Slide 1: Parkinson's Disease KOL Event
Corporate Presentation GAIN THERAPEUTICS September 2024 Parkinson’s Disease KOL Event Understanding GCase Substrates in Parkinson’s Disease Perspectives on Biomarkers and Disease Modification January 6, 2026 NASDAQ: GANX
Slide 2: Forward-Looking Statements
Forward-Looking Statements Certain statements set forth in this presentation are forward-looking and reflect the Company’s plans, beliefs, expectations andcurrent views with respect to, among other things, future events and financial performance (collectively referred to herein as “forward-looking s
Slide 3: Gene Mack, President & CEO, Gain Therapeutics
Gene Mack, President & CEO, Gain Therapeutics
Slide 4: Today's Agenda
Today’s Agenda Gene Mack President & Chief Executive Officer 01 Opening comments, Overview of Parkinson’s Disease and Phase 1b study of GT-02287 02 Roy Alcalay, M.D., M.Sc. – GBA1/PD link: How important is glucosylsphingosine? Peter Lansbury, Ph.D. – The utility of glucosylsphingosine 03 Jonas Hanne
Slide 5: About Roy Alcalay, M.D., M.Sc.
About Roy Alcalay, M.D., M.Sc. Roy Alcalay, M.D., M.Sc. Is is chief of the Movement Disorders Division at Tel Aviv Sourasky Medical Center and the Norma and Alan Aufzien Professor of Neurology at the Gray Faculty of Medical & Health Sciences, Tel Aviv University, Israel. He moved from Columbia Unive
Slide 6: About Peter Lansbury, Ph.D.
About Peter Lansbury, Ph.D. Peter Lansbury, Ph.D. is a Professor of Neurology at Harvard University. For the past thirty years, he has studied the biochemical processes underlying Alzheimer's disease, Parkinson's disease, prion disease, and ALS, with the goal of translating this knowledge into novel
Slide 7: Parkinson's Disease
Parkinson’s Disease Parkinson’s Disease GBA1-Parkinson’s Disease Up to15% Genetically defined subpopulation of Parkinson’s disease is the second most common of PD Parkinson's disease neurodegenerative disease1 Parkinson’s GBA1mutations cause misfolding of an But current therapies only Disease (PD) i
Slide 8: Phase 1b study overview
Phase 1b study overview • GANX-001-V102 is a two-part, open-label, Phase 1b study in people with Parkinson’s disease • Objectives: Safety and tolerability, plasma PK, mechanistic biomarkers, and clinical progression • CSF samples at beginning and end of Part 1; plasma samples at multiple timepoints
Slide 9: Phase 1b MDS-UPDRS Scores
Phase 1b MDS-UPDRS Scores A total of 19 participants completed the first 90- day administration of GT-02287 4 participants were excluded from the MDS- UPDRS analysis Average improvement of 0.6 and 2 participants were SAA negative; another 2 were 1.6 in MDS-UPDRS Pt. II and Pt. III, respectively, aft
Slide 10: Roy Alcalay, M.D., M.Sc.
Roy Alcalay, M.D., M.Sc.
Slide 11: GBA-1/PD link: How important is glucosylsphingosine?
GBA-1/PD link: How important is glucosylsphingosine?
Slide 12: Disclosures
Funding: Dr. Alcalay research is funded by the Parkinson’s Foundation, the Disclosures Michael J. Fox Foundation and the Silverstein Foundation. Dr. Alcalay received consultation fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Genzyme/Sanofi, Janssen, SK Biopharmaceuticals, Takeda and Vanqua
Slide 13: Glucocerebrosidase (GCase) metabolic pathway
Glucocerebrosidase (GCase) metabolic pathway 13
Slide 14: Glucocerebrosidase (GCase) metabolic pathway
Glucocerebrosidase (GCase) metabolic pathway 14
Slide 15: Venglustat reduced GCase substrate levels in plasma and CSF in GBA1-PD patients
Venglustat reduced GCase substrate levels in plasma and CSF in GBA1-PD patients Plasma GL-1 level a CSF GL-1 level b 15
Slide 16: Change in MDS-UPDRS Part II+III by GBA1 Mutation Severity
Change in MDS-UPDRS Part II+III by GBA1 Mutation Severity: Venglustat-treated patients did not perform better than untreated patients (A) Non-severe (B) Severe Absolute difference at Week 52: 3.68 Absolute difference at Week 52:–0.69 95% CI: –0.65 to 8.01 95% CI: –7.47 to 6.08 MDS-UPDRS Part II+III
Slide 17: Glucocerebrosidase (GCase) metabolic pathway
Glucocerebrosidase (GCase) metabolic pathway 17
Slide 18: Glucosylsphingosine levels in GBA1 heterozygotes in plasma
Glucosylsphingosine levels in GBA1 heterozygotes in plasma 18
Slide 19: Peter Lansbury, Ph.D.
Peter Lansbury, Ph.D. © 2025 - GA IN T HE RAP EUT IC S 19
Slide 20: GluCer levels vary widely and are not sensitive to GBA mutations
GluCer levels vary widely between individuals and is NOT sensitive to GBA mutations. PD does not change GluCer levels. Reducing GluCer levels has no clinical effect in GBA-PD (venglustat). Therefore, GluCer is not a good PD marker for target engagement. Ser + palmitic acid SPT 3KDS elimination Lysos
Slide 21: Lower GCase activity in GBA-PD brain does not result in higher GluCer
Lower GCase activity in GBA-PD brain does not result in higher GluCer. Putamen GCase activity is lower in GBA-PD(green) as compared to iPD (Red) and healthy controls (blue), but GluCer levels are not significantly different. Cerebellum M Gegg et al Movement Disorders 2015
Slide 22: GBA-PD have comparable GluCer levels in PBMCs, brain, and CSF
GBA-PD have comparable GluCer levels in PBMCs, brain, and CSF as iPD patients or healthy controls (published data from Lysosomal Therapeutics, Inc.) LTI (phase 0) LTI (from Tel Aviv cohort) MAD & Phase 2a Basal CSF 2 2
Slide 23: When GCase activity is low, GluSph can be produced
When GCase activity is low, GluSph can be produced. GluSph is a very poor substrate for GCase, hence it accumulates. Lysosome/Degradation ER, Golgi/synthesis Sphingosine Sphingosine Ceramide GCase ACR SPHINGOLIPID RECYCLING Ceramide GluSph GCase GalCer GalCer ACR GluCer LacCer LacCer GluCer Sphingom
Slide 24: GluSph is elevated when GCase activity is low, in blood and brain
GluSph is elevated when GCase activity is low, in blood (left) and in brain (right). GluSph level correlates with synuclein level in brain. 2023 GD patients Very low GCase GBA carriers; elevated risk of PD
Slide 25: Jonas Hannestad, M.D. Chief Medical Officer, Gain Therapeutics
Jonas Hannestad, M.D. Chief Medical Officer, Gain Therapeutics © 2025 - GA IN T HE RAP EUT IC S 25
Slide 26: Phase 1b study overview
Phase 1b study overview • GANX-001-V102 is a two-part, open-label, Phase 1b study in people with Parkinson’s disease • Objectives: Safety and tolerability, plasma PK, mechanistic biomarkers, and clinical progression • CSF samples at beginning and end of Part 1; plasma samples at multiple timepoints
Slide 27: Mean Change in MDS-UPDRS Pt III From Baseline: GT-02287 vs Exenatide and Tavapadon
Mean Change in MDS-UPDRS Pt III From Baseline to 90 days of GT-02287 UPDRS Part III Scores: GT-02287 vs AC-7104.056 • Tavapadon is a dopamine D1/D5 receptor agonist which produces an acute effect on the MDS -UPDRS and is thus able to demonstrate a treatment effect in a 6-month trial. • Exenatide is
Slide 28: GluSph is a biomarker for biologically-relevant GCase activity
GluSph is a biomarker for biologically-relevant GCase activity In Gaucher disease, GluSph, not GluCer, is used as a marker for disease activity and treatment response Mitochondrial GluCer exceeding threshold is dysfunction converted into GluSph Acid ceramidase Lysosomal GluSph dysfunction GluCer Agg
Slide 29: No correlation between plasma and CSF GluSph
No correlation between plasma and CSF GluSph CSF GluSph is better biomarker for brain GluSph Plasma CSF correlation for GluSph 350 300 250 CSF GluSph (pg/mL) 200 150 100 50 0 0 0.2 0.4 0.6 0.8 1 1.2 Plasma GluSph (ng/mL) © 2 02 6 - GAI N THER AP EUTI CS 29
Slide 30: Decrease in CSF GluSph Suggests CNS Target Engagement
Decrease in CSF GluSph Suggests CNS Target Engagement CNS GluSph (2 pts excluded*) 400 400 GluSph (pg/ml) 300 300 GluSph (pg/ml) 200 200 100 * 100 Data are shown as mean + s.e.m. n=13. * Significant difference 0 compared to pretreatment Two- 0 way ANOVA P<0.05 Pretreatment 0 90 t en 90 time (days) a
Slide 31: Plasma GluSph Levels Higher in GBA1-PD subjects than in subjects with iPD
Plasma GluSph Levels Higher in GBA1-PD subjects than in subjects with iPD ➢ Elevated plasma GluSph levels brought down to iPD levels following GT-02287 treatment in2/3 GBA1-PD patients ➢ Subject 001-001 is a PRKN mutation carrier ➢ No CSF collected from subject 004-001 Plasma GluSph d18:1 levels 100
Slide 32: Correlation between MDS-UPDRS Score and CSF GluSph
Correlation between MDS-UPDRS Score and CSF GluSph Total UPDRS Part II+ III GluSph CSF Patient ID SAA Part II change Part III change change change (%) 001-001 positive -6 -4 0 -4 -99 001-004 positive -6 -2 -3 -5 -93 001-005 positive -2 -2 -2 -4 -56 002-001 positive -6 0 -4 -4 -76 002-004 positive -1
Slide 33: What's Next?
What’s Next? Continued analysis of participants enrolled in Phase 1b study extension. Designed to demonstrate 01 Analysis potential: • Safety and tolerability • Target Engagement and biomarker activity • Evidence of disease stabilization/slowing of disease progression Final results from Phase 1b stu
Slide 34: Q&A
Q&A © 2026 - GA IN T HE RAP EUT IC S 34
Slide 35: Thank You
Corporate Presentation Thank You September 2024
Slide 36: Appendix
Corporate Presentation Appendix September 2024