International Parkinson and Movement Disorder Society 2025 – InBrainPharma Presentation

October 8th, 2025 CIRCADIAN INTRACEREBROVENTRICULAR A-DOPAMINE INFUSION FOR PARKINSONIANS REFRACTORY TO L-DOPA InBrainPharma I 2025.10.08 PARKINSON’S DISEASE Olanow CW, et al. Lancet Neurol. 2006;5(8):677-687. / 2. Nyholm D. Parkinsonism Relat Disord. 2007;13 Suppl:S13-S17. Striatal Dopamine deficit L-dopa: Pivotal treatment with major PK/PD problems BBB L-DOPA Digestive barrier AA AA L-DOPA Digestive barrier Blood brain barrier → Not crossing digestive & blood brain barrier → Dopamine oxidation → No dopamine based treatment available up to now → Reduction of dopamine availability & misdistribution → Pulsatility of dopamine receptor stimulation → L-dopa complications in 50% of patients after 5 years Dopamine : impossible treatment ? Current Device -Aided Therapies BBB Dopamine Digestive barrier Dopamine Digestive barrier Blood brain barrier 1/ Antonini A, et al. Curr Med Res Opin 2018; 34:2063–2073; 2. Martínez-Castrillo JC, et al. Brain Sci 2021; 11:1–13.→ Increasing L-dopa refractoriness (complications) → Need of dopamine (not L-dopa) InBrainPharma I 2025.10.08 Very strict anaerobia (<0.1% of O2) No excipient High concentration Intracerebroventricular Continuous & circadian Patient personalized The innovativeness of this neuropharmacological modulation relies on a double invention Anaerobic A-dopamine Administered by precision dosing pump (20 mL) Through intracerebroventricular route close to the striatum 1. A-dopamine suitable for CNS 2. NEW ROUTE OF ADMINISTRATION A-dopamine An innovative antiparkinsonian agent for PD patients refractory to L-dopa based therapies 2. New route of administration InBrainPharma I 2025.10.08 DIVE-1: A-dopamine Surgery & implantable system C P Based upon 30 years of experience with deep brain stimulation; but less invasive, shorter and less risky. Patients recover very quickly without pain and are up and about on the evening of the operation. InBrainPharma I 2025.10.08 DIVE-1 Study design Patient baseline characteristics NCT04332276: Dopaminergic restoration by intraventricular Administration InBrainPharma I 2025.10.08 • No serious adverse effects associated with A-dopamine • Dose requirement between 150 and 250 mg / 24h (lower nocturnal doses) • Transient and mild side effects if dose increased too rapidly (nausea, vomiting, drowsiness) • Massive reduction in time spent per day with inadequate control of motor symptoms, improving daily life and patient autonomy. • Significant improvement on actimetry (PTO & dyskinesia) • Additional 4.4h of perfect control • Additional 6.6h of autonomy • Drastic reduction in the daily dose of oral antiparkinsonian drugs by around 60%. • Excellent safety profile • Positive trend on neurofilament biomarker DIVE-1 Main results (Nature Medicine, jan 7th 2025) → Brain infusion POC validation / Promise (increased autonomy, improved quality of life, reduced impact of the disease burden on patients, caregivers and the healthcare systems (expected savings) 30,5% 9,9% 20,5% 22,5% 6,6% 10% Perfect control Slight dyskinesia Slight off Mild off Severe off Mild severe dyskinesia 50% 7,0% 30,3% 9,1% 2,4% 1,3% Perfect control Slight dyskinesia Slight off Mild off Severe off Mild severe dyskinesia A-Dopamine + residual optimized background regimen Oral optimized background regimen alone PHASE IPHASE IILONG TERM • Cumulative experience up to 4.5 years • No tachyphylaxis: sustained efficacy over time on motor symptom control • Very safe: no severe adverse event related with A-dopamine • No abnormalities on Brain MRI InBrainPharma I 2025.10.08 A-Dopamine World's first titration of a neurotransmitter in the brain for therapeutic use Massive shortening of spent time per day with inadequate control of motor symptomatology improving patient’s daily life & autonomy → 4,4h in On without dyskinesia (perfect); → 4,2h in On without troublesome dyskinesia → 6.6h in On without troublesome dyskinesia or troublesome bradykinesia (autonomy) → Levodopa Equivalent Daily Dose reduction of 60% 4,4H > 6.6H Excellent safety profile Only mild and transient adverse events such as nausea, vomiting, fatigue occurring during the titration phase, should this titration be too rapid. Cumulative clinical experience over 4,5 years showing a sustainable therapy efficacy over time without any safety & toxicity signals. → Feasibility of the approach → Validation of the brain infusion concept for correcting symptoms from brain disease → No external pump → No daily refills: only one refill at home every 1 to 2 weeks → No digestive or skin complications → More than 4.5 years of experience with thousands of refills without any problems) COMFORT EFFICACY ** TOLERABILITY INTERNAL PUMP Continuous circadian administration, personalized to each patient's needs Dopamine: a medical practice – and life – changing therapeutic agent for PD ANY QUESTIONS? Pr. Caroline MOREAU Neurologist Pr. David DEVOS Neurologist & pharmacologist Dr. Matthieu FISICHELLA CSO Dr. Véronique FOUTEL CEO www.inbrainpharma.com BACK UP InBrainPharma I 2025.10.08 DIVE-1: A-dopamine Positive trend on neurofilament biomarker 0 50 100 150 200 250 5 6 9 12 13 14 15 16 A-Dopamine Oral L-Dopa Patients (Screening N°) 50% remained relatively stable 50% of patients improved the NFL level under A-dopamine as compared with L-dopa NFL (pg/mL)

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