Slide 1: R&D Webinar: SAN2668 (GABAA PAM) for the Treatment of Developmental Epileptic Encephalopathies
R&D Webinar: SAN2668 (GABAA PAM) for the Treatment of Developmental Epileptic Encephalopathies June 2026
Slide 2: Agenda and Speakers
Agenda and Speakers Thomas 1 Introduction Feldthus Developmental Epileptic Encephalopathies (DEE) landscape Nicola 2 and unmet need Specchio Thomas Feldthus Nicola Specchio CEO, Saniona Bambino Gesù Children's Hospital, Rome Karin S. 3 SAN2668 mechanism of action and preclinical data Nielsen Pierand
Slide 3: Developmental Epileptic Encephalopathies (DEE) landscape and unmet need
Developmental Epileptic Encephalopathies (DEE) landscape and unmet need 3 Nicola Specchio – Bambino Gesù Children's Hospital, Rome
Slide 4: DEE in 1 slide
DEE in 1 slide A diagnosis of a DEE includes the following criteria: 1. Frequent seizures and/or EEG showing frequent epileptiform discharges 2. History of developmental slowing or regression 3. The underlying aetiology also contributes to developmental impairment DEE, Developmental Epileptic Enceph
Slide 5: Non-seizure clinical manifestations of DEEs
Non-seizure clinical manifestations of DEEs Intellectual disability2 Mortality Developmental (SUDEP)3 delay2 It is generally accepted that the impact of epilepsies, and mainly Individual DEEs, reaches far with DEEs Motor skills Behavioural beyond seizures and and function1 problems#2 clinical featur
Slide 6: Degrees of disability
Degrees of disability Severe disability and dependence in 4 functional domains*1 Requires No functional Cannot feed Does not effectively stroller/wheelchair grasp independently, communicate with 100 (N=247)** (N=242) G-tube (N=241)† familiar persons (N=247)# 81 84 80 75 71 63 63 Patients (%) 60 53 5
Slide 7: Precision treatments
Precision treatments EE - DEEs Disease Modifying? normal development ASMs age
Slide 8: Primary Treatment Goal #1: Seizure Control
Primary Treatment Goal #1: Seizure Control • Type of seizure • Type of syndrome • EEG abnormalities • Etiology • Tolerability PK, pharmacokinetics; PD, pharmacodynamics
Slide 9: Potential for impact?
Potential for impact? Trivisano – Specchio, Current Opinion 2020
Slide 10: What Are We Really Treating: Seizures, Encephalopathy, or Both?
What Are We Really Treating: Seizures, Encephalopathy, or Both? Absence of a consensus definition of “disease Morbidities modification” Seizure often control ≠ full determine disease quality of life Addresses the underlying control more than neurobiological process seizures leading epileptogenesis S
Slide 11: Polytherapy in DEE
Polytherapy in DEE • Often used early and aggressively Usually, we accept because of high seizure burden polytherapy early Polytherapy because the risk of • Exponential side effect which uncontrolled seizures in DEE may worsen developmental outweighs the burden of outcomes multiple drugs If differen
Slide 12: Developmental and Epileptic Encephalopathy and Spike-and-Waves Activation during sleep
Developmental and Epileptic Encephalopathy and Spike-and-Waves Activation during sleep (aka ESES): pathophysiological insights and treatment options (ESES) Specchio et al., Epilepsia 2026 EE; Epileptic Encephalopathy; SWAS, Spike Wave Activation in Sleep; ADHD, Attention-Deficit/Hyperactivity Disord
Slide 13: Developmental and Epileptic Encephalopathy and Spike-and-Waves Activation during sleep
Developmental and Epileptic Encephalopathy and Spike-and-Waves Activation during sleep (aka ESES): pathophysiological insights and treatment options Specchio et al., Epilepsia 2026
Slide 14: Primary Treatment Goal #2: Morbidity Management
4 Primary Treatment Goal #2: Morbidity Management • Preliminary data on parents’ top 3 priorities for non-seizure improvements from treatments GI, gastrointestinal Hecker J, et al. Ther Adv Rare Dis. 2024;18:26330040241249762
Slide 15: Unmet Needs
Biomarkers of encephalopathy progression (EEG complexity, CSF markers, neurofilaments) Lifecycle of care: Predictors of treatment transition from Unmet responders (genotype– pediatric to adult phenotype–therapy DEE medicine Needs match) Inclusion of non- Equity and access: seizure end points in glob
Slide 16: Take-Home Messages
Take-Home Messages • In DEE, seizure control is necessary but not sufficient • Comorbidities drive the lifelong disability burden • Precision medicine is shifting DEE care from seizure suppression to disease modification • Success must be measured in developmental, behavioral, and QoL outcomes • Not
Slide 17: SAN2668 Mechanism of Action, Preclinical Data
SAN2668 Mechanism of Action, Preclinical Data 17 Karin Sandager Nielsen – CSO, Saniona
Slide 18: The GABAA Receptor Is The Molecular Target of SAN2668
The GABAA Receptor Is The Molecular Target of SAN2668 CI- Benzodiazepine site GABA - SAN2668 binds here ➢ The GABAA receptor is a ligand-gated ion-channel activated by GABA ➢ The channel consists of 5 subunits, normally composed of: ▪ two α subunits (from subtypes α1, α2, α3 and α5) ▪ two
Slide 19: Efficacy and Adverse Events Map to Distinct GABAA Subtypes
Leveraging >30 Years of Scientific Discoveries: Efficacy and Adverse Events Map to Distinct GABAA Subtypes Symptoms can be differentially addressed by subtype selective GABAA PAMs Effect/Subtype GABA α1 GABA α2 GABA α3 GABA α5 ➢ Benzodiazepines are non-selective – Seizure control ++ ++ + + potentiat
Slide 20: SAN2668 Engineered to Selectively Potentiate GABAA α3/α2
SAN2668 is Engineered to Selectively Potentiate GABAA α3/α2, while Maintaining Balanced GABAA α1 Modulation to Preserve Benzodiazepine Class Efficacy and Minimize Adverse Effects SAN2668 Functional Activity Strong α3 modulation α3 Seizures (SWD) ↓ targeting thalamocortical circuits implicated in Spi
Slide 21: Improved Seizure Control at Higher Receptor Occupancy vs Clobazam
Preclinical Evidence of Improved Seizure Control with SAN2668 at Higher Receptor Occupancy Relative to Human-Equivalent Clobazam (BZD) Exposure ➢ SAN2668, at a dose achieving 70 % receptor occupancy, demonstrates superior seizure control compared with Clobazam at clinically equivalent plasma exposu
Slide 22: Spike-and-Wave Discharges Drive Absence Seizures and Severe Paediatric Epilepsies
Spike-and-Wave Discharges are the Abnormal EEG Rhythms which Drive Absence Seizures and Define the EEG Signature of Severe Paediatric Epilepsies such as ESES ➢ SPIKE AND WAVE DISCHARGES (SWDs) arise from pathological oscillations in the cortico-thalamic (Thalamic Reticular Nucleus - TRN) system ➢ Co
Slide 23: SAN2668 Fully Suppresses Spike-Wave-Discharges in GAERS Rats
SAN2668 Fully Suppresses Pathological Spike-Wave-Discharges in GAERS Rats Suggesting Potent Efficacy in DEEs with Generalized SWDs ➢ The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model recapitulates cortico-thalamic network-driven Spike-Wave-Discharges underlying generalized absence seiz
Slide 24: SAN2668 Suppresses Epileptiform Activity in Amygdala Kindling Model
SAN2668 Potently Suppresses Epileptiform Activity and Reduces Seizure Severity in Amygdala Kindling Model Indicating Potent Efficacy in Focal and Focal-to-Generalized Seizures ➢ The amygdala kindling models progressive epileptogenesis and seizure propagation, offering strong predictive validity for
Slide 25: SAN2668 Efficacy in Zebrafish Models of Monogenetic Epilepsy
SAN2668 Efficacy in Zebrafish Models of Monogenetic epilepsy, Extends Beyond Seizure Protection Supporting Potential Benefit in Behavioural Symptoms in DEEs ➢ Zebrafish constitutes a validated rapid, in vivo phenotypic screening of genetically defined disease models to identify drug candidates1 ➢ SA
Slide 26: SAN2668 Avoids Motor Impairment and Sedation
SAN2668 Avoids Adverse Effects such as Motor impairment and Sedation at Pharmacologically Relevant Dose Levels Adverse effects, Rotarod: Adverse effects, locomotor activity: SAN2668 does not cause motor impairments in rodents at SAN2668 does not cause sedation in rodents at pharmacologically relevan
Slide 27: Key take home message
Key take home message SAN2668 shows strong preclinical efficacy and tolerability, supporting a differentiated profile ▪ Superior seizure control at high receptor occupancy vs. clobazam ▪ Broad efficacy across chronic epilepsy models (SWDs and focal seizures) ▪ Benefits extend to behavioural comorbid
Slide 28: SAN2668 Clinical Development Plan, Market Opportunity
SAN2668 Clinical Development Plan, Market Opportunity 28 Pierandrea Muglia – CMO, Saniona
Slide 29: SAN2668 Designed to Separate Efficacy from Benzodiazepine Liabilities
SAN2668 is Designed to Separate Efficacy from the Liabilities that Limit Chronic Benzodiazepine Use Potential Potential Potential Tolerability Disease Control Clinical Impact Reduced sedation ↓ Seizure Chronic use (reduced tolerance) Preserved motor function ↓ EEG (Spike-Wave Discharges) ↓ Developme
Slide 30: SAN2668 Differentiating Potential versus SoC
SAN2668 Differentiating Potential versus SoC Current SoC 1,2 SAN2668 (Benzodiazepines & Available ASMs*) ✓ Effective ✓ Effective ✗ Sedating ✓ Reduced Sedation ✗ Cognitive Burden ✓ Improved Cognitive Profile ✗ Tolerance ✓ Reduced Tolerance * ASM: Antiseizure Medications 30 1. Strzelczyk and Schubert-
Slide 31: Phase 1 to Rapidly De-risk SAN2668 and Establish Proof of Concept
Phase 1 to Rapidly De-risk SAN2668 and Establish Proof of Concept in Patients SAN2668 Phase 1 expected late 2026 with Phase 1B/2 Ped DEE basket study early 2028 2026 2027 2028 2029 Phase 1 Phase 1B/2 SAN2668 qEEG + PET Pediatric DEE GABAA (1),2, 3 PoM Photosensitive Healthy volunteers Patients St
Slide 32: Biomarkers Provide Evidence of Target Engagement and Differentiated Pharmacology
Biomarkers will Provide Objective Evidence of Target Engagement and Differentiated Pharmacology Pharmacodynamic Biomarkers to Objectively Differentiate vs Benzodiazepines NeuroCart® - CHDR platform Benzodiazepine (e.g., lorazepam) qEEG Demonstrate reduced sedative effect • Power changes (i.e. reduce
Slide 33: Human PET Imaging During Phase 1 Will Support Dose Selection
SAN2668 Human PET Imaging During Phase 1 will Support Human Dose Selection PET imaging with [11C] flumazenil to establish exposure-receptor occupancy and inform phase 2 dose selection GABA A Receptor Occupancy Plasma Exposure 33
Slide 34: Photosensitivity Study May Provide Early Human Evidence of Antiseizure Activity
Photosensitivity Study may Provide Early Human Evidence of Antiseizure Activity EEG – Photic stimulation ➢ Validated experimental medicine paradigm* ➢ To be conducted during Phase 1 – in epilepsy patients* ➢ Establish doses expected to have antiseizure effect* ➢ Support Ph. 2 dose selection and paed
Slide 35: Proof of Concept: Phase 1b in DEE Supported by EEG Endpoint
Proof of Concept: Phase 1b in DEE Supported by Hard Endpoint/Biomarker (EEG) Part A: Open-Label to establish pediatric safety, tolerability PK, with initial estimates of efficacy on seizures & EEG Part B: Randomized, placebo-controlled to establish efficacy on seizures, EEG and non-seizure endpoints
Slide 36: DEEs Represent an Attractive CNS Opportunity
DEEs Represent an Attractive CNS Opportunity ➢ High unmet need ➢ Defined patient population ▪ > 240,000 DEE patients (EU4+UK+US) ▪ ~60,000 addressable patients* ➢ Favorable pricing environment ▪ Commercial potential demonstrated by Fintepla® and Epidiolex® 36 *Assuming: 85% diagnoses rate; 90% of pa
Slide 37: Three Recent Transactions in DEEs
Three Recent Transactions in DEEs 2021 2022 2024 Jazz → GW UCB → Zogenix Lundbeck → Longboard Acquisition Deal value US $ 7.2 billion US $ 1.9 billion US $ 2.6 billion Commercial asset Commercial asset Phase 3 ready asset Epidiolex (cannabidiol) Fintepla (fenfluramine) Bexicaserin (5-HT2C superagoni
Slide 38: SAN2668 Positioned as High-Value CNS Asset
SAN2668 Positioned as High-Value CNS Asset, Offering Potency and Differentiated Selectivity Enabling a Potentially Superior Safety Profile in DEE SAN2668 combines ➢ robust preclinical efficacy across seizure and disease-relevant models ➢ activity against spike-wave pathology ➢ differentiated tolerab
Slide 39: Q&A
Q&A 39