Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Population pharmacokinetics of immunoglobulin G after intravenous, subcutaneous, or hyaluronidase-facilitated subcutaneous administration in immunoglobulin-naive patients with primary immunodeficiencies.

Immunoglobulin G (IgG) replacement therapy is the standard of care for patients with primary immunodeficiencies with antibody deficiencies. Intravenous (IVIG), subcutaneous (SCIG), and hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) therapies differ in their pharmacokinetic (PK) profiles, administration routes, and dosing regimens. Information on use of subcutaneous therapy in IgG treatment-naive patients is limited. This study used population pharmacokinetic (popPK) model-based simulations to characterize IgG PKs in IgG-naive patients with varying disease severity across several IVIG, SCIG, and fSCIG dosing regimens. An integrated popPK model, developed and validated using data from eight clinical trials, was utilized to simulate scenarios that varied by therapy, loading regimen, maintenance dose (equivalent to 400, 600, or 800 mg/kg every 4 weeks [Q4W]), and baseline endogenous total IgG concentration (1.5 or 4.0 g/L). Simulations were performed for age groups of 2-<6, 6-<12, 12-<18, and ≥18 years. Steady-state serum trough IgG concentrations (Cmin,ss), proportion of patients achieving Cmin,ss ≥ 7 g/L, and days taken to reach this threshold were summarized. SCIG provided greater mean Cmin,ss values than IVIG and fSCIG for any scenario. Across all therapies, Cmin,ss tended to increase with age, dose, and endogenous concentration. Although the findings are model-based and not a summarization of real-world observations, doses ≥ 800 mg/kg Q4W with corresponding loading regimens are likely to be clinically appropriate for achieving target IgG concentrations in treatment-naive patients in a timely manner, especially at low endogenous starting concentrations. Therapy-specific dose adjustment based on baseline endogenous IgG concentration, clinical status, and patient characteristics may be warranted.

Facilitated subcutaneous immunoglobulin (fSCIg) therapy--practical considerations.

There is an increasing range of therapeutic options for primary antibody-deficient patients who require replacement immunoglobulin. These include intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), rapid push SCIg and most recently recombinant human hyaluronidase-facilitated SCIg (fSCIg). Advantages of fSCIg include fewer needle punctures, longer infusion intervals and an improved adverse effect profile relative to IVIg. Limited real-life experience exists concerning the practical aspects of switching or starting patients on fSCIg. We describe the first 14 patients who have been treated with fSCIg at the Immunodeficiency Centre for Wales (ICW), representing more than 6 patient-years of experience. The regimen was well tolerated, with high levels of satisfaction and no increase in training requirement, including for a treatment-naive patient. Two patients discontinued fSCIg due to pain and swelling at the infusion site, and one paused therapy following post-infusion migraines. Ultrasound imaging of paired conventional and facilitated SCIg demonstrated clear differences in subcutaneous space distribution associated with a 10-fold increase in rate and volume delivery with fSCIg. Patient profiles for those choosing fSCIg fell into two main categories: those experiencing clinical problems with their current treatment and those seeking greater convenience and flexibility. When introducing fSCIg, consideration of the type and programming of infusion pump, needle gauge and length, infusion site, up-dosing schedule, home training and patient information are important, as these may differ from conventional SCIg. This paper provides guidance on practical aspects of the administration, training and outcomes to help inform decision-making for this new treatment modality.