PRAX-562: A Novel Sodium Channel Inhibitor with Greater Potency and Selectivity for Persistent Sodium Current Compared to Standard of Care

Abstract number : 2.241
Submission category : 7. Anti-seizure Medications / 7E. Other
Year : 2021
Submission ID : 1826477
Source : www.aesnet.org
Presentation date : 12/5/2021 12:00:00 PM
Published date : Nov 22, 2021, 12:54 PM

Authors :
Kristopher Kahlig, PhD - Praxis Precision Medicines; Mark Chapman - Icagen LLC; Andrew Griffin - Praxis Precision Medicines; Robert Hatch - The Florey Institute of Neuroscience and Mental Health; Gabriel Martinez-Botella - Praxis Precision Medicines; Marion Wittmann - Praxis Precision Medicines

Rationale: Voltage-gated sodium channels (NaV) are important therapeutic targets for anti-epileptic drugs (AEDs) due to their role in the initiation and propagation of action potentials (APs). Variants in human NaV genes, such as SCN8A encoding hNaV1.6, are the most common cause of de novo genetic epilepsy and can exhibit gain-of-function profiles that include enhanced persistent sodium current (INa). Persistent INa has been proposed as a pharmacological target for reducing pathologic hyperexcitabilty, while sparing peak INa is critical to ensuring normal neuronal activity. This study investigates the effects of PRAX-562 on persistent INa, peak INa, and intrinsic neuronal excitability.

Methods: Persistent and peak INa inhibition was studied using automated patch clamp recordings of NaV expressed in HEK cells (hNaV1.6, hNaV1.6-N1768D). Voltage protocols measured INa inhibition in multiple modes: persistent INa (Vm -120 mV, 200 ms), tonic block (TB; Vm -120 mV, 0.2 Hz), voltage-dependent block (VDB; Vm inactivation V1/2), and use-dependent block (UDB, Vm -120 mV, 10 Hz). PRAX-562 was compared to a panel of antiepileptic drugs (AEDs), non-AEDs, and investigational compounds.

Effects on intrinsic neuronal excitability were measured using evoked APs recorded from hippocampal CA1 pyramidal neurons in mouse brain slices. AP frequency was used to evaluate excitability while AP amplitude was used to evaluate peak INa inhibition. PRAX-562 was compared to carbamazepine (CBZ).

Results: PRAX-562 blocked hNaV1.6 persistent INa with an IC50 of 141 nM, which was at least 550x more potent than the other tested INa blocking agents. PRAX-562 also blocked persistent INa expressed by the disease variant hNaV1.6-N1768D with an IC50 of 75 nM. PRAX-562 demonstrated 60x selectivity for persistent INa over peak INa TB, which was larger than for all other agents. Importantly, PRAX-562 also exhibited potent UDB (31x selectivity to TB), which has been suggested to convey beneficial activity during periods of hyperexcitability. This profile was different than that of CBZ (persistent INa IC50 of 77,500 nM, 30x selectivity to TB, no UDB observed) and cenobamate (persistent INa IC50 of 71,690 nM, 24x selectivity to TB, UDB 2.3x selectivity to TB).

At concentrations that had equivalent effects on peak INa VDB, PRAX-562 reduced neuronal excitability less than CBZ (15% versus 39%). Importantly, PRAX-562 had minimal effects on AP amplitude, but CBZ caused a pronounced reduction (6% versus 20%). These data demonstrate that CBZ blocks both persistent INa and peak INa, which could compromise neuronal response to physiological stimuli. In contrast, PRAX-562 reduces excitability in a manner that likely maintains physiological activity.

Conclusions: PRAX-562 is a next generation NaV blocker with increased potency and selectivity for persistent INa. The profile of PRAX-562 may translate to efficacy in epilepsy (as well as other indications caused by neuronal hyperexcitability) without tolerability issues caused by blocking peak INa.

Funding: Please list any funding that was received in support of this abstract.: All work was funded by Praxis Precision Medicines.

Categories : Anti-seizure Medications
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