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FDA APPR 2021/2/26, NULIBRY
a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.
|Formula||C10H14N5O8P. 2H2O. HBr|
1,3,2-DIOXAPHOSPHORINO(4′,5′:5,6)PYRANO(3,2-G)PTERIDIN-10(4H)-ONE, 8-AMINO-4A,5A,6,9,11,11A,12,12A-OCTAHYDRO-2,12,12-TRIHYDROXY-, 2-OXIDE, HYDROBROMIDE, HYDRATE (1:1:2), (4AR,5AR,11AR,12AS)-
|CYCLIC PYRANOPTERIN MONOPHOSPHATE MONOHYDROBROMIDE DIHYDRATE|
(4aR,5aR,11aR,12aS)-8-Amino-2,12,12-trihydroxy-4a,5a,6,7,11,11a,12,12aoctahydro-2H-2lambda5-(1,3,2)dioxaphosphinino(4′,5′:5,6)pyrano(3,2-g)pteridine-2,10(4H)-dione, hydrobromide (1:1:2)
1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide, hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-
1,3,2-Dioxaphosphorino(4′,5′:5,6)pyrano(3,2-g)pteridin-10(4H)-one, 8-amino-4a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-, 2-oxide,hydrobromide, hydrate (1:1:2), (4aR,5aR,11aR,12aS)-
C10H14N5O8P, Average: 363.223
- WHO 11150
- Synthesis ReferenceClinch K, Watt DK, Dixon RA, Baars SM, Gainsford GJ, Tiwari A, Schwarz G, Saotome Y, Storek M, Belaidi AA, Santamaria-Araujo JA: Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. J Med Chem. 2013 Feb 28;56(4):1730-8. doi: 10.1021/jm301855r. Epub 2013 Feb 19.
Fosdenopterin (or cyclic pyranopterin monophosphate, cPMP), sold under the brand name Nulibry, is a medication used to reduce the risk of death due to a rare genetic disease known as molybdenum cofactor deficiency type A (MoCD-A).
Mechanism of action
People with MoCD-A cannot produce cyclic pyranopterin monophosphate (cPMP) in their body. Fosdenopterin is an intravenous medication that replaces the missing cPMP. cPMP is a precursor to molybdopterin, which is required for the enzyme activity of sulfite oxidase, xanthine dehydrogenase/oxidase and aldehyde oxidase.
The effectiveness of fosdenopterin for the treatment of MoCD-A was demonstrated in thirteen treated participants compared to eighteen matched, untreated participants. The participants treated with fosdenopterin had a survival rate of 84% at three years, compared to 55% for the untreated participants.
The U.S. Food and Drug Administration (FDA) granted the application for fosdenopterin priority review, breakthrough therapy, and orphan drug designations along with a rare pediatric disease priority review voucher. The FDA granted the approval of Nulibry to Origin Biosciences, Inc., in February 2021. It is the first medication approved for the treatment of MoCD-A.
- ^ Jump up to:a b c d e f g h i j “FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A”. U.S. Food and Drug Administration (FDA) (Press release). 26 February 2021. Retrieved 26 February 2021. This article incorporates text from this source, which is in the public domain.
- ^ DrugBank DB16628 . Accessed 2021-03-05.
- ^ Santamaria-Araujo JA, Fischer B, Otte T, Nimtz M, Mendel RR, Wray V, Schwarz G (April 2004). “The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor”. The Journal of Biological Chemistry. 279 (16): 15994–9. doi:10.1074/jbc.M311815200. PMID 14761975.
- ^ Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Gröne HJ, et al. (June 2004). “Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli”. Human Molecular Genetics. 13 (12): 1249–55. doi:10.1093/hmg/ddh136. PMID 15115759.
- ^ Tedmanson S (5 November 2009). “Doctors risk untried drug to stop baby’s brain dissolving”. TimesOnline.
- ^ Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, et al. (November 2015). “Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study”. Lancet. 386 (10007): 1955–63. doi:10.1016/S0140-6736(15)00124-5. PMID 26343839. S2CID 21954888.
- “Fosdenopterin”. Drug Information Portal. U.S. National Library of Medicine.
Molybdenum cofactor deficiency (MoCD) is an exceptionally rare autosomal recessive disorder resulting in a deficiency of three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde oxidase.1 Signs and symptoms begin shortly after birth and are caused by a build-up of toxic sulfites resulting from a lack of SOX activity.1,5 Patients with MoCD may present with metabolic acidosis, intracranial hemorrhage, feeding difficulties, and significant neurological symptoms such as muscle hyper- and hypotonia, intractable seizures, spastic paraplegia, myoclonus, and opisthotonus. In addition, patients with MoCD are often born with morphologic evidence of the disorder such as microcephaly, cerebral atrophy/hypodensity, dilated ventricles, and ocular abnormalities.1 MoCD is incurable and median survival in untreated patients is approximately 36 months1 – treatment, then, is focused on improving survival and maintaining neurological function.
The most common subtype of MoCD, type A, involves mutations in MOCS1 wherein the first step of molybdenum cofactor synthesis – the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP) – is interrupted.1,3 In the past, management strategies for this disorder involved symptomatic and supportive treatment,5 though efforts were made to develop a suitable exogenous replacement for the missing cPMP. In 2009 a recombinant, E. coli-produced cPMP was granted orphan drug designation by the FDA, becoming the first therapeutic option for patients with MoCD type A.1
Fosdenopterin was approved by the FDA on Februrary 26, 2021, for the reduction of mortality in patients with MoCD type A,5 becoming the first and only therapy approved for the treatment of MoCD. By improving the three-year survival rate from 55% to 84%,7 and considering the lack of alternative therapies available, fosdenopterin appears poised to become a standard of therapy in the management of this debilitating disorder.
Fosdenopterin replaces an intermediate substrate in the synthesis of molybdenum cofactor, a compound necessary for the activation of several molybdenum-dependent enzymes including sulfite oxidase (SOX).1 Given that SOX is responsible for detoxifying sulfur-containing acids and sulfites such as S-sulfocysteine (SSC), urinary levels of SSC can be used as a surrogate marker of efficacy for fosdenopterin.7 Long-term therapy with fosdenopterin has been shown to result in a sustained reduction in urinary SSC normalized to creatinine.7
Animal studies have identified a potential risk of phototoxicity in patients receiving fosdenopterin – these patients should avoid or minimize exposure to sunlight and/or artificial UV light.7 If sun exposure is necessary, use protective clothing, hats, and sunglasses,7 in addition to seeking shade whenever practical. Consider the use of a broad-spectrum sunscreen in patients 6 months of age or older.8
Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder in which patients are deficient in three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde dehydrogenase.1 The loss of SOX activity appears to be the main driver of MoCD morbidity and mortality, as the build-up of neurotoxic sulfites typically processed by SOX results in rapid and progressive neurological damage. In MoCD type A, the disorder results from a mutation in the MOCS1 gene leading to deficient production of MOCS1A/B,7 a protein that is responsible for the first step in the synthesis of molybdenum cofactor: the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP).1,4
Fosdenopterin is an exogenous form of cPMP, replacing endogenous production and allowing for the synthesis of molybdenum cofactor to proceed.7
- Mechler K, Mountford WK, Hoffmann GF, Ries M: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015 Dec;17(12):965-70. doi: 10.1038/gim.2015.12. Epub 2015 Mar 12. [PubMed:25764214]
- Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, Konig K, McGregor TL, Font-Montgomery E, Santamaria-Araujo JA, Santra S, Vaidya M, Vierzig A, Wassmer E, Weis I, Wong FY, Veldman A, Schwarz G: Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet. 2015 Nov 14;386(10007):1955-63. doi: 10.1016/S0140-6736(15)00124-5. Epub 2015 Sep 3. [PubMed:26343839]
- Iobbi-Nivol C, Leimkuhler S: Molybdenum enzymes, their maturation and molybdenum cofactor biosynthesis in Escherichia coli. Biochim Biophys Acta. 2013 Aug-Sep;1827(8-9):1086-101. doi: 10.1016/j.bbabio.2012.11.007. Epub 2012 Nov 29. [PubMed:23201473]
- Mendel RR: The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. [PubMed:23539623]
- FDA News Release: FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A [Link]
- OMIM: MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A (# 252150) [Link]
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
- Health Canada: Sun safety tips for parents [Link]
Journal of Biological Chemistry (1995), 270(3), 1082-7.
Journal of Medicinal Chemistry (2013), 56(4), 1730-1738
Cyclic pyranopterin monophosphate (1), isolated from bacterial culture, has previously been shown to be effective in restoring normal function of molybdenum enzymes in molybdenum cofactor (MoCo)-deficient mice and human patients. Described here is a synthesis of 1 hydrobromide (1·HBr) employing in the key step a Viscontini reaction between 2,5,6-triamino-3,4-dihydropyrimidin-4-one dihydrochloride and d-galactose phenylhydrazone to give the pyranopterin (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one (10) and establishing all four stereocenters found in 1. Compound 10, characterized spectroscopically and by X-ray crystallography, was transformed through a selectively protected tri-tert-butoxycarbonylamino intermediate into a highly crystalline tetracyclic phosphate ester (15). The latter underwent a Swern oxidation and then deprotection to give 1·HBr. Synthesized 1·HBr had in vitro efficacy comparable to that of 1 of bacterial origin as demonstrated by its enzymatic conversion into mature MoCo and subsequent reconstitution of MoCo-free human sulfite oxidase–molybdenum domain yielding a fully active enzyme. The described synthesis has the potential for scale up.
European Journal of Organic Chemistry (2014), 2014(11), 2231-2241.
The first synthesis of an oxygen‐stable analogue of the natural product cyclic pyranopterin monophosphate (cPMP) is reported. In this approach, the hydropyranone ring is annelated to pyrazine by a sequence comprising ortho‐lithiation/acylation of a 2‐halopyrazine, followed by nucleophilic aromatic substitution. The tetrose substructure is introduced from the chiral pool, from D‐galactose or D‐arabitol.
Molybdenum cofactor (Moco) deficiency is a lethal hereditary metabolic disease. A recently developed therapy requires continuous intravenous supplementation of the biosynthetic Moco precursor cyclic pyranopterin monophosphate (cPMP). The limited stability of the latter natural product, mostly due to oxidative degradation, is problematic for oral administration. Therefore, the synthesis of more stable cPMP analogues is of great interest. In this context and for the first time, the synthesis of a cPMP analogue, in which the oxidation‐labile reduced pterin unit is replaced by a pyrazine moiety, was achieved starting from the chiral pool materials D‐galactose or D‐arabitol. Our synthesis, 13 steps in total, includes the following key transformations: i) pyrazine lithiation, followed by acylation; ii) closure of the pyrane ring by nucleophilic aromatic substitution; and iii) introduction of phosphate.
Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder. Moco consists of molybdenum covalently bound to one or two dithiolates attached to a unique tricyclic pterin moiety commonly referred to as molybdopterin (MPT). Moco is synthesized by a biosynthetic pathway that can be divided into four steps, according to the biosynthetic intermediates precursor Z (cyclic pyranopterin monophosphate; cPMP), MPT, and adenylated MPT. Mutations in the Moco biosynthetase genes result in the loss of production of the molybdenum dependent enzymes sulfite-oxidase, xanthine oxidoreductase, and aldehyde oxidase. Whereas the activities of all three of these cofactor-containing enzymes are impaired by cofactor deficiency, the devastating consequences of the disease can be traced to the loss of sulfite oxidase activity. Human Moco deficiency is a rare but severe disorder accompanied by serious neurological symptoms including attenuated growth of the brain, untreatable seizures, dislocated ocular lenses, and mental retardation. Until recently, no effective therapy was available and afflicted patients suffering from Moco deficiency died in early infancy.
It has been found that administration of the molybdopterin derivative precursor Z, a relatively stable intermediate in the Moco biosynthetic pathway, is an effective means of therapy for human Moco deficiency and associated diseases related to altered Moco synthesis (see U.S. Pat. No. 7,504,095). As with most replacement therapies for illnesses, however, the treatment is limited by the availability of the therapeutic active agent.
EXAMPLESExample 1Preparation of Precursor Z (cPMP)
Air sensitive reactions were performed under argon. Organic solutions were dried over anhydrous MgSO4 and the solvents were evaporated under reduced pressure. Anhydrous and chromatography solvents were obtained commercially (anhydrous grade solvent from Sigma-Aldrich Fine Chemicals) and used without any further purification. Thin layer chromatography (t.l.c.) was performed on glass or aluminum sheets coated with 60 F254 silica gel. Organic compounds were visualized under UV light or with use of a dip of ammonium molybdate (5 wt %) and cerium(IV) sulfate 4H2O (0.2 wt %) in aq. H2SO4 (2M), one of I2 (0.2%) and KI (7%) in H2SO4 (1M), or 0.1% ninhydrin in EtOH. Chromatography (flash column) was performed on silica gel (40-63 μm) or on an automated system with continuous gradient facility. Optical rotations were recorded at a path length of 1 dm and are in units of 10−1 deg cm2 g−1; concentrations are in g/100 mL. 1H NMR spectra were measured in CDCl3, CD3OD (internal Me4Si, δ 0 ppm) or D2O(HOD, δ 4.79 ppm), and 13C NMR spectra in CDCl3 (center line, δ 77.0 ppm), CD3OD (center line, δ 49.0 ppm) or DMSO d6 (center line δ 39.7 ppm), D2O (no internal reference or internal CH3CN, δ 1.47 ppm where stated). Assignments of 1H and 13C resonances were based on 2D (1H—1H DQF-COSY, 1H—13C HSQC, HMBC) and DEPT experiments. 31P NMR were run at 202.3 MHz and are reported without reference. High resolution electrospray mass spectra (ESI-HRMS) were recorded on a Q-TOF Tandem Mass
Spectrometer. Microanalyses were performed by the Campbell Microanalytical Department, University of Otago, Dunedin, New Zealand.
A. Preparation of (5aS,6R,7R,8R,9aR)-2-amino-6,7-dihydroxy-8-(hydroxymethyl)-3H,4H,5H,5aH,6H,7H,8H,9aH,10H-pyrano[3,2-g]pteridin-4-one mono hydrate (1)
2,5,6-Triamino-3,4-dihydropyrimidin-4-one dihydrochloride (Pfleiderer, W.; Chem. Ber. 1957, 90, 2272; Org. Synth. 1952, 32, 45; Org. Synth. 1963, Coll. Vol. 4, 245, 10.0 g, 46.7 mmol), D-galactose phenylhydrazone (Goswami, S.; Adak, A. K. Tetrahedron Lett. 2005, 46, 221-224, 15.78 g, 58.4 mmol) and 2-mercaptoethanol (1 mL) were stirred and heated to reflux (bath temp 110° C.) in a 1:1 mixture of MeOH—H2O (400 mL) for 2 h. After cooling to ambient temperature, diethyl ether (500 mL) was added, the flask was shaken and the diethyl ether layer decanted off and discarded. The process was repeated with two further portions of diethyl ether (500 mL) and then the remaining volatiles were evaporated. Methanol (40 mL), H2O (40 mL) and triethylamine (39.4 mL, 280 mmol) were successively added and the mixture seeded with a few milligrams of 1. After 5 min a yellow solid was filtered off, washed with a little MeOH and dried to give 1 as a monohydrate (5.05 g, 36%) of suitable purity for further use. An analytical portion was recrystallized from DMSO-EtOH or boiling H2O. MPt 226 dec. [α]D 20 +135.6 (c1.13, DMSO). 1H NMR (DMSO d6): δ 10.19 (bs, exchanged D2O, 1H), 7.29 (d, J=5.0 Hz, slowly exchanged D2O, 1H), 5.90 (s, exchanged D2O, 2H), 5.33 (d, J=5.4 Hz, exchanged D2O, 1H), 4.66 (ddd, J˜5.0, ˜1.3, ˜1.3 Hz, 1H), 4.59 (t, J=5.6 Hz, exchanged D2O, 1H), 4.39 (d, J=10.3 Hz, exchanged D2O, 1H), 3.80 (bt, J˜1.8 Hz, exchanged D2O, 1H), 3.70 (m, 1H), 3.58 (dd, J=10.3, 3.0 Hz, 1H), 3.53 (dt, J=10.7, 6.4 Hz, 1H), 3.43 (ddd, J=11.2, 5.9, 5.9 Hz, 1H), 3.35 (t, J=6.4 Hz, 1H), 3.04 (br m, 1H). 13C NMR (DMSO d6 center line 6 39.7): δ 156.3 (C), 150.4 (C), 148.4 (C), 99.0 (C), 79.4 (CH), 76.5 (CH), 68.9 (CH), 68.6 (CH), 60.6 (CH2), 53.9 (CH). Anal. calcd. for C10H15N5O5H2O 39.60; C, 5.65; H, 23.09; N. found 39.64; C, 5.71; H, 22.83; N.
B. Preparation of Compounds 2 (a or b) and 3 (a, b or c)
Di-tert-butyl dicarbonate (10.33 g, 47.3 mmol) and DMAP (0.321 g, 2.63 mmol) were added to a stirred suspension of 1 (1.5 g, 5.26 mmol) in anhydrous THF (90 mL) at 50° C. under Ar. After 20 h a clear solution resulted. The solvent was evaporated and the residue chromatographed on silica gel (gradient of 0 to 40% EtOAc in hexanes) to give two product fractions. The first product to elute was a yellow foam (1.46 g). The product was observed to be a mixture of two compounds by 1H NMR containing mainly a product with seven Boc groups (2a or 2b). A sample was crystallized from EtOAc-hexanes to give 2a or 2b as a fine crystalline solid. MPt 189-191° C. [α]D 20 −43.6 (c 0.99, MeOH). 1H NMR (500 MHz, CDCl3): δ 5.71 (t, J=1.7 Hz, 1H), 5.15 (dt, J=3.5, ˜1.0, 1H), 4.97 (t, J=3.8, 1H), 4.35 (br t, J=˜1.7, 1H), 4.09-3.97 (m, 3H), 3.91 (m, 1H), 1.55, 1.52, 1.51, 1.50, 1.45 (5s, 45H), 1.40 (s, 18H). 13C NMR (125.7 MHz, CDCl3): δ 152.84 (C), 152.78 (C), 151.5 (C), 150.9 (C), 150.7 (2×C), 150.3 (C), 149.1 (C), 144.8 (C), 144.7 (C), 118.0 (C), 84.6 (C), 83.6 (C), 83.5 (C), 82.7 (3×C), 82.6 (C), 76.3 (CH), 73.0 (CH), 71.4 (CH), 67.2 (CH), 64.0 (CH2), 51.4 (CH), 28.1 (CH3), 27.8 (2×CH3), 27.7 (CH3), 27.6 (3×CH3). MS-ESI+ for C45H72N5O19 +, (M+H)+, Calcd. 986.4817. found 986.4818. Anal. calcd. for C45H71N5O19H2O 54.39; C, 7.39; H, 6.34; N. found 54.66; C, 7.17; H, 7.05; N. A second fraction was obtained as a yellow foam (2.68 g) which by 1H NMR was a product with six Boc groups present (3a, 3b or 3c). A small amount was crystallized from EtOAc-hexanes to give colorless crystals. [α]D 2O −47.6 (c, 1.17, CHCl3). 1H NMR (500 MHz, CDCl3): δ 11.10 (br s, exchanged D2O, 1H), 5.58 (t, J=1.8 Hz, 1H), 5.17 (d, J=3.4 Hz, 1H), 4.97 (t, J=3.9 Hz, 1H), 4.62 (s, exchanged D2O, 1H), 4.16 (dd, J=11.3, 5.9 Hz, 1H), 4.12 (dd, J=11.3, 6.4 Hz, 1H), 3.95 (dt, J=6.1, 1.1 Hz, 1H), 3.76 (m, 1H), 1.51, 1.50, 1.49, 1.48, 1.46 (5s, 54H). 13C NMR (125.7 MHz, CDCl3): δ 156.6 (C), 153.0 (C), 152.9 (C), 151.9 (C), 150.6 (C), 149.4 (2×C), 136.2 (C), 131.8 (C), 116.9 (C), 85.0 (2×C), 83.3 (C), 82.8 (C), 82.49 (C), 82.46 (C), 73.3 (CH), 71.5 (CH), 67.2 (CH), 64.5 (CH2), 51.3 (CH), 28.0, 27.72, 27.68, 27.6 (4×CH3). MS-ESI+ for C40H64N5O17 +, (M+H)+calcd. 886.4287. found 886.4289.
C. Preparation of Compound 4a, 4b or 4c
Step 1—The first fraction from B above containing mainly compounds 2a or 2b (1.46 g, 1.481 mmol) was dissolved in MeOH (29 mL) and sodium methoxide in MeOH (1M, 8.14 mL, 8.14 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.
Step 2—The second fraction from B above containing mainly 3a, 3b or 3c (2.68 g, 3.02 mmol) was dissolved in MeOH (54 mL) and sodium methoxide in MeOH (1M, 12.10 mL, 12.10 mmol) added. After leaving at ambient temperature for 20 h the solution was neutralized with Dowex 50WX8 (H+) resin then the solids filtered off and the solvent evaporated.
The products from step 1 and step 2 above were combined and chromatographed on silica gel (gradient of 0 to 15% MeOH in CHCl3) to give 4a, 4b or 4c as a cream colored solid (1.97 g). 1H NMR (500 MHz, DMSO d6): δ 12.67 (br s, exchanged D2O, 1H), 5.48 (d, J=5.2 Hz, exchanged D2O, 1H), 5.43 (t, J=˜1.9 Hz, after D2O exchange became a d, J=1.9 Hz, 1H), 5.00 (br s, exchanged D2O, 1H), 4.62 (d, J=5.7 Hz, exchanged D2O, 1H), 4.27 (d, J=6.0 Hz, exchanged D2O, 1H), 3.89 (dt, J=5.2, 3.8 Hz, after D2O became a t, J=3.9 Hz, 1H), 3.62 (dd, J=6.0, 3.7 Hz, after D2O exchange became a d, J=3.7 Hz, 1H), 3.52-3.39 (m, 4H), 1.42 (s, 9H), 1.41 (s, 18H). 13C NMR (125.7 MHz, DMSO d6): δ 157.9 (C), 151.1, (C), 149.8 (2×C), 134.6 (C), 131.4 (C), 118.8 (C), 83.5 (2×C), 81.3 (C), 78.2 (CH), 76.5 (CH), 68.1 (CH), 66.8 (CH), 60.6 (CH2), 54.4 (CH), 27.9 (CH3), 27.6 (2×CH3). MS-ESI+ for C25H40N5O11 +, (M+H)+ calcd. 586.2719. found 586.2717.
D. Preparation of Compound 5a, 5b or 5c
Compound 4a, 4b or 4c (992 mg, 1.69 mmol) was dissolved in anhydrous pyridine and concentrated. The residue was dissolved in anhydrous CH2Cl2 (10 mL) and pyridine (5 mL) under a nitrogen atmosphere and the solution was cooled to −42° C. in an acetonitrile/dry ice bath. Methyl dichlorophosphate (187 μL, 1.86 mmol) was added dropwise and the mixture was stirred for 2 h 20 min. Water (10 mL) was added to the cold solution which was then removed from the cold bath and diluted with ethyl acetate (50 mL) and saturated NaCl solution (30 mL). The organic portion was separated and washed with saturated NaCl solution. The combined aqueous portions were extracted twice further with ethyl acetate and the combined organic portions were dried over MgSO4 and concentrated. Purification by silica gel flash column chromatography (eluting with 2-20% methanol in ethyl acetate) gave the cyclic methyl phosphate 5a, 5b or 5c (731 mg, 65%). 1H NMR (500 MHz, CDCl3,): δ 11.72 (bs, exchanged D2O, 1H), 5.63 (t, J=1.8 Hz, 1H), 5.41 (s, exchanged D2O, 1H), 4.95 (d, J=3.2 Hz, 1H), 4.70 (dt, J=12.4, 1.8 Hz, 1H), 4.42 (dd, J=22.1, 12.1 Hz, 1H). 4.15 (q, J=3.7 Hz, 1H), 3.82 (s, 1H), 3.75 (s, 1H), 3.58 (d, J=11.7 Hz, 3H), 2.10 (bs, exchanged D20, 1H+H2O), 1.50 (s, 9H), 1.46 (s, 18H). 13C NMR (125.7 MHz, CDCl3, centre line δ 77.0): δ 157.5 (C), 151.2 (C), 149.6 (2×C), 134.5 (C), 132.3 (C), 117.6 (C), 84.7 (2×C), 82.8 (C), 77.3 (CH), 74.8 (d, J=4.1 Hz, CH), 69.7 (CH2), 68.8 (d, J=4.1 Hz, CH), 68.6 (d, J=5.9 Hz, CH), 56.0 (d, J=7.4 Hz, CH3), 51.8 (CH), 28.1 (CH3), 27.8 (CH3). MS-ESI+ for C26H40N5NaO13P+ (M+Na)+, calcd. 684.2252. found 684.2251.
E. Preparation of Compound 6a, 6b or 6c
Compound 5a, 5b or 5c (223 mg, 0.34 mmol) was dissolved in anhydrous CH2Cl2 (7 mL) under a nitrogen atmosphere. Anhydrous DMSO (104 μL, 1.46 mmol) was added and the solution was cooled to −78° C. Trifluoroacetic anhydride (104 μL, 0.74 mmol) was added dropwise and the mixture was stirred for 40 min. N,N-diisopropylethylamine (513 μL, 2.94 mmol) was added and the stirring was continued for 50 min at −78° C. Saturated NaCl solution (20 mL) was added and the mixture removed from the cold bath and diluted with CH2Cl2 (30 mL). Glacial acetic acid (170 μL, 8.75 mmol) was added and the mixture was stirred for 10 min. The layers were separated and the aqueous phase was washed with CH2Cl2 (10 mL). The combined organic phases were washed with 5% aqueous HCl, 3:1 saturated NaCl solution:10% NaHCO3 solution and saturated NaCl solution successively, dried over MgSO4, and concentrated to give compound 6a, 6b or 6c (228 mg, quant.) of suitable purity for further use. 1H NMR (500 MHz, CDCl3): δ 5.86 (m, 1 H), 5.07 (m, 1 H), 4.70-4.64 (m, 2 H), 4.49-4.40 (m, 1 H), 4.27 (m, 1 H), 3.56, m, 4 H), 1.49 (s, 9 H), 1.46 (s, 18 H) ppm. 13C NMR (500 MHz, CDCl3): δ 157.5 (C), 151.1 (C), 150.6 (2 C), 134.6 (C), 132.7 (C), 116.6 (C), 92.0 (C), 84.6 (2 C), 83.6 (C), 78.0 (CH), 76.0 (CH), 70.4 (CH2), 67.9 (CH), 56.2 (CH3) δ6.0 (CH), 28.2 (3CH3), 26.8 (6 CH3) ppm. 31P NMR (500 MHz, CDCl3): δ−6.3 ppm.
F. Preparation of compound 7: (4aR,5aR,11aR,12aS)-1,3,2-Dioxaphosphorino[4′,5′:5,6]pyrano[3,2-g]pteridin-10(4H)-one,8-amino-4-a,5a,6,9,11,11a,12,12a-octahydro-2,12,12-trihydroxy-2-oxide
Compound 6a, 6b or 6c (10 mg, 14.8 μmol was dissolved in dry acetonitrile (0.2 mL) and cooled to 0° C. Bromotrimethylsilane (19.2 μL, 148 μmol) was added dropwise and the mixture was allowed to warm to ambient temperature and stirred for 5 h during which time a precipitate formed. HCl(aq) (10 μl, 37%) was added and the mixture was stirred for a further 15 min. The mixture was centrifuged for 15 min (3000 g) and the resulting precipitate collected. Acetonitrile (0.5 mL) was added and the mixture was centrifuged for a further 15 min. The acetonitrile wash and centrifugation was repeated a further two times and the resulting solid was dried under high vacuum to give compound 7 (4 mg, 75%). 1H NMR (500 MHz, D2O): δ 5.22 (d, J=1.6 Hz, 1H), 4.34 (dt, J=13, 1.6 Hz, 1H), 4.29-4.27 (m, 1H), 4.24-4.18 (m, 1H), 3.94 (br m, 1H), 3.44 (t, J=1.4 Hz, 1H). 31P NMR (500 MHz, D2O): δ −4.8 MS-ESI+ for C10H15N5O8P+, (M+H)+calcd. 364.0653. found 364.0652.
Example 2Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. Coli in the In vitro Synthesis of Moco
In vitro synthesis of Moco was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. Moco synthesis also involved the use of the purified components E. coli MPT synthase, gephyrin, molybdate, ATP, and apo-sulfite oxidase. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. The assay is based on the conversion of cPMP into MPT, the subsequent molybdate insertion using recombinant gephyrin and ATP, and finally the reconstitution of human apo-sulfite oxidase.
As shown in FIG. 1, Moco synthesis from synthetic cPMP was confirmed, and no differences in Moco conversion were found in comparison to E. coli purified cPMP.
Example 3Comparison of Precursor Z (cPMP) Prepared Synthetically to that Prepared from E. coli in the In vitro Synthesis of MPT
In vitro synthesis of MPT was compared using samples of synthetic precursor Z (cPMP) and cPMP purified from E. coli. MPT synthesis also involved the use of in vitro assembled MPT synthase from E. coli. See U.S. Pat. No. 7,504,095 and “Biosynthesis and molecular biology of the molybdenum cofactor (Moco)” in Metal Ions in Biological Systems, Mendel, Ralf R. and Schwarz, Gunter, Informa Plc, 2002, Vol. 39, pages 317-68. Three repetitions of each experiment were performed and are shown in FIGS. 2 and 3.
As shown in FIGS. 2 and 3, MPT synthesis from synthetic cPMP confirmed, and no apparent differences in MPT conversion were found when compared to E. coli purified cPMP. A linear conversion of cPMP into MPT is seen in all samples confirming the identity of synthetic cPMP (see FIG. 2). Slight differences between the repetitions are believed to be due to an inaccurate concentration determination of synthetic cPMP given the presence of interfering chromophores.
Example 4Preparation of Precursor Z (cPMP)
A. Preparation of Starting Materials
B. Introduction of the protected Phosphate
The formation of the cyclic phosphate using intermediate  (630 mg) gave the desired product  as a 1:1 mixture of diastereoisomers (494 mg, 69%).
C. Oxidation and Overall Deprotection of the Molecule
Oxidation of the secondary alcohol to the gem-diol did prove successful on intermediate , but the oxidized product  did show significant instability and could not be purified. For this reason, deprotection of the phosphate was attempted before the oxidation. However, the reaction of intermediate  with TMSBr led to complete deprotection of the molecule giving intermediate . An attempt to oxidize the alcohol to the gem-diol using Dess-Martin periodinane gave the aromatized pteridine .
Oxidation of intermediate  with Dess-Martin periodinane gave a mixture of starting material, oxidized product and several by-products. Finally, intermediate  was oxidized using the method described Example 1. Upon treatment, only partial oxidation was observed, leaving a 2:1 mixture of /. The crude mixture was submitted to the final deprotection. An off white solid was obtained and analyzed by 1H-NMR and HPLC-MS. These analyses suggest that cPMP has been produced along with the deprotected precursor .
Because the analytical HPLC conditions gave a good separation of cPMP from the major impurities, this method will be repeated on a prep-HPLC in order to isolate the final material.
BridgeBio Pharma And Affiliate Origin Biosciences Announces FDA Acceptance Of Its New Drug Application For Fosdenopterin For The Treatment Of MoCD Type A
Application accepted under Priority Review designation with Breakthrough Therapy Designation and Rare Pediatric Disease Designation previously grantedThere are currently no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury for infants and children.This is BridgeBio’s first NDA acceptanceSAN FRANCISCO, September 29, 2020 – BridgeBio Pharma, Inc. (Nasdaq: BBIO) and affiliate Origin Biosciences today announced the US Food and Drug Administration (FDA) has accepted its New Drug Application (NDA) for fosdenopterin (previously BBP-870/ORGN001), a cyclic pyranopterin monophosphate (cPMP) substrate replacement therapy, for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.The NDA has been granted Priority Review designation. Fosdenopterin has previously been granted Breakthrough Therapy Designation and Rare Pediatric Disease Designation in the US and may be eligible for a priority review voucher if approved. It received Orphan Drug Designation in the US and Europe. This is BridgeBio’s first NDA acceptance.“We want to thank the patients, families, scientists, physicians and all others involved who helped us reach this critical milestone,” said BridgeBio CEO and founder Neil Kumar, Ph.D. “MoCD Type A is a devastating disease with a median survival of less than four years and we are eager for our investigational therapy to be available to patients, who currently have no approved treatment options. BridgeBio exists to help as many patients as possible afflicted with genetic diseases, no matter how rare. We are grateful that the FDA has accepted our first NDA for priority review and we look forward to submitting our second NDA later this year for infigratinib for second line treatment of cholangiocarcinoma.”About Fosdenopterin
Fosdenopterin is being developed for the treatment of patients with MoCD Type A. Currently, there are no approved therapies for the treatment of MoCD Type A, which results in severe and irreversible neurological injury with a median survival between 3 to 4 years. Fosdenopterin is a first-in-class cPMP hydrobromide dihydrate and is designed to treat MoCD Type A by replacing cPMP and permitting the two remaining MoCo synthesis steps to proceed, with activation of MoCo-dependent enzymes and elimination of sulfites.About Molybdenum Cofactor Deficiency (MoCD) Type A
MoCD Type A is an ultra-rare, autosomal recessive, inborn error of metabolism caused by disruption in molybdenum cofactor (MoCo) synthesis which is vital to prevent buildup of s-sulfocysteine, a neurotoxic metabolite of sulfite. Patients are often infants with severe encephalopathy and intractable seizures. Disease progression is rapid with a high infant mortality rate.Those who survive beyond the first few month’s experience profuse developmental delays and suffer the effects of irreversible neurological damage, including brain atrophy with white matter necrosis, dysmorphic facial features, and spastic paraplegia. Clinical presentation that can be similar to hypoxic-ischemic encephalopathy (HIE) or other neonatal seizure disorders may lead to misdiagnosis and underdiagnosis. Immediate testing for elevated sulfite levels and S-sulfocysteine in the urine and very low serum uric acid may help with suspicion of MoCD.About Origin Biosciences
Origin Biosciences, an affiliate of BridgeBio Pharma, is a biotechnology company focused on developing and commercializing a treatment for Molybdenum Cofactor Deficiency (MoCD) Type A. Origin is led by a team of veteran biotechnology executives. Together with patients and physicians, the company aims to bring a safe, effective treatment for MoCD Type A to market as quickly as possible. For more information on Origin Biosciences, please visit the company’s website at www.origintx.com.
About BridgeBio Pharma
BridgeBio is a team of experienced drug discoverers, developers and innovators working to create life-altering medicines that target well-characterized genetic diseases at their source. BridgeBio was founded in 2015 to identify and advance transformative medicines to treat patients who suffer from Mendelian diseases, which are diseases that arise from defects in a single gene, and cancers with clear genetic drivers. BridgeBio’s pipeline of over 20 development programs includes product candidates ranging from early discovery to late-stage development. For more information visit bridgebio.com.
|Other names||Precursor Z, ALXN1101|
|License data||US DailyMed: Fosdenopterin|
|Legal status||US: ℞-only |
|CompTox Dashboard (EPA)||DTXSID90934067|
|Chemical and physical data|
|Molar mass||363.223 g·mol−1|
|3D model (JSmol)||Interactive image|
//////////Fosdenopterin hydrobromide, ホスデノプテリン臭化水素酸塩水和物 , ALXN1101 HBr, UNII-X41B5W735T, X41B5W735T, D11780, BBP-870/ORGN001, Priority Review designation, Breakthrough Therapy Designation, Rare Pediatric Disease Designation, Orphan Drug Designation, molybdenum cofactor deficiency, ALXN-1101, WHO 11150, FDA 2021, APPROVALS 2021
#Fosdenopterin hydrobromide, #ホスデノプテリン臭化水素酸塩水和物 , #ALXN1101 HBr, #UNII-X41B5W735T, X41B5W735T, #D11780, #BBP-870/ORGN001, #Priority Review designation, #Breakthrough Therapy Designation, #Rare Pediatric Disease Designation, #Orphan Drug Designation, #molybdenum cofactor deficiency, #ALXN-1101, #WHO 11150, #FDA 2021, #APPROVALS 2021
Company: Horizon Therapeutics plc
Date of Approval: January 21, 2020
Treatment for: Thyroid Eye Disease
R-1507 / R1507 / RG-1507 / RG1507 / RO-4858696 / RO-4858696-000 / RO-4858696000 / RO4858696 / RO4858696-000 / RV-001 / RV001
Tepezza (teprotumumab-trbw) is a fully human monoclonal antibody (mAb) and a targeted inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) for the treatment of active thyroid eye disease (TED).
FDA Approves Tepezza (teprotumumab-trbw) for the Treatment of Thyroid Eye Disease (TED) – January 21, 2020
Today, the U.S. Food and Drug Administration (FDA) approved Tepezza (teprotumumab-trbw) for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis). Today’s approval represents the first drug approved for the treatment of thyroid eye disease.
“Today’s approval marks an important milestone for the treatment of thyroid eye disease. Currently, there are very limited treatment options for this potentially debilitating disease. This treatment has the potential to alter the course of the disease, potentially sparing patients from needing multiple invasive surgeries by providing an alternative, non surgical treatment option,” said Wiley Chambers, M.D., deputy director of the Division of Transplant and Ophthalmology Products in the FDA’s Center for Drug Evaluation and Research. “Additionally, thyroid eye disease is a rare disease that impacts a small percentage of the population, and for a variety of reasons, treatments for rare diseases are often unavailable. This approval represents important progress in the approval of effective treatments for rare diseases, such as thyroid eye disease.”
Thyroid eye disease is associated with the outward bulging of the eye that can cause a variety of symptoms such as eye pain, double vision, light sensitivity or difficulty closing the eye. This disease impacts a relatively small number of Americans, with more women than men affected. Although this condition impacts relatively few individuals, thyroid eye disease can be incapacitating. For example, the troubling ocular symptoms can lead to the progressive inability of people with thyroid eye disease to perform important daily activities, such as driving or working.
Tepezza was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive Tepezza or a placebo. Of the patients who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than 2 millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The most common adverse reactions observed in patients treated with Tepezza are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Tepezza should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for 6 months following the last dose of Tepezza.
The FDA granted this application Priority Review, in addition to Fast Track and Breakthrough Therapy Designation. Additionally, Tepezza received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases or conditions. Development of this product was also in part supported by the FDA Orphan Products Grants Program, which provides grants for clinical studies on safety and efficacy of products for use in rare diseases or conditions.
The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
Teprotumumab (RG-1507), sold under the brand name Tepezza, is a medication used for the treatment of adults with thyroid eye disease, a rare condition where the muscles and fatty tissues behind the eye become inflamed, causing the eyes to be pushed forward and bulge outwards (proptosis).
The most common adverse reactions observed in people treated with teprotumumab-trbw are muscle spasm, nausea, alopecia (hair loss), diarrhea, fatigue, hyperglycemia (high blood sugar), hearing loss, dry skin, dysgeusia (altered sense of taste) and headache. Teprotumumab-trbw should not be used if pregnant, and women of child-bearing potential should have their pregnancy status verified prior to beginning treatment and should be counseled on pregnancy prevention during treatment and for six months following the last dose of teprotumumab-trbw.
Teprotumumab was first investigated for the treatment of solid and hematologic tumors, including breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, non-small cell lung cancer and sarcoma. Although results of phase I and early phase II trials showed promise, research for these indications were discontinued in 2009 by Roche. Phase II trials still in progress were allowed to complete, as the development was halted due to business prioritization rather than safety concerns.
Teprotumumab was subsequently licensed to River Vision Development Corporation in 2012 for research in the treatment of ophthalmic conditions. Horizon Pharma (now Horizon Therapeutics, from hereon Horizon) acquired RVDC in 2017, and will continue clinical trials. It is in phase III trials for Graves’ ophthalmopathy (also known as thyroid eye disease (TED)) and phase I for diabetic macular edema. It was granted Breakthrough Therapy, Orphan Drug Status and Fast Track designations by the FDA for Graves’ ophthalmopathy.
In a multicenter randomized trial in patients with active Graves’ ophthalmopathy Teprotumumab was more effective than placebo in reducing the clinical activity score and proptosis. In February 2019 Horizon announced results from a phase 3 confirmatory trial evaluating teprotumumab for the treatment of active thyroid eye disease (TED). The study met its primary endpoint, showing more patients treated with teprotumumab compared with placebo had a meaningful improvement in proptosis, or bulging of the eye: 82.9 percent of teprotumumab patients compared to 9.5 percent of placebo patients achieved the primary endpoint of a 2 mm or more reduction in proptosis (p<0.001). Proptosis is the main cause of morbidity in TED. All secondary endpoints were also met and the safety profile was consistent with the phase 2 study of teprotumumab in TED. On 10th of July 2019 Horizon submitted a Biologics License Application (BLA) to the FDA for teprotumumab for the Treatment of Active Thyroid Eye Disease (TED). Horizon requested priority review for the application – if so granted (FDA has a 60-day review period to decide) it would result in a max. 6 month review process.
Teprotumumab-trbw was approved for use in the United States in January 2020, for the treatment of adults with thyroid eye disease.
Teprotumumab-trbw was approved based on the results of two studies (Study 1 and 2) consisting of a total of 170 patients with active thyroid eye disease who were randomized to either receive teprotumumab-trbw or a placebo. Of the subjects who were administered Tepezza, 71% in Study 1 and 83% in Study 2 demonstrated a greater than two millimeter reduction in proptosis (eye protrusion) as compared to 20% and 10% of subjects who received placebo, respectively.
The U.S. Food and Drug Administration (FDA) granted the application for teprotumumab-trbw fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation. The FDA granted the approval of Tepezza to Horizon Therapeutics Ireland DAC.
- “FDA approves first treatment for thyroid eye disease”. U.S. Food and Drug Administration (FDA) (Press release). 21 January 2020. Retrieved 21 January 2020. This article incorporates text from this source, which is in the public domain.
- Smith, TJ; Kahaly, GJ; Ezra, DG; Fleming, JC; Dailey, RA; Tang, RA; Harris, GJ; Antonelli, A; Salvi, M; Goldberg, RA; Gigantelli, JW; Couch, SM; Shriver, EM; Hayek, BR; Hink, EM; Woodward, RM; Gabriel, K; Magni, G; Douglas, RS (4 May 2017). “Teprotumumab for Thyroid-Associated Ophthalmopathy”. The New England Journal of Medicine. 376 (18): 1748–1761. doi:10.1056/NEJMoa1614949. PMC 5718164. PMID 28467880.
- “Horizon Pharma plc Announces Phase 3 Confirmatory Trial Evaluating Teprotumumab (OPTIC) for the Treatment of Active Thyroid Eye Disease (TED) Met Primary and All Secondary Endpoints”. Horizon Pharma plc. Retrieved 22 March 2019.
- “Horizon Therapeutics plc Submits Teprotumumab Biologics License Application (BLA) for the Treatment of Active Thyroid Eye Disease (TED)”. Horizon Therapeutics plc. Retrieved 27 August 2019.
- “Teprotumumab”. Drug Information Portal. U.S. National Library of Medicine.
|Other names||teprotumumab-trbw, RG-1507|
|Chemical and physical data|
|Molar mass||145.6 kg/mol g·mol−1|
/////////Teprotumumab-trbw, APPROVALS 2020, FDA 2020, ORPHAN, BLA, fast track designation, breakthrough therapy designation, priority review designation, and orphan drug designation, Tepezza, Horizon Therapeutics, MONOCLONAL ANTIBODY, 2020 APPROVALS, active thyroid eye disease, Teprotumumab
MGADDVVDSS KSFVMENFSS YHGTKPGYVD SIQKGIQKPK SGTQGNYDDD WKGFYSTDNK
YDAAGYSVDN ENPLSGKAGG VVKVTYPGLT KVLALKVDNA ETIKKELGLS LTEPLMEQVG
TEEFIKRFGD GASRVVLSLP FAEGSSSVEY INNWEQAKAL SVELEINFET RGKRGQDAMY
EYMAQACAGN RVRRSVGSSL SCINLDWDVI RDKTKTKIES LKEHGPIKNK MSESPNKTVS
EEKAKQYLEE FHQTALEHPE LSELKTVTGT NPVFAGANYA AWAVNVAQVI DSETADNLEK
TTAALSILPG IGSVMGIADG AVHHNTEEIV AQSIALSSLM VAQAIPLVGE LVDIGFAAYN
FVESIINLFQ VVHNSYNRPA YSPGHKTRPH MAPMTQTTSL KTSWVNCSNM IDEIITHLKQ
PPLPLLDFNN LNGEDQDILM ENNLRRPNLE AFNRAVKSLQ NASAIESILK NLLPCLPLAT
AAPTRHPIHI KDGDWNEFRR KLTFYLKTLE NAQAQQTTLS LAIF
(disulfide bridge: 187-202, 407-475)
methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,https://www.who.int/medicines/publications/druginformation/issues/PL_118.pdf
FDA 2018/12/21, Elzonris APPROVED
Antineoplastic, Immunotoxin, Peptide
DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401
Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)
FDA approves first treatment for rare blood disease
>>tagraxofusp<<< MGADDVVDSSKSFVMENFSSYHGTKPGYVDSIQKGIQKPKSGTQGNYDDDWKGFYSTDNK YDAAGYSVDNENPLSGKAGGVVKVTYPGLTKVLALKVDNAETIKKELGLSLTEPLMEQVG TEEFIKRFGDGASRVVLSLPFAEGSSSVEYINNWEQAKALSVELEINFETRGKRGQDAMY EYMAQACAGNRVRRSVGSSLSCINLDWDVIRDKTKTKIESLKEHGPIKNKMSESPNKTVS EEKAKQYLEEFHQTALEHPELSELKTVTGTNPVFAGANYAAWAVNVAQVIDSETADNLEK TTAALSILPGIGSVMGIADGAVHHNTEEIVAQSIALSSLMVAQAIPLVGELVDIGFAAYN FVESIINLFQVVHNSYNRPAYSPGHKTRPHMAPMTQTTSLKTSWVNCSNMIDEIITHLKQ PPLPLLDFNNLNGEDQDILMENNLRRPNLEAFNRAVKSLQNASAIESILKNLLPCLPLAT AAPTRHPIHIKDGDWNEFRRKLTFYLKTLENAQAQQTTLSLAIF
December 21, 2018
The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.
“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.
The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.
Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.
The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.
The FDA granted this application Breakthrough Therapy and Priority Reviewdesignation. Elzonris also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.
The FDA granted the approval of Elzonris to Stemline Therapeutics.
Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin. It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[6, 7] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm. This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status. Tagraxofusp has been designed as an orphan drug in EU since November 2015.
Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.
BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens. A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.
PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale. One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.
In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.
Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC). To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.[4,6]
As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.
Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.[Label]
Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.
MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.
Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.
Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.
ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.[Label]
- Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
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/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ , Stemline Therapeutics, Breakthrough Therapy, Priority Review designation, Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 , Molecule 129 , Molecule-129 , SL-401,
Hydrocodone bitartrate is morphinan-6-one, 4,5-epoxy-3-methoxy-17-methyl-, (5α)-, [R-(R*,R*)]-2,3-dihydroxybutanedioate (1:1), hydrate (2:5); also known as 4,5α-Epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5); a fine white crystal or crystalline powder, which is derived from the opium alkaloid, thebaine; and may be represented by the following structural formula:
Molecular weight = 494.5
Purdue’s hydrocodone bitartrate tablets granted priority review designation
Purdue Pharma has been granted priority review designation by the US Food and Drug Administration (FDA) for its hydrocodone bitartrate extended-release tablets for treatment of chronic pain.
The once-daily, single-entity pain medication was formulated to incorporate abuse-deterrent properties designed to make the product more difficult to manipulate for misuse or abuse by various routes of administration.http://www.pharmaceutical-technology.com/news/newspurdues-hydrocodone-bitartrate-tablets-granted-priority-review-designation-4313765?WT.mc_id=DN_News