Lennox-Gastaut Syndrome (LGS) 

About

Lennox-Gastaut Syndrome is a refractory childhood epilepsy which falls under the disease category ultra-orphan drug destination. Less than 20,000 children in the US are diagnosed with this severe form of developmental epileptic encephalopathy.  Read more about orphan drug status...

LGS has:

• Strong unmet medical need for seizure control as well as needed decrease of comorbidities like memory impairment.
• Low therapeutic indices for currently approved drugs like Epidiolex® or Rufinamide®. Adjunctive approved therapies have only short efficacy time frames as well as tolerance issues or even cause addiction (this is especially true for the benzodiazepine drugs).
• Low patient adherence in regard to approved chronic dosing profiles.

Rationale for NRP2945 working for LGS patients

1. Extra-synaptic and synaptic GABA A receptors cause either inhibitory tonic or phasic responses in the CNS showing impairment in epilepsy.
2. Identification of GABA A receptor de novo mutations in LGS and infantile spasms revealed highest frequency of GABRB3 gene mutations.
3. Downregulation of phasic inhibition in generalized forms of epilepsy.
4. GABRB3 protein strongly involved in phasic inhibition but also in extra-synaptic location (tonic inhibition).
5. NRP2945 quickly upregulates GABRA1, GABRA5, GABRB3 in dorsal epileptic thalamus that shows said subunits to be downregulated during epilepsy; this effect restores fast synaptic phasic inhibition.
6. Seizure cessation and increased memory consolidation and retrieval is quickly caused by NRP2945 action.

Why does the differential protein expression effect on the GABA A receptor subunit composition have direct implications for the therapeutic effect of NRP2945?

In humans with drug-resistant Genetic Generalized Absence Epilepsy (GGE), NRP2945 achieved very quickly transient seizure freedom after near acute dosing.

These pharmaco-resistant GGE patients display downregulated phasic inhibition that can be re-established by NRP2945 action.

So far, the family of Neural Regeneration Peptides with the clinical lead NRP2945 are the only compounds which can boost phasic inhibition at the post-synaptic compartment resulting in neural regeneration, seizure cessation and effective memory consolidation and retrieval.

LGS patients show highly similar electroclinical features like drug-resistant GGE patient display and NRP2945’s ability to downregulate generalized paroxysmal fast activity (GPFA) profiles provides promise for memory improvement in these LGS children and adolescents.