Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress-Regulated Protein Translation.
PTC299 is a novel small molecule that specifically blocks the production of protein from selected mRNAs that under certain conditions use noncanonical ribosomal translational pathways. Hypoxia, oncogenic transformation, and viral infections limit normal translation and turn on these noncanonical translation pathways that are sensitive to PTC299. Vascular endothelial cell growth factor (VEGF) is an example of a transcript that is posttranscriptionally regulated. Single doses of PTC299 (0.03 to 3 mg/kg) were administered orally to healthy volunteers in a phase 1 single ascending-dose study. In a subsequent multiple ascending-dose study in healthy volunteers, multiple-dose regimens (0.3 to 1.2 mg/kg twice a day or 1.6 mg/kg 3 times a day for 7 days) were evaluated. PTC299 was well tolerated in these studies. As expected in healthy volunteers, mean plasma VEGF levels did not change. Increases in Cmax and AUC of PTC299 were dose-proportional. The target trough plasma concentration associated with preclinical efficacy was achieved within 7 days at doses of 0.6 mg/kg twice daily and above. These data demonstrate that PTC299 is orally bioavailable and well tolerated and support clinical evaluation of PTC299 in cancer, certain viral infections, or other diseases in which deregulation of translational control is a causal factor.
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Marla
M
Weetall
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Thomas
T
Davis
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Gary
G
Elfring
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Valerie
V
Northcutt
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Liangxian
L
Cao
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Young-Choon
YC
Moon
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Peter
P
Riebling
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Mandar
M
Dali
Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
Samit
S
Hirawat
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
John
J
Babiak
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Joseph
J
Colacino
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Neil
N
Almstead
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Robert
R
Spiegel
PTC Therapeutics, Inc, South Plainfield, NJ, USA.
Stuart W
SW
Peltz
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D055815:Young Adult
D000970:Antineoplastic Agents; D007093:Imidazoles; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole
PTC299; noncanonical mRNA translation; pharmacokinetics; phase 1 clinical trial; safety and tolerability