Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers
Tetrahydrobiopterin (BH4) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural pr...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article (Journal) |
| Language: | English |
| Published: |
10 February 2019
|
| In: |
Molecular genetics and metabolism
Year: 2019, Volume: 126, Issue: 4, Pages: 406-412 |
| ISSN: | 1096-7206 |
| DOI: | 10.1016/j.ymgme.2019.02.001 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.ymgme.2019.02.001 Verlag: http://www.sciencedirect.com/science/article/pii/S1096719218307315 
|
| Author Notes: | Neil Smith, Nicola Longo, Keith Levert, Keith Hyland, Nenad Blau |
MARC
| LEADER | 00000caa a2200000 c 4500 | ||
|---|---|---|---|
| 001 | 1684196930 | ||
| 003 | DE-627 | ||
| 005 | 20230426073031.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 191204s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.ymgme.2019.02.001 |2 doi | |
| 035 | |a (DE-627)1684196930 | ||
| 035 | |a (DE-599)KXP1684196930 | ||
| 035 | |a (OCoLC)1341280444 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rda | ||
| 041 | |a eng | ||
| 084 | |a 33 |2 sdnb | ||
| 100 | 1 | |a Smith, Neil |e VerfasserIn |0 (DE-588)1201053757 |0 (DE-627)1684196795 |4 aut | |
| 245 | 1 | 0 | |a Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers |c Neil Smith, Nicola Longo, Keith Levert, Keith Hyland, Nenad Blau |
| 264 | 1 | |c 10 February 2019 | |
| 300 | |a 7 | ||
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Gesehen am 04.12.2019 | ||
| 520 | |a Tetrahydrobiopterin (BH4) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH4, is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH4 as a pharmacological agent for diseases associated with BH4-deficient conditions. We report the results of a first-in-humans, randomized, double-blind, placebo-controlled, dose-ranging, Phase I clinical trial in 83 healthy volunteers of CNSA-001, a novel formulation of sepiapterin. Single oral doses of 2.5-80mg/kg CNSA-001 caused dose-related increases in plasma sepiapterin (mean Cmax 0.58-2.92ng/mL) and BH4 (mean Cmax 57-312ng/mL). Maximum plasma concentrations were achieved in about 1-2h (sepiapterin) or about 4h (BH4) after CNSA-001 oral intake. Increases in plasma BH4 were substantially larger in absolute terms and on a dose-for-dose basis following treatment with CNSA-001 vs. sapropterin dihydrochloride, a synthetic form of BH4. The pharmacokinetics of plasma sepiapterin and BH4 were similar before and after seven days of repeat daily dosing with CNSA-001 at 5, 20 or 60mg/kg indicating little or no drug accumulation. Oral administration of CNSA-001 resulted in higher concentrations of sepiapterin in fasted vs. fed subjects, but overall BH4 plasma exposure following CNSA-001 intake increased by 1.7-1.8-fold in fed subjects. CNSA-001 was well tolerated, with no clear dose-relationship for adverse events (AE), no serious AE and no study discontinuations for AE. These data indicate that CNSA-001 is rapidly and efficiently converted to BH4 in humans supporting further clinical evaluation of CNSA-001 for the management of PKU, primary BH4 deficiencies and other diseases associated with deficient BH4 metabolism. | ||
| 650 | 4 | |a CNSA-001 | |
| 650 | 4 | |a PKU | |
| 650 | 4 | |a Primary BH deficiency | |
| 650 | 4 | |a Sepiapterin, tetrahydrobiopterin, BH, Phenylketonuria | |
| 700 | 1 | |a Blau, Nenad |d 1946- |e VerfasserIn |0 (DE-588)11474632X |0 (DE-627)500421803 |0 (DE-576)176516107 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Molecular genetics and metabolism |d Orlando, Fla. : Academic Press, 1998 |g 126(2019), 4, Seite 406-412 |h Online-Ressource |w (DE-627)268125260 |w (DE-600)1471393-7 |w (DE-576)106869493 |x 1096-7206 |7 nnas |a Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers |
| 773 | 1 | 8 | |g volume:126 |g year:2019 |g number:4 |g pages:406-412 |g extent:7 |a Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers |
| 856 | 4 | 0 | |u https://doi.org/10.1016/j.ymgme.2019.02.001 |x Verlag |x Resolving-System |3 Volltext |
| 856 | 4 | 0 | |u http://www.sciencedirect.com/science/article/pii/S1096719218307315 |x Verlag |
| 951 | |a AR | ||
| 992 | |a 20191204 | ||
| 993 | |a Article | ||
| 994 | |a 2019 | ||
| 998 | |g 11474632X |a Blau, Nenad |m 11474632X:Blau, Nenad |d 910000 |d 910500 |e 910000PB11474632X |e 910500PB11474632X |k 0/910000/ |k 1/910000/910500/ |p 5 |y j | ||
| 999 | |a KXP-PPN1684196930 |e 355647686X | ||
| BIB | |a Y | ||
| SER | |a journal | ||
| JSO | |a {"type":{"bibl":"article-journal","media":"Online-Ressource"},"recId":"1684196930","note":["Gesehen am 04.12.2019"],"language":["eng"],"person":[{"display":"Smith, Neil","given":"Neil","role":"aut","roleDisplay":"VerfasserIn","family":"Smith"},{"given":"Nenad","role":"aut","roleDisplay":"VerfasserIn","display":"Blau, Nenad","family":"Blau"}],"relHost":[{"note":["Gesehen am 14.02.20"],"recId":"268125260","part":{"volume":"126","issue":"4","text":"126(2019), 4, Seite 406-412","pages":"406-412","extent":"7","year":"2019"},"pubHistory":["63.1998 -"],"type":{"bibl":"periodical","media":"Online-Ressource"},"id":{"issn":["1096-7206"],"zdb":["1471393-7"],"eki":["268125260"]},"title":[{"title_sort":"Molecular genetics and metabolism","title":"Molecular genetics and metabolism"}],"origin":[{"dateIssuedDisp":"1998-","publisher":"Academic Press","publisherPlace":"Orlando, Fla.","dateIssuedKey":"1998"}],"physDesc":[{"extent":"Online-Ressource"}],"language":["eng"],"disp":"Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteersMolecular genetics and metabolism"}],"origin":[{"dateIssuedDisp":"10 February 2019","dateIssuedKey":"2019"}],"name":{"displayForm":["Neil Smith, Nicola Longo, Keith Levert, Keith Hyland, Nenad Blau"]},"id":{"doi":["10.1016/j.ymgme.2019.02.001"],"eki":["1684196930"]},"physDesc":[{"extent":"7 S."}],"title":[{"title_sort":"Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers","title":"Phase I clinical evaluation of CNSA-001 (sepiapterin), a novel pharmacological treatment for phenylketonuria and tetrahydrobiopterin deficiencies, in healthy volunteers"}]} | ||
| SRT | |a SMITHNEILBPHASEICLIN1020 | ||