Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation

Abstract

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.

Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties

“…Comprehensive preclinical IND-enabling safety pharmacology, toxicology and genotoxicity studies (Supplementary Materials and Methods in the Supplementary Data file) demonstrated that PTC299 is safe and well tolerated in pre-clinical studies (Supplementary Table S5). Subsequently, several clinical trials in healthy volunteers and in patients with solid tumors were conducted to assess PTC299(28, 29), including a prospective Phase 2a study in 2009–2010 in patients with neurofibromatosis type 2, an autosomal dominant tumor suppressor syndrome characterized by bilateral vestibular Schwannomas. Eleven patients were enrolled including 4 males and 7 females with a median age of 25 (range 19–44) at the time of enrollment.…”

“…PTC299 was identified as an inhibitor of the translation of VEGFA mRNA using PTC Therapeutics’ proprietary GEMS™ technology phenotypic screening platform(27). PTC299 was in clinical trials for the treatment of solid tumors (28, 29) and is currently being reevaluated for use in hematologic cancers. To guide safe and effective precision cancer treatment, we performed extensive biochemical characterization of PTC299 and demonstrated that it interacts with and inhibits dihydroorotate dehydrogenase (DHODH), a rate limiting enzyme in the de novo biosynthesis of pyrimidine nucleotides(5).…”

Discovery of Novel Small Molecule Inhibitors of VEGF Expression in Tumor Cells Using a Cell-Based High Throughput Screening Platform

“…PTC-510 inhibited tumor growth in a mouse xenograft model at an oral dose as low as 10 mg/kg, bid . Through further lead optimization and preclinical studies, we selected a Drug Candidate, PTC299 that is more potent than PTC-510 in controlling tumor growth in vivo and is currently under further preclinical and clinical evaluation [42;43]. The data on in vitro and in vivo characterization of PTC299 will be published separately as this is beyond the scope of this paper.…”

“…This can result in severe or life threatening side effects such as bleeding, arterial and venous thrombosis, hypertension, asymptomatic proteinuria and nasal septal perforation in some individuals [44]. Moreover, growing evidence suggests that blockage of global VEGF signaling stimulates the body to respond by initiating by-pass processes that can then be co-opted by the tumor, leading to evasive resistance [42;45;46]. One of the underlying mechanisms of this evasive resistance range from greater production of VEGF itself to elevation of other pro-angiogenic factors.…”

The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines

“…PTC299 was originally identified as a compound that modulates expression of stressregulated proteins like VEGF and was only subsequently found to be a DHODH inhibitor (Cao et al, 2019;Weetall et al, 2016). DHODH inhibitors have been shown to suppress virallyinduced inflammatory cytokine production (Xiong et al, 2020).…”