Authors :
Archis Patel, PharmD – Praxis Precision Medicines
Presenting Author: Noam Epstein, MD – Praxis Precision Medicines
Karl Hansen, PhD – Praxis Precision Medicines
Silvana Frizzo, MD – Praxis Precision Medicines
Henry Jacotin, MD – Praxis Precision Medicines
Dharit Patel, MD – Praxis Precision Medicines
Hong Sun, MD, PhD – Praxis Precision Medicines
Steven Petrou, PhD – Praxis Precision Medicines
Marcio Souza, PharmD, MBA – Praxis Precision Medicines
Rationale:
Vormatrigine, a functional state modulator that selectively targets the hyperexcitable state of CNS sodium channels, is currently in development for adult focal onset seizures and generalized epilepsy, with emerging preclinical and clinical data pointing to an ideal precision antiseizure medication (ASM) profile.
Given that polytherapy is common in epilepsy management, understanding the drug-drug interaction (DDI) potential of vormatrigine is critical. A combination of extensive preclinical studies and dedicated clinical DDI trials was undertaken to evaluate vormatrigine’s liability for metabolic or transporter-mediated interactions, with the goal of supporting its use alongside a broad spectrum of ASMs.
Methods:
An integrated nonclinical and clinical approach was used to assess the DDI profile of vormatrigine. Preclinical evaluations included in vitro studies of cytochrome P450 (CYP450) and uridine diphosphate glucoronosyltransferase (UGT) metabolism, transporter interaction profiling, and hepatocyte induction assays. Key enzymes assessed included CYP1A2, 2C19, 3A4, and UGT isoforms, along with major efflux and uptake transporters.
Clinically, the Phase 1 PRAX-628-102 study enrolled healthy adults and examined the pharmacokinetics (PK) of single 10 mg doses of vormatrigine alone and in combination with fluvoxamine (CYP1A2/2C19 inhibitor), itraconazole (CYP3A4 inhibitor) and probenecid (non-selective UGT inhibitor). Additionally, the effects of cigarette smoking (CYP1A2 inducer) were evaluated in parallel cohorts.
Results:
Combined preclinical and clinical findings demonstrated minimal overall DDI risk.
Preclinically, vormatrigine showed:
- Low metabolic turnover in human hepatocytes
- Minor involvement of CYPs and UGTs in its clearance
- Weak inhibition of CYP2D6 and intestinal CYP3A at supratherapeutic concentrations
- Minimal transporter interaction risk, with some in vitro BCRP and MDR1 inhibition not expected to be clinically relevant
Clinically, coadministration with:
- Fluvoxamine increased vormatrigine exposure, implicating CYP1A2 in its clearance
- Itraconazole and probenecid had no significant impact on vormatrigine PK
- Smoking modestly reduced vormatrigine exposure, consistent with CYP1A2 induction
Conclusions:
Vormatrigine exhibits a highly favorable DDI profile, supported by both preclinical mechanistic studies and human PK data. With no clinically meaningful interactions observed with inhibitors or inducers of major CYP and UGT pathways—except a moderate effect via CYP1A2—vormatrigine is well-suited for use in multi-drug epilepsy regimens, including a broad array of ASMs without the need for dose adjustments. These findings reinforce vormatrigine’s potential as a best-in-class sodium channel modulator and support its continued clinical development in the ENERGY program for epilepsy.
Funding:
Praxis Precision Medicines.