A Phase 1/2 Trial of GH001, a Vaporized 5-Methoxy-N,N-Dimethyltryptamine Formulation, inPatients with Treatment-Resistant Depression (TRD) 1 Clinicaltrials.gov ID NCT04698603 GH001-TRD-102 ICPR 2022 Johannes Reckweg1, Ce

A Phase 1/2 Trial of GH001, a Vaporized 5-Methoxy-N,N-Dimethyltryptamine Formulation, inPatients with

Treatment-Resistant Depression (TRD) 1 Clinicaltrials.gov ID NCT04698603 GH001-TRD-102 ICPR 2022 Johannes Reckweg1, Cees van Leeuwen1, C cile Henquet2, Th r se van Amelsvoort2, Natasha Mason1, Riccardo Paci1, Theis Terwey3, Johannes

G Ramaekers1 Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands School Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands GH Research, Dublin, Ireland

Grants The study was funded by GH Research Advisory Board/Consultant Johannes Reckweg and Jan

Ramaekers work as consultants for GH Research 2 GH001-TRD-102 ICPR 2022 Disclosures

... Remission Rates in TRD < 15% Established Therapies are Slow-Acting ~33% no remission despite

4 treatment steps Adapted from Trivedi et al., Am J Psychiatry 2006 and Rush et al., Am J Psychiatry 2006 Average time to remission is ~6 weeks (STARD study, Remission Rate Over Time, Treatment Step 1 = Citalopram) (STARD study,

Remission Rates Treatment Steps 1 to 4) 3 2 or more prior therapies = TRD The Problem for Patients with Depression GH001-TRD-102 ICPR 2022

5-MeO-DMT (5-Methoxy-N,N-Dimethyltryptamine) Naturally-occurring psychoactive substance from

tryptamine class Highly potent agonist on 5-HT1A and 5-HT2A receptors Psychoactive effects with ultra-rapid onset (within seconds) and short duration (5 to 30 min) GH001 (5-MeO-DMT administration via a proprietary inhalation

approach) Intraday individualized dosing regimen (IDR) for maximization of ultra-rapid remissions Single visit initial treatment, with no structured psychotherapy 5-MeO-DMT and GH001 4 5-MeO-DMT GH001-TRD-102 ICPR 2022

5-MeO-DMT and Peak Experiences High propensity to induce peak experiences (PE) Feelings of ego

dissolution Experience of unity or oneness Profound and meaningful May be a surrogate marker for therapeutic effects Assessed through proprietary Peak Experience Scale Three visual analogue scales (0 - 100): Intensity Loss of

control Profoundness PE defined as total average of 75 5 GH001-TRD-102 ICPR 2022

Phase 1 Trial in Healthy Volunteers (GH001-HV-101, n=22) GH001 single doses of 2 mg, 6 mg, 12 mg, 18

mg and GH001 IDR (6, 12, 18 mg intra-subject dose escalation) No SAEs, all ADRs mild (except two moderate), all ADRs resolved spontaneously, inhalation well-tolerated GH001 single dose with psychoactive effect dose response but high

inter-subject variability GH001 IDR controls inter-subject variability achieving a PE1 in all healthy volunteers 6 Clinicaltrials.gov ID NCT04640831; Reckweg et al, 2021 IDR, Individualized Dosing Regimen; SAE, Serious Adverse Event;

ADR, Adverse Drug Reaction (an adverse event with a relationship code to the investigational product of definite, probable, or possible, or where code is missing). PE Scale PE Threshold GH001-TRD-102 ICPR 2022

GH001 Single Dose: GH001 Individualized Dosing Regimen (IDR): More Chances for Remission MADRS

score MADRS score MADRS score MADRS score Dose 1 Dose 1 Dose 2 Dose 3 Dose 2 Dose 1 No remission Remission Remission Remission Remission Hypothetical Patient 1 Hypothetical Patient 2 Hypothetical Patient 3 Hypothetical

Patient 1 Hypothetical Patient 2 No remission No remission No remission Dose 1 GH001 - Individualized Dosing Regimen (IDR) Designed to Achieve Ultra-Rapid and Durable Remissions 7 MADRS score Dose 1 GH001-TRD-102 ICPR

2022 MADRS, Montgomery- sberg Depression Rating Scale

Key Assessments MADRS 2-hrs PE Scale Safety MADRS 1-day Cognitive function Safety MADRS

7-day Cognitive function Safety GH001 Administration Day 1 Day 7 Phase 1/2 Trial in TRD (GH001-TRD-102, n=16) 8 PE, Peak Experience; MADRS, Montgomery- sberg Depression Rating Scale;IDR, Individualized Dosing Regimen 1Defined as

inadequate response to at least two adequate courses of pharmacological therapy or one adequate course of pharmacological therapy and at least one adequate course of evidence-based psychotherapy Phase 1 (Single Dose) Phase 2 (IDR) GH001

12 mg (n=4) GH001 18 mg (n=4) TRD1 (n=8) Primary Endpoint: Safety until day 7 TRD1 (n=8) Primary Endpoint: MADRS remission day 7 (MADRS 10) GH001 IDR6, 12, 18 mg to achieve PE (up to 3 doses, 3h interval) GH001-TRD-102 ICPR 2022

Phase 1 (Single Dose) - Efficacy (MADRS) 9 2 of 4 patients in the 12 mg group and 1 of 4 patients in

the 18 mg group had a MADRS remission at day 7 2 of 4 patients in the 12 mg group had a PE and both had a MADRS remission at day 7, 0 of 4 patients in the 18 mg group had a PE PE, Peak Experience; MADRS, Montgomery- sberg Depression Rating

Scale, MADRS remission, MADRS of 10; MADRS response, Reduction of 50% from baseline in MADRS; S, Screening; D0-B, Day 0 Baseline; D0-H2, Day 0 2 hours. MADRS Remission, Response, Improvement Rate at Day 7 MADRS from Screening to Day

7 GH001-TRD-102 ICPR 2022

Phase 2 (IDR) - Efficacy (MADRS) 10 PE, Peak Experience; MADRS, Montgomery- sberg Depression Rating

Scale; MADRS remission, MADRS of 10; MADRS response, Reduction of 50% from baseline in MADRS; S, Screening; D0-B, Day 0 Baseline; D0-H2, Day 0 2 hours. Primary endpoint met: 7 of 8 patients (87.5%) had a MADRS remission at day 7,

p<0.0001 7 of 8 patients had a PE and 6 of those had a MADRS remission at day 7 MADRS Remission, Response, Improvement Rate at Day 7 MADRS from Screening to Day 7 GH001-TRD-102 ICPR 2022

Phase 1 (Single Dose) and Phase 2 (IDR) - Safety 11 Adverse Drug Reaction, or ADR, an adverse event

with a relationship code to the investigational product of definite, probable, or possible, or where code is missingIDR, Individualized Dosing Regimen; C-SSRS, Columbia-Suicide Severity Rating Scale ADRs Phase 1 (Single Dose) Phase 2

(IDR) ADRs 12 mg (N=4) 18 mg (N=4) IDR1 (N=8) MedDRA Preferred Term n n n Abdominal discomfort 1 Anxiety 2 Depressive symptom 1* Dizziness 1 Feeling

abnormal 1 1 Flashback 1 1 2 Headache 2 1 3 Muscle discomfort 1 Muscle spasms 1 Nausea 2* Paresthesia 1 Sensory disturbance 3 16-12 mg (N=6); 6-12-18 mg (N=2) Study Safety Group review No SAEs All

ADRs mild, except three moderate* All ADRs resolved spontaneously Inhalation well-tolerated No noteworthy changes in vital parameters, except for temporary, non-clinically relevant increase in heart rate and blood pressure shortly after

administration of GH001 No clinically significant changes in safety laboratory analyses, psychiatric safety assessments or measures of cognitive function No safety signal relating to suicidal ideation or suicidal behavior, based on C-SSRS

and MADRS subscore item "suicidal thoughts" GH001-TRD-102 ICPR 2022

12 GH001 allows rapid and individualized dosing optimization A single dosing day with GH001 IDR

achieved a rapid (within 24 hours) and sustained full remission (7 days) of symptoms of depression in 7/8 patients (87.5%) with TRD GH001 was well tolerated, and no serious adverse events were reported Contacts GH Research: info@ghres.com

/ clinicaltrials@ghres.com Maastricht University: johannes.reckweg@maastrichtuniversity.nl / j.ramaekers@maastrichtuniversity.nl Twitter: @PIMaastricht Conclusions GH001-TRD-102 ICPR 2022