Study of Belimumab Administered Subcutaneously to Healthy Subjects

This study is designed to evaluate the absolute bioavailability, pharmacokinetics, tolerability, and safety of a single dose (groups 1-4) or multiple doses (groups 5-6) of belimumab administered subcutaneously (SC) to healthy subjects.

• Single Dose Group: Belimumab IV 240 mg (Biological), also known as BENLYSTA™: Belimumab IV 240 mg administered on Day 0
• Single Dose Group: Belimumab SC 2 x 120 mg (Biological), also known as BENLYSTA™: Belimumab SC 120 mg x 2 injections (equal to 240 mg) administered immediately one after the other on Day 0
• Single Dose Group: Belimumab SC 1 x 240 mg (Biological), also known as BENLYSTA™: Belimumab SC 240 mg x 1 injection on Day 0
• Single Dose Group: Belimumab SC 1 x 200 mg (Biological), also known as BENLYSTA™: Belimumab SC 200 mg x 1 injection on Day 0
• Multiple Dose Group: Belimumab SC 2 x 120 mg weekly (Biological), also known as BENLYSTA™: Belimumab 120 mg x 2 injections (equal to 240 mg) administered immediately one after the other on Days 0, 7, 14, and 21
• Multiple Dose Group: Belimumab SC 1 x 200 mg weekly (Biological), also known as BENLYSTA™: Belimumab 200 mg x 1 injection administered on Days 0, 7, 14, and 21

Primary outcomes

• Time to Reach Maximum Serum Drug Concentration (Tmax) Following a Single Dose of Belimumab Given as Intravenous Infusion (IV) or Subcutaneous Injection (SC) [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and 70]
• Maximum Serum Drug Concentration (Cmax) Following a Single Dose of Belimumab Given as IV or SC [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and 70]
• Area Under the Serum Drug Concentration-time Curve From Time 0 to Infinite Time (AUC0-∞) Following a Single Dose of Belimumab Given as IV or SC [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and 70]: AUC (0-∞) = Area under the serum drug concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-last) plus C (last)/λz. C (last) is the last measurable concentration. λz was determined by linear regression (r2 ≥ 0.8) with uniform weighting of all data in the terminal linear portion of the log-transformed drug concentration-time profile.
• Terminal Elimination Half-life (t1/2,Term) Following a Single Dose of Belimumab Given as IV or SC [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and 70]: Terminal elimination half-life is the time measured for the serum drug concentration of belimumab to decrease by one half.
• Absolute Bioavailability of a Single Dose of Belimumab Given as IV or SC [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 10, 14, 21, 28, 42, 56, and 70]: Bioavailability (F) is a measurement of the rate and extent to which a drug reaches the systemic circulation. The bioavailability of belimumab administered by IV is compared to the bioavailability of belimumab administered via single-SC injection.

Secondary outcomes

• Time to Reach Maximum Serum Drug Concentration (Tmax) Following Weekly (x 4) SC Injections of Belimumab [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119]
• Maximum Serum Drug Concentration (Cmax) Following Weekly (x 4) SC Injections of Belimumab [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119]
• Area Under the Serum Drug Concentration-time Curve From Time 0 to Infinite Time (AUC0-∞) Following Weekly (x 4) SC Injections of Belimumab [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119]: AUC (0-∞) = Area under the serum drug concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0-∞). It is obtained from AUC (0-last) plus C (last)/λz. C (last) is the last measurable concentration. λz was determined by linear regression (r2 ≥ 0.8) with uniform weighting of all data in the terminal linear portion of the log-transformed drug concentration-time profile.
• Terminal Elimination Half-life (t1/2,Term) Following Weekly (x 4) SC Injections of Belimumab [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119]: Terminal elimination half-life is the time measured for the serum drug concentration of belimumab to decrease by one half.
• Absolute Bioavailability of Weekly (x 4) SC Injections of Belimumab [Pre-dose, Post-dose on Days 0, 1, 2, 3, 4, 5, 6, 7, 14, 21, 22, 23, 24, 25, 26, 27, 28, 31, 35, 42, 49, 63, 77, 91, and 119]: Bioavailability (F) is a measurement of the rate and extent to which a drug reaches the systemic circulation. The bioavailability following weekly (x 4) SC injections of belimumab was calculated by comparing the bioavailability of belimumab administered IV to the bioavailability of belimumab administered via 4 weekly SC injections.
• Number of Participants Who Experienced Adverse Events [Up to Day 119]: Includes AEs reported in participants from the first dose of belimumab throughout the study through Day 70/Exit (single dose groups) or Day 119/Exit (multiple dose groups).

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Key Inclusion Criteria:

* Healthy subjects defined as no clinically relevant abnormalities identified by a detailed medical history, full physical exam, 12-lead electrocardiogram (ECG), and clinical laboratory tests.
* Body weight between 45 to 120 kg (99 to 264 lbs).
* Must agree to use effective contraception throughout the study and for 14 weeks after administration of belimumab.
* Have the ability to understand the requirements of the study, provide written informed consent, and comply with the study protocol procedures.

Key Exclusion Criteria:

* Pregnant or nursing.
* Test positive for drugs or alcohol or have had a drug or alcohol dependence within the past year.
* Have used any prescription medicines within the past 30 days or herbal/botanical supplements within the past 7 days or anticipate use during the study. May use prescription contraceptives, hormone replacement therapy, and over-the-counter medicines such as antihistamines or nutritional support such as vitamins, minerals, or amino acids.
* Have received a live vaccine within the past 30 days or anticipate receipt of a live vaccine during the study and within 4 months after last injection of belimumab.
* Have a history of an allergic or anaphylactic reaction to drugs, food, or insect bite or sting requiring medical intervention.
* Have a history of allergic reaction to contrast agents or biological medicines.
* Have participated in a clinical trial and received an experimental medicine within the past 60 days.
* Have received treatment with a B cell targeted therapy at any time.
* Have required management of an infection within the past 14 days.

Participant flow

Outcome results

• Time to Reach Maximum Serum Drug Concentration (Tmax) Following a Single Dose of Belimumab Given as Intravenous Infusion (IV) or Subcutaneous Injection (SC) (Primary), Median, days: Belimumab IV 240 mg 0.09 (0.05 to 0.30); Belimumab SC 2 x 120 mg 3.9 (0.9 to 9.8); Belimumab SC 1 x 240 mg 4.9 (2.9 to 13.9); Belimumab SC 1 x 200 mg 5.9 (1.9 to 13.9)
• Time to Reach Maximum Serum Drug Concentration (Tmax) Following Weekly (x 4) SC Injections of Belimumab (Secondary), Mean, days: Belimumab SC 2 x 120 mg Weekly 5.8 +/- 1.5; Belimumab SC 1 x 200 mg Weekly 5.5 +/- 1.2
• Maximum Serum Drug Concentration (Cmax) Following a Single Dose of Belimumab Given as IV or SC (Primary), Geometric mean, µg/mL: Belimumab IV 240 mg 86.2 +/- 20.0; Belimumab SC 2 x 120 mg 32.7 +/- 29.0; Belimumab SC 1 x 240 mg 31.6 +/- 27.9; Belimumab SC 1 x 200 mg 24.3 +/- 40.3
• Area Under the Serum Drug Concentration-time Curve From Time 0 to Infinite Time (AUC0-∞) Following a Single Dose of Belimumab Given as IV or SC (Primary), Geometric mean, µg∙day/mL: Belimumab IV 240 mg 1030 +/- 32.1; Belimumab SC 2 x 120 mg 788 +/- 36.1; Belimumab SC 1 x 240 mg 812 +/- 36.2; Belimumab SC 1 x 200 mg 612 +/- 37.9
• Terminal Elimination Half-life (t1/2,Term) Following a Single Dose of Belimumab Given as IV or SC (Primary), Mean, days: Belimumab IV 240 mg 18.2 +/- 6.3; Belimumab SC 2 x 120 mg 15.9 +/- 5.3; Belimumab SC 1 x 240 mg 18.2 +/- 6.0; Belimumab SC 1 x 200 mg 16.0 +/- 5.1
• Absolute Bioavailability of a Single Dose of Belimumab Given as IV or SC (Primary), Mean, percentage bioavailability: Belimumab IV 240 mg NA (NA to NA); Belimumab SC 2 x 120 mg 76.1 (64.5 to 89.9); Belimumab SC 1 x 240 mg 81.8 (70.1 to 95.5); Belimumab SC 1 x 200 mg 73.5 (59.7 to 90.5)
• Maximum Serum Drug Concentration (Cmax) Following Weekly (x 4) SC Injections of Belimumab (Secondary), Geometric mean, µg/mL: Belimumab SC 2 x 120 mg Weekly 21.6 +/- 23.2; Belimumab SC x 1 200 mg Weekly 19.5 +/- 25.1
• Area Under the Serum Drug Concentration-time Curve From Time 0 to Infinite Time (AUC0-∞) Following Weekly (x 4) SC Injections of Belimumab (Secondary), Geometric mean, µg∙day/mL: Belimumab SC 2 x 120 mg Weekly 763 +/- 29.8; Belimumab SC 1 x 200 mg Weekly 661 +/- 31.2
• Terminal Elimination Half-life (t1/2,Term) Following Weekly (x 4) SC Injections of Belimumab (Secondary), Mean, days: Belimumab SC 2 x 120 mg Weekly 20.3 +/- 5.2; Belimumab SC 1 x 200 mg Weekly 19.8 +/- 4.9
• Absolute Bioavailability of Weekly (x 4) SC Injections of Belimumab (Secondary), Mean, percentage bioavailability: Belimumab SC 2 x 120 mg Weekly 74.7 (62.6 to 89.1); Belimumab SC 1 x 200 mg Weekly 77.9 (67.0 to 90.6)
• Number of Participants Who Experienced Adverse Events (Secondary), Number, participants: Belimumab IV 240 mg 14; Belimumab SC 2 x 120 mg 11; Belimumab SC 1 x 240 mg 16; Belimumab SC 1 x 200 mg 14; Belimumab SC 2 x 120 mg Weekly 18; Belimumab SC 1 x 200 mg Weekly 19

Adverse events

Time frame: up to Day 119

Serious adverse events by term

Other adverse events by term

33 more terms not shown.

• Results publication: Gupta SV, Fanget MC, MacLauchlin C, Clausen VA, Li J, Cloutier D, Shen L, Robbie GJ, Mogalian E. Clinical and Preclinical Single-Dose Pharmacokinetics of VIR-2218, an RNAi Therapeutic Targeting HBV Infection. Drugs R D. 2021 Dec;21(4):455-465. doi: 10.1007/s40268-021-00369-w. Epub 2021 Nov 6. PMID 34741731
• Results publication: Zhou X, Lee TI, Zhu M, Ma P. Prediction of Belimumab Pharmacokinetics in Chinese Pediatric Patients with Systemic Lupus Erythematosus. Drugs R D. 2021 Dec;21(4):407-417. doi: 10.1007/s40268-021-00363-2. Epub 2021 Oct 9. PMID 34628605

• GSK Clinical Trials, Study director, GlaxoSmithKline