphenylmethylpiperazine-l Carbon l)Phenyl)Propan-2-yl) Carbonate (NCP2 Anchor)

Figure imgf000108_0001

3 NCP2 Anchor

To a 100L jacketed flask was charged under nitrogen 4.3kg of compound 5 (weight adjusted based on residual toluene by 1H MR; all reagents here after were scaled accordingly) and 12.7kg pyridine. To this was charged 3.160 kg of DSC (78.91 weight % by 1H NMR) while the internal temperature was maintained at <35° C. The reaction mixture was aged for about 22 hours at ambience then filtered. The filter cake was washed with 200g of pyridine. In two batches each comprising ½ the filtrate volume, filtrate wash charged slowly to a 100L jacketed flask containing a solution of about 11kg of citric acid in about 50 kg of water and stirred for 30 minutes to allow for solid precipitation. The solid was collected with a filter funnel, washed twice with 4.3kg of water per wash, and dried on the filter funnel under vacuum.

The combined solids were charged to a 100L jacketed flask and dissolved in 28kg of DCM and washed with a solution of 900g of potassium carbonate in 4.3kg of water. After 1 hour, the layers were allowed to separate and the aqueous layer was removed. The organic layer was washed with 10kg of water, separated, and dried over 3.5kg of sodium sulfate. The DCM was filtered, evaporated, and dried under vacuum to 6.16kg of NCP2 Anchor (114% yield).

Example 2: Anchor Loaded Resin Synthesis

To a 75L solid phase synthesis reactor was charged about 52L of NMP and 2600g of aminomethyl polystyrene resin. The resin was stirred in the NMP to swell for about 2 hours then drained. The resin was washed twice with about 39L DCM per wash, then twice with 39L Neutralization Solution per wash, then twice with 39L of DCM per wash. The NCP2 Anchor Solution was slowly added to the stirring resin solution, stirred for 24 hours at room temperature, and drained. The resin was washed four times with 39L of NMP per wash, and six times with 39L of DCM per wash. The resin was treated and stirred with ½ the DEDC Capping Solution for 30 minutes, drained, and was treated and stirred with the 2nd ½ of the DEDC Capping Solution for 30 minutes and drained. The resin was washed six times with 39L of DCM per wash then dried in an oven to constant weight of 3573.71g of Anchor Loaded Resin.

Example 3: Preparation of Activated EG3 Tail

1. Preparation of Trityl Piperazine Phenyl Carbamate 35

Figure imgf000109_0001

To a cooled suspension of NTP in dichloromethane (6 mL/g NTP) was added a solution of potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate). To this two- phase mixture was slowly added a solution of phenyl chloroformate (1.03 eq) in

dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20° C. Upon reaction completion (1-2 hr), the layers were separated. The organic layer was washed with water, and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. Yield=80%

2. Preparation of Carbamate Alcohol (36)

Figure imgf000110_0001

Sodium hydride (1.2 eq) was suspended in l-methyl-2-pyrrolidinone (32 mL/g sodium hydride). To this suspension were added triethylene glycol (10.0 eq) and compound 35 (1.0 eq). The resulting slurry was heated to 95° C. Upon reaction completion (1-2 hr), the mixture was cooled to 20° C. To this mixture was added 30% dichloromethane/methyl tert- butyl ether (v:v) and water. The product-containing organic layer was washed successively with aqueous NaOH, aqueous succinic acid, and saturated aqueous sodium chloride. The product 36 was isolated by crystallization from dichloromethane/methyl tert-butyl ether/heptane. Yield=90%.

3. Preparation of EG3 Tail Acid (37)

Figure imgf000110_0002

To a solution of compound 36 in tetrahydrofuran (7 mL/g 36) was added succinic anhydride (2.0 eq) and DMAP (0.5 eq). The mixture was heated to 50° C. Upon reaction completion (5 hr), the mixture was cooled to 20° C and adjusted to pH 8.5 with aqueous NaHC03. Methyl tert-butyl ether was added, and the product was extracted into the aqueous layer. Dichloromethane was added, and the mixture was adjusted to pH 3 with aqueous citric acid. The product-containing organic layer was washed with a mixture of pH=3 citrate buffer and saturated aqueous sodium chloride. This dichloromethane solution of 37 was used without isolation in the preparation of compound 38. 4. Preparation of Activated EG3 Tail (38)

Figure imgf000111_0001

To the solution of compound 37 was added N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) (1.02 eq), 4-dimethylaminopyridine (DMAP) (0.34 eq), and then l-(3- dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC) (1.1 eq). The mixture was heated to 55° C. Upon reaction completion (4-5 hr), the mixture was cooled to 20° C and washed successively with 1 : 1 0.2 M citric acid/brine and brine. The dichloromethane solution underwent solvent exchange to acetone and then to Ν,Ν-dimethylformamide, and the product was isolated by precipitation from acetone/N,N-dimethylformamide into saturated aqueous sodium chloride. The crude product was reslurried several times in water to remove residual Ν,Ν-dimethylformamide and salts. Yield=70% of Activated EG3 Tail 38 from compound 36.

Example 4: 50L Solid-phase Synthesis of

Golodirsen [Oligomeric Compound (XII)] Crude Drug Substance

1. Materials

Table 2: Starting Materials

Figure imgf000111_0002

Activated Phosphoramidochloridic acid, 1155373-31-1 C37H37CIN5O5P 698.2 C Subunit N,N-dimethyl-,[6-[4-

(benzoylamino)-2-oxo-l(2H)- pyrimidinyl]-4-

(triphenylmethyl)-2- morpholinyljmethyl ester

Activated Propanoic Acid, 2,2-dimethyl- 1155309-89-9 C5iH53ClN707P 942.2

DPG ,4-[[[9-[6-

Subunit [[[chloro(dimethylamino)phosp

hinyl]oxy]methyl]-4-

(triphenylmethyl)-2- morpholinyl]-2-[(2- phenylacetyl)amino]-9H-purin-

6-yl]oxy]methyl]phenyl ester

Activated Phosphoramidochloridic acid, 1155373-34-4 C3iH34ClN405P 609.1 T Subunit N,N-dimethyl-,[6-(3,4-dihydro- 5-methyl-2,4-dioxo- 1 (2H)- pyrimidinyl)]-4- (triphenylmethyl)-2- morpholinyljmethyl ester

Activated Butanedioic acid, 1- 1380600-06-5 C43H47N3Oio 765.9 EG3 Tail [3aR,4S,7R,7aS)-l,3,3a,4,7,7a- hexahydro- 1 ,3 -dioxo-4,7- methano-2H-isoindol-2-yl] 4- [2-[2-[2-[[[4-(triphenylmethyl)- 1- piperazinyl ] carb onyl ] oxy] ethox

y]ethoxy] ethyl] ester

Golodirsen.

Example 5: Purification of Golodirsen Crude Drug Substance

The deprotection solution from Example 4, part E, containing the Golodirsen crude drug substance was loaded onto a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience) and eluted with a gradient of 0-35% B over 17 column volume (Buffer A: 10 mM sodium hydroxide; Buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and fractions of acceptable purity (CI 8 and SCX HPLC) were pooled to a purified drug product solution. HPLC: 93.571% (C18; Fig. 3) 88.270% (SCX; Fig. 4).

The purified drug substance solution was desalted and lyophilized to 1450.72 g purified Golodirsen drug substance. Yield 54.56 %; HPLC: 93.531% (Fig. 5; C18) 88.354% (Fig. 6; SCX).

PATENT

WO 2019067979

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019067979&tab=PCTDESCRIPTION&_cid=P22-K4DLNX-74378-1

Duchenne Muscular Dystrophy (DMD) is a serious, progressively debilitating, and ultimately fatal inherited X-linked neuromuscular disease. DMD is caused by mutations in the dystrophin gene characterized by the absence, or near absence, of functional dystrophin protein that disrupt the mRNA reading frame, resulting in a lack of dystrophin, a critically important part of the protein complex that connects the cytoskeletal actin of a muscle fiber to the extracellular matrix. In the absence of dystrophin, patients with DMD follow a predictable disease course. Affected patients, typically boys, develop muscle weakness in the first few years of life, lose the ability to walk during childhood, and usually require respiratory support by their late teens. Loss of functional abilities leads to loss of independence and increasing caregiver burden. Once lost, these abilities cannot be recovered. Despite improvements in the standard of care, such as the use of glucocorticoids, DMD remains an ultimately fatal disease, with patients usually dying of respiratory or cardiac failure in their mid to late 20s.

Progressive loss of muscle tissue and function in DMD is caused by the absence or near absence of functional dystrophin; a protein that plays a vital role in the structure and function of muscle cells. A potential therapeutic approach to the treatment of DMD is suggested by Becker muscular dystrophy (BMD), a milder dystrophinopathy. Both dystrophinopathies are caused by mutations in the DMD gene. In DMD, mutations that disrupt the pre-mRNA reading frame,

referred to as “out-of-frame” mutations, prevent the production of functional dystrophin. In BMD, “in-frame” mutations do not disrupt the reading frame and result in the production of internally shortened, functional dystrophin protein.

An important approach for restoring these “out-of-frame” mutations is to utilize an antisense oligonucleotide to exclude or skip the molecular mutation of the DMD gene

(dystrophin gene). The DMD or dystrophin gene is one of the largest genes in the human body and consists of 79 exons. Antisense oligonucleotides (AONs) have been specifically designed to target specific regions of the pre-mRNA, typically exons to induce the skipping of a mutation of the DMD gene thereby restoring these out-of-frame mutations in-frame to enable the production of internally shortened, yet functional dystrophin protein.

The skipping of exon 53 in the dystrophin gene has been an area of interest for certain research groups due to it being the most prevalent set of mutations in this disease area, representing 8% of all DMD mutations. A prominent AON being developed by Sarepta

Therapeutics, Inc., for DMD patients that are amenable to exon 53 skipping is golodirsen.

Golodirsen is a phosphorodiamidate morpholino oligomer, or PMO. Another AON being developed by Nippon Shinyaku CO., LTD., for DMD patients that are amenable to exon 53 skipping is viltolarsen (NS-065 which is a PMO.

Exondys 51 ® (eteplirsen), is another PMO that was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. However, the current standard of care guidelines for the treatment of DMD in patients that are not amenable to exon 51 skipping include the administration of glucocorticoids in conjunction with palliative interventions. While glucocorticoids may delay the loss of ambulation, they do not sufficiently ameliorate symptoms, modify the underlying genetic defect or address the absence of functional dystrophin characteristic of DMD.

Previous studies have tested the efficacy of an antisense oligonucleotides (AON) for exon skipping to generate at least partially functional dystrophin in combination with a steroid for reducing inflammation in a DMD patient (see WO 2009/054725 and van Deutekom, et al., N. Engl. J. Med. 2007; 357:2677-86, the contents of which are hereby incorporated herein by reference for all purposes). However, treatment with steroids can result in serious complications, including compromise of the immune system, reduction in bone strength, and growth

suppression. Notably, none of the previous studies suggest administering an antisense

oligonucleotide for exon skipping with a non-steroidal anti-inflammatory compound to a patient for the treatment of DMD.

Thus, there remains a need for improved methods for treating muscular dystrophy, such as DMD and BMD in patients.

EXAMPLE 1

CAT- 1004 in Combination with M23D PMO Reduces Inflammation and Fibrosis in Mdx Mice.

To assess the effectiveness of a combination treatment of an exon skipping antisense oligonucleotide and an F-Kb inhibitor in Duchenne muscular dystrophy, M23D PMO and

CAT-1004 were utilized in the Mdx mouse model. The effect on inflammation and fibrosis was determined by analyzing samples of muscle taken from the quadriceps, of (1) wild-type mice treated with saline, (2) mdx mice treated with saline, (3) mdx mice treated with CAT-1004, (4) mdx mice treated with the M23D PMO, and (5) mdx mice treated with the M23D PMO in combination with CAT-1004. The tissue sections were analyzed for fibrosis by picrosirius red staining and for inflammation and fibrosis by Hematoxylin and Eosin (H&E) staining, as described in the Materials and Methods section above.

Treatment of Mdx mice with either M23D PMO or CAT-1004 as monotherapies resulted in a reduction of inflammation and fibrosis as compared to Mdx mice treated with saline.

Surprisingly, treatment of Mdx mice with the M23D PMO in combination with CAT-1004 resulted in reduced inflammation and fibrosis as compared with mice treated with CAT-1004

alone or M23D alone (Fig. 9). These results indicate the combination treatment enhances muscle fiber integrity.

EXAMPLE 2

Exon Skipping and Dystrophin Production in Mdx Mice Treated with the M23D

PMO and the M23D PMO in Combination with CAT- 1004

To analyze the extent of exon skipping and dystrophin production in mice treated with the M23D PMO in combination with CAT- 1004, samples of muscle were taken from the quadriceps, diaphragm, and heart of (1) wild-type mice treated with saline, (2) mdx mice treated with saline, (3) mdx mice treated with CAT- 1004, (4) mdx mice treated with the M23D PMO, and (5) mdx mice treated with the M23D PMO in combination with CAT- 1004. RT-PCR analysis for exon 23 skipping was performed as well as Western blot analysis to determine dystrophin protein levels.

Exon skipping was observed in the muscle of the quadriceps, diaphragm, and heart of the Mdx mice treated with the M23D PMO as well as mice treated with the M23D PMO in combination with CAT-1004 (Fig. 10). Surprisingly, enhanced dystrophin production was observed in the muscle of the quadriceps, diaphragm, and heart of the mice treated with the M23D PMO in combination with CAT-1004 as compared to treatment with M23D PMO monotherapy (Fig. 11). These results indicated the increase in dystrophin levels extended to the heart, a tissue known to have low efficiency of dystrophin upregulation by these agents when used alone. Notably, neither exon skipping nor dystrophin production were observed in mdx mice treated with CAT-1004 monotherapy (Figs. 10 and 11).

PATENT

WO 2019046755

PAPER

Methods in Molecular Biology (New York, NY, United States) (2018), 1828(Exon Skipping and Inclusion Therapies), 31-55.

PAPER

Human Molecular Genetics (2018), 27(R2), R163-R172.

///////////Golodirsen, ゴロジルセン , FDA 2019, ANTISENSE, Exon 53: NG-12-0163, SRP 4053, OLIGONUCLEOTIDE, Duchenne Muscular Dystrophy

SYN 01


SYN-01, SYN-510

Synthena AG

Preclinical

Synthena , presumed to be under license from  University of Bern , is investigating (presumably SYN-01 ), a lead from the tricyclo(tc)-DNA based antisense oligonucleotides (AON) developed using its proprietary tricyclo-DNA technology platform, for the treatment of Duchenne muscular dystrophy. In January 2017, the drug was listed as being in preclinical development.

Patent

WO-2019142135

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019142135&tab=PCTDESCRIPTION&_cid=P22-JYQVON-19722-1

Process for preparing tricyclo-deoxyribonucleic acid (tc-DNA) which may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Antisense technology is an effective means for reducing the expression of specific gene products and can therefore be useful in therapeutic, diagnostic, and research applications.

Generally, the principle behind antisense technology is that an antisense oligomeric compound (a sequence of nucleotides or analogues thereof) hybridizes to a target nucleic acid and modulates gene expression activities or function, such as transcription and/or translation.

[003] Antisense oligomeric compounds may be prepared from chemically-modified antisense oligonucleotides, which may include a variety of different structural variations depending upon the therapeutic strategy. For example, tricyclo-deoxyribonucleic acids (tc-DNA) are conformationally constrained DNA analogs.

[004] There is a need in the field for processes that allow for the bulk preparation of tc-DNA nucleoside precursors that may be used as building blocks for tc-DNA containing antisense oligonucleotide-based therapies.

Example 4 – Cvclopropanation of Compound 17 with Carbenoid Prepared from CH2I2 and Et2Zn in the Absence of Additives

[00127] According to the following scheme, compound 17 was converted to tc-DNA Nucleoside Precursor 18 using the cyclopropanation conditions set forth in Examples 4 to 7 :

[00128] 1.07 g purified a-anomer (3.736 mmol) 17 was dissolved in 37 ml of dry CH2C12 and cooled to 0 °C (ice). Subsequently, 22.3 ml (22.3 mmol, 6 eq.) Et2Zn 1.0 M in hexane (Aldrich) were added dropwise and stirred under Ar for 30 min at 0 °C. Then, 3.02 ml (37.2 mmol, 10 eq.) of CH2I2 were added dropwise over 15 min at the same temperature and stirred for further 2 h at 0 °C. Afterwards the cooling bath was removed and the mixture was stirred for additional 21 h at ambient temperature. TLC showed substantial amount of unreacted a- 17. It was diluted by addition of EtOAc and quenched with 50 mL of sat. aqueous NH4Cl. Extractive work-up provided 1.79 g of crude which was purified by chromatography on silica-gel giving 0.43 g (39%) of 18 and 0.49 g of mixture of compound 17 and 18 (approximately 20:80).

PATENT

WO2018193428

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018193428

claiming a composition comprising an oligomeric compound having tricyclo-deoxyribonucleic acid (tc-DNA) nucleosides and a lipid moiety.

EXAMPLE 1

Inventive compositions for the treatment of Duchenne muscular dystrophy

Evaluation of efficacy

[00464] Adult mdx mice were treated weekly over 4 weeks with intravenous injections of different 13-mer AONs targeting the donor splice site of exon 23 of the dystrophin pre-mRNA (M23D: +2-11), namely with either SY-0308, SY-0210 and the inventive SY-0299, SY-0343, SY-0442 and SY-0455. SY-0308 (also named “tcDNA-PO M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: l, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorodiester linkage groups, and p being a phosphate moiety at the 5′ end. SY-0210 (also named “tcDNA-PS M23D” interchangeably herein) corresponds to p-CCTCGGCTTACCT-OH of SEQ ID NO: 1, with all nucleotides being tc-DNAs and all internucleosidic linkage groups being phosphorothioate linkage groups, and p being a phosphate moiety at the 5′ end. The inventive composition SY-0343 is herein interchangeably referred to as “Palm-2PS-tcDNA-PO M23D” which is depicted in the following:

[00465] The inventive composition SY-0442 is herein interchangeably referred to as “Palm-lPS-tcDNA-PO M23D” which is depicted in the following:

[00466] The inventive composition SY-0299 is herein interchangeably referred to as “Palm-2PO-tcDNA-PO M23D” which is depicted in the following:

//////////////////SYN-01, SYN 01, SYN01, preclinical , Duchenne muscular dystrophy, University of Bern,

FDA approves drug to treat Duchenne muscular dystrophy


FDA approves drug to treat Duchenne muscular dystrophy

Feb. 9, 2017

The U.S. Food and Drug Administration today approved Emflaza (deflazacort) tablets and oral suspension to treat patients age 5 years and older with Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness. Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system.

Read more.

New FDA Logo Blue

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy


Image result for Exondys 51

Image result for eteplirsen

CAS 1173755-55-9
eteplirsen, eteplirsén [Spanish], étéplirsen [French] , eteplirsenum [Latin], этеплирсен [Russian], إيتيبليرسان [Arabic]

Structure credit http://lgmpharma.com/eteplirsen-still-proves-efficacious-duchenne-drug/

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy
New therapy addresses unmet medical need

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

Read more

Image result for Duchenne muscular dystrophy

FDA grants accelerated approval to first drug for Duchenne muscular dystrophy

September 19, 2016

Release

The U.S. Food and Drug Administration today approved Exondys 51 (eteplirsen) injection, the first drug approved to treat patients with Duchenne muscular dystrophy (DMD). Exondys 51 is specifically indicated for patients who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13 percent of the population with DMD.

“Patients with a particular type of Duchenne muscular dystrophy will now have access to an approved treatment for this rare and devastating disease,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “In rare diseases, new drug development is especially challenging due to the small numbers of people affected by each disease and the lack of medical understanding of many disorders. Accelerated approval makes this drug available to patients based on initial data, but we eagerly await learning more about the efficacy of this drug through a confirmatory clinical trial that the company must conduct after approval.”

DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. It is the most common type of muscular dystrophy. DMD is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. The first symptoms are usually seen between three and five years of age, and worsen over time. The disease often occurs in people without a known family history of the condition and primarily affects boys, but in rare cases it can affect girls. DMD occurs in about one out of every 3,600 male infants worldwide.

People with DMD progressively lose the ability to perform activities independently and often require use of a wheelchair by their early teens. As the disease progresses, life-threatening heart and respiratory conditions can occur. Patients typically succumb to the disease in their 20s or 30s; however, disease severity and life expectancy vary.

Exondys 51 was approved under the accelerated approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments. Approval under this pathway can be based on adequate and well-controlled studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients (how a patient feels or functions or whether they survive). This pathway provides earlier patient access to promising new drugs while the company conducts clinical trials to verify the predicted clinical benefit.

The accelerated approval of Exondys 51 is based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. The FDA has concluded that the data submitted by the applicant demonstrated an increase in dystrophin production that is reasonably likely to predict clinical benefit in some patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. A clinical benefit of Exondys 51, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with the drug, the life-threatening and debilitating nature of the disease for these children and the lack of available therapy.

Under the accelerated approval provisions, the FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Exondys 51 improves motor function of DMD patients with a confirmed mutation of the dystrophin gene amenable to exon 51 skipping. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

The most common side effects reported by participants taking Exondys 51 in the clinical trials were balance disorder and vomiting.

The FDA granted Exondys 51 fast track designation, which is a designation to facilitate the development and expedite the review of drugs that are intended to treat serious conditions and that demonstrate the potential to address an unmet medical need. It was also granted priority review and orphan drug designation.Priority review status is granted to applications for drugs that, if approved, would be a significant improvement in safety or effectiveness in the treatment of a serious condition. Orphan drug designation provides incentives such as clinical trial tax credits, user fee waiver and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

The manufacturer received a rare pediatric disease priority review voucher, which comes from a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare pediatric diseases. This is the seventh rare pediatric disease priority review voucher issued by the FDA since the program began.

Exondys 51 is made by Sarepta Therapeutics of Cambridge, Massachusetts.

Image result for Exondys 51 (eteplirsen) injection

ChemSpider 2D Image | eteplirsen | C364H569N177O122P30

CAS 1173755-55-9 [RN]
eteplirsén [Spanish] [INN]
étéplirsen [French] [INN]
eteplirsenum [Latin] [INN]
этеплирсен [Russian] [INN]
إيتيبليرسان [Arabic] [INN]
Eteplirsen
Systematic (IUPAC) name
(P-deoxy-P-(dimethylamino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2’a→5′)(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),5′-(P-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)carbonyl)-1-piperazinyl)-N,N-dimethylphosphonamidate) RNA
Clinical data
Routes of
administration
Intravenous infusion
Legal status
Legal status
  • Investigational
Identifiers
CAS Number 1173755-55-9
ATC code None
ChemSpider 34983391
UNII AIW6036FAS Yes
Chemical data
Formula C364H569N177O122P30
Molar mass 10305.738

///////////Exondys 51, Sarepta Therapeutics, Cambridge, Massachusetts, eteplirsen,  Orphan drug designationPriority reviewfast track designation, Duchenne muscular dystrophy, этеплирсен ,  إيتيبليرسان ,

Ataluren (Translarna) drug for Duchenne Muscular Dystrophy


ChemSpider 2D Image | Ataluren | C15H9FN2O3

Ataluren (Translarna)

3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid

3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

CAS 775304-57-9

PTC Therapeutics (Originator)

  • Molecular FormulaC15H9FN2O3
  • Average mass284.242 Da
  • EC-000.2051
    NCGC00168759-02
    PTC-124, PTC124, 
    UNII:K16AME9I3V
  • EU 2014-07-31 APPROVED

Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy and potentially other genetic disorders. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union.

Ataluren was approved by European Medicine Agency (EMA) on July 31, 2014. It was developed and marketed as Translarna® by PTC Therapeutics.

Ataluren was regulator of nonsense mutations indicated for the treatment of Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.

Translarna® is available as granules for oral use, containing 125 mg, 250 mg or 1000 mg of free Ataluren. The recommended dose is 10 mg/kg body weight in the morning, 10 mg/kg body weight at midday, and 20 mg/kg body weight in the evening.

Medical uses

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[1][2] such as some people with cystic fibrosis and Duchenne muscular dystrophy. It is approved for the use in Duchenne in the European Union.

Mechanism of action

Ataluren makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. Studies have demonstrated that PTC124 treatment increases expression of full-length dystrophin protein in human and mouse primary muscle cells containing the premature stop codon mutation for Duchenne muscular dystrophy and rescues striated muscle function.[3] Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function.[4] The European Medicines Agency review on the approval of ataluren concluded that “the non-clinical data available were considered sufficient to support the proposed mechanism of action and to alleviate earlier concerns on the selectivity of ataluren for premature stop codons.” [5]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[6] Ataluren appears to be most effective for the stop codon ‘UGA’.[1]

History

Clinical trials

In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.[7] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug.

Phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[8] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[9]

Approval

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).[10]Translarna was first available in Germany, the first EU country to launch the new medicine.[11]

In August 2014, ataluren received market authorization from the European Commission to treat patients with nonsense mutation Duchenne muscular dystrophy. A confirmatory phase III clinical trial is ongoing.[11] The drug does not yet have approval by the US Food and Drug Administration.

In October 2015, NICE asked for further evidence of benefit to justify the “very high cost”.[12] NICE estimated that for a typical patient, treatment would cost £220,256 per year.

In February 2016, FDA declined to approve or even discuss PTC Therapeutics application for ataluren because it deemed the data presented by the developer “insufficient to warrant a review”.[13]

Ataluren Molecule

PAPER

Auld, Douglas S.; Proceedings of the National Academy of Sciences of the United States of America 2009, V106(9), P3585-3590

http://www.pnas.org/content/106/9/3585.full

http://www.pnas.org/content/suppl/2009/02/10/0813345106.DCSupplemental

http://www.pnas.org/content/suppl/2009/02/10/0813345106.DCSupplemental/Appendix_PDF.pdf

STR1

Samples were analyzed for purity on an Agilent 1200 series LC/MS equipped with a Luna® C18 reverse phase (3 micron, 3 x 75 mm) column having a flow rate of 0.8-1.0 mL/min. The mobile phase was a mixture of acetonitrile (0.025% TFA) and H2O (0.05% TFA), and temperature was maintained at 50 °C. A gradient of 4% to 100% acetonitrile over 7 minutes was used during analytical analysis. Purity of final compounds was determined to be >95%, using a 5 μL injection with quantitation by AUC at 220 and 254 nM. High resolution mass spectra were obtained with an Agilent 6210 Time-of-Flight LC/MS with a 3.5 um Zorbax SB-C18 column (2.1 x 30 mm) (solvents are Water and ACN with 0.1% Formic Acid). A 3 minute gradient at 1 mL/min from 5% to 100% acetonitrile was used.

3-[5-(2-fluorophenyl)-[1,2,4]-oxadiazol-3-yl]-benzoic acid (1a, PTC124).

1 H NMR (d6-DMSO, 400 MHz) δ 13.15-13.68 (bs, 1H), 8.62 (s, 1H), 8.31 (d, 1H, JHH = 6.8 Hz), 8.24 (t, 1H, JHH = 7.2 Hz), 8.17 (d, 1H, JHH = 7.4 Hz), 7.77-7.82 (m, 1H), 7.73 (t, 1H, JHH = 7.6 Hz), 7.53 (dd, 1H, JHH = 10.8 Hz, JHH = 8.4 Hz), 7.48 (t, 1H, JHH = 6.8 Hz).

13C NMR (d6-DMSO, 400 MHz) δ 172.72 (d, JCF = 4.4 Hz), 167.39, 166.52, 159.95 (d, JCF = 258.0 Hz), 135.80 (d, JCF = 8.8 Hz), 132.28, 131.97, 131.97, 131.04, 130.94, 129.86, 127.76, 125.4 (d, JCF = 3.6 Hz), 117.2 (d, JCF = 20.4 Hz), 111.6 (d, JCF = 11.2 Hz). LC-

MS: rt (min) = 5.713; [M+H]+ 285.1;

HRMS: (CI+, m/z), calcd for C15H10FN2O3 (MH+ ), 285.06814; found, 285.06769.

CLIP

Ataluren (Translarna) Ataluren is a drug marketed under the trade name Translarna which was developed by PTC Therapeutics and approved by the European Union in May 2014 for the treatment of Duchenne’s muscular dystrophy (DMD) and potentially other genetic disorders.50

Ataluren renders ribosomes less sensitive to premature stop or ‘read-through’ codons, which are thought to be beneficial in diseases such as DMD and cystic fibrosis.51 Of the reported synthetic approaches to ataluren,52–55 the most likely process-scale approach consists of the sequence described in Scheme 7, which reportedly has been exemplified on kilogram scale.56

The sequence to construct ataluren, which was described by the authors at PTC Therapeutics, commenced with commercially available methyl 3-cyanobenzoate (38).56 This ester was exposed to hydroxylamine in aqueous tert-butanol and warmed gently until the reaction was deemed complete.

Then this mixture was treated with 2-fluorobenzoyl chloride dropwise and subsequently triethylamine dropwise. To minimize exotherm and undesired side products, careful control of the addition of reagents was achieved through slow dropwise addition of these liquid reagents.

Upon complete consumption of starting materials and formation of amidooxime 39, the aqueous reaction mixture was then heated to 85 C to facilitate 1,2,4-oxadiazole formation, resulting in the tricyclic ester 40 in excellent yield across the three steps.

Finally,saponification of ester 40 through the use of sodium hydroxide followed by acidic quench gave ataluren (V) in 96% over the two-step sequence.57

STR1

50. Welch, E. M.; Barton, E. R.; Zhuo, J.; Tomizawa, Y.; Friesen, W. J.; Trifillis, P.;Paushkin, S.; Patel, M.; Trotta, C. R.; Hwang, S.; Wilde, R. G.; Karp, G.; Takasugi,J.; Chen, G.; Jones, S.; Ren, H.; Moon, Y. C.; Corson, D.; Turpoff, A. A.; Campbell,J. A.; Conn, M. M.; Khan, A.; Almstead, N. G.; Hedrick, J.; Mollin, A.; Risher, N.;Weetall, M.; Yeh, S.; Branstrom, A. A.; Colacino, J. M.; Babiak, J.; Ju, W. D.;Hirawat, S.; Northcutt, V. J.; Miller, L. L.; Spatrick, P.; He, F.; Kawana, M.; Feng,H.; Jacobson, A.; Peltz, S. W.; Sweeney, H. L. Nature 2007, 447, 87.
51. Hirawat, S.; Welch, E. M.; Elfring, G. L.; Northcutt, V. J.; Paushkin, S.; Hwang,S.; Leonard, E. M.; Almstead, N. G.; Ju, W.; Peltz, S. W.; Miller, L. L. J. Clin.Pharmacol. 2007, 47, 430.

52Karp, G. M.; Hwang, S.; Chen, G.; Almstead, N. G. US Patent 2004204461A1,2004.
53. Andersen, T. L.; Caneschi, W.; Ayoub, A.; Lindhardt, A. T.; Couri, M. R. C.;Skrydstrup, T. Adv. Synth. Catal. 2014, 356, 3074.
54. Gupta, P. K.; Hussain, M. K.; Asad, M.; Kant, R.; Mahar, R.; Shukla, S. K.; Hajela,K. New J. Chem. 2014, 38, 3062.
55. Lentini, L.; Melfi, R.; Di Leonardo, A.; Spinello, A.; Barone, G.; Pace, A.; PalumboPiccionello, A.; Pibiri, I. Mol. Pharm. 2014, 11, 653.
56. Almstead, N. G.; Hwang, P. S.; Pines, S.; Moon, Y. -C.; Takasugi, J. J. WO Patent2008030570A1, 2008.
57. Almstead, N. G.; Chen, G.; Hirawat, S.; Hwang, S.; Karp, G. M.; Miller, L.; Moon,Y. C.; Ren, H.; Takasugi, J. J.; Welch, E. M.; Wilde, R. G. WO Patent2007117438A2, 2007.

CLIP

Ataluren trial success: trial aborted.

07 September 2011 – Pharma……..http://chem.vander-lingen.nl/info/item/September_2011/id/190/mid/140

Last week the newspaper NRC Handelsblad reported on a court case in which the parents of two young boys sued a pharmaceutical company over access to one of their developmental drugs. The drug in question wasAtaluren, the pharmaceutical companyPTC Therapeutics. The boys suffer from Duchenne muscular dystrophyand had taken part in a clinical trial. Whereas the results of this trial on the whole were inconclusive the boys did seriously benefit from the drug. Hardly any wonder the parents took action when the whole development program was canceled.

And the judge? He threw the case out arguing that doctors do not make the compound themselves and arguing that the compound is not commercially available. Are these arguments valid? and do the boys have options?

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

Except for the fluorine atom in it the compound is unremarkable. If you have to believe the Internet many Chinese companies produce and sell it. Ataluren is also still in the running as a potential treatment for some other diseases. So if need be the compound will be around for some time to come.

CLIP

Ataluren [3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid] is an orally available, small molecule compound that targets nonsense mutation. It is the first drug in its class and appears to allow cellular machinery to read through premature stop codons in mRNA, and thus enables the translation process to produce full-length, functional proteins.
Ataluren is developed and approved for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD) by EU in July 2014 [1].

Ataluren: 2D and 3D Structure

Nonsense Mutations as Target for DMD

A single nucleotide change in the DNA sequence that introduces a premature stop codon is known as a nonsense mutation, a subset of a major class of premature termination codon (PTC) mutations. Nonsense mutations cause premature termination of translation resulting in the production of truncated polypeptides, which in turn halts the ribosomal translation process at an earlier site than normal, producing a truncated, non-functional protein [1].

Nonsense mutations are implicated in 5-70 % of individual cases of most inherited diseases, including Duchenne muscular dystrophy (DMD) and cystic fibrosis. Ataluren appears to allow cellular machinery to read through premature stop codons in mRNA, enabling the translation process to produce full length, functional proteins.

Ataluren Synthesis

New J Chem 2014, 38, 3062-3070: The text reports one pot synthesis of Ataluren with an overall yield of 40%. It also reports few interesting and potent derivatives too.


WO 2007117438A2: It appears to be the industrial process. The patent also reports various pharmaceutically relevant assay and their results wrt Ataluren.
Identifications:

1H NMR (Estimated) for Ataluren

Experimental: 1H NMR (d6-DMSO, 400 MHz) δ 13.15-13.68 (bs, 1H), 8.62 (s, 1H), 8.31 (d, 1H, JHH= 6.8 Hz), 8.24 (t, 1H, JHH = 7.2 Hz), 8.17 (d, 1H, JHH = 7.4 Hz), 7.77-7.82 (m, 1H), 7.73 (t, 1H, JHH = 7.6 Hz), 7.53 (dd, 1H, JHH = 10.8 Hz, JHH = 8.4 Hz), 7.48 (t, 1H, JHH = 6.8 Hz).

13C-NMR (Estimated) for Ataluren

Experimental: 13C NMR (d6-DMSO, 400 MHz) δ 172.72 (d, JCF = 4.4 Hz), 167.39, 166.52, 159.95 (d, JCF = 258.0 Hz), 135.80 (d, JCF = 8.8 Hz), 132.28, 131.97, 131.97, 131.04, 130.94, 129.86, 127.76, 125.4 (d, JCF = 3.6 Hz), 117.2 (d, JCF = 20.4 Hz), 111.6 (d, JCF = 11.2 Hz)……https://ayurajan.blogspot.in/2016/05/ataluren-treatment-for-duchenne.html

CLIP

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).
CLIP
Route 1

Reference:1. WO2004091502A2 / US6992096B2.

2. WO2008045566A1 / US2008114039A1.

3. WO2008030570A1 / US2008139818A1.

4. Mol. Pharmaceutics 2014, 11, 653-664.

Route 2
Route 3

CLIP

Carcinogenicity

Carcinogenicity bioassays in transgenic mice (26 weeks) and in rats (24 months):

●    For Tg.rasH2 mouse: Ataluren did not increase the incidence of tumors up to the HDs in males (600 mg/kg/day) and in females (300 mg/kg/day).  The non-neoplastic findings included endometrial hyperplasia and nephropathy in females.

●    For rats: Urinary bladder tumors (benign urothelial cell papilloma [2 rats] and malignant urothelial cell carcinoma [1 rat]) were observed in 3/60 female rats dosed at 300 mg/kg/day.  In addition, one case of malignant hibernoma was observed in 1/60 male rats at the dose of 300 mg/kg/day.  The non-neoplastic toxicity consisted of a decrease of body weight.

PATENT

Example 1 (prepared by known ataluren)

Method ataluren according to Patent Document 2 is described in Example W02004091502A2 prepared.

Specific methods of preparation:

To a solution of 0.6 l of DMF was 44. 14g3- cyano acid 62.19 g of potassium carbonate was added, followed by stirring at room temperature for 30 minutes. 20 minutes To the suspension was added 28 ml of methyl iodide (450mmol), and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1.2 l of ice water, stirred for 30 minutes, the precipitate was filtered out thereof. The white cake was dissolved in 70 ml of methanol, and then reprecipitated in cold water. To give 79% yield of 3-cyano-benzoic acid methyl ester.

50 g of 3-cyano-benzoic acid methyl ester was dissolved in 500 ml of ethanol, to which was added 41 ml of 50% aqueous hydroxylamine (620mmol). 100 ° C and the reaction mixture was stirred for 1 hour, the solvent was removed under reduced pressure. So that the oily residue is dissolved in 100 ml of 20/80 ethanol / toluene, concentrated again. To give 61 g 3- (N- hydroxy amidino (carbamimidoyl)) – benzoic acid methyl ester.

60 g of 3- (N- hydroxy amidino (carbamimidoyl)) – benzoic acid methyl ester was dissolved in 200 ml of anhydrous tetrahydrofuran, followed by adding thereto 75 ml of diisopropylethylamine (434 mmol), and then 20 minutes this mixture was added 48.1 ml 2- fluorobenzoyl chloride (403mmol). The reaction mixture was stirred at room temperature for 1 hour. The precipitate was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in 400 ml of ethyl acetate, washed with 400 ml of water and then twice. The solvent was removed under reduced pressure, containing 60% ethyl acetate in hexane to give the desired product, generating 81 g 3- (N-2- amidino-fluorobenzoyl) – benzoate.

at 130 ° C with a Dean-Stark apparatus was dissolved in 500 ml of toluene was heated under reflux in 44 g of 3- (N-2- fluorobenzoyl) -1,2,3,4-_ benzoate 4 hours. 5 ° C and the reaction mixture was stirred for 18 hours. The white precipitate was filtered off, the filtrate was concentrated, recrystallized in toluene. To give 38 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester.

33 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester was dissolved in 400 ml of tetrahydrofuran, to which was added 100 ml of 1. 5M aqueous sodium hydroxide solution. At 100 ° C and the reaction mixture was heated at reflux for 2 hours. The solvent was removed under reduced pressure at 5 ° C the solution was stirred for 2 hours. The organic solvent was removed, washed with 50 mL of water. The aqueous solution was then acidified with hydrochloric acid to pH 1. The white precipitate was filtered off, the filter cake washed with cold water, then dried with a freeze dryer. To give 3.0 g of 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] benzoic acid. 1H-NMR (500MHz, d6-DMS0): 8. 31 (1H), 8 18 (2H), 8 08 (1H), 7 88 (2H), 7 51 (2H)….. Display: ataluren- Sample Preparation Example 1 prepared in Preparation Example 2 and TO2004091502A2 induced.

Each prepared in Example 2 (prepared according to known Form A)

Method [0084] A known polymorph according to Patent Document W02008039431A2 Example 5. 1. 1.1 prepared as described. Specifically: ataluren be prepared 1 100 mg Preparation Example, 60 ° C add 16.2 ml of isopropanol ultrasound clear solution, the solution by 2 square micron filter and the filtrate was kept covered with aluminum foil having a small hole. vial, 60 ° C and evaporated. The solid formed was isolated to give ataluren the A polymorph.

as needles.

its XRPD shown in Figure 1, the display ataluren polymorph A disclosed in Patent Document W02008039431A2 consistent.

SEE
European Journal of Organic Chemistry (2016), 2016(3), 438-442
Russian Chemical Bulletin (2015), 64(1), 142-145.
European Journal of Medicinal Chemistry (2015), 101, 236-244.
Bioorganic & Medicinal Chemistry Letters (2014), 24(11), 2473-2476.
New Journal of Chemistry (2014), 38(7), 3062-3070.
Proceedings of the National Academy of Sciences of the United States of America (2010), 107(11), 4878-4883, S4878/1-S4878/14.
WO 2008039431
WO 2008045566
WO 2008030570
WO 2007117438
WO 2006110483
WO 2007117438
WO 2006110483
US 20040204461
PATENT

novel crystalline forms of 3-[5-(2-fluorophenyl)-

[l,2,4]oxadiazol-3-yl]-benzoic acid, which has the following chemical structure (I):

Figure imgf000003_0001

(I)

In particular, crystalline forms of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]- benzoic acid are useful for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, as described in U.S. Patent No. 6,992,096 B2, issued January 31, 2006, which is incorporated herein by reference in its entirety. In addition, the present provides a crystalline form of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]-benzoic acid which is substantially pure, i.e., its purity greater than about 90%.

Processes for the preparation of 3-[5-(2-fluorophenyl)-[l,2,4]oxadiazol-3-yl]- benzoic acid are described in U.S. Patent No. 6,992,096 B2, issued January 31, 2006, and U.S. patent application no. 1 1/899,813, filed September 9, 2007, both of which are incorporated by reference in their entirety.

PATENT

CN101535284

https://worldwide.espacenet.com/publicationDetails/originalDocument?CC=CN&NR=101535284A&KC=A&FT=D&ND=&date=20090916&DB=&locale=

STR1

STR1

Example

3- ‘5- (2-fluorophenyl) – “1,2,41 oxadiazol-3-yl benzoate 1- Batch 1

The 3-cyano-benzoic acid methyl ester (105 kg) and t-butanol was added molten drying reactor. Under an inert atmosphere for about 2 hours 48 minutes, 50. /. Aqueous hydroxylamine (43L, 47.4 kg) was added to a clear solution of 3-cyano benzoic acid methyl ester in a molten in t-butanol. The addition of a 50% aqueous solution of hydroxylamine period, the maximum temperature batch of about 43 ° C. 50% aqueous solution of hydroxylamine addition rate of from about 9L / h when the changes start adding to about 30L / hr. To maintain the temperature of the batch by varying the reactor jacket set point. In particular, the set value is about 40.5 ° C, with the addition of a rate increase at the beginning join, change the setting to about 29.6 ° C. After about 40-45t stirred for about 4 hours, the reaction was deemed complete (i.e., less than about 0.5% ester).

The batch was transferred to a drying reactor, additional (chased through) approximately 10L molten tert-butanol. Jacket setpoint from about 33 when the batch was received when dried reactor. C is reduced to about 27 after the completion of the transfer. C. Batch crystallization was observed part, which does not adversely affect stirring. The batch was cooled to about 34.4 ° C, triethylamine (72.6 kg, IOOL) added to the reactor. The jacket temperature set value from about 20.4. C is increased to about 31.0 ° C, in order to maintain the batch temperature in the range of about 30-35t. With molten tert-butanol (IO L) was washed with a linear (line rinse) After the batch was added to the 2-fluorobenzoyl chloride (113.7 kg, 86.0L).Charge is added to the first third of the rate of about 25L / hr. In the meantime, the jacket inlet temperature was lowered to about 15 ° C, the batch temperature is maintained at about 34.6 ° C. In about 5.5 hours after the addition was complete.During the addition, the maximum temperature of the batch was about 38.8 ° C. Near the end of the addition, the addition rate slowed to about 11L / hr was added last 27 liters of 2-fluoro-benzoyl chloride. 30-35. C After stirring for about 2 hours, that the reaction was complete (i.e., less than about 0.5% of methyl 3-amidinophenoxy). Then, after about 1 hour 42 minutes, the batch was heated to reflux temperature (about 82 ° C), and then stirred for about 18 hours. During the stirring, a number of product partially crystallized to form a slurry. The slurry was cooled to about 40. C thus sampled, during which complete crystallization occurs. The batch was then heated to reflux temperature and stirred for about 1 hour 50 minutes.Then, after about two hours, the batch was cooled to about 69 ° C, and after about four hours and 15 minutes, slowly added 630L of pure water, while maintaining the batch temperature at about 66-69 ° C. After about 3 hours 14 minutes, the slurry was cooled to about 22.4 ° C, and transferred to 2x200L ceramic filter, the ceramic filter equipped 25-30n polypropylene mesh filter cloth. In about 55 minutes after the completion of material from the container to the filter transfer. With 50n /. The tert-butanol solution (210L) was washed cake was washed for about 10 minutes so that the cleaning liquid can penetrate into each cake. Then, the cake was dried in a vacuum for about 5-10 minutes. The purified water as a second washing (158L / cake) applied to the filter cake to remove residual t-butanol and triethylammonium chloride salt. Dried in a vacuum for about 5 minutes, the solution was removed. In vacuo and then the cake was dried for about 2 hours, and then sampled using liquid chromatography. The filter cake was measured by liquid chromatography purity of about 99.6%.

The filter cake was dried in vacuo for about 8 hours 25 minutes later, the wet cake (207.4kg) is transferred to an air oven. At about 50-55. C, the oven dried in air for about 52 hours. The product was isolated in a total yield of about 89.9% (174.65kg), in the calculation of cost of materials sampling, you can adjust the overall yield of about 90.7%.

Batch 2

The 3-cyano-benzoic acid methyl ester (105 kg) and t-butanol was added molten drying reactor. Under an inert atmosphere for about 3 hours 29 minutes, 50% aqueous solution of hydroxylamine (47.85 kg) was added to the reactor. During the addition, the temperature is maintained at about 40-45 ° C. At about 40-45. C After stirring for about 3 hours 16 minutes, that the reaction was complete (i.e., less than about 0.5% ester). As for the drying reactor, the batch was transferred to one of the batch in. The batch was cooled

To about 34.4 ° C, and triethylamine (72.6 kg, 100 L). During about 45 minutes was added, while maintaining the batch temperature between about 30-35 ° C. During the addition, the jacket inlet temperature of from about 31.4. C increased to about 32.6. C. After the molten tert-butanol linear washed, was added to the batch 2- fluorobenzoyl chloride (l 13.7 kg, 86.0 L). After about 3 hours, 27 minutes, add the acid chloride. 35. C under stirring for about 8 hours, that the reaction is not complete (i.e., more than about 0.5% residual 3-amidino-benzoyl ester). Then, 1.5% by weight of the original charge of triethylamine and 2-fluorobenzoyl chloride was added to the batch. Linear washed with tert-butanol (IO L) associated with each additional charge. During the addition of the acid chloride, no additional cooling. The batch was maintained at a temperature of about 30-35 ° C, the jacket inlet temperature range was maintained at about 30.3. C to about 33.0 ° C. After stirring for about 2 hours at 30-35t, that reaction was complete (i.e., less than 0.5% of methyl 3-amidinophenoxy).

After about 1 hour and 44 minutes, the batch was heated to reflux temperature (about 83 ° C), and stirred for about 18 hours.The same batch 1, during cooling the sample, the solid was completely crystallized. The batch was then heated to reflux temperature and stirred for about 1 hour and 2 minutes. Then, after about 2 hours and 20 minutes, the batch was cooled to about 69.2 ° C, and after about four hours and 30 minutes, slowly added 630 L of pure water, while the temperature of the batch was maintained at about 65.6-69.2 ° C. After about 3 hours and 30 minutes, the slurry was cooled to about 23.4 ° C, and, as for, the contents were transferred to one of the double batch of the ceramic filter. About 5 hours and 6 minutes, to complete the transfer of the material. With about 50% of t-butanol (2 volumes / cake) was washed filter cake was washed with 10 minutes to allow the cleaning liquid to penetrate into each cake, then dried in vacuo. About 1 hour and 40 minutes, the filter is completed. The purified water was added to a final wash the filter cake. The liquid was removed by drying under vacuum for about 10 minutes. In vacuo and then the cake was dried for about 2 hours and 5 minutes, and then sampled using liquid chromatography. The cake purity liquid chromatography were about 99.5% and 99.6%. After the cake was then dried in vacuo for about 2 hours and 5 minutes, the wet cake (191.5 kg) is transferred to an air oven. At about 50-55. C under dry in an air oven for about 48 hours. The product was isolated in a total yield of about 92.5% (179.7 kg).

Lot 3

The 3-cyano-benzoic acid methyl ester (52.5 kg) and molten tert-butanol (228 kg) added to the reaction vessel. The vessel was sealed, the batch temperature set of about 40-45 ° C, and the stirrer is started. Under an inert atmosphere, after 2 hours 40 minutes, 50% of the shoes amine solution (24 kg) was added to the reactor. During the addition, the temperature is maintained at about 40-45 ° C. In about 42. Under C, then further stirred for about 5 hours to complete the reaction.

The batch was cooled to 30-35 ° C, and after 15 minutes, was added triethylamine (36 kg). After about 2 hours 44 minutes, was added 2-fluorobenzoyl chloride (57 kg). During the addition, batch temperature was maintained at about 30-35 ° C.Under the 32t, the batch was stirred for 2 hours 10 minutes to complete the reaction.

After about 50 minutes, the batch was heated to reflux temperature (about 83-86 ° C), at about 8rc, stirred for about 18 hours. Then, over about two hours, the batch was cooled to about 65-70 ° C, and after about 6 hours 25 minutes, slowly added to purified water (315 L), while the batch temperature was maintained at about 65- 70 ° C. After about 2 hours and 15 minutes, the slurry was cooled to about 22 ° C, and the contents were transferred to a centrifuge filter (2 batches). About 1 hour and 40 minutes, the filter is completed. After about 20 minutes, with about 50% aqueous solution of tert-butyl alcohol (90 kg / cake), dried cake. The purified water (79 kg / cake) as the last added to the filter cake washed. At about 900 rpm drying the cake for about 1 hour and 5 minutes, then filled cylinder. Liquid chromatography wet cake (91.5 kg, LOD = 5% w / w) of a purity of about 99.75% area.

3- ‘5- (2-fluorophenyl) -fl, 2,41 oxadiazol-3-yl l- acid batch 1

3- [5- (2-fluorophenyl) – [l, 2,4] oxadiazol-3-yl] – benzoic acid methyl ester (74.0kg) added to the reaction vessel, the vessel is sealed, evacuated and purification. Jacket set value of about 35. C, start the stirrer in the container. Molten tert-butanol (222 L, 3 volumes) and purified water (355 L, 4.8 vol) was added to the vessel. After the addition was added 25.1% w / w aqueous sodium hydroxide solution (43.5 kg, 1.1 molar equivalents), and with additional purified water (100L, 1.35 mol) was washed linear. During the addition, the batch temperature from about 39.0t reduced to about 38.8 ° C. After about 1 hour and 54 minutes, the batch temperature to about 63-67. C, and then, after about 30 minutes, which was adjusted to about 68-72.C. About 68-72t, stirring the mixture for about 3 hours. Then, after about five hours 11 minutes, the solution was cooled to about 40-45 ° C. Then, after the above process, after about three hours 33 minutes, the solution was then heated to about 68-72. C.

Jacket temperature of the reaction vessel was set to about 60 ° C, the stirrer started, and at about 70 ° C, a slightly positive pressure of nitrogen (1.5 to 5.6 psig), the heat transfer liquid through a micron filter . During the transfer, the product temperature is reduced to about 64.3 ° C, the transfer is completed in about 45 minutes. Was added to the purified water container (61 L, 0.82 vol) and the contents were heated to about 68-72. C.

The batch temperature was adjusted to about 69.4 ° C, and after about four hours and 18 minutes, with 13.9% w / w sulfuric acid (100.7 kg, 1.15 mol equiv.). During the addition, batch temperature was maintained at about 68.0-70.8 ° C. After the addition of the acid, with purified water (50 L, 0.68 vol) line wash at about 68-72 ° C, the stirring was continued for 31 minutes.

After about 4 hours and 10 minutes, the batch in a linear fashion from about 69.2t cooled to about 41.2 ° C. The stirrer Rosenmund filter / dryer was elevated to the highest position and jacket set value is set at about 40 ° C. The slurry was transferred to the two portions of the filter / drier. Applying a constant nitrogen pressure to the first portion (less than about 15 psig). During the transfer, a pressure of about 23.9 to about 28.8 psi, the transfer is complete in about 1 hour and 5 minutes. The second part of the slurry was transferred onto the filter cake, and the composite was stirred briefly to homogenize the batch. Use about 26.1 to about 29.1 psi nitrogen pressure filters the second part, after about three hours, squeeze the cake so that it does not contain liquid. With about 38-42 ° C hot tert-butanol solution (352 kg, 5 volumes) and about 65-70 ° C in 3x hot purified water (370 L, 5 volumes) and the filter 々.

Said filter / dryer jacket temperature was set to about 43 ° C, the product was dried under vacuum for about 26 hours while stirring periodically. Determination of purity of about 99.7%. The product was isolated in a total yield of about 74.4% (52.45 kg).

Batch 2

Was added to the reactor vessel 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester (47 kg, wet cake) and melt-hyun tert-butyl alcohol (111.4 kg). A sealed container, and the batch temperature was set at 30-40t, and start the stirrer. The purified water (51.6 kg) was added to the vessel. After the addition was added 3.47% w / w aqueous sodium hydroxide solution (202.4 kg). After about l hour, the batch temperature to about 67-73. C, then, at about 7 (under TC, stirred for about three hours.

Under a slight positive pressure of nitrogen, with a 1 micron polypropylene bag filter the batch, and then transferred to the new reactor. Was added to the vessel pure water (146 kg), and heating the batch to about 68-72. C.

After about four hours, the 10.7% aqueous hydrochloric acid was added to the batch. During the addition, batch temperature was maintained at about 68-72 ° C. PH was measured by using the batch pH of about 2.2, and then stirring was continued at about 7 (under TC about 1 hour.

After about two hours, the batch in a linear fashion from about 70. C is cooled to about 60 ° C. After about two hours, about 60. C of the batch in a linear fashion from about 6 (TC was cooled to about 40 ° C. In 40t, the batch was stirred for 2 hours, and the slurry was transferred to a centrifuge filter. After about 30 minutes, filtered completion . After about 30 minutes, with about 42Mw / w in t-butanol solution (165kg) cake was washed. The purified water (118kg, 4 (TC) as the last added to the filter cake was washed. The filter cake was dried at about 900rpm about 1 hour, then filled cylinder.

The wet cake was transferred to a paddle dryer (a double cone drier also suitable for this step), the jacket temperature was set to about 70. C. At about 70. C, the product was dried under vacuum for about 48 hours while stirring periodically.Determination of purity of about 99.8%. The product was isolated overall yield of about 74% (68.5 kg).

Lot 3

To the reaction vessel was added 3- [5- (2-fluorophenyl) – [1,2,4] oxadiazol-3-yl] – benzoic acid methyl ester (10 g) and t-butanol fused (128mL ). The batch temperature was set to 30-40 ° C, and the stirrer is started. After about 30 minutes, the aqueous sodium hydroxide solution 4.48% w / w of (32.5 g) was added to the vessel. The batch was maintained at a temperature of about 40-50 ° C. After about l hour, the batch temperature is raised to about 78-82 ° C, and then, at about 78-82t, and then stirred for about one hour. Under positive pressure of nitrogen, a polyethylene bag with a 5 micron filter the batch, and then transferred to a new reaction vessel. The batch was maintained at a temperature of about 78-82 ° C.

It was added to a new vessel 37% aqueous hydrochloric acid (4 mL) and tert-butanol molten (8 mL). The temperature was maintained at about 30-40. Under C, and stirring the mixture for about 30 minutes.

After about four hours, using a metering pump was added to the batch of hydrochloric acid in tert-butanol. After about SO-SO minutes before adding half filled. The stirrer speed is set at about 200rpm. After about 3.5 hours, add the remaining charge. The stirrer speed is set at about 100 rpm. During the addition, batch temperature was maintained at about 78-82 ° C.PH meter with a final batch pH was adjusted to about 1.2, at about 78-82t, then continue stirring for about l hour. After about one hour, the batch in a linear fashion from about 78-82. C is cooled to about 70 ° C. After about four hours, about 7 (TC batches in a linear fashion from 70.C cooled to about 50 ° C, and the stirrer speed was set at about 80 rpm. After about four hours, about 50 ° C Batch linearly cooled from 50 ° C to about 40t, and stirrer speed was set at approximately 60rpm. In 40.C, the batch was stirred for a further 4 hours.

The temperature of the filter is set to about 40-45 ° C. The slurry was transferred to the filter. After about one minute to complete filtration. After about two minutes, with tert-butanol (50 mL, 50.C) washing the filter cake. The pure water (IOO mLx2, 60.C) as the last wash was added to the cake. Under vacuum at about 60-70 ° C the cake was dried for about 12 hours, and then loaded into the container.

Determination of HPLC purity of about 99.9% of the area. The yield of isolated product was about 94% (9.0g).

3- “5- (2-fluorophenyl) -” 1,2,41-oxadiazol-3-yl 1- acid: One-pot

The methyl 3-cyanophenyl Yue (7.35 g) and tert-butanol molten (100 mL) added to the reactor vessel. Sealed containers, the batch temperature was set to 60 ° C, and the stirrer is started. The suspension was stirred for 1 hour and then the batch temperature was set to 40. C. Under an inert atmosphere, after three hours, 50% aqueous solution of hydroxylamine (3.63 g) was added to the reactor. During the addition, batch temperature was maintained at 38-41 ° C. 40. C After stirring for 18 hours, to complete the reaction.

The batch was cooled to 27 ° C, and after two minutes, triethylamine (5.56 g). After 3 hours, was added 2-fluorobenzoyl chloride (7.82 g). During the addition, batch temperature was maintained at 24-27 ° C. 40. C, the batch was stirred for a further 4 hours.

After 30 minutes, the batch was heated to 79 ° C, and at about 79. C was stirred for 16 hours. After 3 hours, the white suspension was added to the water (IOO mL), while the batch temperature was maintained at 70 ° C. After 20 minutes, a 37% aqueous hydrochloric acid were added to the batch. PH was measured by using the batch pH of about 2.2, stirring was continued at about 70t for about 1 hour.

After three hours, the batch in a linear manner from 7 (TC cooled to 30 ° C, and the slurry is transferred to the filter. After 5 minutes, the filtering is done. After five minutes, with tert-butanol (50mL, 40 .C) filter cake was washed. The purified water (IOO mL, 60.C) is added to a final wash the filter cake. In 70.C of the filter cake was dried in a vacuum oven for 18 hours and then removed. Determination of purity approximately 98.68%. The total yield of isolated product of about 76% (10.8g).

PICS

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.
The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation —  also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.
Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.
The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.
PTC124 has been developed by PTC Therapeutics.

References

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  6. Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery Medicine 15 (81): 127–133. PMID 23449115.
  7.  “PTC Therapeutics and Genzyme Corporation announce preliminary results from the phase 2b clinical trial of ataluren for nonsense mutation Duchenne/Becker muscular dystrophy (NASDAQ:PTCT)”. Ptct.client.shareholder.com. Retrieved 2013-11-28.
  8.  Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271.Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (November 2010). “Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis”. American Journal of Respiratory and Critical Care Medicine 182 (10): 1262–1272. doi:10.1164/rccm.201001-0137OC. PMID 20622033.
  9.  “PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)”. Ptct.client.shareholder.com. 2010-12-21. Retrieved2013-11-28.
  10. http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23
  11.  “PTC Therapeutics Announces Launch of Translarna™ (ataluren) in Germany”.marketwatch.com. 3 Dec 2014. Retrieved 27 Dec 2014.
  12.  “NICE asks for further evidence for the benefits of a new treatment for Duchenne muscular dystrophy to justify its very high cost”.
  13. http://uk.reuters.com/article/us-ptc-therapeutics-fda-idUKKCN0VW1FG

External links

References:
1. Ryan, N. J. Ataluren: first global approval. Drugs 2014, 74(14), 1709-14. (FMO only)
2. Gupta, P. K.; et. al. A metal-free tandem approach to prepare structurally diverse N-heterocycles: synthesis of 1,2,4-oxadiazoles and pyrimidinones. New J Chem 2014, 38, 3062-3070 (FMO only)
3. Almstead, N. G.; et. al. Methods for the production of functional protein from dna having a nonsense mutation and the treatment of disorders associated therewith. WO2007117438A2

WO2004091502A2 Apr 9, 2004 Oct 28, 2004 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acid compounds
Citing Patent Filing date Publication date Applicant Title
US8486982 Jun 22, 2012 Jul 16, 2013 Ptc Therapeutics, Inc. 1,2,4-oxadiazole benzoic acids
US8796322 Jun 19, 2013 Aug 5, 2014 Ptc Therapeutics, Inc. Methods for using 1,2,4-oxadiazole benzoic acid compounds
US8975287 Jun 18, 2014 Mar 10, 2015 Ptc Therapeutics, Inc. Methods for using 1,2,4-Oxadiazole benzoic acid compounds
US9205088 Jan 28, 2015 Dec 8, 2015 Ptc Therapeutics, Inc. Compositions of 1,2,4-oxadiazol benzoic acid compounds and methods for their use
US9289398 Mar 29, 2007 Mar 22, 2016 Ptc Therapeutics, Inc. Methods for the production of functional protein from DNA having a nonsense mutation and the treatment of disorders associated therewith
Preparation CN101535284A CN101535284B
10 Crystal CN101541770A
11 Crystal CN104341371A
12 Crystal CN102382075A
Formula CN1802360A CN1802360B
2 Combination CN104056278A
3 Indication CN101076703A
4 Indication CN101076332A
5 Indication CN101076337A
6 Indication CN101193632A
7 Formulation CN103720688A
8 Indication CN101505739A

Ataluren
Ataluren.svg
Ataluren ball-and-stick model.png
Names
IUPAC name

3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Other names

PTC124
Identifiers
775304-57-9 
ChEMBL ChEMBL256997 Yes
ChemSpider 9394889 Yes
7341
Jmol 3D model Interactive image
KEGG D09323 Yes
PubChem 11219835
UNII K16AME9I3V Yes
Properties
C15H9FN2O3
Molar mass 284.24 g/mol
Pharmacology
M09AX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////ORPHAN DRUG, Ataluren, Translarna, Duchenne Muscular Dystrophy, EU, 775304-57-9, PTC Therapeutics, PTC 124

O=C(O)c1cccc(c1)c2nc(on2)c3ccccc3F

PTC Therapeutics’ large-scale multinational trial of ataluren for nonsense-mutation Duchenne or Becker MD has opened its first site in Cincinnati, Ohio


ATALUREN

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation —  also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

Ataluren, formerly known as PTC124, is a novel small-molecular agent designed to makeribosomes become less sensitive to, or possibly ignore premature stop codons. This may be particularly beneficial in genetic disorders where the mRNA contains a mutation causing premature stop codon or nonsense codon. However, it is not equally effective with every stop codon, working best on the sequence ‘UGA’.

PTC124 has been tested on healthy humans and humans carrying genetic disorderscaused by nonsense mutations,such as some people with cystic fibrosis andDuchenne muscular dystrophy. Clinical trials are proceeding for several genetic disorders, in the subset of affected people who have nonsense mutations (typically <10% of those with the disorder). PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.However, phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.

PTC124 has been developed by PTC Therapeutics.

Phase 2 , Sarepta, shows eteplirsen for Duchenne muscular dystrophy


ETEPLIRSEN

27 MAR 2013

The clock is ticking for Sarepta Therapeutics , a multitude of biotech investors and the boys who suffer from Duchenne muscular dystrophy.

Armed with promising Phase IIb data from a small study of eteplirsen involving only 12 patients with the lethal disease, Sarepta CEO Chris Garabedian is completing one of the most closely-watched high wire acts in the industry. At a time most companies would be focused solely on organizing a pivotal late-stage study, there’s intense speculation that the biotech will shoot for an accelerated approval with the data in hand. And it all comes down to their sit-down with the FDA to review mid-stage data.

Eteplirsen, also called AVI-4658, is an experimental drug, currently in clinical trials. It is designed for treatment of some mutations which cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease. Eteplirsen is a product of Sarepta Therapeutics Inc.

The drug is a Morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin;[1] giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular frameshifting mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (though internally-truncated) dystrophin.[2] Eteplirsen is given by intravenous infusion for systemic treatment of DMD.

Several clinical trials have been conducted to test eteplirsen, one in the UK involving local injection to the foot,[3][4] one in the UK involving systemic injection at low doses[5][6] and one in the USA at higher systemic doses[7] that progressed to a rollover extension study.[8]

  1.  “Exon Skipping Quantification by qRT-PCR in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen”. Hum Gene Ther Methods. 17 Oct 2012.
  2.  “Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy.”. Biochim Biophys Acta. 1798 (12): 2296–303. 17 Feb 2010.
  3.  Gary Roper/Manager Clinical Research Governance Organisation, Imperial College London. “Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  4.  Lancet Neurol. 8 (10): 918–28. 25 Aug 2009.
  5. Professor Francesco Muntoni, University College of London Institute of Child Health. “Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  6.  “Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.”. Lancet. 378 (9791): 595–605. 23 Jul 2011.
  7.  Sarepta Therapeutics. “Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  8. Sarepta Therapeutics. “Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects With Duchenne Muscular Dystrophy”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
shark

Phase 2, Sarepta Therapeutics, Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects With Duchenne Muscular Dystrophy


 
structure of eteplirsen (AVI-4658)
173755-55-9  cas no
check str, name etc
ClinicalTrials.gov Identifier:
NCT01540409
The primary objective of this study is to assess the ongoing efficacy, safety, and tolerability of an additional 80 weeks of treatment with eteplirsen (AVI-4658) in Duchenne muscular dystrophy (DMD) subjects who have successfully completed the 28-week eteplirsen study: Study 4658-US-201. This study will also evaluate the correlation between biomarkers for DMD and the clinical status of participating DMD subjects
Eteplirsen will be administered once weekly via an IV infusion over a period of at least 60 minutes. Their are two treatment groups, 30 mg/kg and 50 mg/kg.

Eteplirsen, also called AVI-4658, is an experimental drug, currently in clinical trials. It is designed for treatment of some mutations which cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease. Eteplirsen is a product of Sarepta Therapeutics Inc.

s excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin;[1] giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular frameshifting mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (though internally-truncated) dystrophin.[2] Eteplirsen is given by intravenous infusion for systemic treatment of DMD.

Clinical studies

Several clinical trials have been conducted to test eteplirsen, one in the UK involving local injection to the foot,[3][4] one in the UK involving systemic injection at low doses[5][6] and one in the USA at higher systemic doses[7] that progressed to a rollover extension study.[8]

References

  1.  “Exon Skipping Quantification by qRT-PCR in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen”. Hum Gene Ther Methods.. 17 Oct 2012.
  2.  “Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy.”. Biochim Biophys Acta. 1798 (12): 2296–303.. 17 Feb 2010.
  3.  Gary Roper/Manager Clinical Research Governance Organisation, Imperial College London. “Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  4.  Lancet Neurol. 8 (10): 918–28. 25 Aug 2009.
  5.  Professor Francesco Muntoni, University College of London Institute of Child Health. “Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  6.  “Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.”. Lancet. 378 (9791): 595–605. 23 Jul 2011.
  7.  Sarepta Therapeutics. “Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
  8. Sarepta Therapeutics. “Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects With Duchenne Muscular Dystrophy”. ClinicalTrials.gov. US Government, NIH. Retrieved 30 October 2012.
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