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About Lennox-Gastaut Syndrome (LGS)

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 epileptic encephalopathy. Read more about orphan drug indications....

  • There is strong unmet need for memory improving drugs because the majority of affected children are not able to finish secondary school.
  • Adjunctive approved therapies have only short time frames of efficacy and also cause tolerance or even addiction (this is especially true for the benzodiazepine drugs). All of the AEDs have relatively poor tolerability profiles and therefore display weak patient compliance. At CuroNZ, we are aiming to bring the first monotherapy for LGS to market which would make a huge difference to seizure control as well as to tolerability profiles. Lennox-Gastaut Syndrome - high unmet need

What is the rationale why NRP2945 will work for Lennox-Gastaut Syndrome patients?

For long time it has been hypothesized that the GABAergic system which sets either inhibitory tonic or phasic responses in the brain is impaired within various neurodegenerative diseases.

More recently, the EpiK4 consortium has identified de novo mutations (only in patients not in parents) in Lennox-Gastaut Syndrome and infantile spasm patients with the highest frequency of patients for the beta 3 subunit of the GABA A receptor (GABRB3 gene) but also with occurring mutations in GABRB1 and GABRA2and3.

Why does this genetic finding have direct implications for the therapeutic effect of NRP2945?

Curonz has shown that NRP2945 has the capacity to prevent convulsive seizures in PTZ-dosed rats completely.

  • In an acute rat PTZ study we have shown that NRP2945 is able to upregulate the GABA A receptor beta-subunit by approximately 80% at protein level at 120 minutes after NRP2945 exposure within the hippocampal CA1-region and by 30% within the somatosensory cortex.
  • We found significant GABA receptor alpha and beta-subunit upregulation in CA1 region and neocortex after NRP2945 exposure.
  • Furthermore, we found a significant increase of the GAD-65 protein – the enzyme that is crucial for converting glutamate into the inhibitory transmitter GABA in all tested brain regions after NRP2945 administration.

In conclusion, NRP2945 is restoring the GABAergic system after chemically induced injury (PTZ) and is “setting” a strong inhibitory tonus in the brain circuits.

Curonz has also evaluated NRP2945 in thalamocortical driven absence seizures and myoclonic seizures in 2017. NRP2945 is now poised to enter clinical phase 2 development in 2020 by treating children diagnosed with Lennox-Gastaut Syndrome.

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