MIJ821 (onfasprodil) in healthy volunteers: First‐in‐human, randomized, placebo‐controlled study (single ascending dose and repeated intravenous dose)

Abstract

This single‐center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40‐min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study. Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. Median age in Part 1 and Part 2 was 45.0 and 43.5 years, respectively, with the majority being Caucasian (Part 1: 84%; Part 2: 92%). 19 subjects (44.2%) in Part 1 and 8 subjects (66.7%) in Part 2 experienced at least one adverse event (AE). Following single dose in Part 1 and Part 2, the AUC_inf values of MIJ821 increased in a dose‐proportional manner across the dose range 0.016–0.48 mg/kg and the C _max values in a slight overproportional manner across the dose range 0.048–0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUC_inf was 708 h ng/mL and the geometric mean C _max was 462 ng/mL. Inspection of 1‐h post‐dose resting electroencephalography activity across cohorts showed a relationship to administered dose, providing exploratory evidence of distal target engagement. In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative AEs were mild, transient, and dose‐dependent.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

N‐Methyl‐D‐aspartate receptor (NMDAR) antagonist, ketamine, and the selective NMDAR‐containing subunit type 2B (NR2B) negative allosteric modulator (NAM), traxoprodil (CP‐101,606), have been reported to have rapid clinical antidepressant effects. MIJ821 (onfasprodil) is being developed to evaluate its potential for rapid‐onset antidepressant efficacy in treatment‐resistant depression (TRD). This was a first‐in‐human, randomized, subject‐blinded, placebo‐controlled study of a new molecule MIJ821.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The study assessed the safety, tolerability, pharmacokinetics, and electroencephalography (EEG)‐measured pharmacodynamic effects of single ascending doses and two repeated doses of MIJ821 after intravenous infusion in healthy volunteers.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

The study provides the first clinical data in healthy volunteers with a novel, selective NR2B NAM, MIJ821. In this study MIJ821 showed a good safety and tolerability profile in healthy volunteers. Dissociative adverse events were mild, transient, and dose‐dependent.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The study results pave the way for the informed dose selection of a proof‐of‐concept study to support further clinical development of MIJ821 in patients with TRD.

INTRODUCTION

Treatment‐resistant depression (TRD) is a common problem in psychiatric practice. ¹ This report provides the first clinical data in healthy volunteers on a new agent with a novel N‐methyl‐D‐aspartate (NMDA) mechanism. Data from the clinical studies have shown that a single intravenous administration of a sub‐anesthetic dose of the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist, ketamine, alleviates depressive symptoms within hours, and the antidepressant effects are sustained for up to 2 weeks in patients with TRD. ² However, the adverse effects associated with the use of ketamine ³ raise a concern regarding its widespread and long‐term use. The efficacy of ketamine provides rationale for targeting NMDAR inhibition as a rapid‐onset antidepressant mechanism, but compounds with a reduced side effect profile are highly desirable. ²

Chronic stress and depression are associated with atrophy of neurons and loss of synapses in the cortex, hippocampus, and other brain regions. Synaptic density correlates inversely with depression severity in humans. ⁴ In rodent models of depression, NMDA receptor blockade (via ketamine and other blockers) at rest triggers rapid behavioral antidepressant responses ⁵ and rapidly reverses behavioral and synaptic deficits caused by chronic stress exposure in animal models of depression. ⁶ NMDAR‐containing subunit type 2B (NR2B) of NMDA receptors is hypothesized to play a critical role in mediating the efficacy of ketamine, ⁷ and the selective NR2B negative allosteric modulator (NAM), traxoprodil (CP‐101606), has previously been reported to have rapid clinical antidepressant effects in patients with treatment‐refractory major depressive disorder. ⁸

MIJ821 (onfasprodil) is a highly potent, selective, and reversible low‐molecular‐weight NR2B NAM. By inhibiting the activity of NR2B‐NMDA receptors, MIJ821 is expected to have similar effects on protein synthesis and synaptogenesis and exert a rapid antidepressant effect like traxoprodil and ketamine. MIJ821 was therefore developed to evaluate its potential for rapid‐onset antidepressant efficacy in TRD.

Electroencephalography (EEG) was used to explore the pharmacokinetic–pharmacodynamic (PK–PD) relationship of the novel drug agent. In previous studies, the effects of ketamine on brain electrophysiology consistently showed increased gamma power and decreased alpha power ⁹ , ¹⁰ , ¹¹ , ¹² as well as changes in other frequency bands. ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ The EEG profile of some NR2B NAMs has also been evaluated in non‐human primates, ¹⁸ providing rationale for using this approach with MIJ821.

The current study assessed the safety, tolerability, PK, and EEG‐measured PD effects of single ascending doses (SAD) and two repeated doses of MIJ821 after intravenous infusion in healthy volunteers.

METHODS

Study population

The study included male and female subjects (aged 18–55 years) in good health as determined by past medical history, physical and neurological examination, vital signs, electrocardiogram (ECG), and laboratory tests at screening or baseline. The key exclusion criteria were as follows: diagnosis of depression (DSM‐5 criteria for a major depressive episode); use of any prescription drugs or herbal supplements within 4 weeks prior to initial dosing, and/or over‐the‐counter medication or dietary supplements (vitamins included) within 2 weeks before initial dosing; and use of other investigational drugs at the time of enrollment, or within a period corresponding to less than five half‐lives of the drug before enrollment, or within 30 days, whichever was longer, or longer if required by local regulations. Patients with a history of clinically significant ECG abnormalities, or the presence of any of the defined ECG abnormalities at screening or baseline, were excluded. Women of child‐bearing potential (defined as all women physiologically capable of becoming pregnant) were also excluded from participation in the study.

Study design

This was a first‐in‐human, randomized, subject‐blinded, placebo‐controlled study in healthy volunteers (Figure 1; Table 1). This single‐center study included two parts: Part 1, an intravenous SAD study and Part 2, a repeated intravenous dose study. Subjects in both parts of the study participated in a screening period (Day −28 to Day −2), a baseline visit (Day −1) (to confirm eligibility), a treatment period, and a follow‐up period (includes the end of study evaluation). Healthy volunteers were only allowed to participate either in Part 1 or Part 2, but not both.

FIGURE 1.

Study design – Part 1 and 2. Note: An optional cohort was reserved for exploring additional doses. SD, single dose for the first five cohorts; D1 and D8, two doses for cohort 6.

TABLE 1.

Subject disposition – Part 1 and Part 2 (safety analysis set).

Part 1	MIJ821, 0.016 mg/kg	MIJ821, 0.048 mg/kg	MIJ821, 0.16 mg/kg	MIJ821, 0.24 mg/kg	MIJ821, 0.32 mg/kg	MIJ821, 0.48 mg/kg	Pooled placebo	Total
	N = 6	N = 6	N = 6	N = 3	N = 6	N = 5	N = 11	N = 43
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Screening phase
Randomized	6 (100)	6 (100)	6 (100)	3 (100)	6 (100)	5 (100)	11 (100)	43 (100)
Completed	6 (100)	6 (100)	6 (100)	3 (100)	6 (100)	5 (100)	11 (100)	43 (100)
Discontinued	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)
Treatment phase
Completed	6 (100)	6 (100)	6 (100)	3 (100)	6 (100)	5 (100)	11 (100)	43 (100)
Discontinued	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)

Part 2	MIJ821, 0.32 mg/kg	Placebo	Total
	N = 6	N = 6	N = 12
	n (%)	n (%)	n (%)
Study phase: Screening
Randomized	6 (100)	6 (100)	12 (100)
Completed	6 (100)	6 (100)	12 (100)
Discontinued	0 (0)	0 (0)	0 (0)
Study phase: Treatment
Completed	6 (100)	6 (100)	12 (100)
Discontinued	0 (0)	0 (0)	0 (0)

Part 1: Single ascending intravenous dose study

The dosing was performed on Day 1 (40‐min intravenous infusion), followed by an inpatient observation period (Day 1–8) and an outpatient period (Day 9–14) to ensure thorough safety observation and to allow complete collection of samples for PK analysis. The starting dose was 0.016 mg/kg. Eight subjects in each cohort were randomized (6:2) to receive either active MIJ821 infusion or matching placebo. In each cohort, two sentinel subjects (1:1, active:placebo) were dosed first; then the rest of the cohort (5:1, active:placebo) were dosed. Subjects were assigned to single dose of MIJ821 or single dose of placebo (0.9% NaCl aqueous solution).

Part 2: Repeated intravenous dose

Dosing (40‐min intravenous infusion) was performed on Day 1 and Day 8. An inpatient observation period (Day 1–15) was followed by an outpatient period (Day 16–21) to ensure thorough safety observation and to allow complete collection of samples for PK analysis. The highest dose that was well tolerated in Part 1 was administered to subjects included in Part 2 (0.32 mg/kg of MIJ821). Twelve subjects were randomized (1:1) to receive either MIJ821 or matching placebo. Subjects were assigned to single repeated intravenous dose of MIJ821 or single repeated dose of placebo (0.9% NaCl aqueous solution).

Conduct of the study

The study protocol and all amendments were reviewed by the Institutional Review Board (IRB; Schulman Associates IRB) for the center. The study was conducted according to International Council for Harmonisation (ICH) E6 Guideline for Good Clinical Practice and the Declaration of Helsinki. Informed consent was obtained from each subject before or at screening prior to any study‐specific procedure being performed. Subjects were allowed to voluntarily withdraw consent to participate in the study for any reason at any time. Withdrawal of consent only occurred when a subject did not want to participate in the study anymore and did not allow further collection of personal data.

Study objectives

The primary objective was to evaluate the safety and tolerability of MIJ821 after its single ascending intravenous infusion for 40 min and after two repeated intravenous infusions (1 week apart) for 40 min in healthy volunteers. Safety and tolerability assessments included adverse events (AEs), cardiovascular safety parameters (12‐lead electrocardiogram [ECG], 12‐lead Holter, and vital signs), central nervous system safety parameters (see Supplemental Material 1 in Data S1: Brief Psychiatry Rating Scale [BPRS; see Protocol amendment 2], Columbia Suicide Severity Rating Scale [C‐SSRS] and Clinician‐Administered Dissociative States Scale [CADSS]), and general safety parameters (blood and urine laboratory parameters). The secondary objectives assessed the PK of intravenous doses of MIJ821 in Part 1 and Part 2 of the study (see Supplemental Material 2 in Data S1). Exploratory objectives were to explore the PD effects of MIJ821 (PD biomarker; see Supplemental Material 3 in Data S1). The exploratory endpoints (PD) included electrophysiological measures acquired with the Brain Network Analytics (BNA™) tool (see Supplemental Material 4 in Data S1 for EEG data acquisition and preprocessing). The EEG power spectrum in delta/theta/alpha/beta/gamma frequency bands during resting with eyes closed was analyzed.

Statistical analysis

The study was planned with a sample size of approximately 55 healthy volunteers (up to ~63 including Cohort 7). Eight subjects were recruited into each dose level cohort in Part 1 of whom 6 received active treatment and 2 received placebo. For Part 2, 6 subjects received two doses of active treatment, and 6 received two doses of placebo. With 6 subjects in a treatment cohort, it was highly probable that AEs were observed if the underlying AE rate was medium to high. For instance, if the underlying AE rate was 1 in every 5 subjects, then there was a 74% chance that this AE would be detected in at least 1 subject on active treatment. Conversely, AEs with low event rates are unlikely to be detected in this part of the study. For instance, if the underlying AE rate was 1 in every 100 subjects, then the probability of observing this AE in at least 1 subject on active treatment was only 6%.

The safety analysis set included all subjects who received any study drug. All subjects within the safety analysis set were included in the safety data analysis. Descriptive analyses were used to analyze the safety data. The primary safety variables were assessed at baseline until Day 15 (Day 2 for sentinel, Day 8 for dose escalation review) in SAD and until Day 22 in repeated dose regimen.

The PK analysis set included all subjects with at least one available valid (i.e., not flagged for exclusion) PK concentration measurement, who received any study drug and with no protocol deviations that impact the PK data. For Part 1, the subjects on placebo were pooled together into one placebo group.

All subjects within the PK analysis set were included in the PK/PD analysis. The PK/PD analysis explored relationships between MIJ821 plasma concentration and 12‐lead Holter ECG parameters (HR, PR, QRS, QT, and QTc intervals). The plasma, urine, and cerebrospinal fluid (CSF) concentrations and PK parameters of MIJ821 were summarized using descriptive statistics. A linear mixed‐effects modeling approach was used in an exploratory manner to investigate the relationship between MIJ821 plasma concentrations and change from baseline in QTc. No formal imputation method was performed for missing data.

All data analyses were performed using SAS version 9.3 software.

RESULTS

Study participants

Overall, 43 subjects in Part 1 and 12 subjects in Part 2 were randomized in the study. The median age in Part 1 was 45.0 and 43.5 years in Part 2, with the majority being Caucasian (Part 1: 84%; Part 2: 92%) (Table 2). There were no serious AEs and deaths during the study. No AEs led to study treatment discontinuation. All the subjects (Part 1 and Part 2) completed the treatment.

TABLE 2.

Subject demographics by treatment group – Part 1 and Part 2 (safety analysis set).

Part 1	MIJ821, 0.016 mg/kg	MIJ821, 0.048 mg/kg	MIJ821, 0.16 mg/kg	MIJ821, 0.24 mg/kg	MIJ821, 0.32 mg/kg	MIJ821, 0.48 mg/kg	Pooled placebo	Total
	N = 6	N = 6	N = 6	N = 3	N = 6	N = 5	N = 11	N = 43
Age (years) a
Mean (SD)	45.5 (5.75)	39.3 (12.19)	38.8 (8.93)	39.7 (5.69)	45.8 (6.11)	45.0 (9.25)	39.2 (11.47)	41.7 (9.29)
Median	47.5	37.5	36.5	38.0	48.0	45.0	43.0	45.0
Range	37–51	24–56	29–51	35–46	36–52	30–54	22–54	22–56
Sex, n (%)
Female	3 (50)	2 (33)	3 (50)		3 (50)	3 (60)	3 (27)	17 (40)
Male	3 (50)	4 (67)	3 (50)	3 (100)	3 (50)	2 (40)	8 (73)	26 (60)
Race, n (%)
African American	2 (33)	1 (17)		1 (33)	1 (17)	1 (20)	1 (9)	7 (16)
Caucasian	4 (67)	5 (83)	6 (100)	2 (67)	5 (83)	4 (80)	10 (91)	36 (84)
Ethnicity, n (%)
Hispanic or Latino	6 (100)	6 (100)	6 (100)	3 (100)	6 (100)	5 (100)	11 (100)	43 (100)
BMI (kg/m2)
Mean (SD)	27.1 (2.60)	26.5 (2.81)	25.7 (1.39)	28.2 (1.67)	28.2 (1.58)	26.6 (1.35)	27.2 (1.83)	27.0 (2.00)
Median	27.2	26.1	25.3	28.7	29.1	26.5	27.0	26.7
Range	24–30	22–30	24–28	26–30	26–30	25–29	23–30	22–30

Part 2	MIJ821, 0.32 mg/kg	Placebo	Total
	N = 6	N = 6	N = 12
Age (years) a
Mean (SD)	37.0 (10.97)	44.3 (3.88)	40.7 (8.73)
Median	34.5	46.5	43.5
Range	23–51	38–47	23–51
Sex, n (%)
Female	2 (33)	2 (33)	4 (33)
Male	4 (67)	4 (67)	8 (67)
Race, n (%)
African American	1 (17)		1 (8)
Caucasian	5 (83)	6 (100)	11 (92)
Ethnicity, n (%)
Hispanic or Latino	6 (100)	6 (100)	12 (100)
BMI (kg/m2)
Mean (SD)	26.2 (2.31)	26.3 (3.44)	26.3 (2.79)
Median	26.4	26.8	26.4
Range	23–30	21–30	21–30

Abbreviations: BMI, body mass index; SD, standard deviation.

^a The date of birth for all subjects was set to be the 1 January (since the day/month is missing), with the corresponding year of birth.

In Part 1 (single ascending intravenous dose), a total of 43 subjects randomized to six cohorts received a single dose of MIJ821 or matching placebo. Of 43 subjects, 32 subjects were exposed to single dose of MIJ821 (0.016, 0.048, 0.16, 0.24, 0.32, and 0.48 mg/kg) and 11 subjects to placebo. In Part 2 (repeated single intravenous dose), a total of 12 subjects were randomized (1:1) into one cohort of MIJ821 (0.32 mg/kg) and one placebo cohort.

Safety

Part 1: Single ascending intravenous dose

In Part 1, a total of 19 subjects (44.2%) experienced at least one AE, of which 3 subjects received placebo (Table 3). The proportion of subjects experiencing AEs increased with increasing doses; from 16.7% (1 of 6 subjects at 0.016 mg/kg) to 33.3% (1 of 3 subjects at 0.24 mg/kg) subjects at the lower doses (0.016–0.24 mg/kg) to 100% (6 of 6 subjects at 0.32 mg/kg and 5 of 5 subjects at 0.48 mg/kg) at the higher doses (0.32 and 0.48 mg/kg). Most of the AEs were mild in severity. In 2 subjects (1 subject each in the 0.16 and 0.32 mg/kg dose cohorts), AEs of moderate severity were observed. AEs related to study treatment were reported in 12 subjects (27.9%) in the dose cohorts above 0.16 mg/kg, with most of them being reported in the 0.32 and 0.48 mg/kg cohorts. There were no subjects with AEs of severe grade, serious adverse effects (SAEs), and AEs leading to discontinuation of study treatment. The most commonly reported AEs in Part 1 were amnesia (7 subjects, 16.3%), medical device site dermatitis (6 subjects, 14.0%), depersonalization/derealization disorder (4 subjects, 9.3%), dizziness (4 subjects, 9.3%), dissociative amnesia (3 subjects, 7.0%), repetitive speech (3 subjects, 7.0%), and derealization (2 subjects, 4.7%). Amnesia, depersonalization/derealization disorder, dizziness, dissociative amnesia, repetitive speech, and derealization were reported commonly in either the 0.32 or 0.48 mg/kg cohorts, whereas there were none in the placebo cohort.

TABLE 3.

Overall incidence of adverse events (AEs) and incidence of AEs by preferred term – Part 1 and Part 2 (safety analysis set).

	MIJ821, 0.016 mg/kg	MIJ821, 0.048 mg/kg	MIJ821, 0.16 mg/kg	MIJ821, 0.24 mg/kg	MIJ821, 0.32 mg/kg	MIJ821, 0.48 mg/kg	Pooled placebo	Total
	N = 6	N = 6	N = 6	N = 3	N = 6	N = 5	N = 11	N = 43
	nE, nS (%)	nE, nS (%)	nE, nS (%)	nE, nS (%)	nE, nS (%)	nE, nS (%)	nE, nS (%)	nE, nS (%)
Part 1
AEs, subjects with AEs	1, 1 (16.7)	1, 1 (16.7)	5, 2 (33.3)	1, 1 (33.3)	15, 6 (100.0)	16, 5 (100.0)	3, 3 (27.3)	42, 19 (44.2)
Mild	1, 1 (16.7)	1, 1 (16.7)	3, 1 (16.7)	1, 1 (33.3)	14, 5 (83.3)	16, 5 (100.0)	3, 3 (27.3)	39, 17 (39.5)
Moderate	0	0	2, 1 (16.7)	0	1, 1 (16.7)	0	0	3, 2 (4.7)
Severe	0	0	0	0	0	0	0	0
Study drug‐related AEs	0	0	1, 1 (16.7)	1, 1 (33.3)	14, 6 (100.0)	12, 4 (80.0)	0	28, 12 (27.9)
SAEs	0	0	0	0	0	0	0	0
AEs leading to discontinuation of study treatment	0	0	0	0	0	0	0	0

Preferred term	MIJ821, 0.016 mg/kg	MIJ821, 0.048 mg/kg	MIJ821, 0.16 mg/kg	MIJ821, 0.24 mg/kg	MIJ821, 0.32 mg/kg	MIJ821, 0.48 mg/kg	Pooled placebo	Total
	N = 6	N = 6	N = 6	N = 3	N = 6	N = 5	N = 11	N = 43
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Amnesia	0	0	0	0	5 (83.3)	2 (40.0)	0	7 (16.3)
Medical device site dermatitis	0	1 (16.7)	0	0	0	3 (60.0)	2 (18.2)	6 (14.0)
Depersonalization/derealization disorder	0	0	0	0	2 (33.3)	2 (40.0)	0	4 (9.3)
Dizziness	0	0	1 (16.7)	0	2 (33.3)	1 (20.0)	0	4 (9.3)
Dissociative amnesia	0	0	0	1 (33.3)	0	2 (40.0)	0	3 (7.0)
Repetitive speech	0	0	0	0	0	3 (60.0)	0	3 (7.0)
Derealization	0	0	0	0	2 (33.3)	0	0	2 (4.7)
Confusional state	0	0	0	0	1 (16.7)	0	0	1 (2.3)
Diarrhea	0	0	0	0	0	1 (20.0)	0	1 (2.3)
Dissociative identity disorder	0	0	0	0	1 (16.7)	0	0	1 (2.3)
Dyspepsia	0	0	0	0	0	0	1 (9.1)	1 (2.3)
Fall	0	0	1 (16.7)	0	0	0	0	1 (2.3)
Gait disturbance	0	0	0	0	1 (16.7)	0	0	1 (2.3)
Headache	1 (16.7)	0	0	0	0	0	0	1 (2.3)
Hypotension	0	0	1 (16.7)	0	0	0	0	1 (2.3)
Ligament sprain	0	0	1 (16.7)	0	0	0	0	1 (2.3)
Medical device site irritation	0	0	1 (16.7)	0	0	0	0	1 (2.3)
Nausea	0	0	0	0	0	1 (20.0)	0	1 (2.3)
Presyncope	0	0	0	0	1 (16.7)	0	0	1 (2.3)
Tremor	0	0	0	0	0	1 (20.0)	0	1 (2.3)

Part 2
	MIJ821 0.32 mg/kg	Placebo	Total
	N = 6	N = 6	N = 12
	nE, nS (%)	nE, nS (%)	nE, nS (%)
AEs, subjects with AEs	16, 4 (66.7)	8, 4 (66.7)	24, 8 (66.7)
Mild	15, 3 (50.0)	8, 4 (66.7)	23, 7 (58.3)
Moderate	1, 1 (16.7)	0	1, 1 (8.3)
Severe	0	0	0
Study drug‐related AEs	14, 3 (50.0)	0	14, 3 (25.0)
SAEs	0	0	0
AEs leading to discontinuation of study treatment	0	0	0

Preferred term	MIJ821, 0.32 mg/kg	Placebo	Total
	N = 6	N = 6	N = 12
	n (%)	n (%)	n (%)
‘Radiculopathy	0	3 (50.0)	3 (25.0)
Back pain	1 (16.7)	1 (16.7)	2 (16.7)
Depersonalization/derealization disorder	2 (33.3)	0	2 (16.7)
Derealization	2 (33.3)	0	2 (16.7)
Medical device site dermatitis	0	2 (33.3)	2 (16.7)
Anxiety	1 (16.7)	0	1 (8.3)
Burns first degree	0	1 (16.7)	1 (8.3)
Dissociative amnesia	1 (16.7)	0	1 (8.3)
Dissociative identity disorder	1 (16.7)	0	1 (8.3)
Dizziness	1 (16.7)	0	1 (8.3)
Furuncle	0	1 (16.7)	1 (8.3)
Headache	1 (16.7)	0	1 (8.3)
Nightmare	1 (16.7)	0	1 (8.3)
Palpitations	1 (16.7)	0	1 (8.3)
Somnolence	1 (16.7)	0	1 (8.3)

Note: Preferred terms are arranged in descending order of frequency (in total group) and alphabetically. N = number of subjects studied; nE = number of AE events in the category; nS = number of subjects with at least one AE in the category; % is based on the number of subjects.

Abbreviations: AE, adverse event; SAE, serious adverse event.

Part 2: Repeated single intravenous dose

In Part 2, a total of 8 subjects (66.7%) experienced at least one AE. All AEs with the exception of one were of mild severity (58.3%) (Table 3). One subject reported an AE of moderate severity in the MIJ821 0.32 mg/kg dose cohort. Three subjects (50.0%) in the MIJ821 0.32 mg/kg dose cohort reported AEs related to study treatment. There were no subjects with AEs of severe grade, SAEs, and AEs leading to discontinuation of study treatment. The most commonly reported AEs in Part 2 were radiculopathy (3 subjects; placebo cohort), back pain (1 subject each in MIJ821 0.32 mg/kg and placebo cohorts), depersonalization/derealization disorder (2 subjects exhibited both depersonalization and derealization; MIJ821 0.32 mg/kg dose cohort), derealization (2 subjects; MIJ821 0.32 mg/kg dose cohort), and medical device site dermatitis (2 subjects; placebo cohort). The incidence of depersonalization/derealization disorder (2 subjects, 16.7%) and derealization (2 subjects, 16.7%) in Part 2 (0.32 mg/kg dose cohort) was similar to that in Part 1.

Cardiovascular safety

Electrocardiography

The concentration–response analyses revealed a linear increasing trend with a change in QTcF interval (dQTcF) with increasing concentration of MIJ821, which was statistically significant (Figure 2), with a mean dQTcF (90% CI) estimated to be −6.7 ms (90% CI: −8.2, −5.2) for placebo; −2.5 ms (90% CI: −4.2, −0.8) for the geometric mean C _max at 0.16 mg/kg (112 ng/mL); and 3.6 ms (90% CI: 0.5, 6.8) for the geometric mean C _max at 0.32 mg/kg (227 ng/mL, Parts I and II pooled). There was a positive concentration‐effect in placebo‐adjusted change from baseline of Holter ECG parameters, QTcF and QT (Figure 2); whereas, HR and QRS had a slightly positive concentration effect. PR, however, was observed to have a negative concentration‐effect.

FIGURE 2.

Relationship between plasma concentrations and change from baseline in QTcF on Day 1 – Part 1 and 2 (dQTcF (ms)) (Safety analysis set). Note: dQTc estimate (90% CI) for placebo is −2.2 (−3.9, −0.5), geometric mean C _max at 0.16 mg/kg is 2.8 (1, 4.7), and geometric mean C _max at 0.32 mg/kg (Parts 1 and 2 pooled) is 10.3 (7.2, 13.3). The horizontal dotted line indicates the threshold limits of upper bounds of the two‐sided 90% CI which is set as 10 ms. The solid regression line has been derived based on linear regression analysis between MIJ821 plasma concentrations and delta QTcF. EOS, end of study, IV, intravenous.

CNS safety parameters

CADSS score

In Part 1, the CADSS scores were 0 at all the time points in 0.048 mg/kg, 0.16 mg/kg, and placebo cohort. However, in the 0.24, 0.32, and 0.48 mg/kg dose cohorts, there were some subjects who had non‐zero CADSS scores: one subject (0.24 mg/kg dose cohort) had a CADSS score of 1 at 4 h post‐dose. Six subjects (0.32 mg/kg dose cohort) had a mean CADSS score of 3.7 at 0.25 h post‐dose, which reduced and reached a plateau state with the mean score of 0.2 at 3 h post‐dose. At 24 h post‐dose, the CADSS score reduced to 0.0. Two subjects (0.48 mg/kg dose cohort) had a transient increase in the CADSS score at 3 h (cohort mean: 0.4) and 4 h post‐dose (cohort mean: 2.2). Similarly, in Part 2, the mean CADSS score of placebo was 0.0 at all the time points and in 2 subjects from the 0.32 mg/kg dose cohort it ranged from 0.2 to 2.0 on Day 1 at 0.25 to 2 h post‐dose and from 0.2 to 1.63 on Day 8 at 168.92 to 172.67 h post‐dose. The mean CADSS score was 0.0 at all other time points.

C‐SSRS score

In Part 1 and Part 2 the response to C‐SSRS questionnaire was a “No” response to all questions at all the time points for all MIJ821 dosing cohorts and the placebo cohorts.

Pharmacokinetics

In this study the PK data were available for 32 healthy volunteers from the single ascending intravenous dose (Part 1) and for 6 healthy volunteers from the repeated intravenous dose (Part 2) (Table 4).

TABLE 4.

Summary statistics for plasma pharmacokinetic (PK) parameters per treatment – Part 1 and Part 2 (PK analysis set).

Part 1		MIJ821 0.016 mg/kg	MIJ821 0.048 mg/kg	MIJ821 0.16 mg/kg	MIJ821 0.24 mg/kg	MIJ821 0.32 mg/kg	MIJ821 0.48 mg/kg
		N = 6	N = 6	N = 6	N = 3	N = 6	N = 5
AUCinf (h ng/mL)	Day 1	25.2 (23.0%) [6]	58.3 (16.3%) [6]	214 (14.6%) [6]	304 (8.9%) [3]	434 (21.0%) [6]	708 (17.6%) [4]
AUClast (h ng/mL)	Day 1	22.9 (23.1%) [6]	56.6 (17.0%) [6]	212 (14.9%) [6]	302 (9.0%) [3]	432 (21.1%) [6]	716 (15.4%) [5]
CL (mL/h/kg)	Day 1	634 (23.0%) [6]	823 (16.3%) [6]	749 (14.6%) [6]	791 (8.9%) [3]	738 (21.0%) [6]	678 (17.6%) [4]
C max (ng/mL) a	Day 1	4.79 (37.2%) [6]	19.3 (31.8%) [6]	97.6 (30.5%) [6]	126 (17.7%) [3]	197 (70.2%) [6]	462 (24.7%) [5]
T 1/2 (h)	Day 1	8.44 (17.7%) [6]	6.19 (5.8%) [6]	6.32 (44.4%) [6]	6.31 (8.9%) [3]	5.70 (6.6%) [6]	4.99 (11.7%) [4]
T max (h)	Day 1	0.92 (0.9–0.92) [6]	0.68 (0.68–0.7) [6]	0.67 (0.67–0.92) [6]	0.67 (0.67–0.67) [3]	0.68 (0.67–1.67) [6]	0.67 (0.67–0.67) [5]
V ss (mL/kg)	Day 1	5270 (27.3%) [6]	4260 (20.6%) [6]	2880 (23.9%) [6]	3170 (13.3%) [3]	2990 (33.2%) [6]	2010 (19.8%) [4]
V z (mL/kg)	Day 1	7730 (28.2%) [6]	7350 (13.5%) [6]	6820 (50.1%) [6]	7200 (15.1%) [3]	6070 (22.3%) [6]	4870 (25.6%) [4]

Part 2
Plasma		MIJ821 0.32 mg/kg
		N = 6
AUCinf (h ng/mL)	Day 1	462 (21.5%) [6]
	Day 8	409 (11.6%) [6]
AUClast (h ng/mL)	Day 1	461 (21.7%) [6]
	Day 8	408 (11.6%) [6]
CL (mL/h/kg)	Day 1	692 (21.5%) [6]
	Day 8	783 (11.6%) [6]
C max (ng/mL)	Day 1	261 (34.5%) [6]
	Day 8	198 (31.1%) [6]
T 1/2 (h)	Day 1	6.14 (28.2%) [6]
	Day 8	6.19 (5.9%) [6]
T max (h)	Day 1	0.68 (0.67–0.68) [6]
	Day 8	0.67 (0.67–0.7) [6]
V ss (mL/kg)	Day 1	2110 (18.5%) [6]
	Day 8	2830 (10.6%) [6]
V z (mL/kg)	Day 1	6130 (24.6%) [6]
	Day 8	6990 (15.1%) [6]

Part 2
Urine		MIJ821 0.32 mg/kg
		N = 6
Ae0‐t (ng)	Day 1	381,000 (21.8%) [6]
	Day 8	340,000 (45.1%) [6]
CLr (mL/h/kg)	Day 1	10.8 (27.9%) [6]
	Day 8	10.9 (35.2%) [6]

Note: Statistics are geometric mean (CV% geometric means) [N]. Coefficient of variation (%) (CV%) geometric mean = sqrt (exp (variance for log transformed data)−1) * 100. For T _max, statistics are median (min–max) [N].

Abbreviations: Ae0‐t, amount of unchanged drug excreted into the urine within a time span (0 to t); AUC_inf, AUC from time zero to infinity; AUC_last, AUC from time zero to the last measurable plasma concentration sampling time (tlast); CL, total apparent body clearance of drug; CLr, renal clearance; C _max , maximum observed plasma concentration following a single dose administration; T _1/2, elimination half‐life associated with the terminal slope (Lambda_z [terminal elimination rate constant]) of a semilogarithmic concentration‐time curve; T _max, time to reach maximum (peak) plasma concentration following a single dose administration; V _ss, volume of distribution at steady‐state; V _z, apparent volume of distribution during terminal phase (associated with Lambda_z [terminal elimination rate constant]).

^a In all cohorts, the first pharmacokinetic (PK) sample was collected at the end of infusion (0.667 h after start of infusion) with exception of cohort 1 (Part 1, 0.016 mg/kg, all subjects) in which the first PK sample was collected at 0.917 h after start of infusion.

Part 1: Single ascending intravenous dose

In Part 1, the PK profiles of MIJ821 in plasma were determined at dose levels of 0.016 (n = 6), 0.048 (n = 6), 0.16 (n = 6), 0.24 (n = 3), 0.32 (n = 6), and 0.48 mg/kg (n = 5). Following the start of intravenous infusion, MIJ821 was measured in plasma up to 24.7 h after infusion start in all subjects at the lowest dose of 0.016 mg/kg and up to 72.7 h in 1 subject at the highest dose of 0.48 mg/kg (LLOQ [lower limit of quantification]: 0.1 ng/mL). The median T_max occurred at the end of infusion (0.67 h after start of infusion) in all cohorts of the two study parts with the exception of cohort 1 (single dose, 0.016 mg/kg), in which the first plasma collection was executed at 0.92 h after start of infusion. The variability of the geometric mean exposure parameters described by the coefficient of variation (CV) was low‐to‐moderate and ranged between 17.7% and 70.2% for C _max values and between 8.9% and 23.0% for AUC_inf values. The AUC_inf values of MIJ821 increased in a dose‐proportional manner across the dose range 0.016–0.48 mg/kg and the C _max values in a slight overproportional manner across the dose range 0.048–0.48 mg/kg. At the highest dose of 0.48 mg/kg, the geometric mean AUC_inf was 708 h ng/mL and the geometric mean was C _max 462 ng/mL. The geometric means of plasma clearance ranged between 634 and 823 mL/h/kg, being between 66% and 85% of the hepatic liver blood flow (1240 mL/h/kg, Davies and Morries, ¹⁹ clearance was calculated by dividing the plasma CL by the blood‐to‐plasma concentration ratio 0.778), volume of distribution at apparent terminal elimination phase (V _z) ranged between 4870 and 7730 mL/kg being about 8‐ to 13‐fold higher than the total body water (600 mL/kg, Davies and Morries),¹⁹ and the mean apparent terminal elimination half‐life (T_1/2) was between 4.99 and 8.44 h.

Part 2: Repeated single intravenous dose

In Part 2, the PK profiles of MIJ821 in plasma were determined at 0.32 mg/kg (n = 6) after the first (Day 1) and second intravenous infusion (Day 8). The variability in the geometric mean exposure parameters described by the coefficient of variation (CV) was considered for both dosing events to be low‐to‐moderate: 34.5% (1st dose) and 31.1% (2nd dose) for C _max values and 21.5% (1st dose) and 11.6% (2nd dose) for AUC_inf values. The geometric mean MIJ821 exposure parameters (C _max, AUC_inf) were only between 1.1‐ and 1.3‐fold higher after the first dose than those after the second dose, indicating no obvious difference between the two dosing events. The MIJ821 exposure parameters (C _max, AUC_inf) derived from both dosing events in the repeated intravenous dose part were comparable to those determined in the SAD part at 0.32 mg/kg. The geometric mean CL (692 and 783 mL/h/kg), V _z (6130 and 6990 mL/kg), and T_1/2 values (6.14 and 6.19 h) derived from both dosing events were in the range determined in the different cohorts of SAD.

MIJ821 was recovered in urine as a minor fraction of the administered dose (0.32 mg/kg) ranging for both dosing events between 0.764% and 2.08% of the administered dose on the individual level. The geometric mean CLr values (10.8 and 10.9 mL/h/kg after the first and the second intravenous infusion, respectively) were between 1.6% (first dosing event) and 1.4% (second dosing event) of the respective mean plasma CL values indicating that renal elimination of MIJ821 was minor.

MIJ821 distributed into CSF after intravenous infusion resulting in geometric mean concentration ratios CSF/plasma of 0.0435 (CV geometric mean: 27.2%) and 0.159 (CV geometric mean: 12.4%) at 0.917 and 4.67 h after start of infusion (0.32 mg/kg), respectively. The higher ratio at the later time suggests that the decrease of MIJ821 in plasma was faster than that in the CSF, which may be a result of a potential time delay in the distribution of MIJ821 into the CSF compartment. The related CSF/free plasma ratio at the later collection time, which is considered to reflect the steady state condition more appropriately, was estimated to be 0.9 using the fraction unbound in plasma of 0.178.

Pharmacodynamics: Resting‐state EEG analysis

Part 1 and Part 2: Dose‐dependent changes (dose vs. EEG measures)

Inspection of ratios (post‐dose/pre‐dose) in all study cohorts shows clear trends for a relationship between 1‐h post‐dose resting EEG activity and dose administered, providing exploratory evidence of distal target engagement. Delta relative power: numerically increasing trend observable at 0.32 mg/kg (Figure 3a, p = 0.078), Part 2 data showed a significant difference from placebo in post/pre ratio (p < 0.01 in both doses). Theta relative power: increasing trend with increasing dose and a significant difference from placebo is observable at 0.16 and 0.32 mg/kg (Figure 3b left, p = 0.023 and p = 0.030, respectively), Part 2 data also show a significant increase from placebo at the second dosing event (Figure 3b right, p = 0.008). Alpha relative power: decreasing trend with increasing dose and a significant difference from placebo is observable at 0.32 and 0.48 mg/kg (Figure 3c, p = 0.013 and p = 0.031, respectively), Part 2 data also show a significant decrease from placebo at the first dosing event (Figure 3c right, p = 0.008). Beta relative power: decreasing trend with increasing dose and a significant difference from placebo is observable at 0.32 and 0.48 mg/kg (Figure 3d, p = 0.010 and p = 0.005, respectively), Part 2 data show a non‐significant trend of relative power decrease. Gamma relative power: increasing trend with increasing dose and a significant difference from placebo is observable at 0.16 and 0.24 mg/kg (Figure 3e, p = 0.018 and p = 0.043, respectively), Part 2 data also show a significant increase from placebo at the first dosing event (Figure 3e right, p = 0.030). Overall, the trends seen in Part 1 were also repeated in Part 2. For all frequency bands there was no significant difference in post/pre ratio between the repeated doses.

FIGURE 3.

Relationship between dose of MIJ821 and EEG relative power (as a fraction from pre‐dose) in Part 1 (left) and Part 2 (right), at 1‐h post‐intravenous infusion for (a) delta, (b) theta, (c) alpha, (d) beta, and (e) gamma frequency bands. Error bars indicate standard error of the mean (SEM). Asterisks represent doses for which electroencephalogram relative power change from pre‐dose was significantly different than that of placebo (0 mg/kg). N indicates the number of subjects with available data for each dose.

DISCUSSION

This was a first‐in‐human, randomized, subject‐blinded, placebo‐controlled study of a new molecule MIJ821. The single‐dose study design in healthy volunteers was supported by the toxicology studies (2‐week non‐Good Laboratory Practice [GLP] and 6‐week GLP study) demonstrating adequate preclinical data to support the safe use of MIJ821 at doses up to 0.48 mg/kg in clinical trials. Data from this study will help inform dose selection for a proof‐of‐concept study to support further clinical development of MIJ821 in patients with treatment‐resistant depression (TRD).

In this study, the safety profile of MIJ821 was well characterized in all the cohorts evaluated. The safety and tolerability profile of MIJ821 is generally favorable across all the cohorts with either no or small number of AEs suspected due to MIJ821 treatment in the cohorts of 0.016, 0.048, 0.16, and 0.24 mg/kg and a moderate number of AEs related to MIJ821 treatment in the 0.32 and 0.48 mg/kg cohorts. Most of these AEs were mild and transient and did not require any treatment. There were no subjects with AEs of severe grade, SAEs, and AEs leading to discontinuation of study treatment. After intravenous infusion of MIJ821 for 0.67 h, maximum plasma concentration was observed at the end of the infusion. AUC_inf values of MIJ821 increased after single administration in a dose‐proportional manner and the C _max values in a slight overproportional manner. No obvious PK difference has been identified between the two dosing events in the repeated dose part of the study. Renal CL was considered to be minor. MIJ821 distributed into CSF with a maximum mean concentration ratio CSF/free plasma of 0.9 which indicated that the distribution of MIJ821 into the CSF is not strongly restricted.

The concentration–response analyses revealed a positive correlation between the MIJ821 plasma concentration and the placebo‐adjusted mean change from baseline in QTcF (ΔΔQTcF). The EEG changes, including alpha power decrease and gamma power increase following MIJ821 administration, are consistent with previous findings using ketamine in human subjects. ⁹ , ¹⁰ , ¹¹ , ¹² The decrease in alpha power and increase in gamma power (consistent with previous findings using ketamine in human subjects) may reflect increased cortical excitability, enhanced cognitive processing, and changes in sensory integration and binding of neural networks. These changes correspond with the effect of low doses of ketamine on brain plasticity processes and prefrontal connectivity, which are mediated by glutamatergic and GABAergic modulation and may influence the excitation–inhibition balance in neural circuits and lead to alterations in EEG power, including the alpha and gamma bands. Interestingly, a study investigating the EEG signature of NR2B‐NAMs in non‐human primates showed dose‐related decreased alpha and beta power and increased delta power, similar to the current findings, while no effect was found on gamma power. ¹⁸

An objective brain assessment technology, like the BNA™ platform used in the current study, may hold potential for a novel PK–PD evaluation tool: the main exploratory endpoints (i.e., EEG measures) can be utilized to validate primary endpoint‐guided dose selection for further clinical development of MIJ821 in patients with TRD; evaluate the effect of MIJ821 on the brain functionality (PD) and vice versa, through the quantification of changes in brain measures the PK can be estimated and potentially lead to a more accurate drug development and patient‐adjusted treatment; provide a biomarker of distal target engagement; and help in the interpretation of future negative results by comparing therapeutic effects (or lack thereof) and the effects on EEG PD neuromarkers.

The limitations of the study are a small sample size and study population which included only healthy volunteers, with a maximum age of 56 years.

In conclusion, MIJ821 showed a good safety and tolerability profile in healthy volunteers, with no AEs of severe grade, and no SAEs and AEs leading to discontinuation of the study treatment. Dissociative AEs were mild, transient, and dose‐dependent. Effects of MIJ821 on brain electrophysiology were similar to those of ketamine in previous human studies, and to those of NR2B‐NAMs in primates.

AUTHOR CONTRIBUTIONS

B.G.‐M., T.F., G.I., Z.P., O.L., R.S.‐H., K.B., M.P.H., O.S., S.D., S.N.G., J.‐H.C., and Y.G.S. wrote the manuscript. B.G.‐M., J.A.L., S.G., Z.P., E.W., M.P.H., O.S., J.‐H.C., and Y.G.S. designed the research and performed the research. B.G.‐M., T.F., G.I., Z.P., O.L., R.S.‐H., K.B., O.S., S.D., S.N.G., J.‐H.C., and Y.G.S. analyzed the data.

FUNDING INFORMATION

This study was funded by Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

CONFLICT OF INTEREST STATEMENT

B.G.‐M. was an employee of Novartis Pharma AG at the time of this study and is a current employee of STALICLA. J.A.L. is an employee of Quotient Sciences. S.G. was an employee of Novartis Healthcare Pvt. Ltd. at the time of this study and is a current employee of Certara Inc. T.F. is an employee of Novartis Pharma AG and owns stocks in Novartis. G.I., Z.P., O.L., and R.S.‐H. were working in Elminda Ltd., Herzliya, Israel while working on the manuscript. Due to rebranding of Elminda, O.L. and G.I. are now affiliated with Firefly Neuroscience Ltd., Herzliya, Israel. Z.P. and R.S.‐H. left Elminda before the rebranding process. K.B. was an employee of Novartis Institutes for BioMedical Research, Cambridge, MA, USA. E.W. is an employee of Novartis Pharma AG and owns stocks in Novartis. M.P.H. is an employee of Novartis Institutes for BioMedical Research and owns stocks in Novartis. O.S. is an employee of Novartis Pharmaceuticals Corporation and owns stocks in Novartis. S.D. is an employee of Novartis Institutes for BioMedical Research and owns stocks in Novartis. S.N.G. was an employee of Novartis Institutes for BioMedical Research. He is Professor of Psychiatry at Tufts University and Lecturer on Psychiatry at Harvard Medical School, Boston, MA, USA. J.‐H.C. was an employee of Novartis Institutes for BioMedical Research at the time of this study and is a current employee of Latus Bio. Y.G.S. was an employee of Novartis at the time of this study and is a current employee of Beam Therapeutics.

Supporting information

Data S1

Gomez‐Mancilla B, Levy JA, Ganesan S, et al. MIJ821 (onfasprodil) in healthy volunteers: First‐in‐human, randomized, placebo‐controlled study (single ascending dose and repeated intravenous dose). Clin Transl Sci. 2023;16:2236‐2252. doi: 10.1111/cts.13623

DATA AVAILABILITY STATEMENT

All relevant data are included in the article and its supplementary files. Novartis is committed to sharing with qualified external researchers access to patient‐level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described at www.clinicalstudydatarequest.com.