A randomized, double-blind, placebo-controlled, Phase 2b trial with an open-label extension to determine the safety and efficacy of GH001 in patients with treatment-resistant depression.

Major depressive disorder (MDD) is a serious mental health condition
characterized by recurring episodes where feelings of sadness, loss of
interest, and other heightened negative emotions occur most of the day, nearly
every day. A collaborative study funded by the United States National Institute
of Mental Health demonstrated that approximately 37% of patients with MDD did
not achieve a response despite 2 treatment steps, a patient population referred
to by regulatory authorities as patients with treatment-resistant depression
(TRD). Only 2 pharmacotherapies have been approved specifically for the
treatment of TRD: esketamine (Spravato®) and a combination of olanzapine and
fluoxetine (Symbyax®). The latter is not approved in EU.
mebufotenin is a psychoactive drug from the class of tryptamines with high
potency, fast onset (generally within 30 seconds), and short duration
(generally 5 to 30 minutes) of psychedelic effects, with no apparent
tachyphylaxis (based on assessment of psychedelic effect intensity) even after
short-term re-administration. It can be found in a wide variety of trees and
shrubs, as well as in the venom of Bufo alvarius toads. mebufotenin from
natural or synthetic sources has a long history of naturalistic use, where its
ability to induce altered states of consciousness, often described as *ego-
dissolution*, has been applied in spiritual or self-exploratory contexts. Due
to significant first pass metabolism via monoamine oxidase A, mebufotenin is
not orally active, which is why in naturalistic use it has been most commonly
consumed via inhalation after vaporization.
GH001 is an inhalation formulation of synthetic mebufotenin for use with a
vaporizer device to form an aerosol for inhalation. The sponsor has completed
two Phase 1 trials of GH001 in healthy volunteers (GH001-HV-101 [n = 22] and
GH001-HV-103 [n = 46]) and a Phase 1/2 trial in patients with TRD
(GH001-TRD-102 [n = 16]). In all trials, administration of GH001 via inhalation
was observed to be well-tolerated with no severe or serious adverse events.
Efficacy was assessed in GH001-TRD-102, where patients were given GH001 as a
single dose (12 mg [n=4] or 18 mg [n=4]) or in an IDR of up to 3 increasing
doses (6 mg, 12 mg, and 18 mg [n=8]) on a single day. Applying the IDR, 7/8
patients (87.5%) achieved remission, defined as a MADRS total score of <=10, at
the primary endpoint at D7 after GH001 dosing, with a mean MADRS reduction
versus baseline of -24.4 (P <0.0001), which was numerically superior to the
outcome achieved with single 12 mg and 18 mg doses of GH001 in the single dose
part of the GH001-TRD-102 trial, where 2/4 patients (50%) and 1/4 patients
(25%) achieved a remission (MADRS <=10) at D7 after dosing, with mean MADRS
reductions versus baseline of -21.0 and -12.5, respectively. These efficacy
data in patients with TRD support further study of the GH001 IDR in a
randomized, controlled setting with larger patient numbers.

To determine the efficacy of a single day individualized dosing regimen (IDR)
of GH001 compared with placebo in improving depressive symptoms as assessed by
MADRS in patients with treatment-resistant depression (TRD) at the end of the
7-day double-blind (DB) Part 1.

This is a Phase 2b clinical trial in patients with TRD consisting of a
screening period of up to 6 weeks prior to Baseline, a 7-day randomized,
placebo-controlled, DB Part 1 and a 6-month, single-arm, OLE Part 2. All
patients directly transition from Part 1 into Part 2 on Day (D) 7 of the DB
Part 1.

GH001 is an inhalation formulation of synthetic
5-methoxy-N,N-dimethyltryptamine (mebufotenin, 5-MeO-DMT) for use with a
vaporizer device (the Volcano Medic 2 Vaporization System) to form an aerosol
for inhalation.
GH001 will be supplied as individually packaged mebufotenin powder in vials and
individually packaged absolute (>=99.5% [volume]) alcohol solvent for
reconstitution at the clinical site. It is administered as an Individualized
dosing regime consisting of up to 3 increasing doses of GH001 (6 mg, 12 mg, and
18 mg) on a single day, where the second and third doses are only administered
if the patient did not achieve intense PsE. After reconstitution, the drug
product solution is transferred using a pipette to a stainless-steel filling
pad within an aluminium dosing capsule. The dosing capsule is then loaded into
the filling chamber of a first Volcano Medic 2 vaporizer to evaporate the
alcohol at a low temperature and is then transferred to a second Volcano Medic
2 vaporizer to vaporize the mebufotenin at a high temperature. The vaporized
mebufotenin is collected in a balloon that is subsequently detached from the
vaporizer. After a mouthpiece is attached to the balloon, the mebufotenin
aerosol is inhaled by the patient.
Placebo will be prepared using the same preparation process using only alcohol
solvent, leading to an empty dosing capsule after alcohol evaporation in the
first vaporizer, so that after transfer into the second vaporizer, placebo will
consist of air only in the balloon for administration.
During the DB Part 1, a blinding bag is placed over the balloon to conceal the
contents of the balloon.

Section 4.4 of the protocol :

The specific properties of mebufotenin (fast onset and short duration of PsE,
high propensity to induce a PE, and no tolerance development even after
short-term re-administration) may be therapeutically beneficial in TRD.
Based on findings from the previous Phase 1/2 clinical trial in TRD, GH001 IDR
dosing may induce rapid remission in patients with TRD; this will be assessed
as the primary endpoint in the present trial.
Based on the results from previous GH001 clinical trials in healthy volunteers
(GH001-HV-101 and GH001-HV-103) and patients with TRD (GH001-TRD-102), the
administration of mebufotenin appears to have a low risk of adverse reactions
across the tested doses (refer to the current GH001 Investigator*s Brochure).
This is supported by reports from naturalistic use of mebufotenin, despite
large variability in dosing and wide inter-patient variability in the
occurrence of psychedelic experiences. Possible acute effects of treatment
during the psychoactive phase may include enhancement of tactile awareness,
distortions of the perception of time and space, intense emotions such as fear
or euphoria, visual and auditory hallucinations, loss of physical control and
coordination, confusion or dissociation, and short-term unresponsiveness. Signs
such as closing or blinking eyes, crying, laughing, movement (including
thrashing and rolling around), heavy breathing, nausea, vocalization (including
grunting, mumbling, talking, or shouting), and delusional interactions with the
environment may be observed. Complete or partial amnesia for the experience is
possible after higher doses. To mitigate the risk of accidental injury,
including possible vomiting and subsequent aspiration, administration of GH001
will only be performed in the clinic under the supervision of 2 study personnel
in a clinical setting equipped for emergency care.
With the exception of temporary, non-clinically relevant increases in heart
rate and blood pressure shortly after administration of GH001, no noteworthy
changes in vital signs were reported in the completed clinical trials with
GH001. In particular, no respiratory symptoms of clinical significance have
been reported in the clinical trials, and no signs of bronchoconstriction were
seen from the peak expiratory flow rate assessments systematically performed in
GH001-HV-103. To address potential risks, patients with clinically significant
heart and/or lung disease, and hypertension are excluded from this trial and
vital signs will be measured before and after dosing and as required to monitor
for potential hypertension, tachycardia, and impaired respiration. To avoid
interference with the psychoactive experience, intense stimuli such as blood
pressure measurements with an upper arm cuff should be avoided during the acute
psychoactive phase and, in this phase, only heart and oxygen saturation should
be monitored with a simple finger cuff method.
A potential risk associated with administration of psychedelics is the
occurrence of acute challenging experiences, which can be characterized by
anxiety, panic, or paranoia. The risk of such experiences will be mitigated by
patient selection and preparation, and the availability of support during and
after the experience. In the GH001 program, only 4 instances of mild anxiety
were reported to date.
A further risk described with administration of psychedelics is a phenomenon of
reoccurring, mild, self-limiting drug-like experiences after the acute
substance effects have worn off. With GH001, re-experiencing of parts of the
acute psychoactive experience (as defined by Medical Dictionary for Regulatory
Activities [MedDRA] preferred terms flashback, hallucination, and sensory
disturbance) was seen infrequently in the GH001-HV-101 and GH001-TRD-102
studies, primarily in periods of rest; all cases were mild in intensity and
resolved spontaneously during the 7-day study period. No such cases were seen
in the GH001-HV-103 study during the 30-day study period. From the literature,
some users of this class of drugs have also reported that psychological
difficulties, including resurfacing of acute effects, can last for prolonged
periods after the experience, referred to as hallucinogen persistent perception
disorder. No such lasting psychological difficulties have been described in the
GH001 program or in other modern clinical studies with psychedelic agents. In
the present trial, telephone support (TPnD1) and follow-up visits (TPnD7) are
provided to identify issues early, and to provide support and therapy as
required.
No cases of frequent use of mebufotenin with development of tolerance and/or
withdrawal symptoms have been reported and the class of psychedelics in general
is considered to have very low dependence potential.
The reproductive toxicity of GH001 has not yet been investigated. Reproductive
and embryofetal developmental risks from IDR dosing in this trial will be
mitigated through use of effective means of birth control in male patients who
are not surgically sterilized and female patients of childbearing potential,
exclusion of pregnant women, pregnancy testing, and restriction of sperm
donation in male patients.
The withdrawal of antidepressant medication in patients with severe or
treatment-resistant mood disorders can be conducted safely and ethically. In
the present trial, withdrawal of such medication will only take place in a
patient that has been evaluated objectively as having very limited response or
no response to said therapy, and only after diligent clinical evaluation, for
which the patient*s general practitioner and/or psychiatrist will be involved
as needed. Antidepressant medication will not be discontinued for the sole
purpose of allowing patients to participate in the trial. Any patient who has
their antidepressant or other therapy withdrawn will be instructed to contact
the clinical site on the emergence of deterioration or negative consequences of
such withdrawal, and appropriate measures will be taken to ensure adequate
care.