IP Library › Granted Patent US 12,667,569
Granted Patent B2
US 12,667,569 · App. 17/631,995 · Granted Jun 30, 2026

Use of sepiapterin and metabolites thereof to treat radiation exposure

Inventors: Eleonora Mezzaroma (Glen Allen, VA); Christopher Rabender (Chesterfield, VA); Ross Mikkelsen (Richmond, VA); Vasily Yakovlev (Richmond, VA); Neil Smith (Cary, NC)
Assignees: PTC Therapeutics MP, Inc.; Virginia Commonwealth University
A61K31/519A61P39/00
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Quick Facts
Patent No.
US 12,667,569
App. No.
17/631,995
Filed
Feb 1, 2022
Granted
Jun 30, 2026
Kind
B2
Art Unit
1627
USPC
514/249
Abstract

The invention provides methods for treating radiation exposure in a subject by administering sepiapterin, tetrahydrobiopterin, or dihydrobiopterin.

Claims (12)

1 . A method of treating a subject exposed to radiation comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt or co-crystal thereof, to the subject, wherein the administering occurs at least once daily for at least six days, wherein:

(a) the subject is exposed to at least 0.3 Gy in less than one day; or

(b) the subject is exposed to at least 0.7 Gy over a period of more than one day.

2 . The method of claim 1 , wherein the effective amount is from about 0.1 to about 200 mg/kg/day.

3 . The method of claim 1 , wherein the subject has chronic radiation syndrome.

4 . The method of claim 1 , wherein the administering occurs at least daily for at least 14 days.

5 . A method of treating a subject exposed to radiation comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt or co-crystal thereof, to the subject, wherein the administering occurs at least once daily for at least six days, wherein the subject has acute radiation syndrome, and wherein:

(a) the administering occurs within 24 hours after exposure to radiation; or

(b) the administering occurs at least 24 hours after exposure to radiation.

6 . The method of claim 5 , wherein the administering occurs within 24 hours after exposure to radiation.

7 . The method of claim 5 , wherein the administering occurs at least 24 hours after exposure to radiation.

8 . A method of treating a subject exposed to radiation comprising administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt or co-crystal thereof, to the subject, wherein the administering occurs at least once daily for at least six days, wherein the subject has cutaneous radiation syndrome.

Assignments (2)
TERMINATION AND RELEASE OF PATENT SECURITY AGREEMENT @ REEL 061584 AND FRAME 0377 Recorded Oct 23, 2023
From: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS ADMINISTRATIVE AGENT
To: PTC THERAPEUTICS MP, INC.
Reel/Frame 065321/0025 →
SECURITY INTEREST Recorded Oct 28, 2022
From: PTC THERAPEUTICS MP, INC.
To: WILMINGTON TRUST, NATIONAL ASSOCIATION
Reel/Frame 061584/0377 →
Continuity (2)
Provisional Application 62882937 · Aug 5, 2019
Related Publication 20220273661A1 · Sep 1, 2022
References Cited (118)
US 4758571A · Curtius et al. · 1988 [cited by applicant]
US 4774244A · Curtius et al. · 1988 [cited by applicant]
US 7566462B2 · Jungles et al. · 2009 [cited by applicant]
US 7566714B2 · Oppenheimer et al. · 2009 [cited by applicant]
US 7582799B2 · Yoshino et al. · 2009 [cited by applicant]
US 7612073B2 · Oppenheimer et al. · 2009 [cited by applicant]
US 7727987B2 · Moser et al. · 2010 [cited by applicant]
US 7732599B2 · Moser et al. · 2010 [cited by applicant]
US 7947681B2 · Oppenheimer et al. · 2011 [cited by applicant]
US 8003126B2 · Jungles et al. · 2011 [cited by applicant]
US 8067416B2 · Oppenheimer et al. · 2011 [cited by applicant]
US 8188043B2 · Cooke et al. · 2012 [cited by applicant]
US RE43797E · Oppenheimer et al. · 2012 [cited by applicant]
US 8318745B2 · Moser et al. · 2012 [cited by applicant]
US 9181254B2 · Yoshino et al. · 2015 [cited by applicant]
US 9433624B2 · Oppenheimer et al. · 2016 [cited by applicant]
US 9492451B2 · Rustomjee et al. · 2016 [cited by applicant]
US 9993481B2 · Oppenheimer et al. · 2018 [cited by applicant]
US 11072614B2 · Levy · 2021 [cited by applicant]
US 11130760B2 · Yoshino et al. · 2021 [cited by applicant]
US 11173158B2 · Hasegawa et al. · 2021 [cited by applicant]
US 20060040946A1 · Oppenheimer et al. · 2006 [cited by applicant]
US 20070270581A1 · Jungles et al. · 2007 [cited by applicant]
US 20080075666A1 · Dudley et al. · 2008 [cited by applicant]
US 20100130500A1 · Kakkis · 2010 [cited by applicant]
US 20110144117A1 · Widmann et al. · 2011 [cited by applicant]
US 20130108694A1 · Chou et al. · 2013 [cited by applicant]
US 20130237543A1 · Oppenheimer et al. · 2013 [cited by applicant]
US 20150119574A1 · Yoshino et al. · 2015 [cited by applicant]
US 20180078557A1 · Hasegawa et al. · 2018 [cited by applicant]
US 20190308975A1 · Levy · 2019 [cited by applicant]
US 20200009145A1 · Hasegawa et al. · 2020 [cited by applicant]
US 20200010469A1 · Yoshino et al. · 2020 [cited by applicant]
US 20200061070A1 · Levy · 2020 [cited by applicant]
US 20210161901A1 · Smith et al. · 2021 [cited by applicant]
US 20210220363A1 · Smith et al. · 2021 [cited by applicant]
US 20210269443A1 · Levy et al. · 2021 [cited by applicant]
US 20210300930A1 · Levy · 2021 [cited by applicant]
US 20220081443A1 · Yoshino et al. · 2022 [cited by applicant]
US 20220362249A1 · Smith · 2022 [cited by applicant]
US 20230110351A1 · Smith · 2023 [cited by applicant]
CN 110354133A · 2019 [cited by applicant]
JP 2008520574A · 2008 [cited by applicant]
TW 200808320A · 2008 [cited by applicant]
WO WO2005049000A2 · 2005 [cited by applicant]
WO WO2008128049A2 · 2008 [cited by applicant]
WO WO2011132435A1 · 2011 [cited by applicant]
WO WO2013168693A1 · 2013 [cited by applicant]
WO WO2018019931A1 · 2018 [cited by applicant]
WO WO2018102314A1 · 2018 [cited by applicant]
WO WO2018102315A1 · 2018 [cited by applicant]
WO WO2019046849A1 · 2019 [cited by applicant]
WO WO2019232120A1 · 2019 [cited by applicant]
WO WO2019232126A1 · 2019 [cited by applicant]
WO WO2021026247A1 · 2021 [cited by applicant]
WO WO2021062264A1 · 2021 [cited by applicant]
WO WO2021150983A1 · 2021 [cited by applicant]
WO WO2022173823A1 · 2022 [cited by applicant]
WO WO2022173834A1 · 2022 [cited by applicant]
WO WO2023055923A1 · 2023 [cited by applicant]
Berbée, M. (2011). Novel pharmacological strategies to reduce acute radiation injury. [Doctoral Thesis, Maastricht University]. Datawyse / Universitaire Pers Maastricht. https://doi.org/10.26481/dis.20111021mb (Year: 20… [cited by examiner]
Xue J, Yu C, Sheng W, et al. The Nrf2/GCH1/BH4 Axis Ameliorates Radiation-Induced Skin Injury by Modulating the ROS Cascade. J Invest Dermatol. 2017;137(10):2059-2068. doi:10.1016/j.jid.2017.05.019 (Year: 2017). [cited by examiner]
Pannirselvam M, Simon V, Verma S, Anderson T, Triggle CR. Chronic oral supplementation with sepiapterin prevents endothelial dysfunction and oxidative stress in small mesenteric arteries from diabetic (db/db) mice. Br J… [cited by examiner]
Berbee et al. Reduction of radiation-induced vascular nitrosative stress by the vitamin E analog γ-tocotrienol: evidence of a role for tetrahydrobiopterin. Int J Radiat Oncol Biol Phys. Mar. 1, 2011;79(3): 884-91. doi: … [cited by examiner]
Sawabe et al. (2002). Sepiapterin Administration Raises Tissue BH4 Levels More Efficiently Than BH4 Supplement in Normal Mice. In: Milstien et al (eds) Chemistry and Biology of Pteridines and Folates. Springer, Boston, … [cited by examiner]
Akleyev, A.V. (2014). Definition, Classification, and Clinical Presentation of Chronic Radiation Syndrome (CRS) Associated with Total Exposure to External Radiation. In: Chronic Radiation Syndrome. Springer, Berlin, Hei… [cited by examiner]
Bruno, N. “Normalizing Tumor Vasculature Using Sepiapterin to Increase Radiosensitivity,” Thesis, Virginia Commonwealth University (Nov. 2015) (45 pages). [cited by applicant]
Abell et al., “Effect of oral CNSA-001 (sepiapterin, PTC923) on gastric accommodation in women with diabetic gastroparesis: a randomized, placebo-controlled, phase 2 trial,” J Diabetes Complications. 35(9):107961 (2021)… [cited by applicant]
Almudéver et al., “Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis,” Thorax. 68(10):938-948 (2013). [cited by applicant]
Berbée et al., “Novel strategies to ameliorate radiation injury: a possible role for tetrahydrobiopterin.” Curr Drug Targets. 11(11): 1366-1374 (2010). [cited by applicant]
Bernegger et al., “High frequency of tetrahydrobiopterin-responsiveness among hyperphenylalaninemias: a study of 1,919 patients observed from 1988 to 2002,” Mol Genet Metab. 77(4):304-13 (2002). [cited by applicant]
Blau et al., “Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of DOPA-responsive dystonia and sepiapterin reductase deficiency,” Mol Genet Metab. 74(1-2):172-85 (2001). [cited by applicant]
Bratkovic et al., “PTC923 (sepiapterin) lowers elevated blood phenylalanine in subjects with phenylketonuria: a phase 2 randomized, multi-center, three-period crossover, open-label, active controlled, all-comers study,”… [cited by applicant]
Cardnell et al., “Sepiapterin Ameliorates Chemically Induced Murine Colitis and Azoxymethane-Induced Colon Cancer,” J Pharmacol Exp Ther. 347(1):117-125 (2013). [cited by applicant]
ClinicalTrials.gov Identifier: NCT03519711, “A Study of CNSA-001 in Primary Tetrahydrobiopterin (BH4) Deficient Participants with Hyperphenylalaninemia,” <https://clinicaltrials.gov/ct2/show/study/NCT03519711>, first po… [cited by applicant]
Cronin et al., “The metabolite BH4 controls T-cell proliferation in autoimmunity and cancer,” available in PMC Mar. 28, 2019, published in final edited form as: Nature. 563(7732):564-568 (2018) (44 pages). [cited by applicant]
Curtius et al., “Atypical phenylketonuria due to tetrahydrobiopterin deficiency. Diagnosis and treatment with tetrahydrobiopterin, dihydrobiopterin and sepiapterin.” Clin Chim Acta. 93(2):251-62 (1979). [cited by applicant]
Grant et al., “Relationships among rat ultrasonic vocalizations, behavioral measures of striatal dopamine loss, and striatal tyrosine hydroxylase immunoreactivity at acute and chronic time points following unilateral 6-… [cited by applicant]
Hennermann et al., “Partial and total tetrahydrobiopterin-responsiveness in classical and mild phenylketonuria (PKU),” J Inherit Metab Dis. 25(Suppl 1):21:041-P (2002) (Abstract only). [cited by applicant]
Ichiyama et al., “Enzymic studies on the biosynthesis of serotonin in mammalian brain,” J Biol Chem. 245(7):1699-709 (1970). [cited by applicant]
International Search Report and Written Opinion for International Application No. PCT/US2020/045026, mailed Oct. 15, 2020 (15 pages). [cited by applicant]
Kaufman, “Phenylalanine hydroxylation cofactor in phenylketonuria,” Science. 128(3337):1506-8 (1958). [cited by applicant]
Klaiman et al., “Tetrahydrobiopterin as a treatment for autism spectrum disorders: a double-blind, placebo-controlled trial,” J Child Adolesc Psychopharmacol. 23(5):320-8 (2013) (11 pages). [cited by applicant]
Kuplennik et al., “Enhanced nanoencapsulation of sepiapterin within PEG-PCL nanoparticles by complexation with triacetyl-beta cyclodextrin,” Molecules. 24(15):2715 (Jul. 2019) (19 pages). [cited by applicant]
Kure et al., “Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency,” J Pediatr. 135(3):375-8 (1999). [cited by applicant]
Kuznetsova et al., “Nitric Oxide: Properties, Biological Role, Mechanisms of Action,” Modern Problems of Science and Education. 4, <https://science-education.ru/ru/article/view?id=21037>, published Jul. 31, 2015, retrie… [cited by applicant]
Kwon et al., “Reduced biopterin as a cofactor in the generation of nitrogen oxides by murine macrophages,” J Biol Chem. 264(34):20496-501 (1989). [cited by applicant]
Matalon et al., “Tetrahydrobiopterin (BH4) responsive phenylalanine hydroxylase (PAH) mutations,” J Inherit Metab Dis. 25(Suppl 1):23:045-P (2002) (Abstract only). [cited by applicant]
Mayer et al., “Brain nitric oxide snythase is a biopterin- and flavin-containing multi-functional oxido-reductase,” FEBS Lett. 288(1-2):187-91 (1991). [cited by applicant]
Mikkelsen et al., “Oral sepiapterin mitigates radiation induced lung and heart toxicity,” Radiation Research Society 65th Annual Meeting, Nov. 3-6, San Diego, CA. Abstract (2019). [cited by applicant]
Muntau et al., “Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria,” N Engl J Med. 347(26):2122-32 (2002). [cited by applicant]
Nagatsu et al., “Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis,” J Biol Chem. 239(9):2910-7 (1964). [cited by applicant]
Niederwieser et al., “Atypical phenylketonuria with defective biopterin metabolism. Monotherapy with tetrahydrobiopterin or sepiapterin, screening and study of biosynthesis in man,” Eur J Pediatr. 138(2):110-2 (1982). [cited by applicant]
Opladen et al., “Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies.” Orphanet J Rare Dis. 15(1):126 (May 2020) (30 pages). [cited by applicant]
Park et al., “Optimization of expression conditions enhances production of sepiapterin, a precursor for tetrahydrobiopterin biosynthesis, in recombinant [cited by applicant]
Pfleiderer, “Pteridine, LXVIII. Überführung von biopterin in sepiapterin und absolute konfiguration des sepiapterins,” Chem Ber. 112:2750-2755 (1979). [cited by applicant]
Ponzone et al., “Hyperphenylalaninemia and pterin metabolism in serum and erythrocytes,” Clin Chim Acta. 216(1-2):63-71 (1993). [cited by applicant]
Rabender et al., “Mitigation of Radiation-Induced Lung and Heart Injuries in Mice by Oral Sepiapterin after Irradiation,” available in PMC May 1, 2022, published in final edited form as: Radiat Res. 195(5):463-473 (2021… [cited by applicant]
Rabender et al., “Sepiapterin Enhances Tumor Radio- and Chemosensitivities by Promoting Vascular Normalization,” J Pharmacol Exp Ther. 365(3):536-543 (2018). [cited by applicant]
Rabender et al., “The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression,” Mol Cancer Res. 13(6):1034-1043 (2015) (11 pages). [cited by applicant]
Sawabe et al., “Cellular uptake of sepiapterin and push-pull accumulation of tetrahydrobiopterin,” Mol Genet Metab. 94(4):410-6 (2008). [cited by applicant]
Sawabe et al., Sepiapterin administration raises tissue BH4 levels more efficiently than BH4 supplement in normal mice, [cited by applicant]
Schircks et al., “Herstellung von (6 R,S)-5,6,7,8-Tetrahydro-L-biopterin, 7,8-Dihydro-L-biopterin, L-Sepiapterin, Deoxysepiapterin, (6 R,S)-5,6-Dihydrodeoxysepiapterin und 2'-Deoxybiopterin,” Helvetica Chimica Acta. 61(… [cited by applicant]
Schircks et al., “Über Pterinchemie. 65 Mitteilung [1]. Herstellung von (6 R,S)-5,6,7,8-Tetrahydro-L-biopterin, 7,8-Dihydro-L-biopterin, L-Sepiapterin, Deoxysepiapterin, (6 R,S)-5,6-Dihydrodeoxysepiapterin and 2′-Deoxyb… [cited by applicant]
Shimazu et al., “Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction,” Am J Physiol Heart Circ Physiol. 301(5):H2061-H2072 (2011). [cited by applicant]
Schircks Laboratories, “Data Sheet: L-Sepiapterin. Product No. 11.225,” published Jan. 26, 2016 (1 page). [cited by applicant]
Schircks Laboratories, “Data Sheet: Tetrahydrobiopterin Tablets,” published Jul. 1, 2009 (1 page). [cited by applicant]
Smith et al., “Exploratory study of the effect of one week of orally administered CNSA-001 (sepiapterin) on CNS levels of tetrahydrobiopterin, dihydrobiopterin and monoamine neurotransmitter metabolites in healthy volun… [cited by applicant]
Smith et al., “Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers,” Mol Genet Metab. 126(4):406-12 (F… [cited by applicant]
Spaapen et al., “Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art,” Mol Genet Metab. 78(2):93-9 (2003). [cited by applicant]
Sugiura et al., “The structures of the reoxidation products of 7,8-dihydroneopterin,” Bull Chem Soc Jpn. 46(3):939-42 (1973). [cited by applicant]
“Tetrahydrobiopterin Deficiency,” NORD, <https://web.archive.org/web/20160901103424/https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/>, last updated Sep. 1, 2016, retrieved Feb. 11, 2021 (10 pages). [cited by applicant]
Tietz et al., “A new pteridine-requiring enzyme system for the oxidation of glyceryl ethers,” J Biol Chem. 239(12):4081-90 (1964). [cited by applicant]
Viscontini et al., “Fluoreszierende Stoffe aus Drosophila melanogaster. 12. Mitteilung. Die gelb fluoreszierenden Pterine: Sepiapterin und Isosepiapterin,” Helvetica Chimica Acta. 42:836-41 (1959) (7 Pages). [cited by applicant]
Woo et al., “Production of sepiapterin in [cited by applicant]
Yan et al., “Ionizing radiation induces BH4 deficiency by downregulating GTP-cyclohydrolase 1, a novel target for preventing and treating radiation enteritis.” Biochemical Pharmacology. 180: 114102 (Jun. 2020) (10 pages… [cited by applicant]
Zhang et al., “Tetrahydrobiopterin protects against radiation-induced growth inhibition in H9c2 cardiomyocytes.” Chin Med J (Engl). 129(22):2733-2740 (2016). [cited by applicant]
Zheng et al., “Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH4-induces immunostimulatory-shift of breast cancer,” available in PMC Jan. 28, 2021, published in final… [cited by applicant]