ATXA Therapeutics have today published a new paper in Frontiers in Pharmacology detailing results of its lead drug candidate NTP42 in a first-in-human clinical trial in healthy adult participants.
The Phase 1 results showed that NTP42, administered as the oral formulation NTP42:KVA4, was safe and well tolerated, with favorable pharmacokinetic/pharmacodynamic characteristics and evidence of specific thromboxane receptor (TP) target engagement.
NTP42:KVA4 was found to be safe and well-tolerated after single oral dosing up to 243 mg and repeat once-daily oral dosing up to 135 mg. In all parts of the trial, there were no significant adverse events (AEs) or serious adverse events (SAEs) that either stopped dose escalation or resulted in subject withdrawal. Any drug- or placebo-related treatment-emergent adverse events (TEAEs) were considered mild or moderate in severity, with no SAEs and no overall correlation in incidence or severity of the TEAE to NTP42:KVA4 dose. NTP42 was rapidly absorbed after single and repeat oral dosing of NTP42:KVA4, with dose proportional increases in exposure and favorable clearance rates indicating that NTP42:KVA4 may be suited for use as a once-a-day oral medication. The findings of the study also suggest that NTP42:KVA4 may be taken with or without food, another key benefit for patient compliance. At doses ≥1 mg, NTP42:KVA4 led to complete and sustained inhibition of thromboxane (TXA2)-, but not adenosine diphosphate (ADP)-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of these pharmacodynamic effects.
These findings, combined with our compelling preclinical efficacy data, support the continued development of NTP42 for the treatment of cardiopulmonary diseases, including PAH, or other conditions involving aberrant TXA2/TP signaling.
Read the full abstract below and click here to download the complete Open Access manuscript.
Background: The thromboxane receptor (TP) antagonist NTP42 is in clinical development for treatment of cardiopulmonary diseases, such as pulmonary arterial hypertension. In this randomized, placebo-controlled Phase I clinical trial, NTP42, administered as the oral formulation NTP42:KVA4, was evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy males.
Methods: The first-in-human trial had three Parts: A, single ascending dose (SAD) study with seven groups given 0.25–243 mg NTP42:KVA4 or placebo; B, food effect study where one SAD group (9 mg) was also given NTP42:KVA4 or placebo after a high-fat breakfast; C, multiple ascending dose study with three groups given 15–135 mg NTP42:KVA4 or placebo once-daily for 7 days.
Results: Seventy-nine volunteers participated. No serious adverse events occurred, where any drug- or placebo-related adverse events were mild to moderate, with no correlation to NTP42:KVA4 dose. NTP42 was rapidly absorbed, yielding dose proportional increases in exposure after single and repeat dosing. PK confirmed that, with a clearance (T1/2) of 18.7 h, NTP42:KVA4 is suited to once-daily dosing, can be taken with or without food, and does not accumulate on repeat dosing. At doses ≥1 mg, NTP42 led to complete and sustained inhibition of thromboxane-, but not ADP-, induced platelet aggregation ex vivo, with direct correlation between NTP42 exposure and duration of PD effects.
Conclusion: Orally administered NTP42:KVA4 was well tolerated, with favorable PK/PD profiles and evidence of specific TP target engagement. These findings support continued clinical development of NTP42:KVA4 for cardiopulmonary or other relevant diseases with unmet needs.
Clinical Trial Registration: clinicaltrials.gov, identifier NCT04919863.