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 ASCP 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 ASCP 2022 Johannes Reckweg1, Cees van Leeuwen1, C cile Henquet2, Therese 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

... 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) 2 2 or more prior therapies = TRD GH001-TRD-102 ASCP 2022 The Problem for Patients with Depression

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) High propensity to induce peak experiences (PE), which may be a surrogate marker for therapeutic effects 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 3 5-MeO-DMT GH001-TRD-102 ASCP 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 4 Clinicaltrials.gov ID NCT04640831; Reckweg et al, 2021 1The occurrence of a Peak Experience (PE) is assessed using the proprietary PE Scale, which averages

answers scored by the patient from 0 to 100 on a visual analog scale for three parameters of the experience: intensity, feelings of loss of control and profoundness. A PE is defined as an average score across these three parameters of at

least 75. PE ratings shown for IDR group represent values for the final administration of GH001. 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). GH001-TRD-102 ASCP 2022 PE Scale PE Threshold

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) 5 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 ASCP 2022

Phase 1 (Single Dose) - Efficacy (MADRS) 6 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 GH001-TRD-102 ASCP 2022 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

Phase 2 (IDR) - Efficacy (MADRS) 7 GH001-TRD-102 ASCP 2022 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

Phase 1 (Single Dose) and Phase 2 (IDR) - Safety 8 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) GH001-TRD-102 ASCP 2022 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"

Conclusions 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:

j.ramaekers@maastrichtuniversity.nl Twitter: @PIMaastricht