Slide 1: GT-02287 Shows Disease-Modifying Effects in Preclinical Models of GBA1 and Idiopathic Parkinson's Disease
GT-02287, A CLINICAL STAGE ALLOSTERIC GLUCOCEREBROSIDASE MODULATOR, SHOWS DISEASE-MODIFYING EFFECTS IN PRECLINICAL MODELS OF BOTH GBA1 AND IDIOPATHIC PARKINSON’S DISEASE J Taylor1, Beatriz Guzman2, Natalia Pérez-Carmona3, Ana Maria García-Collazo3 1 Gain Therapeutics Inc, Bethesda, Maryland, USA; 2
Slide 2: Talk Outline
Talk Outline ▪ Background to GT-02287 ▪ Disease prevention Paradigm in CBE Mouse Model ▪ Therapeutic Paradigm in low dose CBE/PFF (GBA1-PD) and PFF alone (iPD) models ▪ GT-02287 washout studies demonstrate disease modifying potential in both GBA1 and iPD ▪ Summary © 2025 - GA I N T HE RAP EUT I C S
Slide 3: GT-02287 addresses the primary pathophysiological effects in disease cascade resulting from GCase dysfunction
GT-02287 addresses the primary pathophysiological effects in disease cascade resulting from GCase dysfunction ❑ Orally available, brain-penetrant, small molecule allosteric GCase regulator Motor & ER Stress Cog. ❑ Chaperones GCase to the lysosomes and Deficits mitochondria, and reduces proteolytic d
Slide 4: GT-02287 Prevents GBA1 Disease Cascade in Mouse CBE Model of GBA1 PD
GT-02287 Prevents GBA1 Disease Cascade in Mouse CBE Model of GBA1 PD © 2025 - GA I N T HE RAP EUT I C S
Slide 5: GT-02287 Rescues Motor Deficits in Therapeutic Paradigm
GT-02287 Rescues Motor Deficits in Therapeutic Paradigm GBA1- PD Model (CBE+PFFs) Idiopathic PD Model (PFFs only) α-Syn PFFs α-Syn PFFs Mouse Wire Hang Low Level CBE No CBE GT-02287 GT-02287 300 300 Control PFFs Latency to fall Latency to fall 200 200 + GT-02287 60mg/kg + GT-02287 90mg/Kg 100 100 0
Slide 6: Fast-onset rescue effect of GT-02287 driven by enhanced GCase activity
Fast-onset rescue effect of GT-02287 driven by enhanced GCase activity, reduced ER stress and increased lysosomal and mitochondrial integrity 2h post-treatment GCase Activity IRE-1 LAMP-1 Miro1 ER stress Lysosomal Integrity Lamp-1 Mitochondrial Integrity GCase activity Miro-1 ✱✱✱ ✱ ns ✱✱✱✱ ✱✱✱✱ Fluo
Slide 7: Longer-term rescue in therapeutic paradigm driven by same GCase pathway
Longer-term rescue in therapeutic paradigm driven by same GCase pathway as fast-onset effect of GT-02287 d29 GCase IRE-1 LAMP-1 Miro1 Activity ER stress Lysosomal Integrity Mitochondrial Integrity LAMP-1 (fluorescence intensity) $$ IRE-1 (fluorescence intensity) Miro1 (fluorescence intensity 60000
Slide 8: GT-02287 Improves Nest Building Performance in Therapeutic Model of GBA1-PD
GT-02287 Improves Nest Building Performance in Therapeutic Model of GBA1-PD Improvements in Nest-building Performance Improvements in Relevant Biomarkers Nest building is a non- invasive test to study activities of daily living Aggregated α-syn (SN) Plasma NfL and cognitive performance in rodent mod
Slide 9: Translational plasma-based biomarkers of GT-02287 rescue effect
Translational plasma-based biomarkers of GT-02287 rescue effect Plasma GlcCer Plasma GlcSph Plasma NfL Control plasma NFL CBE/PFFs ✱✱ + GT-02287 30mg/kg ✱ + GT-02287 60mg/kg p=0.09 + GT-02287 90mg/kg ns ✱✱ 1000 Vehicle Controls 800 CBE + PFF CBE+PFF+GT-02287 600 pg/ml post-8days 400 CBE+PFF+GT-02287
Slide 10: GT-02287 displays a disease-modifying effect in animal models of GBA1 and iPD
GT-02287 displays a disease-modifying effect in animal models of GBA1 and iPD GBA1- PD Model (CBE+PFFs) Idiopathic PD Model (PFFs only) α-Syn PFFs α-Syn PFFs Mouse Wire Hang Washout Low Level CBE No CBE No drug GT-02287 Washout No drug GT-02287 Washout 300 300 Latency to fall Latency to fall 200 200
Slide 11: Nesting score unaffected by drug washout
Nesting score unaffected by drug washout: evidence of disease modifying effect on complex behaviors CBE+PFFs (GBA1-PD) Mouse Nesting Building PFFs only (iPD) WASHOUT WASHOUT Washout 5 Control 5 Control CBE+PFFs PFFs Nesting Score Nesting Score GT-02287 90mg/Kg GT-02287 90mg/Kg 4 4 GT-02287 90mg/Kg +
Slide 12: Brain biomarker changes maintained following GT-02287 washout
Brain biomarker changes maintained following GT-02287 washout ➢ Taken together, data support GT-02287’s disease modifying effect d29 GCase activity IRE-1 LAMP-1 MIRO-1 Aggregated α-syn (ER stress) (lysosomal integrity) (mitochondrial health) $$ LAMP-1 (fluorescence intensity) IRE-1 (fluorescence i
Slide 13: Brain biomarker changes maintained following GT-02287 washout 2/2
Brain biomarker changes maintained following GT-02287 washout 2/2 ➢ Data support GT-02287’s disease modifying effect d29 Tyrosine Hydroxylase (SN) Striatal dopamine Phospho Tau (SN) Iba-1 (SN) CBE+PFFS PFFS CBE+PFFS PFFS CBE+PFFS PFFS CBE+PFFS PFFS $$ $$ **** 100 Striatal Dopamine (pg/mg) $$ I
Slide 14: Summary
Summary ❑ GT-02287 is a small molecule, orally available, brain penetrant allosteric glucocerebrosidase (GCase) modulator discovered using Gain’s Magellan computational drug discovery platform. ❑ In in vitro and in vivo rodent models, GT-02287 reduces ER stress, prevents proteosomal GCase degradatio
Slide 15: Acknowledgements
Acknowledgements Gain Team Beatriz Guzman Natalia Perez Ana Maria Garcia Sara Cano Ana Ruano Manolo Bellotto Elena Cubero Xavier Barril Terenzio Ignoni Pierre Yves Martin Manuela Bosetti Raffaella Pozzi Ana Barassi Jonas Hannestad 15