NEUROSTEROIDSFOR THE TREATMENT OF EPILEPSY

Developed by:

Presented by:

Epilepsy - Key unmet needs 01

Pharmacoresistance

30% to 40%of epilepsy patients respondpoorly to treatment.

Tolerability

.

Other

Disease-modifying treatments.Rare epilepsies.Comorbidities.

Source: https://www.epilepsy.com/learn/types-epilepsy-syndromesSource: https://www.frontiersin.org/articles/10.3389/fneur.2017.00301/full Source: https://clinicalgate.com/epilepsy-8/

Common adverse effects of AEDs

Our solution – Neurosteroids 02

Neurosteroids: small molecules based on steroidal structure. NO HORMONES.

• Target: allosteric modulation of NMDA and GABA receptors.

• Efficacy: efficacy in several seizure models in vivo comparable or superior toclinically used active comparators (evaluated in 3 independent laboratories).

• Safety: low toxicity, no secondary targets (Eurofins/CEREP 44 Safety Screen).

Adressing pharmacoresistance:Assessment in 6-Hz model of psychomotor seizures (model of pharmacoresistant partial seizures).

Adressing comorbidities:preliminary data show anxiolytic and antidepressant-like effect.

Neurosteroids in seizure modelsProof of concept 1. 03

Pentylenetetrazole (PTZ) model:chemically induced seizures

PTZ (100 mg/kg i.p.)Compound X i.p.

30 min observation period20 min

Neurosteroids in seizure modelsProof of concept 2. 04

Model of partial psychomotor seizures (6 Hz model)

Neurosteroid X also tested in: PTZ model in zebrafish, TMDT model in rats.

0 min 10 min 50 min

Electricalstimulation

compound X10 mg/kg, i.p.

Evaluation period

30 min

Evaluation periodElectricalstimulation

• Transcorneal electrical stimulation.

• Frequency 6 Hz, 3-s series of biphasic pulses with 0.3-ms durationinduces seizures that are reminiscent of “psychomotor seizures”occurring in human limbic epilepsy.

• 15-day-old rats: 60, 80 mA• 25-day-old rats: 40, 60 mA

• Most AEDs reported to lose efficacy at higher current intensities.

CTRL

Cmpd X 10 mg/kg

Commercial potential 05

Epidemiology

up to 1 in 26people will develop epilepsy at some point in their lifetime.(US data, source: Hesdorffer et al., 2011)

Epilepsy Market:

EU Sales Forecast for 2026: ≥ $ 1.1 Billion (Source: Global Data, prediction for 5 biggest EU markets).Global Sales Forecast for 2026: ≥ $ 7.5 Billion (Source: Global Data)

Major AEDs global sales:

First line treatments: levetiracetam $ 1,270 Million (2018), lamotrigine $ 794 Million (2018)Orphan: cannabidiol (Epidiolex) $ 1,809 Million (forecast for 2018 – 2025)(Source: Global Data)

How are our neurosteroids different? 06

• Unique mechanism of action:• use-dependent activity at the NMDA receptor, positive allosteric modulation of GABA• No apparent serious side effects associated with NMDA antagonism.

Competition

Other neurosteroids in the pipeline:

ganaxolone (Marinus Pharmaceuticals)SAGE-324 (Sage Therapeutics)

Similar receptor profile:

felbamate – “last resort” drug, but has serious off-site toxicity issues

GABA modulators only

ganaxolone

felbamate

Preclinical Development Plan2019-2021 07

Efficacy: estimated timeline 6-12 months- Epilepsy Therapy Screening Program (NIH/NINDS)

Safety: estimated timeline 24 months

Long-term safety:- subchronic and chronic administration- Effects on cognition, learning, and memoryOther (as defined by Module 4 CTD)

Pharmaceutical development:estimated timeline 24 monthsAPI synthesis, oral formulation

EUR 0 (free of charge)highly selective admission process

EUR 1 mil

EUR 1.5 mil

IP: Czech patent application submitted (03/2019)PCT application planned (2020)

Contribution of the NIH ETSP(formerly Anticonvulsant Screening Program)to new AED development

(Porter and Kupferberg, 2017)

Risks and bottlenecks 08

Translational gap – limitations of available rodent models

“Old Models Identify Old Drugs”

- bias by endpoints (seizure types)

- lack of uniform seizure definition

- “one size fits all” approach

- drug potency ≠ clinical efficacy

- sex bias

- mechanisms of action bias

- gaps and shortcomings in study design

…

Loescher W., Epilepsy Research, Volume 126, October 2016, Pages 157-184

Our goals 09

We are looking for a partner for further pre-clinical and clinicaldevelopment.

We prefer licensing-out or co-development partnership.

THANK YOU FOR YOUR ATTENTION!