First‐in‐Human Dose Selection and Safety, Tolerability, Pharmacokinetics, and Immunogenicity of the Muscle‐Specific Kinase Agonist Adimanebart (ARGX‐119)

Abstract

Adimanebart (ARGX‐119), a first‐in‐class, humanized, agonistic monoclonal antibody, specifically targets and activates muscle‐specific kinase, stabilizing the neuromuscular junction, increasing muscle strength, and decreasing muscle weakness and fatigability in nonclinical, proof‐of‐concept studies. Adimanebart may have broad therapeutic potential in neuromuscular junction disorders. This Phase I, first‐in‐human, double‐blinded, placebo‐controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of adimanebart in healthy participants. With no pharmacodynamic marker for muscle‐specific kinase dimerization by adimanebart, human dose predictions were based on the minimum anticipated biological effect level in nonclinical studies. In this two‐part study, 112 healthy participants were randomized to receive adimanebart or placebo in single ascending intravenous doses (0.005‐15 mg/kg) or a single subcutaneous dose (5 mg/kg; Part A; n = 76), or weekly multiple ascending intravenous doses (0.3‐5 mg/kg; Part B; n = 36). Adimanebart was well tolerated with a favorable safety profile. In single‐ascending dose (SAD) cohorts, adimanebart demonstrated nonlinear pharmacokinetics at low concentrations, a dose‐proportional increase in maximum concentration (mean range: 0.1‐343 µg/mL), and a ≈6‐fold increase in area under the concentration–time curve (0 to infinity) following a single intravenous dose, indicating target‐mediated drug disposition. Incidence and prevalence of adimanebart anti‐drug antibodies were comparable between treatment groups in SAD cohorts (adimanebart: 16.0% and 18.0%, placebo: 16.7% and 22.2%, respectively) and were not detected in multiple‐ascending‐dose cohorts. There was no apparent impact of anti‐drug antibodies on adimanebart pharmacokinetics or safety. This study supports investigation of adimanebart as an agonistic muscle‐specific kinase monoclonal antibody treatment for neuromuscular junction disorders.

Introduction

Muscle‐specific kinase (MuSK) is a receptor tyrosine kinase essential for the establishment, preservation, maintenance, and function of the neuromuscular junction (NMJ). ¹ , ² , ³ During NMJ development, the heparan sulfate proteoglycan, agrin, produced by motor neurons, binds to lipoprotein‐related receptor 4 (LRP4) in muscle, leading to the dimerization and activation of MuSK. ⁴ , ⁵ Recruitment of downstream kinase 7 (DOK7) amplifies MuSK dimerization and phosphorylation of downstream targets, activating the signaling cascades that promote presynaptic and postsynaptic differentiation ⁶ , ⁷ essential for synaptic transmission, and muscle contraction. ¹ , ³ , ⁸

Disruption of the agrin‐LRP4‐MuSK‐DOK7 signaling pathway, or the structure and function of the NMJ, impairs synaptic transmission and may lead to debilitating and potentially life‐threatening muscle weakness and disorders, including congenital myasthenic syndromes (CMS), myasthenia gravis, and spinal muscular atrophy (SMA). ³ , ⁹ , ¹⁰ , ¹¹ Current treatments are limited in their effectiveness, can have significant side effects, and may lose efficacy with long‐term use. ⁶ , ¹² , ¹³ , ¹⁴ There remains an unmet need for treatment options that improve NMJ stability and muscle function in patients with CMS and SMA.

In mouse models, activation of MuSK and MuSK agonist antibodies has been shown to promote neuromuscular synapse differentiation and improve the outcome of DOK7‐CMS ¹⁵ and SMA. ¹⁶ Adimanebart (ARGX‐119) is a first‐in‐class, humanized, agonistic monoclonal antibody that specifically binds with high affinity to the frizzled‐like domain in MuSK to facilitate its dimerization, phosphorylation, and activation, and the stabilization of the NMJ. ¹⁷ In nonclinical, proof‐of‐concept studies with DOK7‐CMS mice, adimanebart mostly restored NMJ formation and signaling, prevented NMJ deterioration, and reversed disease relapse. ¹⁷ By stabilizing NMJ function and facilitating synaptic transmission, adimanebart has a broad therapeutic potential to restore or improve muscle function in patients with neuromuscular diseases and disorders, such as CMS and SMA. ¹⁷

The US Food and Drug Administration (FDA) and the European Medicines Agency advise evaluating the no observed adverse effect level (NOAEL) from animal toxicity studies, ¹⁸ , ¹⁹ together with determining the minimum anticipated biological effect level (MABEL) in humans, ¹⁸ to select the starting dose for first‐in‐human (FIH) studies. Here, we present the use of functional efficacy parameters identified in nonclinical studies ¹⁷ as an approach for adimanebart dose selection in the absence of a pharmacodynamic marker, and report the outcomes of a Phase I, FIH, double‐blinded, placebo‐controlled study assessing the safety, tolerability, pharmacokinetics (PK), and immunogenicity of single ascending doses (SAD) and multiple ascending doses (MAD) of adimanebart in healthy participants.

Methods

Nonclinical Studies

Methodological details of the nonclinical pharmacology and toxicology studies used to determine the NOAEL are provided in the Supplemental Material.

Adimanebart FIH Study

The study was approved by the independent ethics committee (Stichting Beoordeling Ethiek Biomedisch Onderzoek; Assen, the Netherlands). Participants were 18 to 65 years of age, inclusive, at the time of signing the consent form. This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki, and other locally applicable laws and regulations.

Study Design

From February 3, 2023 to August 8, 2024, a Phase I, FIH, single‐center, randomized, double‐blinded, placebo‐controlled study designed to evaluate the safety, tolerability, PK, and immunogenicity of single and multiple ascending doses of adimanebart in healthy participants was undertaken (registered at ClinicalTrials.gov as NCT05670704 on December 20, 2022). The study took place at the Contract Research Organization ICON Plc, Groningen, the Netherlands. The primary endpoints included the assessment of adverse events (AEs), clinical laboratory tests, electrocardiograms (ECGs), and vital signs. Secondary endpoints included assessment of PK parameters of adimanebart and the incidence/prevalence of anti‐drug antibodies (ADAs) against adimanebart. Healthy male and female participants of nonchildbearing potential were eligible for inclusion in the study if they were aged between 18 and 65 years (inclusive), with a body mass index (BMI) of 18 to 30.5 kg/m² (inclusive), a body weight of 50 to 100 kg (inclusive), and no clinically meaningful laboratory abnormalities, medical or psychiatric conditions, or abnormalities detected in screening assessments.

Randomization and Dose Escalation

Details regarding dose selection are provided in the Supplemental Material. SAD cohort participants were randomized 2:1 (cohorts A01 and A02) or 3:1 (cohorts A03 to A10) to receive adimanebart or placebo in escalating single intravenous (IV)) infusion doses (0.005, 0.025, 0.1, 0.3, 0.9, 2.5, 5, 10, and 15 mg/kg) administered over 1 h or a single subcutaneous (SC) injection (5 mg/kg) in the abdomen. Participants in Part B (MAD cohorts) were randomized 3:1 in four cohorts to receive adimanebart or placebo as four once‐weekly IV infusions (days 1, 8, 15, and 22) in escalating doses (0.3, 0.9, 2.5, and 5 mg/kg) administered over 1 h. Adimanebart was diluted from 150 mg/mL to the appropriate dose in 0.9% NaCl.

Dose escalation and Part B dose levels were based on review of blinded clinical safety and PK results by the data review team. Participants completed three study periods: screening (28 days), treatment (1 day for Part A, 3 weeks for Part B), and follow‐up (5 months), for ≤7 months. Participants or investigators could interrupt or discontinue treatment, or withdraw from the study, for safety, tolerability, or administrative reasons (e.g., withdrawal of participant consent).

Assessments

Safety was monitored continuously throughout the study up to the participants’ last visit. Assessments included occurrences of AEs after screening and up to the last treatment visit, physical examination, vital signs, ECG and ECG telemetry, and routine laboratory tests. AEs were considered to be treatment emergent (TEAE) if they started or worsened following first administration of treatment (adimanebart or placebo). Blood samples were collected pre‐dose on day 1 and post‐dose, relative to the start of study drug infusion, to assess PK parameters of single and multiple doses of adimanebart (IV or SC) over time. Samples were collected on days 1 to 6, 8, 9 (Part B only), 15, 16 (Part B only), 22, 22 to 28 (Part B only), 29, 36, 43 (Part B only), 50, 57 (Part B only), 64 (Part A only), 71 (Part B only), 92 (Part A only), 99 (Part B only), 120 (Part A only), 127 (Part B only), and 157 (Part B only), at the end‐of‐study visit (day 150 in Part A and day 177 in Part B), and at any unscheduled visits. Blood samples for immunogenicity analysis were collected to evaluate serum levels of ADAs to adimanebart (pre‐dose, days 15 [Part A only], 29, 57 [Part B only], 64 [Part A only], 92 [Part A only], 99 [Part B only], 120 [Part A only], 127 [Part B only], and 157 [Part B only], and at the end‐of‐study visit).

Pharmacokinetics of Adimanebart

A validated, quantitative, enzyme‐linked immunosorbent assay was used to determine free adimanebart concentrations in human serum samples. In brief, adimanebart was captured by an anti‐idiotypic antibody fragment (3G11‐hFab) and detected with a second anti‐idiotypic antibody fragment (2C11‐hFab). The limit of detection of this assay is 20.0 ng/mL adimanebart in human sera. Selectivity in hemolytic and lipemic sera was validated. Freeze/thaw and long‐term stability were also assessed during validation. All samples were analyzed within documented stability.

Immunogenicity of Adimanebart

Anti‐adimanebart antibodies were detected using a multitiered electrochemiluminescence immunoassay method validated with a pre‐treatment step to meet drug tolerance requirements. Serum samples were pre‐treated with acid to dissociate ADAs from adimanebart before capturing ADAs with biotinylated adimanebart on a streptavidin‐coated plate. The plate was washed to remove excess free adimanebart, and ADAs eluted by acid dissociation were neutralized in a buffer containing both biotinylated and SULFO‐tag‐labeled adimanebart. ADAs against adimanebart bridge the biotinylated and SULFO‐tag‐labeled molecules, and these complexes were captured on a second streptavidin‐coated plate, followed by electrochemiluminescent signal detection. All samples were analyzed within documented stability.

Statistical Analyses

Sample size was selected based upon prior experience from comparable clinical study designs, with the selected number of participants per cohort considered sufficient to achieve clinical objectives. Statistical calculations were performed using SAS (v9.4 or higher) and/or Phoenix WinNonlin (v8.3.4 or higher) for PK analyses. Continuous data were summarized using descriptive statistics (mean, standard deviation [SD], median, maximum, minimum, and range); categorical data, using counts, and percentages. The safety analysis set consisted of all randomized participants who received ≥1 dose of either placebo or adimanebart; placebo‐treated participants were combined within Parts A and B. The PK analysis set comprised all randomized participants who received ≥1 dose of adimanebart and for whom PK data were considered sufficient/interpretable. Demographics, baseline characteristics, and safety/tolerability analyses were undertaken on the safety set.

Number of events, frequency, and percentage of TEAEs were calculated and presented by system organ class and preferred term and summarized descriptively by dose level, route of administration, study part, severity, and relationship to study treatment. Changes in clinical laboratory tests (hematology, clinical chemistry, coagulation, urinalysis), ECG variables (heart rate, PR interval, QRS interval, QT interval), telemetry, and vital signs were summarized using descriptive statistics on actual value, change from baseline, and at each assessment point by dose level and route of administration, overall for the study and by part of the study. QTc were derived using Fridericia's formula as the primary correction parameter. Categorical assessment was performed on the absolute corrected QT interval (QTcF) interval prolongation (categories: >450, >480, and >500 ms) and change from baseline (categories: >30 and >60 ms).

PK parameters were calculated using noncompartmental methods (Phoenix WinNonlin version 8.3.4 or higher) and summarized using descriptive statistics by study part and dose regimen. Parameters calculated include area under the concentration–time curve (AUC) from 0 to 168 h (AUC_0‐168 h) and from 0 to infinity (AUC_0‐inf), maximum concentration (C_max), median time to C_max (T_max), half‐life (t_1/2), total drug clearance (CL; IV cohorts only), apparent volume of distribution during the terminal phase (V_z; IV cohorts only), and accumulation ratio (Part B, day 22 only). Dose proportionality was assessed via the power model for C_max, AUC_0‐168 h, and AUC_0‐inf. Absolute bioavailability of adimanebart SC versus IV administration was determined by ANOVA on PK parameters (C_max and AUC_0‐inf) in Part A; PK parameters were compared across each IV single‐dose level to assess dose proportionality.

Immunogenicity of adimanebart was evaluated by assessment of incidence and prevalence of ADA against adimanebart. ADA status for each participant was derived based on adimanebart ADA sample status (unevaluable, negative, positive), and expressed as unevaluable, negative, treatment unaffected, treatment induced, or treatment boosted, by dose level and study part.

Results

Nonclinical Studies

Nonclinical pharmacology and toxicology results used to inform the MABEL calculations are provided in the Supplemental Material.

Adimanebart FIH Study

Participants

Of 313 participants screened, 112 healthy participants were randomized to receive adimanebart or placebo. In Part A, 76 participants were randomized 2:1 (cohorts A01 and A02) or 3:1 (cohorts A03 to A10) to receive a single IV infusion of adimanebart (n = 50) or placebo (n = 18) or a single SC injection of adimanebart (n = 6) or placebo (n = 2) (Figure S1). All participants (100%) in Part A completed the study (Figure S2). In Part B, 36 participants were randomized 3:1 to receive IV adimanebart (n = 27) or IV placebo (n = 9); 31 participants (86.1%) completed the study. Four participants who received adimanebart discontinued the study: 3 (11.1%) due to TEAEs and 1 (3.7%) participant withdrawal. One (11.1%) participant who received a dose of placebo discontinued (physician's decision).

In Part A, all participants received a single dose of adimanebart or placebo (IV or SC), with mean administered volumes of 0.9 to 36.4 mL (adimanebart IV), 9.7 mL (placebo IV), 2.5 mL (adimanebart SC), and 2.7 mL (placebo SC). In Part B, 36 participants received ≥1 IV dose of adimanebart or placebo (mean administered volumes of 2.9 to 35.6 mL [adimanebart IV] and 16.0 mL [placebo IV]), and 31 received all planned IV doses: adimanebart 0.3 to 5.0 mg/kg (23 [85.2%] participants) or placebo (8 [88.9%] participants).

Across both study parts, most participants were male (84.8%) and White (88.4%), with a mean (SD) age and BMI of 42.0 (15.6) years and 24.6 (2.9) kg/m², respectively. Demographics were comparable across both study parts and treatment groups (Table 1).

Table 1.

Participant Demographics: Parts A (SAD Cohorts) and B (MAD Cohorts) (Safety Analysis Set)

	Part A				Part B
Category or Statistic	Adimanebart IV (N = 50)	Placebo IV (N = 18)	Adimanebart SC (N = 6)	Placebo SC (N = 2)	Adimanebart IV (N = 27)	Placebo IV (N = 9)
Sex – n (%)
Male	39 (78.0)	15 (83.3)	6 (100)	2 (100)	25 (92.6)	8 (88.9)
Female	11 (22.0)	3 (16.7)	0	0	2 (7.4)	1 (11.1)
Race – n (%)
American Indian or Alaska Native	0	0	1 (16.7)	0	1 (3.7)	0
Asian	3 (6.0)	0	0	0	1 (3.7)	1 (11.1)
Black or African American	1 (2.0)	1 (5.6)	0	0	2 (7.4)	0
White	45 (90.0)	17 (94.4)	5 (83.3)	2 (100)	22 (81.5)	8 (88.9)
Multiple	–	–	–	–	1 (3.7)	0
Ethnicity – n (%)
Hispanic or Latino	0	0	1 (16.7)	0	3 (11.1)	0
Not Hispanic or Latino	50 (100)	18 (100)	5 (83.3)	2 (100)	24 (88.9)	9 (100)
Age (years) a
n	50	18	6	2	27	9
Mean	41.8	41.5	36.0	40.0	44.9	40.1
SD	16.1	17.1	15.8	21.2	12.6	18.7
BMI (kg/m2) a
n	50	18	6	2	27	9
Mean	24.1	24.9	24.1	24.8	25.7	24.5
SD	2.6	3.3	2.6	4.4	3.2	2.0
Height (cm) a
n	50	18	6	2	27	9
Mean	177.8	176.8	177.3	181.5	177.7	177.7
SD	10.4	10.7	5.8	3.5	7.4	4.6
Weight (kg) a
n	50	18	6	2	27	9
Mean	76.1	77.9	75.6	81.9	80.9	77.3
SD	10.3	12.9	8.0	17.7	10.6	7.8

BMI, body mass index; IV, intravenous; MAD, multiple ascending doses; N, number of participants per dose group; n, number of participants in the category; SAD, single ascending dose; SC, subcutaneous; SD, standard deviation.

^aProvided at screening.

Safety and Tolerability

Adimanebart IV and SC were well tolerated in healthy participants at the doses investigated and demonstrated a favorable safety profile. Overall, 258 AEs occurred in 94 (83.9%) participants across the study (adimanebart IV [Parts A and B]: 62 participants; adimanebart SC: six participants; total placebo [IV and SC; Parts A and B]: 16 participants) (Table 2), with comparable rates reported across all study cohorts (Tables S1 and S2). One mild (grade 1) AE (abdominal pain), experienced by a participant in cohort A04 who received a single dose of adimanebart IV 0.3 mg/kg, was considered related to adimanebart by the investigator and resolved without intervention. No AEs reported in Part B of the study were considered related to treatment by the investigator. All AEs were mild to moderate in severity, with no severe (grade ≥ 3) or serious AEs reported in any cohort or treatment group. Three adimanebart‐treated participants discontinued study treatment due to AEs: Two participants due to COVID‐19, and one due to nasopharyngitis. These AEs were mild (grade 1), considered unrelated to study treatment, and led to study withdrawal. One (11.1%) participant who received placebo discontinued (physician's decision) due to a risk of infection to other participants following an arthropod bite. No deaths, anaphylactic reactions, or moderate/severe cases of hypersensitivity occurred.

Table 2.

Treatment‐Emergent Adverse Events (Safety Analysis Set)

	Part A (SAD) IV (N = 68)		Part A (SAD) SC (N = 8)		Part B (MAD) IV (N = 36)
	Adimanebart (n = 50) n (%) [E]	Placebo (n = 18) n (%) [E]	Adimanebart (n = 6) n (%) [E]	Placebo (n = 2) n (%) [E]	Adimanebart (n = 27) n (%) [E]	Placebo (n = 9) n (%) [E]
All AEs	40 (80.0) [102]	16 (88.9) [46]	6 (100) [13]	2 (100) [6]	22 (81.5) [67]	8 (88.9) [24]
AEs by relationship to study drug
Related	1 (2.0) [1]	0	0	0	0	0
Not related	40 (80.0) [101]	16 (88.9) [46]	6 (100) [13]	2 (100) [6]	22 (81.5) [67]	8 (88.9) [24]
AEs by relationship to study procedure
Related	12 (24.0) [14]	1 (5.6) [1]	3 (50.0) [3]	2 (100) [2]	11 (40.7) [16]	3 (33.3) [4]
Not related	36 (72.0) [88]	16 (88.9) [45]	5 (83.3) [10]	2 (100) [4]	18 (66.7) [51]	8 (88.9) [20]
AEs by severity
Grade 1 (Mild)	40 (80.0) [101]	16 (88.9) [45]	6 (100) [13]	2 (100) [6]	22 (81.5) [66]	8 (88.9) [24]
Grade 2 (Moderate)	1 (2.0) [1]	1 (5.6) [1]	0	0	1 (3.7) [1]	0
Grade ≥3 (Severe)	0	0	0	0	0	0
AEs leading to study discontinuation	0	0	0	0	3 (11.1) [3] a	1 (11.1) [1] b
Serious AEs	0	0	0	0	0	0
Serious AEs related to IMP	0	0	0	0	0	0
Serious AEs leading to study discontinuation	0	0	0	0	0	0
Injection‐site reaction AEs	N/A	N/A	0	0	N/A	N/A
Infusion‐site reaction AEs	2 (4.0) [2]	0	N/A	N/A	0	0

AE, adverse event; E, number of events; IMP, investigational medicinal product; IV, intravenous; MAD, multiple ascending doses; N, number of participants per cohort in the analysis set; n, number of participants with ≥1 event; N/A, not applicable; SAD, single ascending dose; SC, subcutaneous.

Note: Missing AE severity or relationship is assumed to be severe or related, respectively.

^aTwo participants discontinued the study due to COVID‐19 (MAD study, doses 0.9 mg/kg and 2.5 mg/kg) and one discontinued due to nasopharyngitis (MAD study, dose 0.9 mg/kg).

^bOne participant who received placebo discontinued (physician's decision) due to a risk of infection to other participants following an arthropod bite.

The most frequent AEs across all study participants (≥5% in either treatment group in Part A or Part B) included nasopharyngitis, headache, fatigue, back pain, myalgia, catheter‐site bruise, medical device site irritation, oropharyngeal pain, and catheter‐site pain (Table 3). No injection‐site reactions were reported in the eight participants receiving SC injections in Part A; 2/50 (4%) participants receiving IV adimanebart in Part A reported infusion‐site reactions (grade 1 infusion‐site hematoma), considered unrelated to adimanebart by the investigator. No participant in Part B reported infusion‐site reactions.

Table 3.

Most Frequent Adverse Events (≥5% of Participants in Any Cohort) by SOC and PT (Safety Analysis Set)

	Part A (SAD) IV (N = 68)		Part A (SAD) SC (N = 8)		Part B (MAD) IV (N = 36)
MedDRA Preferred Term, System Organ Class	Adimanebart (n = 50) n (%) [E]	Placebo (n = 18) n (%) [E]	Adimanebart (n = 6) n (%) [E]	Placebo (n = 2) n (%) [E]	Adimanebart (n = 27) n (%) [E]	Placebo (n = 9) n (%) [E]
All adverse events	40 (80.0) [102]	16 (88.9) [46]	6 (100) [13]	2 (100) [6]	22 (81.5) [67]	8 (88.9) [24]
General disorders and administration‐site conditions
Fatigue	3 (6.0) [3]	3 (16.7) [3]	0	0	5 (18.5) [5]	1 (11.1) [1]
Catheter site bruise	3 (6.0) [3]	0	1 (16.7) [1]	0	4 (14.8) [5]	1 (11.1) [1]
Catheter site swelling	0	0	0	0	2 (7.4) [2]	1 (11.1) [1]
Catheter site pain	0	0	0	0	4 (14.8) [4]	1 (11.1) [1]
Catheter site related reaction	0	0	0	0	1 (3.7) [1]	1 (11.1) [1]
Medical device site irritation	4 (8.0) [4]	0	1 (16.7) [1]	0	2 (7.4) [2]	1 (11.1) [1]
Medical device site dermatitis	0	0	0	0	2 (7.4) [2]	0
Infections and infestations
Nasopharyngitis	11 (22.0) [14]	6 (33.3) [7]	3 (50.0) [3]	1 (50.0) [2]	4 (14.8) [5]	3 (33.3) [3]
COVID‐19	0	0	0	0	2 (7.4) [2]	0
Influenza	0	0	0	0	2 (7.4) [2]	0
Nervous system disorders
Headache	10 (20.0) [11]	6 (33.3) [6]	1 (16.7) [1]	0	2 (7.4) [2]	3 (33.3) [4]
Musculoskeletal and connective tissue disorders
Back pain	3 (6.0) [3]	3 (16.7) [4]	0	0	4 (14.8) [4]	0
Arthralgia	0	0	0	0	2 (7.4) [2]	0
Myalgia	3 (6.0) [3]	1 (5.6) [1]	1 (16.7) [2]	0	0	2 (22.2) [2]
Gastrointestinal disorders
Abdominal distension	0	0	0	0	2 (7.4) [3]	1 (11.1) [1]
Diarrhea	0	0	0	0	3 (11.1) [3]	0
Nausea	0	0	0	0	2 (7.4) [2]	0
Respiratory, thoracic, and mediastinal disorders
Oropharyngeal pain	4 (8.0) [4]	1 (5.6) [3]	0	0	2 (7.4) [2]	1 (11.1) [1]
Psychiatric disorders
Insomnia	3 (6.0) [3]	1 (5.6) [1]	0	0	0	0

E, number of events; IV, intravenous; MAD, multiple ascending doses; MedDRA, Medical Dictionary for Regulatory Activities; N, number of participants per dose group in the analysis set; n, number of participants with ≥1 event; SAD, single ascending dose; SC, subcutaneous.

Mean changes from baseline over time in clinical laboratory values were similar among cohorts, and there were no clinically meaningful findings for vital sign measurements, physical examination parameters, telemetry, or ECGs.

Pharmacokinetics

After a single infusion of adimanebart IV (0.005 to 15.0 mg/kg), the concentration–time profile in Part A was characterized by the C_max being reached within 2 h of the end of the infusion period (T_max range, 1 h [0.005 mg/kg] to 3 h [5 and 15 mg/kg doses]) followed by a short distribution phase and an elimination phase (Figure 1A). In Part B, adimanebart accumulated with subsequent infusions due to the long t_1/2 of adimanebart (geometric mean accumulation ratios: 1.8 to 2.1 [C_max] and 2.4 to 2.8 [AUC_0‐168 h]) (Figure 1B). The geometric mean (CV%) C_max achieved at the lowest and highest doses in Part A were 0.10 (6.5%) and 342 (10.0%, respectively) (Table 4).

Figure 1.

Pharmacokinetics of adimanebart in Part A (SAD cohorts) and Part B (MAD cohorts). (a) Healthy participants randomized to SAD cohorts received adimanebart or placebo in escalating single IV infusion doses of 0.005, 0.025, 0.1, 0.3, 0.9, 2.5, 5, 10, and 15 mg/kg or a single SC injection (5 mg/kg). The arithmetic mean serum concentration of adimanebart over time was quantified and presented on a semi‐logarithmic scale. The lower limit of quantification for adimanebart is 20 ng/mL. (b) Healthy participants received adimanebart or placebo as four once‐weekly IV infusions (days 1, 8, 15, and 22) in escalating single doses of 0.3, 0.9, 2.5, or 5.0 mg/kg. The arithmetic mean serum concentration of adimanebart over time was quantified and presented on a semi‐logarithmic scale. The lower limit of quantification for adimanebart is 20 ng/mL. IV, intravenous; MAD, multiple ascending dose; SAD, single ascending dose; SC, subcutaneous.

Table 4.

Adimanebart PK Parameters by Dose Group: Part A (SAD; PK Analysis Set)

	Adimanebart IV									Adimanebart SC
	Cohort A01 0.005 mg/kg (n = 4)	Cohort A02 0.025 mg/kg (n = 4)	Cohort A03 0.1 mg/kg (n = 6)a	Cohort A04 0.3 mg/kg (n = 6)	Cohort A05 0.9 mg/kg (n = 6)	Cohort A06 2.5 mg/kg (n = 6)	Cohort A07 5.0 mg/kg (n = 6)	Cohort A08 10.0 mg/kg (n = 6)	Cohort A09 15.0 mg/kg (n = 6)	Cohort A10 5 mg/kg (n = 6)
Cmax (µg/mL), GM (CV%)	0.10 (6.5)	0.48 (8.8)	2.40 (21.1)	5.86 (14.5)	19.1 (22.6)	51.4 (9.6)	96.6 (25.0)	239 (12.7)	342 (10.0)	35.8 (38.6)
Tmax (h), median (min, max)	1.00 (1.00, 1.05)	1.00 (1.00, 3.00)	1.01 (1.00, 2.02)	2.00 (1.02, 3.00)	2.01 (1.00, 8.00)	2.01 (1.03, 24.00)	3.00 (1.03, 4.00)	2.00 (1.00, 6.02)	3.00 (1.00, 4.03)	120.01 (96.00, 338.42)
AUC0‐168 h (h x µg/mL) GM (CV%)	6.3 (24.7)	39.3 (10.3)	206 (22.2)	567 (16.8)	1,736 (17.1)	5,265 (11.4)	9,789 (20.0)	22,811 (12.7)	29,893 (5.5)	4,329 (51.1)
AUC0‐inf (h x µg/mL) GM (CV%)	7.6 (37.0)	74.9 (19.3)	453 (14.0)	1,779 (10.7)	7,388 (14.6)	22,400 (13.7)	51,353 (12.8)	99,778 (29.4)	144,634 (9.7)	32,402 (27.2)
t1/2 (h) GM (CV%)	61.8 (30.8)	177 (24.1)	228 (17.9)	264 (10.0)	351 (12.0)	409 (24.0)	543 (18.9)	550 (18.9/0	536 (11.9)	468 (21.4)
CL(/F) (L/h) GM (CV%)	0.050 (27.9)	0.024 (7.5)	0.016 (10.1)	0.012 (17.5)	0.010 (15.9)	0.010 (10.7)	0.007 (15.8)	0.008 (25.3)	0.008 (8.3)	NR
Vz(/F) (L) GM (CV%)	4.50 (11.7)	6.09 (16.8)	5.11 (23.0)	4.59 (23.6)	4.82 (14.9)	5.36 (24.2)	5.73 (26.9)	6.10 (24.8)	6.35 (19.8)	NR

AUC_0‐168 h, area under the concentration–time curve from time 0 to 168 h after administration; AUC_0‐inf, area under the concentration–time curve from time 0 extrapolated to infinity; CL, clearance; CL/F, apparent clearance after extravascular administration; C_max, maximum concentration; GM, geometric mean; h, hour(s); IV, intravenous; max, maximum; min, minimum; N, planned number of participants per cohort; NR, not reported; PK, pharmacokinetic; SAD, single ascending dose; SC, subcutaneous; t_1/2, apparent terminal half‐life; T_max, time to C_max; Vz, volume of distribution; Vz/F, apparent volume of distribution after extravascular administration.

^a One participant in cohort A03 had an aberrant time–concentration profile, and AUC_0‐inf, t_1/2, CL, and Vz could not be calculated for the participant. A sensitivity analysis was performed to determine the impact of the participant's PK data on the analysis; overall, PK parameters were slightly lower when the participant's data were excluded.

Across the dose range tested in Part A, C_max increased dose‐proportionally (geometric mean range, 0.1 to 342 µg/mL) and AUC_0‐inf increased more than dose‐proportionally, up to ≈6‐fold (Figure 2). In accordance with these observations, the volume of distribution (Vz) remained constant with increasing doses, whilst clearance (C_L) decreased with higher doses, confirming the nonlinear PK of adimanebart (Table 4). The geometric mean elimination t_1/2 ranged from 2.6 to 22.9 days across the dose levels 0.005 to 15 mg/kg (Table 4). As expected, C_max was lower after SC administration than after IV administration at the same dose level of 5 mg/kg (Table 4). The absolute bioavailability of 5 mg/kg adimanebart SC was 63% (90% confidence interval, 51, 79) based on AUC_0‐inf. In Part B (MAD), geometric mean C_max ranged from 7.0 to 108 µg/mL after the first IV dose of adimanebart and 12.2 to 221 µg/mL after the fourth dose (Table 5). In both Parts A and B, the time to achieve C_max (T_max) was 1 to 4 h after the start of infusion (Tables 4 and 5).

Figure 2.

Dose proportionality in Part A (SAD cohorts). Individual participant (open blue circles) and geometric mean (closed red circles) C_max and AUC_0‐inf values were calculated and plotted against dose (mg/kg). AUC_0‐inf, area under the concentration–time curve from 0 to infinity; C_max, maximum concentration; D, days; IV, intravenous; SAD, single ascending dose.

Table 5.

Adimanebart PK Parameters by Dose Group: Part B (MAD; PK Analysis Set)

		Adimanebart IV Once Weekly
Visit	Parameter	Cohort B01 0.3 mg/kg (N = 6)	Cohort B02 0.9 mg/kg (N = 8)	Cohort B03 2.5 mg/kg (N = 7)	Cohort B04 5.0 mg/kg (N = 6)
Day 1	Cmax (µg/mL) GM (CV%)	7.00 (7.7)	21.1 (19.1)	66.5 (15.6)	108 (16.1)
	Tmax (h) Median (min, max)	3.00 (2.00, 6.02)	4.00 (1.02, 8.02)	2.02 (1.00, 3.00)	2.50 (1.00, 6.00)
	AUC0‐168 h (h x µg/mL) M (CV%)	608 (14.2)	1725 (15.2)	5,G872 (12.6)	10,085 (18.1)
Day 8	Cmax (µg/mL) GM (CV%)	9.39 (12.8)	27.8 (24.6)	88.1 (12.4)	161 (11.2)
	Tmax (h) Median (min, max)	1.02 (1.02, 1.03)	1.00 (1.00, 24.00)	1.00 (1.00, 24.00)	1.00 (1.00, 1.05)
	AUC0‐168 h (h x µg/mL) GM (CV%)	997 (14.8)	3,145 (16.6)	9,759 (7.5)	17,847 (7.6)
Day 15	Cmax (µg/mL) GM (CV%)	10.2 (19.4)	31.7 (32.7)	104 (17.3)	202 (7.0)
	Tmax (h) Median (min, max)	12.51 (1.02, 24.02)	12.50 (1.00, 24.00)	1.00 (1.00, 1.13)	1.00 (1.00, 1.05)
	AUC0‐168h (h x µg/mL) GM (CV%)	1,223 (21.6)	3,685 (15.1)	11,878 (14.1)	21,979 (9.0)
Day 22	Cmax (µg/mL) GM (CV%)	12.2 (17.0)	37.3 (15.4)	123 (11.9)	221 (14.9)
	Tmax (h) Median (min, max)	1.53 (1.00, 8.03)	2.00 (1.02, 3.02)	2.01 (1.00, 4.00)	2.51 (1.02, 4.02)
	AUC0‐168 h (h x µg/mL) GM (CV%)	1,430 (19.4)	4,500 (13.5)	14,065 (11.6)	26,249 (11.3)
	RCmax, GM (CV%)	1.74 (11.6)	1.85 (16.0)	1.82 (12.5)	2.05 (19.0)
	RAUC0‐168 h, GM (CV%)	2.35 (16.4)	2.75 (4.8)	2.35 (14.3)	2.60 (17.4)

AUC_0‐168 h, area under the concentration–time curve from time 0 to 168 h after administration; C_max, maximum concentration; GM, geometric mean; h, hour(s); IV, intravenous; MAD, multiple ascending doses; max, maximum; min, minimum; N, planned number of participants per cohort; PK, pharmacokinetics; R_{AUC0‐168 h}, accumulation ratio of the area under the concentration–time curve from time 0 to 168 h after administration; RC_max, accumulation ratio of the maximum plasma concentration; T_max, time to C_max.

Immunogenicity

In Part A, positive ADA baseline samples were reported in 2 (2.6%) participants: 1 who received 5.0 mg/kg IV adimanebart, 1 who received IV placebo. ADAs were detected in participants receiving adimanebart IV (0.1 mg/kg [n = 1], 0.3 mg/kg [n = 2], 2.5 mg/kg [n = 1], 10 mg/kg [n = 2], and 15 mg/kg [n = 2]), placebo IV (n = 3), and adimanebart SC (n = 1). The incidence and prevalence of adimanebart ADAs were comparable between IV adimanebart (n = 50) and IV placebo (n = 18) treatment groups (16.0% and 18.0% [adimanebart] versus 16.7% and 22.2% [placebo], respectively). The route of administration did not impact the incidence or prevalence of ADAs (both 16.7% in adimanebart SC participants; none detected in the placebo SC cohort). No ADAs against adimanebart were detected in any participant in the Part B cohorts.

Discussion

Here, we have reported the MABEL approach for dose selection using functional readouts of nonclinical models and the outcomes of a FIH Phase I study that will be used to support the clinical development of adimanebart to treat patients with neuromuscular diseases.

To support the selection of a safe human starting dose and dose‐escalation scheme in the absence of a pharmacodynamic marker, minimum anticipated human doses were determined on the basis of nonclinical, in vivo efficacy mouse models, using body surface area‐based allometry and population PK models. The estimated safety margins for the planned FIH doses of adimanebart were calculated based on exposure values at the NOAEL in the 6‐week toxicity study in nonhuman primates (NHPs).

In healthy participants, adimanebart demonstrated a dose‐proportional increase in C_max and a more‐than dose‐proportional increase in AUC_0‐inf after a single dose of adimanebart IV and a nonlinear PK at low doses. This PK profile in healthy participants indicates a main elimination pathway of target‐mediated drug disposition and target engagement, and its consistency with observations in nonclinical mouse, rat, and NHP studies ¹⁷ suggests a common PK behavior across species. Furthermore, the observed AUC_0‐inf was within an average 1.3‐fold (range, 1.0 to 1.8‐fold) of the prediction based on the NHP model and used for human starting dose selection. After single and multiple dosing, T_max occurred 1 to 4 h after infusion start. Observed C_max values at later time points were similar to the theoretical end of infusion maximum, suggesting an early post infusion concentration plateau. Minor assay variability may therefore lead to different T_max values within this window. In this study, the observed exposure at the starting dose, which was defined by the MABEL approach, was in line with the predicted human exposure with the NHP model.

There was no apparent impact of ADAs against adimanebart on PK, with similar profiles observed between ADA‐positive and ADA‐negative participants. Nonetheless, given the low number of participants with adimanebart‐specific ADAs in this study, immunogenicity data should be interpreted cautiously. Adimanebart was well tolerated at all doses investigated and has a favorable safety profile in healthy participants at the doses investigated in this FIH Phase I study.

In conclusion, this Phase I, FIH study demonstrated that the predicted PK of adimanebart, based upon nonclinical functional readouts and an NHP PK model, was achieved and confirms the MABEL approach to be a feasible method for adimanebart dose selection. Adimanebart was shown to have target‐mediated drug disposition, and thus target engagement, at low concentrations. The favorable safety profile and no apparent impact of adimanebart‐specific ADAs support the development of adimanebart, the first agonistic monoclonal antibody targeting human MuSK, as a potential treatment for patients with disorders of the NMJ. Data from this FIH study supported initiation of the double‐blinded, randomized, placebo‐controlled studies to evaluate the safety, tolerability, PK, immunogenicity, and efficacy of adimanebart in adults with DOK7‐CMS (Phase Ib; NCT06436742) and SMA (Phase II SPARKLE Study; NCT07287982).

Author Contributions

Tonke van Bragt, Christa Kneip, Xinghong Leng, Rachelle Mutch, Sonya K. Patel, Peter Vanhoenacker, Cristina Vaghi, Sven Hoefman, Rebecca Shilling, and Roeland Vanhauwaert cowrote the manuscript. Tonke van Bragt, Xinghong Leng, Sven Hoefman, Rebecca Shilling, and Roeland Vanhauwaert designed the research. Rachelle Mutch, Sonya K. Patel, Rebecca Shilling, and Roeland Vanhauwaert performed the research. Tonke van Bragt, Christa Kneip, Sofie Priem, Rachelle Mutch, Cristina Vaghi, Rebecca Shilling, and Roeland Vanhauwaert analyzed the data. Sofie Priem and Roeland Vanhauwaert designed and executed nonclinical safety strategy. Peter Vanhoenacker contributed new reagents/analytical tools.

Conflicts of Interest

Tonke van Bragt is a Partner of Curare Consulting B.V. and holds equity in argenx. Christa Kneip, Sofie Priem, Xinghong Leng, Sonya K. Patel, Peter Vanhoenacker, Cristina Vaghi, Rebecca Shilling, and Roeland Vanhauwaert are all employees of argenx and holders of employee equity in argenx. Rachelle Mutch has no disclosures to declare. Sven Hoefman is a Consultant at LAP&P.

Funding

This study was funded by argenx, Ghent, Belgium. The funders designed the trial; collected, analyzed, and interpreted the data; and supported the manuscript development.

Supporting information

Supporting Information

Data Availability Statement

The datasets presented in this article are not readily available but can be requested by qualified researchers who engage in rigorous independent scientific research. Access can be provided after review and approval of a research proposal and statistical analysis plan and execution of a data sharing agreement. Data requests can be submitted at any time, and the data will be accessible for 12 months. argenx is committed to responsible data sharing regarding the clinical trials they fund. Included in this commitment is access to anonymized individual and trial‐level data (analysis datasets) and other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. Requests to access the datasets should be directed to ESR@argenx.com.