Pharmacokinetics, Immunogenicity, and Safety of a Modified YTE Antibody in Healthy Adults

Abstract

REGN17092, a fully human immunoglobulin (Ig) G1 antibody with M252Y/S254T/T256E (YTE) modification in the Fc portion, was assessed in a first‐in‐human study (ClinicalTrials.gov, NCT05923424). REGN17092 was designed to target the severe acute respiratory coronavirus 2 (SARS‐CoV‐2) S protein. However, due to the emergence of new SARS‐CoV‐2 variants, the program was discontinued. In this single‐center, randomized, placebo‐controlled, single‐ascending‐dose study, participants received a single IV dose of REGN17092 (300, 1200, or 2400 mg) or placebo, or a single SC dose of REGN17092 (300 or 1200) or placebo. Endpoints assessed included pharmacokinetics (PK), safety, and immunogenicity. Allometric scaling was used to predict the terminal half‐life of REGN17092 and to ensure adequate exposure multiples relative to the exposure at the NOAEL. Forty participants were included. Mean concentrations of REGN17092 in serum increased in a dose‐proportional manner and were consistent with linear PK for a single dose administered IV or SC. PK analysis of a single dose of REGN17092 administered IV or SC suggests that REGN17092 has a half‐life of 80–90 days and showed detectable penetration into nasal fluid. No anti‐drug antibody responses were noted. In this Phase 1 study, REGN17092 was tolerable with a long half‐life, highlighting the value of YTE modification.

Monoclonal antibodies are routinely used in the management of many diseases, including cancer, autoimmune diseases, and viral infections, due to their specificity, relative safety, and long circulating half‐lives. ¹ Early in the coronavirus disease 2019 (COVID‐19) pandemic, it was established that neutralizing monoclonal antibodies had the potential for both therapeutic and prophylactic applications. ² Most monoclonal antibodies subsequently developed for the management of COVID‐19 specifically targeted the receptor‐binding domain on the spike protein that allows severe acute respiratory coronavirus 2 (SARS‐CoV‐2), the causative agent for COVID‐19, to interact with the angiotensin‐converting enzyme 2 receptor, thereby preventing the virus from entering the host cell. ² While the effective deployment of COVID‐19 vaccines significantly reduced hospitalizations and deaths due to COVID‐19, many individuals (e.g., those who cannot receive vaccinations or who are immunocompromised) remain at risk of SARS‐CoV‐2 infection, hospitalization, and death. ³ These at‐risk populations may greatly benefit from preventive therapies such as prophylactic monoclonal antibody treatments. Monoclonal antibodies can also be used as a passive immunoprophylactic for rapid protection in unvaccinated individuals or to bolster the immune response of individuals who respond suboptimally to vaccination, such as those with hematologic malignancies or solid organ transplant recipients.

Casirivimab and imdevimab (REGEN‐COV^®, RONAPREVE^®), a combination of two neutralizing monoclonal antibodies administered together in a 1:1 ratio, was developed using the VelociSuite^® technologies by Regeneron Pharmaceuticals, Inc., and was authorized for the treatment and post‐exposure prophylaxis of COVID‐19 in the United States and Europe. ⁴ , ⁵ When given in a prophylactic setting to household contacts of individuals infected with SARS‐CoV‐2, a single 1200 mg dose of casirivimab and imdevimab administered subcutaneously (SC) prevented symptomatic infection in this high‐risk transmission setting. ⁶ During the 7‐month follow‐up period, protection was greatest during Months 2–5, with a 100% relative risk reduction in COVID‐19. ⁷ However, casirivimab and imdevimab was considered unlikely to have activity against Omicron lineage variants and is therefore no longer authorized for use in any US region as of January 24, 2022. ⁸ , ⁹

VelociSuite^® is a proprietary platform of technologies that increases the efficiency of scientific discovery and drug development. VelociSuite^® includes: VelociGene^®, ¹⁰ VelociMouse^®, VelocImmune^®, ¹¹ , ¹² VelociBi^®, VelociHum^®, VelociT^®, and VelociMab^® technologies. ¹³ Leveraging experience from the established VelociSuite^® technology platform, REGN17092 was developed to expand treatment options for COVID‐19 and provide a neutralizing monoclonal antibody with an extended half‐life. REGN17092 is a fully human immunoglobulin (Ig) G1 anti‐spike antibody that binds to an epitope on the S1 domain of the SARS‐CoV‐2 spike protein. It was designed with a triple‐amino‐acid (M252Y/S254T/T256E [YTE]) substitution in the antibody Fc region to increase binding affinity to the neonatal Fc receptor (FcRn) under acidic conditions of the lysosome involved in recycling of IgG molecules. This prevents degradation and extends its elimination half‐life without increasing binding to Fc gamma receptors, ¹ similar to other YTE‐modified antibodies. ³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ This half‐life extension allows for a reduction in both the dose and the frequency of administration, which makes it an attractive option as a prophylactic therapy for long‐term protection against SARS‐CoV‐2 infection in patients who are immunocompromised and cannot mount a protective immune response to vaccines.

Development of REGN17092 was discontinued due to the loss of activity of the drug against newly emerging SARS‐CoV‐2 variants. This study was conducted to guide the development programs of future YTE‐modified monoclonal antibodies developed using the VelociSuite^® technology.

Safety and tolerability of REGN17092 have been presented previously. ¹⁹ Herein, we present the pharmacokinetics (PK) of REGN17092 in serum and nasal fluid, immunogenicity, and safety results across several doses administered intravenously (IV) and SC from the first‐in‐human (FIH) study. In addition, we assess the adequacy of the established scaling factors for engineered monoclonal antibodies with YTE or LS (M428L and N434S) modifications. Although REGN17092 is no longer being developed, the data presented here may help guide future development of monoclonal antibodies for SARS‐CoV‐2 infections, which continue to pose significant health risks across the globe.

Methods

Participants

Eligible participants were male or female adults; aged 18–60 years; with a body mass index of 18–31 kg/m²; who were determined to be healthy according to medical history, physical examination, electrocardiogram (ECG), blood pressure, heart rate, and clinical laboratory profiles in blood and urine; and who had a negative SARS‐CoV‐2 test within 72 h prior to randomization. Participants were required to have completed a primary series of standard‐of‐care COVID‐19 vaccinations per local guidance at least 2 weeks prior to screening. Major exclusion criteria were the presence or history of clinically significant disease or allergies or being pregnant or breastfeeding. Concomitant medications were prohibited, except for the use of oral contraceptives and treatments for adverse events (AEs).

Study Design

This was a Phase 1, single‐center, randomized, placebo‐controlled, single‐ascending‐dose study designed to evaluate the safety, tolerability, immunogenicity, and PK of REGN17092 in healthy adults. The study was conducted between November 28, 2023 (first patient visit) and March 4, 2025 (end‐of‐study visit), in Belgium. The overall study design is illustrated in Figure S1.

The study was approved by the Ethics Committee Research UZ/KU Leuven, Leuven, Belgium. Written informed consent was obtained prior to enrollment. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki, the study protocol, and all applicable national and local laws. All clinical work was conducted in compliance with Good Clinical Practices as referenced in the International Conference on Harmonisation guidelines. The study was registered with ClinicalTrials.gov (NCT05923424) and the EU Clinical Trials Register (EudraCT 2023‐505041‐52‐00).

The study planned to enroll 56 participants randomized into seven cohorts, with four cohorts to receive a single IV dose of REGN17092 (150, 300, 1200, or 2400 mg) or placebo and three cohorts to receive a single SC dose of REGN17092 (150, 300, or 1200 mg) or placebo. Prior to entering the study, participants had a screening visit to establish eligibility within 28 days before study drug administration. Participants were confined to the research unit from Day −1 (1 day prior to drug administration on Day 1) until at least 24 h post dose (Day 2). Participants were discharged on Day 2 after completing all protocol‐specified assessments. After discharge from the research unit, participants were monitored for AEs, and serum samples were periodically collected for the assessment of REGN17092 concentrations and anti‐drug antibodies (ADAs) to REGN17092 over the course of 364 days, in support of to the predicted five terminal half‐lives of the antibody.

The REGN17092 starting dose of 300 mg administered IV and SC was selected based on the casirivimab and imdevimab concentrations in serum predicted to neutralize SARS‐CoV‐2 for a duration of 5 months, adjusted to relative REGN17092 inhibitor concentration activity against the Omicron lineage XBB.1.5 to the original variant and the terminal half‐life of REG17092 predicted from allometric scaling using NHP data (Supplemental Information). Dose escalation within the IV and SC cohorts was initiated after at least six participants in the previous IV or SC cohort had completed Day 7 safety assessments.

Investigators and participants were blinded to REGN17092 or placebo allocation but not to the assignment to dose cohort. Regeneron staff and the committee responsible for dose‐escalation decisions were blinded.

Treatment

The REGN17092 or placebo IV treatments were administered as a 60‐min IV infusion at a total volume of 100 mL. For SC treatments, 1–4 injections of 300 mg/2.5 mL or matching placebo/2.5 mL were administered.

Endpoints

The primary study endpoint was the safety and tolerability of REGN17092 administered IV and SC, as assessed by AEs, serious AEs, clinical laboratory tests, standard 12‐lead safety ECGs, vital signs, and physical examinations. Injection‐site reactions (ISRs) were monitored for the SC cohorts and were recorded as AEs. The secondary PK endpoints included the concentration of REGN17092 in serum and its immunogenicity (i.e., the incidence and titer of ADA response to REGN179092 over time). As an exploratory endpoint, the concentration of REGN17092 in nasal fluid over time was also assessed.

Safety and Tolerability

The safety and tolerability of REGN17092 were evaluated in all participants who received any amount of drug during the study. Dose‐escalation assessments were based on safety and tolerability findings. If stopping criteria were met at any point during the study, the safety review committee was to conduct a safety review meeting to allow for a review of the aggregate data collected to that point. If any participant experienced a dose‐limiting toxicity during their treatment, dose escalation was to be stopped.

In participants of the safety analysis set, local tolerability at the injection site, including infusion‐related reactions (IRRs), ISRs, and hypersensitivity reactions, was assessed by the investigator using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 grading system. ²⁰

Dose Selection: Allometric Scaling From Monkey PK

Population PK modeling of REGN17092 concentration data from a single‐dose PK study in cynomolgus monkeys, which utilized a two‐compartment PK model with linear elimination from the central compartment, was performed to characterize the concentration–time profile in serum. Allometric scaling was applied to extrapolate model‐estimated PK parameters in monkeys to humans, utilizing established scaling factors for monoclonal antibodies engineered with YTE or LS modifications. ²¹ To inform FIH dose selection, simulations were performed using allometrically scaled PK parameters to estimate key PK parameters including area under the concentration–time curve (AUC), maximum serum concentration (C_max), and terminal elimination half‐life (t_1/2). For the proposed FIH dose level, a safety margin relative to the level of no observed adverse effect in the 4‐week rat Good Laboratory Practice toxicity study was determined (Supplemental Information).

PK Evaluations in Serum

Blood samples for the measurement of serum REGN17092 were collected at the following time points for IV cohorts: before dosing; Day 1 (30 min, 6 h, and 12 h post the end of the infusion); and Days 2, 8, 15, 29, 45, 60, 90, 120, 240, and 364 post the end of the infusion. For SC cohorts, the time points were: before dosing; Day 1 (4, 8, and 12 h post dose); and Days 2, 3, 8, 15, 29, 45, 60, 90, 120, 240, and 364 post dose.

REGN17092 concentrations in serum were assessed using a validated enzyme‐linked immunosorbent assay (ELISA) with a lower limit of quantification (LLOQ) of 0.0156 mg/L in neat human serum. Details of the assay have previously been published. ²²

PK Evaluation in Nasal Fluid

Nasal fluid samples for the measurement of REGN17092 concentrations were collected for both IV and SC cohorts before dosing; on Day 1 (12 h post dose); and on Days 3 (SC only), 8, and 29 post dose (see Supplemental Information for details of the nasal fluid sample collection procedure). Blood samples were collected at the same time for the determination of the concentration of urea in plasma. Samples from the placebo groups were not analyzed for drug concentration.

Concentrations of REGN17092 in nasal fluid were assessed using an ELISA assay with an LLOQ of 0.00078 mg/L in neat human nasal fluid. Urea concentrations were measured in nasal fluid and plasma paired samples using a urea assay kit (Invitrogen™ Urea Nitrogen Colorimetric Detection Kit) following the manufacturer's instructions. The analyses of urea concentrations in nasal fluid and plasma were conducted at Eurofins Viracor BioPharma (Lenexa, KS).

Immunogenicity

Blood samples for immunogenicity assessments in serum were collected before dosing and on Days 29, 120, 240, and 364. Anti‐REGN17092 antibodies were quantified in serum samples using a validated tier‐based bridging immunoassay. ²²

Statistical Analyses

All statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC) and were descriptive. The sample size was based on previous experience for FIH studies to assess safety and tolerability.

PK parameters were determined using standard non‐compartmental analysis methods of concentration–time data ²³ using Phoenix WinNonlin (version 8.3, Certara, L.P.). Actual times for blood sampling were used in the calculations of the individual parameters, while nominal times were used for summary statistics. The PK analysis set included all randomized participants who received REGN17092 and provided sufficient samples for the calculation of PK parameters. Concentrations below the LLOQ (BLQ) were set to 0. Serum BLQ concentration values and missing values (e.g., no blood sample collected or no value obtained at analysis) were excluded from the non‐compartmental analyses. The following PK parameters were calculated from concentrations of REGN17092: C_max; time to maximum concentration (t_max); AUC extrapolated to infinity, calculated using the log‐linear trapezoidal rule; AUC from the time of dosing to the time of the last measurable concentration (calculated as time 0 to time t, where t is the last time point at which the concentration was above the LLOQ); t_1/2, clearance (IV only) and apparent clearance (SC only); and volume of distribution (Vd).

Concentrations of urea in plasma and nasal fluid were utilized to correct the dilution of REGN17092 concentration in nasal fluid due to dilution that occurred during the sample collection procedure. The corrected concentrations of REGN17092 in nasal fluid for each participant at each time point were derived using Equation 1 (Supplemental Information). The concentrations of REGN17092 in nasal fluid were summarized descriptively by nominal sampling time and treatment group. In these summary statistics, concentrations BLQ were imputed as LLOQ/2.

Plots of the mean and median concentration (linear and log scales) are presented by nominal sampling time. In the linear‐scaled plots, concentrations BLQ are set to 0; in the log‐scaled plots, concentrations BLQ are imputed as LLOQ/2.

The degree of penetration of REGN17092 in nasal fluid was derived for each participant at each time point using Equation 2 (Supplemental Information). This ratio represents the fraction of drug that had been distributed into nasal fluid from serum, and was summarized descriptively by nominal sampling time and treatment.

Results

Study Participants

The study originally planned to enroll 56 participants randomized into seven cohorts, with four cohorts to receive a single IV dose of REGN17092 (150, 300, 1200, or 2400 mg) or placebo and three cohorts to receive a single SC dose of REGN17092 (150, 300, or 1200 mg) or placebo. However, development of REGN17092 was discontinued due to the loss of activity of the drug against newly emerging SARS‐CoV‐2 variants, so only 40 participants were enrolled into five cohorts. Following randomization, eight participants within each cohort received a single IV infusion (300 mg, 1200 mg, 2400 mg, or placebo) or an SC injection (300 mg, 1200 mg, or placebo) in a 3:1 ratio (drug:placebo). Sentinel dosing was applied, with two participants per cohort randomized 1:1 to REGN17092 or placebo. The remaining participants within the same cohort were randomized 5:1 to REGN17092 or placebo, which began only after the two sentinel participants in the cohort had safety assessments completed for at least 24 h, and the information had been reviewed by the investigator and the sponsor.

Overall, 40 participants (of whom, 15 were male [38%]) aged 19–59 years (mean 35.1 years) met eligibility criteria and were randomized into the study. In both groups, the majority of participants were 18–35 years of age (≥60%) and White (≥93%). All participants completed the end‐of‐study assessment. Body weight was 51–115 kg, with corresponding body mass indices of 18.8–30.1 kg/m². Demographic parameters were comparable amongst the assigned treatments (Table 1).

Table 1.

Demographic and Baseline Characteristics by Treatment and Safety Cohort (Safety Analysis Set)

	Placebo (n = 10)	REGN17092 300 mg IV (n = 6)	REGN17092 1200 mg IV (n = 6)	REGN17092 2400 mg IV (n = 6)	REGN17092 300 mg SC (n = 6)	REGN17092 1200 mg SC (n = 6)	Combined REGN17092 (n = 30)
Weight, kg
Mean (SD)	69.6 (13.40)	73.3 (20.67)	60.1 (11.56)	65.1 (8.68)	64.0 (4.22)	66.9 (8.28)	67.7 (11.66)
Min, max	57, 102	60, 115	55, 83	53, 75	58, 70	51, 74	51,115
BMI, kg/m2
Mean (SD)	23.4 (3.14)	24.2 (2.63)	23.3 (3.29)	21.9 (1.65)	22.3 (3.33)	23.2 (2.47)	23.0 (2.67)
Min, max	19.3, 30.1	22.0, 29.1	20.0, 27.9	19.4, 23.5	18.8, 28.4	19.5, 27.0	18.8, 29.1
Age, years
Mean (SD)	31.3 (10.44)	35 (11.31)	32.7 (8.48)	33.7 (9.77)	34.7 (18.65)	39.5 (11.22)	35.1 (11.76)
Min, max	23, 56	22, 53	24, 48	19, 45	20, 59	28, 54	19, 59
Sex, n (%)
Male	3 (30.0)	2 (33.3)	3 (50)	3 (50)	3 (50.0)	1 (16.7)	12 (40.0)
Female	7 (70.0)	4 (66.7)	3 (50)	3 (50)	3 (50.0)	5 (83.3)	18 (60.0)
Race, n (%)
Asian	0	1 (16.7)	0	0	0	0	1 (3.3)
Multiple	0	0	1 (16.7)	0	0	0	1 (3.3)
White	10 (100)	5 (83.3)	5 (83.3)	6 (100)	6 (100)	6 (100)	28 (93.3)

IV, intravenous; max, maximum; min, minimum; SC, subcutaneous; SD, standard deviation.

PK Results

REGN17092 in Serum

Concentrations of REGN17092 in serum were quantifiable for all participants up to ∼365 days; 18 participants received a single IV infusion of REGN17092 and 12 received a single SC dose. The concentration–time profiles of REGN17092 in serum following IV (300, 1200, and 2400 mg) and SC (300 and 1200 mg) administration are characterized by an initial distribution (IV) or absorption (SC) phase, followed by a prolonged linear terminal elimination phase (Figure 1).

Figure 1.

Mean (+SD) concentrations of total REGN17092 in serum by nominal time and treatment group (log‐scaled, PK analysis set). IV, intravenous; LLOQ, lower limit of quantification; PK, pharmacokinetics; SC, subcutaneous; SD, standard deviation.

The mean concentrations of REGN17092 in serum increased in a dose‑proportional manner and were consistent with linear PK for a single dose administered either IV or SC (Table 2). Following IV administration, C_max of REGN17092 in serum was achieved immediately after the end of the infusion, with mean (standard deviation [SD]) values of 92.3 (12.6) mg/L, 320 (82.4) mg/L, and 623 (112) mg/L for the 300, 1200, and 2400 mg doses, respectively (Table 2). Following SC administration, the C_max of REGN17092 in serum was achieved at 11 days and 15 days, with mean (SD) values of 38.2 (8.36) mg/L and 130 (30.9) mg/L for the 300 and 1200 mg doses, respectively.

Table 2.

PK Parameters After Single‐Dose IV and SC Administration of REGN17092 (Pharmacokinetic Analysis Set)

	IV Dosing			SC Dosing
PK parameter	Cohort 1 REGN17092 300 mg (n = 6)	Cohort 3 REGN17092 1200 mg (n = 6)	Cohort 5 REGN17092 2400 mg (n = 6)	Cohort 2 REGN17092 300 mg (n = 6)	Cohort 4 REGN17092 1200 mg (n = 6)
Cmax, mg/L	92.3 (12.6)	320 (82.4)	623 (112)	38.2 (8.36)	130 (30.9)
Clast, mg/L	2.21 (0.567)	5.94 (3.84)	30.0 (17.6)	2.43 (0.503)	9.85 (5.31)
C0.1667 (4 h), mg/L	‐	‐	‐	3.31 (2.79)	5.73 (5.52)
C28, mg/L	32.9 (5.06)	125 (22.3)	227 (35.8)	32.9 (5.52)	110 (20.7)
C364, mg/L	2.21 (0.567)	5.94 (3.84)	30.0 (17.6)	2.43 (0.503)	9.85 (5.31)
tmax, days	0.0552 (0.0438–1.05)	0.0625 (0.0625–0.0625)	0.0625 (0.0625–0.0625)	11.0 (6.94–45.1)	15.0 (6.92–28.9)
AUClast, days mg/L	5150 (486)	20,100 (5770)	45,600 (10,100)	4940 (802)	19,600 (4240)
AUCinf, days mg/L	5440 (477)	20,800 (6210)	50,300 (12,400)	5270 (872)	21,000 (4700)
Vd, L	6.57 (1.36)	6.42 (1.10)	6.93 (1.27)
CL, L/day	0.0556 (0.00500)	0.0626 (0.0210)	0.0512 (0.0172)
CL/F, L/day				0.0585 (0.0108)	0.0598 (0.0148)
t1/2, days	85 (73–103)	80 (39–108)	82 (68–141)	90 (85–101)	85 (69–133)
Cmax/dose, mg/L/mg	0.308 (0.0421)	0.267 (0.0686)	0.260 (0.0467)	0.127 (0.0279)	0.108 (0.0257)
AUClast/dose, days mg/mg	17.2 (1.62)	16.7 (4.80)	19.0 (4.22)	16.5 (2.67)	16.4 (3.53)
AUCinf/dose, days mg/dose	18.1 (1.59)	17.4 (5.17)	20.9 (5.18)	17.6 (2.91)	17.5 (3.91)

AUC_inf, area under the curve from time 0 to infinity; AUC_last, area under the concentration–time curve from time 0 to the time of the last positive concentration; C_{0.1667 (4 h)}, serum concentration at Day 0.1667 (4 h post dose);C₂₈, serum concentration at Day 28; C₃₆₄, serum concentration at Day 364; CL, clearance; CL/F, clearance over bioavailability (apparent clearance); C_last, last positive concentration; C_max, maximum serum concentration; IV, intravenous; PK, pharmacokinetic; SC, subcutaneous; SD, standard deviation; t_1/2, terminal elimination half‐life; t_max, time to maximum serum concentration; V_d, volume of distribution.

Values are mean (SD) except for t_max, which is shown as median (range).

The estimated clearance and median t_1/2 of REGN17092 ranged from 0.0512 to 0.0626 L/day and from 77.9 to 89.7 days, respectively. Notably, the observed t_1/2 in humans was consistent with the value predicted by the allometric scaling approach. All participants had detectable concentrations of REGN17092 in serum 1 year after either IV or SC dosing; mean (SD) concentrations of REGN17092 following IV administration were 2.21 (0.567) mg/L, 5.94 (3.84) mg/L, and 30.0 (17.6) mg/L for 300, 1200 and 2400 mg, respectively; following SC administration, mean (SD) concentrations were 2.43 (0.503) mg/L and 9.85 (5.31) mg/L for 300 and 1200 mg, respectively (Table 2). Of note, similar serum concentration was observed with REGN17092 at 4 h post dose with 300 mg SC dose, with a mean (SD) of 3.31 (2.79) mg/mL, as compared to Day 364.

For the same dose level administered IV and SC, the mean concentrations of REGN17092 in serum at Day 7 were comparable within variability for the routes of administration. By Day 28, the mean concentrations of REGN17092 in serum were similar across administration routes for the same dose (Figure 2). At Day 7, mean (SD) concentrations of REGN17092 for the 300 mg dose were 35.7 (19.4) mg/L and 30.2 (17.9) mg/L following IV and SC administration, respectively; for the 1200 mg dose, mean (SD) concentrations of REGN17092 were 150 (3.11) mg/L and 121 (40) mg/L for IV and SC administration, respectively. At Day 28, mean (SD) concentrations of REGN17092 for the 300 mg dose were 32.9 (5.06) mg/L and 32.9 (5.52) mg/L following IV and SC administration, respectively; for the 1200 mg dose, mean (SD) concentrations of REGN17092 were 125 (22.3) mg/L and 110 (20.7) mg/L for IV and SC administration, respectively.

Figure 2.

Mean (SD) concentrations of total REGN17092 in serum up to Day 30 by nominal time and treatment group (PK analysis set). IV, intravenous; PK, pharmacokinetics; SC, subcutaneous; SD, standard deviation.

Estimated Absolute Bioavailability

The estimated bioavailability of REGN17092 after SC administration of the 300 and 1200 mg doses was 84% and 100%, respectively (Table 3).

Table 3.

Bioavailability Estimation (Pharmacokinetic Analysis Set)

	REGN17092 300 mg	REGN17092 1200 mg
CL/WT, L/day/kg, IV	0.000767 (0.000151)	0.000900 (0.000316)
CL/F/WT, L/day/kg, SC	0.000900 (0.000126)	0.000900 (0.000228)
Bioavailability	0.85	1.00

CL, clearance; CL/F, clearance over bioavailability; IV, intravenous; SC, subcutaneous; WT, weight.

REGN17092 in Nasal Fluid

Mean (SD) corrected concentrations of REGN17092 in nasal fluid over time are presented by treatment in Figure 3. Concentrations of REGN17092 were detectable in nasal fluid for all participants as early as 12 h post dose for both the IV and SC treatments, except for one participant who received a 1200 mg SC dose and had a concentration that was BLQ. All participants had measurable REGN17092 concentrations at Day 28 for all doses and routes of administration.

Figure 3.

Mean (SD) corrected concentrations of REGN17092 in nasal fluid by nominal time and treatment group (log‐scaled, PK analysis set). IV, intravenous; LLOQ, lower limit of quantification; PK, pharmacokinetics; SC, subcutaneous; SD, standard deviation.

Concentrations of REGN17092 in nasal fluid increased with increasing doses following either IV or SC administration. The highest mean concentration of REGN17092 in nasal fluid was observed at 12 h post dose (the first sampling time) for all IV doses, and at Day 28 for the 300 mg SC dose and Day 7 for the 1200 mg SC dose. The penetration of REGN17092 from serum to nasal fluid ranged from 1% to 5% (Figure 4).

Figure 4.

Mean (SD) ratio of corrected concentrations of REGN17092 in nasal fluid to concentrations of REGN17092 in serum by nominal time and treatment group (PK analysis set). IV, intravenous; PK, pharmacokinetics; SC, subcutaneous; SD, standard deviation.

Safety and Tolerability

Overall, REGN17092 administered IV and SC were generally well tolerated in this study. There were no deaths and no serious or severe treatment‐related treatment‐emergent adverse events (TEAEs) reported. The overall incidence of TEAEs was numerically higher in the combined (IV + SC) REGN17092 group than in the combined (IV + SC) placebo group (86.7% vs 80.0%), including treatment‐related AEs (63.3% vs 40.0%).

Most TEAEs were low grade (Grade 1 or 2). Two Grade 3 TEAEs (presyncope and cholecystitis) were reported in the REGN17092 1200 mg SC group, both of which were assessed as not related to the study drug.

There were no clinically meaningful trends in changes from baseline in clinical chemistry or hematology (data not shown). The results were comparable across the placebo and REGN17092 treatments, and there were no clinically meaningful changes from baseline in vital signs and ECG parameters.

Injection‐Site Reactions

A higher proportion of participants in the pooled REGN17092 SC group (91.7%) than in the placebo group (50.0%) experienced ≥1 ISR (Table 4). The most frequent ISR was erythema in both groups. The proportion of participants with ≥1 ISR was lower in the pooled placebo SC group than the pooled REGN17092 SC group, and was similar between the individual REGN17092 SC groups. However, the number of ISRs was the same in the placebo and REGN17092 300 mg SC group (n = 5) but higher in the REGN17092 1200 mg SC group (n = 24). The higher number of ISRs in the REGN17092 1200 mg SC group was primarily associated with a larger dose administered across more injection sites. There was no evidence of a dose‐related trend for ISRs.

Table 4.

ISRs by Symptoms (Safety Analysis Set)

Symptom	Placebo SC (n = 4)	REGN17092 300 mg SC (n = 6)	REGN17092 1200 mg SC (n = 6)	Total REGN17092 SC (n = 12)
ISRs, n	5	5	24	29
Participants with ≥1 ISR, n (%)	2 (50.0)	5 (83.3)	6 (100)	11 (91.7)
Erythema	2 (50.0)	5 (83.3)	6 (100)	11 (91.7)
Edema	1 (25.0)	2 (33.3)	0	2 (16.7)
Pain	0	1 (16.7)	1 (16.7)	2 (16.7)
Ecchymosis	0	0	1 (16.7)	1 (8.3)
Nodule	0	1 (16.7)	0	1 (8.3)

ISR, injection‐site reaction; SC, subcutaneous.

Infusion‐Related Reactions

The proportion of participants who experienced ≥1 IRR was similar between the pooled REGN17092 IV group (38.9%) and the pooled placebo group (33.3%) (Table 5). The most frequent IRR (≥2 participants) reported at a higher rate in the REGN17092 IV groups than the pooled placebo IV group was diastolic hypotension (2 participants, both in the REGN17092 2400 mg IV group). There was no evidence of a dose‐related trend for IRRs.

Table 5.

IRRs by Preferred Term (Safety Analysis Set)

Preferred term	Placebo IV (n = 6)	REGN17092 300 mg IV (n = 6)	REGN17092 1200 mg IV (n = 6)	REGN17092 2400 mg IV (n = 6)	Total REGN17092 (n = 18)
IRRs, n	2	2	3	2	7
Participants with ≥1 IRR, n (%)	2 (33.3)	2 (33.3)	3 (50.0)	2 (33.3)	7 (38.9)
Diastolic hypotension	0	0	0	2 (33.3)	2 (11.1)
Headache	2 (33.3)	1 (16.7)	1 (16.7)	0	2 (11.1)
Blood pressure systolic increased	0	0	1 (16.7)	0	1 (5.6)
Dysgeusia	0	1 (16.7)	0	0	1 (5.6)
Migraine	0	0	1 (16.7)	0	1 (5.6)

IRR, infusion‐related reaction; IV, intravenous.

Immunogenicity

Immunogenicity was assessed in all study participants. None of the participants developed an ADA response following single‐dose administration of REGN17092.

Discussion

In this FIH, randomized, double‐blind, placebo‐controlled study in healthy adults, the safety, tolerability, and PK in serum and immunogenicity of REGN17092 were characterized following single IV and SC doses ranging from 300 to 2400 mg over a 12‐month period. In addition, the REGN17092 PK in nasal fluid was characterized for over 30 days.

Concentrations of REGN17092 in serum increased in a dose‐proportional manner and displayed no evidence of nonlinearity. The linear, dose‐proportional PK demonstrated by REGN17092 was consistent with a typical monoclonal antibody against an exogenous target and administered at a high dose. ²⁴ The extension of the terminal t_1/2 of a monoclonal antibody secondary to YTE modifications is of significant importance in the prophylactic setting for COVID‐19, particularly in immunocompromised individuals who are unable to mount a protective immune response to vaccines. The extended half‐life is expected to result in prevention of SARS‐CoV‐2 infection with less frequent dosing. REGN17092 elimination from serum is slower than that reported for casirivimab and imdevimab, and its estimated mean clearance (0.0512–0.0626 L/day) is ∼3‐ to 4‐fold lower than the clearance previously reported for casirivimab and imdevimab (0.1926 L/day for casirivimab and 0.2359 L/day for imdevimab). ²⁵ The median terminal t_1/2 of REGN17092 of ∼85 days is approximately three times longer than that reported for casirivimab (32.4 days) and imdevimab (27.0 days). ²⁶ This demonstrates the REGN17092 half‐life extension in humans conferred by the YTE modification. The observed terminal t_1/2 in serum of ∼85 days for REGN17092 is consistent with data published from other YTE‐modified antibodies in healthy adults following single dose administration, ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ and was as predicted based on allometric scaling.

In addition, the extended human terminal half‑life is consistent with what was observed in cynomolgus monkey studies where it also showed a longer terminal half‑life for the YTE‑engineered antibody compared with non‑engineered IgG1 (Supplementary Materials).

This difference in the t_1/2 of REGN17092 in serum could provide a longer durability of protection against SARS‐CoV‐2 infection than that observed with casirivimab and imdevimab. ⁷ The median (range) predicted concentration of casirivimab and imdevimab combined in serum at Month 5 after 1200 mg SC dosing was 2.73 (0.32–11.1) mg/mL. A similar serum concentration was observed with REGN17092 at Month 12 with the 300 mg SC dose, with a mean (SD) of 2.43 (0.502) mg/mL, which indicates that similar protection to casirivimab and imdevimab would have been achieved with REGN17092 for 12 months (assuming that REGN17092 would retain activity against the variants of concern and variants of interest dominant at the time when casirivimab and imdevimab trials were conducted).

SC dosing is critical for ease of administration in outpatient prophylactic settings. The mean bioavailability after SC administration of REGN17092 ranged from 85% to 100%, which is higher than that estimated with casirivimab and imdevimab (72% and 66%, respectively). ²⁵ This is also slightly higher than what has been reported for other YTE‐modified antibodies (tixagevimab–cilgavimab; 68.5% and 65.8%, respectively). ²⁷ Median t_max was achieved 11–15 days following SC administration of REGN17092; this is in line with what has been reported for other YTE‐modified antibodies. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ Despite C_max only being reached 11–15 days after SC administration of REGN17092, all participants who received SC administration had measurable concentrations as early as 4 h post dose. This demonstrates that the minimum protective level could had been achieved by 8–12 h post the 300 mg SC dose (assuming that REGN17092 would retain activity against the variants of concern and variants of interest dominant at the time when casirivimab and imdevimab trials were conducted). These data demonstrate that SC administration could have been an acceptable alternative to IV administration in prophylaxis and treatment settings assuming the same sensitivity of susceptibility to the virus.

The observed t_1/2 of REGN17092 in humans of 80–90 days was consistent with the values predicted by allometric scaling of the preclinical monkey data t_1/2 of 84 days (Supplementary Materials). This agreement supports the reliability of the applied allometric scaling approach from monkeys to humans for engineered antibodies with extended half‐life modifications. ²¹ The ability to accurately predict human PK parameters from animal models is critical for rational FIH dose selection and risk mitigation in early clinical development.

In this study, we sought to investigate the penetration of REGN17092 into the nasal fluid, one of the first entry points for SARS‐CoV‐2 viral entry and infection. The fraction of drug that penetrates into nasal fluid from serum is therefore an important consideration for dose selection for drugs to prevent SARS‐CoV‐2 infections. The reported lung penetration for monoclonal antibodies ranged from 1.0% to 25% ²⁸ , ²⁹ , ³⁰ ; however, a physiologically based PK model of another anti‐SARS‐CoV‐2 antibody utilized a serum‐to‐lung partition coefficient of 6.5%. ³¹ The true degree of penetration of antibodies into nasal fluid is unknown. For the original marketing authorization application for casirivimab and imdevimab, a value of 1% was utilized as a conservative estimate to selected doses tested during the development program. ³² Here, we report nasal penetration rates for REGN17092 of 1–3%.

No immunogenicity response to REGN17092 was observed in the IV and SC groups for all doses tested. The immunogenicity for other YTE‐modified antibodies in healthy participants following a single dose administration is low. For tixagevimab–cilgavimab, Forte‐Soto et al reported an immunogenicity rate of 2% (1 out of 50 participants). ¹⁸ Alprentris et al reported a 2.6% immunogenicity rate for clesrovimab ¹⁵ and Griffin et al reported a 4.9% immunogenicity rate for nirsevimab. ¹⁴ However, it is important to note that the observed incidence of ADAs is highly dependent on the sensitivity and specificity of the assay.

The administration of REGN17092 did not result in any treatment‐related serious AEs or study discontinuations. Overall, REGN17092 administered IV and SC was generally well tolerated, with similar safety as tixagevimab ¹⁸ , ³³ in adult healthy participants at doses up to 2400 mg. The safety results have been previously presented. ¹⁹ In addition, the safety profile of REGN17092 appeared to be in accordance with the known safety profile of casirivimab and imdevimab, ⁴ , ⁵ with no new safety concerns identified.

The limitations of the Phase 1 data presented include the small number of participants in each cohort and a relatively short nasal fluid assessment for a half‑life‐extended antibody that may be present in serum for up to 12–15 months. As the study enrolled healthy adults aged 23–59 years; the PK data presented may not reflect the PK profile of populations more likely to use REGN17092 in the clinic, such as individuals with an increased risk of severe COVID‐19 (i.e., older individuals, individuals with co‐morbidities, and immunocompromised individuals).

In conclusion, this Phase 1 study demonstrated that REGN17092 was tolerable with a long half‐life, highlighting the value of YTE modification.

Author Contributions

Term	Credit (contributor roles taxonomy) definition	Author initials
Conceptualization	Ideas; formulation or evolution of overarching research goals and aims	MR, KT, SG, AGO, IH, TDN, VMC, JDD
Methodology	Development or design of methodology; creation of models	MR, KT, JL, SG, SF, AB, TDN, VMC, JDD
Software	Programming, software development; designing computer programs; implementation of the computer code and supporting algorithms; testing of existing code components	ZWH, HY
Validation	Verification, whether as a part of the activity or separate, of the overall replication/reproducibility of results/experiments and other research outputs
Formal analysis	Application of statistical, mathematical, computational, or other formal techniques to analyze or synthesize study data	MR, SG, ZWH, HY
Investigation	Conducting a research and investigation process, specifically performing the experiments, or data/evidence collection	MR, JdH, FI
Resources	Provision of study materials, reagents, materials, patients, laboratory samples, animals, instrumentation, computing resources, or other analysis tools	LF, IH
Data curation	Management activities to annotate (produce metadata), scrub data and maintain research data (including software code, where it is necessary for interpreting the data itself) for initial use and later reuse	MR, FI
Writing – original draft	Preparation, creation and/or presentation of the published work, specifically writing the initial draft (including substantive translation)	MR, FI
Writing – review & editing	Preparation, creation and/or presentation of the published work by those from the original research group, specifically critical review, commentary, or revision – including pre‐or post‐publication stages	MR, JdH, FI, KT, JK, SG, SF, YP, TDN, JDD
Visualization	Preparation, creation and/or presentation of the published work, specifically visualization/data presentation
Supervision	Oversight and leadership responsibility for the research activity planning and execution, including mentorship external to the core team	JdH, FI, LF, IH
Project administration	Management and coordination responsibility for the research activity planning and execution	JdH, IH
Funding acquisition	Acquisition of the financial support for the project leading to this publication

Conflicts of Interest

Maria Rosario, Flonza Isa, Kenneth Turner, Jing Li, Joel Kantrowitz, Samit Ganguly, Sasha Fraser, Zhongqing Will He, Hong Yan, Ana Gonzalez Ortiz, Lori Faria, Ingeborg Heirman, Alina Baum, Thomas D Norton, Yogesh Patel, Veronica Mas Casullo, and John D. Davis are employees of and stockholders in Regeneron Pharmaceuticals, Inc. Jan de Hoon has nothing to disclose.

Funding

The project described in this manuscript was funded in whole or in part with federal funds from the U.S. Department of Health and Human Services (HHS); the Administration for Strategic Preparedness and Response (ASPR); and the Biomedical Advanced Research and Development Authority (BARDA), under agreement number HHSO100201700020C. The contract and federal funding are not an endorsement of the study results, product, or company.

Data Sharing

Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, and statistical analysis plan) that support the methods and findings reported in this manuscript. Individual anonymized participant data will be considered for sharing: (1) once the product and indication has been approved by major health authorities (e.g., FDA, EMA, PMDA, and so on) or development of the product has been discontinued globally for all indications on or after April 2020 and there are no plans for future development; (2) if there is legal authority to share the data; and (3) there is not a reasonable likelihood of participant re‐identification. Submit requests to https://vivli.org/

Supporting information

Supporting Information