Safety, Tolerability, and Pharmacokinetics of Single Doses of Exidavnemab (BAN0805), an Anti-α-Synuclein Antibody, in Healthy Western, Caucasian, Japanese, and Han Chinese Adults

Abstract

Exidavnemab is a monoclonal antibody (mAb) with a high affinity and selectivity for pathological aggregated forms of α-synuclein and a low affinity for physiological monomers, which is in clinical development as a disease-modifying treatment for patients with synucleinopathies such as Parkinson's disease. Safety, tolerability, pharmacokinetics, immunogenicity, and exploratory biomarkers were assessed in two separate Phase 1 single ascending dose studies, including single intravenous (IV) (100 to 6000 mg) or subcutaneous (SC) (300 mg) administration of exidavnemab in healthy volunteers (HVs). Across the two studies, a total of 98 Western, Caucasian, Japanese, and Han Chinese HVs were enrolled, of which 95 completed the study. Exidavnemab was generally well tolerated. There were no serious adverse events or safety issues identified in laboratory analyses. Headache, asymptomatic COVID-19, back pain, and post lumbar puncture syndrome were the most frequently reported treatment-emergent adverse events. Following IV infusion, the pharmacokinetics of exidavnemab was approximately dose linear in the range 100-6000 mg. The terminal half-life was approximately 30 days, and the exposure was comparable across Western, Caucasian, Japanese, and Han Chinese volunteers. The absolute SC bioavailability was ∼71%. Cerebrospinal fluid exposure relative to serum after single dose was within the range expected for mAbs (approximately 0.2%). The anti-drug antibody rates were low and there was no effect of immunogenicity on the pharmacokinetics or safety. Dose-dependent reduction of free α-synuclein in plasma was observed. In summary, exidavnemab was found to have an excellent pharmacokinetic profile and was well tolerated in HVs, supporting the continued clinical development.

Introduction

Neuronal aggregates of misfolded, pathological species of α-synuclein in Lewy bodies and Lewy neurites are a common pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A common definition for these phenotypically defined clinical entities as “Neuronal Synuclein Disease” (NSD) has recently been proposed^{1, 2} to enable a biological framework to track disease progression and enable development of therapies including those specifically intended to target α-synuclein and thereby slow disease progression.

The prevalence of PD and DLB are increasing and may affect more than 10 million people and their families worldwide,^{3, 4} a number which is projected to increase due to a higher diagnosis rate³ as well as an increasing life expectancy.⁵ The available pharmacological treatments for PD focus on symptom management mainly by targeting the dopaminergic pathway, whereas the symptomatic treatments for DLB mainly address cognitive issues and have adopted treatment options shown to be efficacious in Alzheimer's disease, such as the acetylcholine esterase inhibitors. There is a major unmet need for a disease-modifying treatment for patients with PD and DLB to address the underlying pathophysiology of these NSD conditions.

Therapeutic approaches that act on the underlying pathophysiology of PD and DLB have the potential to slow disease progression. Pathological, genetic, and mechanistic data suggest that accumulation of aggregated α-synuclein plays a key role in the pathogenesis of PD.⁶ Consequently, investigating potential disease modification through removal of aggregated α-synuclein by immunotherapy has become one of the highest priority therapeutic targets in PD.

A large Phase 2b study in subjects with early PD is ongoing with the α-synuclein monoclonal antibody (mAb) prasinezumab,⁷ guided by some indications of improvement in motor impairment in an initial Phase 2a study.⁸ Phase 2 clinical studies are also ongoing in patients with multiple system atrophy (MSA) with the α-synuclein antibodies Lu AF82422 and TAK-341.^{9, 10}

Exidavnemab (BAN0805, ABBV-0805) is a humanized IgG4 mAb that binds to a broad spectrum of aggregated α-synuclein, including small and large aggregates of different conformations.¹¹ Exidavnemab has a very high affinity (KD = 18 pM) and more than 100,000-fold selectivity for pathological aggregated forms of α-synuclein versus monomers, thus enabling a high target engagement of pathological α-synuclein aggregates in the CNS while sparing the physiological monomers.¹¹ Binding of exidavnemab to pathological α-synuclein has further been demonstrated in post-mortem brains of patients with PD, and the murine version of exidavnemab (mAb47) dose-dependently decreased α-synuclein aggregates, delayed the development of motor symptoms, and prolonged survival in mouse models.¹²

Here we present the results from two Phase 1 single dose studies (Study M19-034 and Study M19-465) conducted to investigate safety, tolerability, pharmacokinetics, and immunogenicity of exidavnemab in healthy Western, Caucasian, Japanese, and Han Chinese volunteers after intravenous or subcutaneous administration. Both studies were conducted by AbbVie Inc. under a license agreement with BioArctic, with exidavnemab referred to as ABBV-0805.

Methods

Study Oversight

Studies M19-034 and M19-465 were designed and conducted in compliance with the Declaration of Helsinki and with International Conference on Harmonization Good Clinical Practice guidelines. The study protocols, informed consent documentation, and subject information and/or advertising were reviewed and approved by qualified institutional review boards (IRBs): IntegReview (Austin, TX) reviewed the M19-034 study and Quorum Review Inc IRB (now Advarra, Columbia, MD) reviewed the M19-465 study.

Study M19-034 was conducted at AbbVie Clinical Pharmacology Research Unit (Grayslake, IL). Study M19-465 was conducted at West Coast Clinical trials (WCCT) Global Inc. (Cypress, CA). All study volunteers signed the written informed consent prior to any study-related procedures.

Study Design and Participants

Study M19-034 was a Phase 1, single center, randomized, double-blind, placebo-controlled single ascending dose (SAD) study in healthy Western (of Caucasian, Black, or Multiple race) volunteers. Study M19-465 was a Phase 1, open-label, single center study in healthy Japanese, Han Chinese, and Caucasian (not including Hispanic ethnicity) volunteers.

In both studies, male and female volunteers in general good health, aged 18-65 years and with a body mass index (BMI) ≥18.0 to ≤32.0 kg/m² were selected to participate in the study.

Healthy volunteers (HVs) in both studies received single IV infusion or SC injection of exidavnemab or placebo as described in Figure 1. Briefly, 50 Western HVs (Study M19-034) were randomized in five IV dose groups (N = 8/group; 6 active:2 placebo, except 6000 mg where N = 12; 9 active:3 placebo) and one SC group (N = 6; 4 active:2 placebo).

Figure 1

Study design overview (Studies M19-034 and M19-465 combined).

In Study M19-465, Japanese (N = 32), Han Chinese (N = 8), and Caucasian (N = 8) HVs received exidavnemab in an open-label manner. Japanese HVs were randomized in four dose groups (N = 8/group) to receive a single IV infusion of exidavnemab (300, 1000, 3000, and 6000 mg). Both Han Chinese (N = 8) and Caucasian (non-Hispanic, N = 8) HVs were dosed with single 3000 mg IV exidavnemab.

The SC dose of 300 mg (Study M19-034) in Western HVs was administered in the abdomen (3 × 100 mg) and was not dosed until the evaluation of the safety and tolerability of the IV 300 mg dose was completed.

The HVs were confined to the study site and supervised for approximately 9 days (initial confinement through Study Day 8). Confinement ended after collection of the 168-h blood samples and completion of scheduled study procedures on Study Day 8.

The blood sampling for pharmacokinetics, and immunogenicity was collected by venipuncture pre- and post-dose up to 140 days (168 days for 6000 mg group in M19-034) or early termination. Blood for biomarker analysis and cerebrospinal fluid (CSF) samples was only collected in Study M19-034. For CSF collection, two lumbar punctures were performed, on the day prior to dosing and on Day 7, respectively. Details on sampling times are provided in Table S1.

Bioanalytical Methods

Exidavnemab Concentrations in Serum and CSF

Concentrations of exidavnemab in serum and CSF were measured using a validated bridging electrochemiluminescence (ECL) immunoassays based on biotinylated and Sulfo-Tag-labeled polyclonal anti-exidavnemab idiotypic antibodies as capture and detection reagents. Calibration standard and quality control (QC) samples were prepared by diluting exidavnemab in 100% human blank serum or 100% surrogate CSF matrix and the minimal required dilution (MRD) was set to 1:10. For the serum assay, the lower limit of quantification (LLOQ) was 50 ng/mL and the upper limit of quantification (ULOQ) was 1500 ng/mL in neat serum. Intra- and interassay precision at validation was 4.8%-9.1% CV and 5.5%-14.4% CV, respectively. For the CSF assay, the LLOQ was 19.8 ng/mL and the ULOQ was 1480 ng/mL in 100% surrogate CSF matrix. The intra- and interassay precision was 3.2%-6.2% CV and 3.4%-7.4% CV, respectively.

ADA in Serum

The determination of anti-drug antibodies (ADA) for exidavnemab included an initial screening assay to identify possible positive ADA samples, a confirmatory assay to evaluate whether the ADA were specific to exidavnemab and a titration assay to estimate the levels of positive ADA in a sample. ADA were assessed in serum using a quasi-quantitative validated bridging ECL immunoassay. Serum samples were pre-treated with acetic acid (resulting in an MRD of 1:10) to separate any drug/ADA complexes, followed by incubation with biotinylated and Sulfo-tagged exidavnemab to form bridging complexes. These protein complexes were added into a Mesoscale Discovery (MSD) streptavidin-coated ECL plate following incubation, wash, and reading steps. The relative light units (RLUs) measured were proportional to the number of bridging complexes produced. As authenticated control material, a polyclonal anti-exidavnemab idiotypic antibody was used. The relative sensitivity was 9.03 and 13.87 ng/mL in neat human serum for the screening and titration cut point, respectively. Positive samples from the screening assay based on a plate-specific cut point were confirmed by achieving suppression of ≥10.82% following the addition of 100 μg/mL exidavnemab. The titer of a positive sample was determined by diluting the sample until below the titration cut point. The titer was set to the MRD (titer = 10) if the analytical result was between the screening and the titer cut point.

Total and Free α-Synuclein in Plasma

Total and free α-synuclein were measured as exploratory readouts in plasma in Study M19-034. Free α-synuclein is the unbound α-synuclein, while the total α-synuclein is the sum of the free α-synuclein and the α-synuclein bound to the antibody. Samples were pre-treated as described below and the supernatants were analyzed in accordance with the manufacturer's protocol using the ELISA kit from Biolegend (cat. no. 844101). For the measurement of total α-synuclein, plasma samples were diluted 1:10. The diluted samples were heat denatured for 10 min at 99°C followed by a centrifugation step of 2000 × g for 3 min prior to analysis. For the measurement of free α-synuclein, pre-treatment of plasma samples included an immunodepletion step using protein A/G magnetic agarose beads. Hemoglobin levels were determined in plasma samples using the Human Hemoglobin ELISA Kit from Abcam (cat. no. ab57707). Samples with hemoglobin levels ≥0.1 g/L were omitted from further calculations, to avoid contamination of α-synuclein from erythrocytes.13

Pharmacokinetic Assessments

The pharmacokinetic parameters of exidavnemab in both studies, including the maximum observed serum concentration (C_max), the time to C_max (T_max), terminal phase elimination rate constant (β), terminal phase elimination half-life (t_1/2), the area under the serum concentration–time curve (AUC) from time 0 to the time of the last measurable concentration (AUC_t), AUC from time 0 to infinite time (AUC_inf), clearance (CL), and the volume of distribution during the terminal phase (V_z), were determined using standard non-compartmental methods, using Phoenix WinNonlin, version 8.3 (Certara). Descriptive statistics and analyses were performed using SAS Version 9.4 (SAS Institute Inc., Cary, NC).

Safety Assessments

The following safety evaluations were performed in both studies: adverse event (AE) monitoring, physical examinations, vital signs measurements, electrocardiogram (ECG) variables, clinical laboratory testing, and Columbia-Suicide Severity Rating Scale (C-SSRS). AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 24.1). HVs reporting more than one AE for a given MedDRA preferred term were only counted once for that term using the most severe incident. HVs reporting more than one type of event within a System Organ Class (SOC) were only counted once for that SOC.

In Study M19-034, infusion reactions were considered as Adverse Events of Special Interest (AESI). This included signs and symptoms as well as clinical parameters related to any event of an anaphylactic reaction or other suspected systemic hypersensitivity reaction.

The analysis for safety data was performed on the Safety Analysis Set in each study which contained data from all HVs who were administered any amount of study drug. HVs were included in the analysis according to the study drug that they received, and were classified by dose level. The placebo data of the several IV groups were combined, and placebo was regarded as a dose level.

Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 24.1). Separate summaries for IV administration and SC administration were generated. The number and percentage of HVs reporting treatment-emergent adverse events (TEAEs) were tabulated by MedDRA preferred term (PT) and SOC with a breakdown by dose level. The tabulation of the number of HVs with TEAEs also were provided with further breakdowns by severity rating (mild, moderate, or severe) and by whether or not the TEAE was possibly related to study drug. Infusion reactions were considered as AEs. Laboratory test values and measurements on vital signs that were potentially clinically significant were identified. All laboratory data from samples collected after the beginning of study drug infusion and all measurements on vital signs after the beginning of study drug infusion were assessed against the criteria for potentially clinically significant values. For blood pressure, pulse rate, and quantitative laboratory data, descriptive statistics were provided for the baseline measurement and for each scheduled time of measurement after the initiation of study drug administration. This was done with a breakdown by ethnicity and, for Japanese HVs, by dose level.

Results

Demographics

In Study M19-034, a total of 50 HVs (N = 50) were enrolled, of which 49 completed the study, including 37 HVs who received exidavnemab (all of whom completed the study). One HV in the IV placebo group did not respond for follow-up information regarding adverse event resolution subsequent to the last study visit date. In Study M19-465 a total of 48 HVs (N = 48) were enrolled, and 46 HVs completed the study. Two Caucasian HVs in the 3000 mg cohort withdrew consent from the study (Table S2).

A summary of demographics of the participants in both studies is provided in Table 1.

Table 1. Demographics

	Exidavnemab SAD Study M19-034								Exidavnemab Asian Study M19-465
									IV
	IV						SC		Jap				HC	Cau
Variable	Placebo (N = 11)	100 mg (N = 6)	300 mg (N = 6)	1000 mg (N = 6)	3000 mg (N = 6)	6000 mg (N = 9)	Placebo (N = 2)	3 × 100 mg (N = 4)	300 mg (N = 8)	1000 mg (N = 8)	3000 mg (N = 8)	6000 mg (N = 8)	3000 mg (N = 8)	3000 mg (N = 8)
Age, years
Mean (SD)	48.0 (11.36)	47.0 (11.78)	46.0 (11.87)	48.3 (9.73)	37.3 (6.50)	43.3 (11.66)	46.0 (15.56)	60.8 (5.12)	48.4 (10.54)	48.6 (8.53)	42.4 (10.66)	53.6 (9.84	56.0 (8.28)	56.0 (8.28)
Median	48.0	49.0	45.5	49.5	37.0	38.0	46.0	61.5	52.0	52.0	39.5	56.0	59.0	44.5
Min–max	32, 63	31, 58	31, 59	32, 58	30, 47	30, 61	35, 57	54, 66	33, 59	35, 57	27, 59	38, 64	38, 63	20, 56
Weight, kg
Mean (SD)	81.8 (13.04)	80.1 (10.61)	81.1 (10.07)	82.2 (14.20)	79.2 (9.29)	83.1 (17.24)	82.8 (13.86)	83.3 (12.03)	80.8 (20.16)	67.2 (6.96)	68.3 (10.33))	64.6 (12.20)	82.8 (10.01)	76.2 (11.46)
Median	83.0	81.0	82.4	81.8	76.7	87.5	82.8	82.0	84.9	67.8	70.2	70.1	79.8	77.0
Min–max	62.6, 101.6	64.8, 93.1	67.3, 94.5	60.7, 101.1	69.7, 92.1	59.7, 118.3	73.0, 92.6	70.8, 98.5	45.4, 103.0	54.9, 75.5	53.8, 80.4	42.4, 77.2	68.0, 97.6	56.2, 90.8
Sex
Female n (%)	3 (27.3)	0	1 (16.7)	2 (33.3)	0	3 (33.3)	0	2 (50.0)	2 (25.0)	2 (25.0)	1 (12.5)	4 (50.0)	1 (12.5)	0
Male n (%)	8 (72.7)	6 (100)	5 (83.3)	4 (66.7)	6 (100)	6 (66.7)	2 (100)	2 (50.0)	6 (75.0)	6 (75.0)	7 (87.5)	4 (50.0)	7 (87.5)	8 (100)
Race
Caucasian n (%)^a	7 (63.6)	5 (83.3)	4 (66.7)	4 (66.7)	4 (66.7)	5 (55.6)	1 (50.0)	4 (100)	0	0	0	0	0	8 (100)
Black/African American n (%)	2 (18.2)	1 (16.7)	2 (33.3)	2 (33.3)	2 (33.3)	2 (22.2)	1 (50.0)	0	0	0	0	0	0	0
Multiple	2 (18.2)					2 (22.2)
Asian n (%)	0	0	0	0	0	0	0	0	8 (100)	8 (100)	8 (100)	8 (100)	8 (100)	0

• Note: For the purposes of comparison with the Japanese/Han Chinese/Caucasian groups in Study M19-465, healthy volunteers in Study M19-034 were given the collective term “Western” as a descriptor.
• Cau, Caucasian; HC, Han Chinese; IV, intravenous; Jap, Japanese; min, minimum; max, maximum; SC, subcutaneous.
• ^a Healthy volunteers of Hispanic ethnicity (n = 4) were included in Study M19-034 but not in Study M19-465.

Pharmacokinetics

The geometric mean serum concentration–time profiles for exidavnemab following IV and SC administration from the two trials in healthy volunteers are presented in Figure 2. The systemic exposure of exidavnemab increased with increase in dose from 100 to 6000 mg in Western HVs (Figure 2a) and from 300 to 6000 mg in Japanese HVs (Figure 2b). The mean serum concentration–time profiles at 3000 mg IV were comparable across the Western, Caucasian, Japanese, and Han Chinese populations (Figure 2b).

Figure 2

Serum exidavnemab concentration versus time profiles following intravenous or subcutaneous single dose in healthy Western (a, Study M19-034) and in Caucasian, Japanese, and Han Chinese subjects (b, Study M19-465). Data presented as geometric mean ± SD.

A summary of the pharmacokinetic parameters after administration of exidavnemab is presented in Table 2. After a single IV dose, the C_max of exidavnemab were achieved between 1.7 and 6.0 h, while following SC administration, the C_max was achieved around 144 h (range 120-168 h) and was approximately three-fold lower compared to 300 mg IV (30.4 μg/mL vs 87.4 μg/mL) (Table 2). The estimated absolute bioavailability of the 300 mg SC dose was 71%. The mean t_1/2 for exidavnemab was approximately 30 days (range 24 to 34 days) and was consistent across the doses, populations, and administration routes (Table 2). Following IV administration in Western and Japanese HVs, exidavnemab exposures (C_max and AUC) increased in an approximately dose-proportional manner in the range 100 to 6000 mg (Table 2 and Figure 3). As demonstrated in Figure 3, dose-normalized AUC_inf and C_max are similar across doses, studies, and populations, supporting approximately dose-linear pharmacokinetics of exidavnemab.

Table 2. Pharmacokinetic Parameters (Geometric Mean [% CV]) of Exidavnemab From Phase 1 Trials M19-034 and M19-465

Clinical Trial	Subjects	Exidavnemab Dose (n)	Route	Cmax (μg/mL)	Tmax (h)^a	AUCt (μg·h/mL)	AUCinf (μg·h/mL)	CL (L/h)	Vz (L)	t1/2 (h)^b
M19-034	Western	100 mg (6)	IV	34.7 (55)	4.0 (0.08-6)	14300 (10)	15100 (9)	0.00662 (8)	6.6 (21)	679 (157)
		300 mg (6)	IV	87.4 (7)	4.0 (0.25-10)	44600 (8)	46400 (9)	0.00646 (9)	6.3 (21)	655 (128)
		1000 mg (6)	IV	254 (16)	3.3 (0.6-6.0)	152000 (22)	166000 (32)	0.00604 (27)	7.1 (23)	745 (661)
		3000 mg (6)	IV	675 (32)	4.0 (4-14)	388000 (18)	407000 (18)	0.00736 (21)	6.4 (23)	588 (281)
		6000 mg (9)	IV	2340 (22)	6.0 (2.8-24)	1080000 (32)	1120000 (33)	0.00537 (33)	5.2 (25)	665 (93)
		300 mg (4)	SC	30.4 (11)	144 (120-168)	31300 (47)	33000 (56)	0.0091 (35)^d	9.1 (26)^d	655 (338)
M19-465	Japanese	300 mg (8)	IV	99 (22)	5.0 (1.8-14)	37200 (40)	38900 (41)	0.00772 (44)	8.3 (30)	726 (212)
		1000 mg (8)	IV	335 (15)	1.8 (1.7-6)	168000 (27)	181000 (28)	0.00551 (25)	6.7 (30)	808 (247)
		3000 mg (8)	IV	996 (13)	1.7 (1.6-14)	540000 (18)	570000 (20)	0.00526 (24)	6.0 (14)	772 (140)
		6000 mg (8)	IV	1910 (23)	3.6 (3.0-14)	1040000 (24)	1100000 (25)	0.00545 (26)	6.5 (21)	821 (109)
	Caucasian	3000 mg (8^c)	IV	932 (22)	4.0 (1.7-14)	505000 (19)	541000 (21)	0.00567 (21)	6.9 (29)	810 (190)
	Han Chinese	3000 mg (8)	IV	847 (15)	2.9 (1.8-14)	457000 (27)	479000 (29)	0.00627 (23)	6.5 (18)	716 (102)

• Note: AUC_t was calculated as the area under the serum concentration–time curve from time zero to the last measurable concentration in Trial M19-034. In Trial M19-465 AUC_t was calculated as the area under the serum concentration–time curve from time zero to the time of the serum concentration on Day 141.
• Note: Parameters are rounded to three significant figures.
• AUC_inf, area under the concentration versus time curve to infinity; CL, clearance; C_max, maximum concentration; IV, intravenous; SC, subcutaneous; t_1/2, terminal half-life; T_max, time at which maximum concentration was reached, V_z, volume of distribution during the terminal phase.
• ^a Median (minimum through maximum).
• ^b Harmonic mean (pseudo-standard deviation). For Trial M19-034 this was calculated as QR/1.349. For Trial M19-465 this was calculated as described in Lam et al.¹⁴
• ^c T_max and C_max only; N=7 for all other parameters. For one subject, blood collections were missed on Day 15 and Days 43 to 141; therefore, only C_max and T_max values were estimated.
• ^d CL/F and V_z/F for SC dosing.

Figure 3

Dose adjusted AUC_inf versus dose (a) and dose adjusted C_max versus dose (b) following an intravenous single dose of exidavnemab. Data presented as mean ± SD.

The exidavnemab CSF exposure relative to serum at 144 h after dose was within the range expected for antibodies (approximately 0.2%).

Anti-Exidavnemab Antibodies

In Study M19-034, one HV had a positive ADA titer (defined as >10 units) post exidavnemab administration. This HV had a positive ADA titer on Day 84 but had negative ADA titers for all other time points. One HV administered placebo also showed positive ADA, and one HV was ADA positive pre-dose. In Study M19-465, four (N = 4) HVs had positive ADA titers, whereof one was positive only pre-dose and not after exidavnemab administration, one HV (6000 mg) was positive both pre- and post-exidavnemab dosing, and two HVs were positive post dosing only (one in 3000 mg and one in 6000 mg) (Table S3).

All positive ADA titers, across both studies, were very low (<30 titer units), and there was no apparent decrease in exidavnemab exposure (AUC_inf) in the ADA positive subjects (Table S3). The low incidence of detectable ADA titers after single dosing does not provide any evidence for an effect of immunogenicity on the PK of exidavnemab.

α-Synuclein in Plasma in Study M19-034

An exploratory analysis of the ratio of free α-synuclein/total α-synuclein in plasma was carried out (based on samples with an acceptable hemoglobin cut off). A dose-dependent reduction in free α-synuclein in plasma, beginning at 300 mg with maximum reduction starting at 1000 mg was observed (Figure S1).

Safety

A total of 98 HVs were enrolled in the Phase 1 exidavnemab program (Study M19-465 and Study M19-034), and 85 HVs received exidavnemab. Across the two studies, the most frequently reported TEAEs (≥5%) were headache (15.3%), asymptomatic COVID-19 (7.1%), back pain (7.1%), and post lumbar puncture syndrome (5.9%) (Table 3). There were no severe AEs, serious adverse events (SAEs), AEs leading to discontinuation, or deaths. Six AEs were considered by the investigator as related to study drug, of which headache was the only AE identified in more than a singular HV. A dose–response relationship was not observed for any of the TEAEs collected in Phase 1 clinical trials with exidavnemab.

Table 3. Most Frequently Reported TEAEs in ≥2 Subjects Treated With Exidavnemab

	TEAE Frequency Assessed as Drug related ^a		Overall TEAE Frequency ^b
SOC PT (MedDRA version 24.1)	Grade ≥ 3 N = 85 n (%)	All Grades N = 85 n (%)	Serious N = 85 n (%)	All Grades N = 85 n (%)
Infections and infestations
Asymptomatic COVID-19	0	0	0	6 (7.1) common
Conjunctivitis	0	0	0	2 (2.4) common
Upper respiratory tract infection	0	0	0	4 (4.7) common
Injury, poisoning, and procedural complications
Post lumbar puncture syndrome	0	0	0	5 (5.9) common
Procedural pain	0	0	0	4 (4.7) common
Musculoskeletal and connective tissue disorders
Back pain	0	0	0	6 (7.1) common
Nervous system disorders
Dizziness	0	0	0	2 (2.4) common
Headache	0	2 (2.4) Common	0	13 (15.3) very common
Respiratory, thoracic, and mediastinal disorders
Nasal congestion	0	0	0	2 (2.4) common
Rhinorrhoea	0	0	0	2 (2.4) common
Skin and subcutaneous tissue disorders
Ecchymosis	0	0	0	3 (3.53) common

• Note: Frequencies are defined as: very common (≥1/10 [≥10%]); common (≥1/100 to <1/10 [≥1% to <10%]); uncommon (≥1/1000 to <1/100 [≥0.1% to <1%]); rare (≥1/10,000 to <1/1000 [≥0.01% to <0.1%]); very rare (<1/10000 [<0.01%]).
• PT, preferred term; SOC, System Organ Class; TEAE, treatment-emergent adverse event.
• ^a Occurrence of the PT (serious and nonserious) assessed as related by either the investigator or the sponsor.
• ^b Occurrence of the PT (serious and nonserious) regardless of relatedness or severity.

One HV in the 1000 mg IV group in Study M19-034 met the criteria for a potentially clinically significant sitting systolic value ≥160 mm Hg and ≥45 mm Hg above baseline value on Day 85. A second measurement taken several minutes later was within the normal range, and no other blood pressure values taken during the study in this HV were abnormal.

No interventions were required for the abnormal blood pressures described. No signs or symptoms were noted to be associated with vital sign abnormalities, and no trends were noted. Moreover, no vital sign abnormalities were reported as AEs, and no other clinically significant findings or patterns were identified from the laboratory, ECG, or vital sign results.

In Study M19-034 the most frequently reported (≥5%) TEAEs for IV administration were headache (21.2%), post lumbar puncture syndrome (15.2%), upper respiratory tract infection (12.1%), procedural pain (12.1%), back pain (12.1%), conjunctivitis (6.1%), dizziness (6.1%), nasal congestion (6.1%), and rhinorrhoea (6.1%). Post lumbar puncture syndrome was defined per MedDRA version 24.1 with no further requirements with respect to duration and severity, all events were transient and resolved without intervention. Headache was the only AE reported in more than one SC exidavnemab HV. Other AEs reported in this group were injection site hemorrhage, insomnia, and nightmares.

None of the TEAEs were serious or severe. No signs or symptoms, trends, or AEs were associated with vital sign abnormalities. A single HV in Group 1 (100 mg) experienced a nonserious, asymptomatic ECG finding of ventricular ectopy on Day 1. The subject had four beats of ectopy (premature junctional beat followed by three ventricular ectopic beats, with an average heart rate <100 bpm). Vital signs were stable and the event resolved on the same day. The telemetry monitoring period was increased from 24 to 48 h post dose, no treatment or further interventions were administered and all subsequent ECG findings were normal. One HVs had a QT interval corrected for heart rate using Fridericia's correction formula >60 ms versus baseline; this observation was not assessed as clinically significant nor associated with an AE.

There are no other clinically significant findings or patterns identified from the laboratory, ECG, or vital sign results.

In Study M19-465, the most frequently reported TEAEs (≥5%) were asymptomatic COVID-19 (12.5%), headache (6.3%), and ecchymosis (6.3%). No clinically significant vital signs, ECG, or laboratory measurements were observed during Study M19-465.

Discussion

This work summarizes the results from the first two clinical studies investigating the safety, tolerability, and pharmacokinetics of exidavnemab, an investigational α-synuclein antibody, in healthy volunteers following single dose.

Overall, following IV infusion, exidavnemab exhibited dose-linear pharmacokinetics in the range 100 to 6000 mg with comparable exposures (C_max and AUC) in Western, Caucasian, Japanese, and Han Chinese HVs. Dose-linear pharmacokinetics has also been observed for other mAbs targeting α-synuclein.^15-17 The elimination half-life of exidavnemab was approximately 30 days and was consistent across the doses, ethnic populations, and administration routes studied. This is longer than what has been reported as expected elimination half-life for IgGs¹⁸ and support monthly dosing. Following subcutaneous administration of 300 mg exidavnemab, the absolute bioavailability was 71%, similar to what has been commonly reported for IgGs.¹⁹ The low incidence of detectable ADA titers after single dosing does not provide any evidence for an effect of immunogenicity on the pharmacokinetics nor safety of exidavnemab.

In the present studies, no safety and tolerability concerns could be identified at single doses up to 6000 mg. The experience to date from other clinical programs with mAbs directed at α-synuclein is still quite limited but has so far not identified evidence of target-related adverse findings on laboratory parameters or AEs. Thus, the safety and tolerability data from the initial clinical studies with exidavnemab is consistent with other programs of mAbs directed at α-synuclein.^{8, 15}

α-synuclein is largely expressed at presynaptic terminals in the brain, influencing presynaptic signaling and membrane trafficking.²⁰ Although α-synuclein is mostly an intracellular protein, it has also been found in extracellular fluids such as CSF, blood, and plasma.²¹ Pathological aggregates of α-synuclein in neurons are the hallmark of NSD, the proposed biologically defined construct which encompasses well-recognized clinical diagnoses such as PD and LBD. Similarly, pathological aggregates of α-synuclein in oligodendroglia characterize the more rare and rapidly progressing condition of MSA.^22-24 The vast majority of the total α-synuclein is present as monomers, rather than pathological aggregates²⁵ and therefore a high affinity and selectivity toward the aggregated species of α-synuclein versus monomers is of key importance for a mAb both when aiming to treat NSD or MSA.

Exidavnemab has a very high affinity (KD = 18 pM) and a more than 100,000-fold selectivity for aggregated forms of α-synuclein versus monomers¹¹ making it an ideal candidate to evaluate the potential of immunotherapy targeting α-synuclein-related neurodegenerative disease. Due to its binding profile, exidavnemab is anticipated to reach a high target engagement of pathological α-synuclein aggregates in the CNS while sparing the physiological monomers. In Study M19-034, an exploratory analysis of the ratio of free α-synuclein/total α-synuclein in plasma was carried out. A dose-dependent reduction in free α-synuclein in plasma (i.e., largely reflecting monomeric forms of α-synuclein), beginning at 300 mg with maximum reduction starting at 1000 mg was observed (Figure S1). With the high affinity and selectivity of exidavnemab toward the aggregated species versus the monomers, this indicates that a high central target engagement for aggregated α-synuclein is likely. In the current studies, the levels of aggregated α-synuclein could not be assessed, primarily as no pathologic α-synuclein aggregates are expected in HVs but in addition assays quantifying aggregated species of α-synuclein represent a major challenge for the α-synuclein field. In future studies in patients, tools that support evaluation of central target engagement, that is, the levels of aggregated forms of α-synuclein in the CNS will be of key importance. Novel sensitive biomarker assays are emerging, such as the seeding amplification assay, SAA, measuring aggregated species of α-synuclein in CSF.^26-28 Development of highly sensitive and specific α-synuclein PET ligands would also represent a huge step forward for the field and progress here is eagerly anticipated as several new ligands have been taken forward into clinical assessment.

Successful clinical programs targeting NSD or MSA may also be able to show evidence of downstream impact on biofluid and neuroimaging biomarkers to substantiate that clinical benefits can plausibly be ascribed to modification of the disease pathophysiology and not a symptomatic effect, as has recently been demonstrated in Alzheimer's disease.^{29, 30} Selection of which biomarkers are appropriate tools needs to be carefully considered with respect to the targeted stage of NSD or MSA.

A clinical study of the safety, tolerability, pharmacokinetics, and biomarkers of multiple dosing of exidavnemab in PD patients will be the next step in the clinical development.

Conclusions

Here we present the results of the first clinical studies investigating the safety, tolerability, and pharmacokinetics of the α-synuclein targeting mAb exidavnemab in healthy volunteers. Exidavnemab was well tolerated in Western, Caucasian, Japanese, and Han Chinese HVs after single doses up to 6000 mg administered IV or SC. The pharmacokinetic profile was approximately dose linear and comparable across Western, Caucasian, Japanese, and Han Chinese HVs, with an elimination half-life of ∼30 days and a low incidence of ADA. The excellent elimination half-life, together with the high affinity and selectivity toward the pathological aggregated forms of α-synuclein is key to maintain a high target engagement within the CNS which speaks in favor of exidavnemab as a future option to treat disorders targeting aggregated α-synuclein. The results from these two initial studies support the continued clinical development of exidavnemab.

Acknowledgments

Gary Faulds is acknowledged for medical writing support.

Conflicts of Interest

Emma Boström, Gunilla Osswald, Mikael Moge, Paulina Appelkvist, Johanna Fälting, and Tomas Odergren are employees of BioArctic and hold BioArctic stock or stock options. Hao Xiong, Cindy Zadikoff, Qingbo Li, Eric Cohen, and Ingeborg Dreher are employees of AbbVie and hold AbbVie stock or stock options. Sagar S. Bachhav is a former employee of AbbVie and holds AbbVie stock or stock options. Anna Torrång is an employee of SDS Life Science AB, a Cytel company, received consultancy fees from BioArctic, but otherwise declares no conflict of interest.

Funding

These studies were sponsored by AbbVie Inc, under a license agreement with BioArctic AB.

Data Sharing

Research data are not shared beyond what is provided in the main article and supplementary materials.

Open Research

Data Availability Statement

Research data are not shared beyond what is provided in the main article and Supplemental Information.