Safety, Tolerability, and Pharmacokinetics of High‐Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers

Abstract

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically highvolume s.c. administration (> 10-15 mL) has been challenging. We report results from two phase I studies in healthy participants (GP29523 and GP40201) that evaluated s.c. crenezumab, an anti-Aβ monoclonal antibody in development for individuals at risk for autosomal-dominant Alzheimer's disease. GP29523 assessed safety, tolerability, and pharmacokinetics (PK) in 68 participants (aged 50-80 years) who received single ascending doses (600-7,200 mg) of crenezumab or placebo (4-40 mL). GP40201 assessed safety, tolerability, and PK in 72 participants (aged 18-80 years) who received different combinations of dose (1,700-6,800 mg), infusion volume (10-40 mL), and flow rate (2-4 mL/minute), with/without recombinant human hyaluronidase (rHuPH20). There were no serious or dose-limiting adverse events in either study. There were no meaningful differences in pain scores among reference placebo (4 mL), test placebo (4-40 mL), or crenezumab (600-7,200 mg) in GP29523, or across treatments with varying infusion volume, flow rate, dose, or rHuPH20 co-administration or concentration in GP40201. Transient erythema was the most common infusion site reaction in both studies. In GP40201 at volumes of ≥ 20 mL, rHuPH20 co-administration appeared to reduce infusion site swelling incidence, but, in some cases, was associated with larger areas of infusion site erythema. Crenezumab exhibited approximately doseproportional PK, and s.c. bioavailability was 66% and independent of dose or rHuPH20 co-administration. High-dose, high-concentration, high-volume s.c. crenezumab formulated with/without rHuPH20 was well-tolerated in healthy participants, with an acceptable safety profile.

Impact of Anti-amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer’s Disease: A Focus on Aducanumab and Lecanemab

“…In two phase I studies including healthy participants, it was proved that crenezumab was well-tolerated in healthy participants with an acceptable safety profile ( Dolton et al, 2021 ). However, phase 3 clinical trials recruited 750 patients with prodromal to mild AD, and the outcomes were completely negative, since there was no difference between crenezumab and placebo subgroups or within the prodromal vs. mild AD subgroups assessed by several parameters, such as Alzheimer’s Disease Assessment Scale–Cognitive Subscale score (ADAS-Cog) and MMSE ( Salloway et al, 2018 ), suggesting that crenezumab had no therapeutic effect on AD symptoms.…”

Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume

“… 94 Amivantamab with hyaluronidase Unavailable Unknown An ongoing Phase 1b dose-escalation study with 81 patients with various advanced solid tumors found that SC amivantamab 1600 mg (or 2240 mg in patients weighing ≥80 kg) administered every other week had similar exposure to the approved IV dose (1050 mg every other week, or 1400 mg in patients weighing ≥80 kg); resulted in lower C max and equal or higher C trough and AUC 0-336 h ; and was associated with a lower incidence of infusion-related reactions and related symptoms. 13 Crenezumab with hyaluronidase 66% 96 No A Phase 1 study with 72 adult participants receiving SC crenezumab at different combinations of dose (1,700–6,800 mg), flow rate (2–4 mL/minute), and infusion volume (10–40 mL) and with and without co-formulation with hyaluronidase found that hyaluronidase decreased infusion site swelling incidence but was associated with larger areas of infusion site erythema, and co-formulation with hyaluronidase did not significantly affect patient pain, dose proportionality, bioavailability, drug half-life, or systemic exposure. 96 VYVGART HYTRULO® (efgartigimod with hyaluronidase) ~50% 97 Unknown VYVGART HYTRULO® has comparable half-life to that of IV administration but is associated with more injection site reactions (reported in 21 of 55 patients, or 38%), including rash, skin redness, itching, bruising, pain, and hives.…”

Modeling the subcutaneous pharmacokinetics of antibodies co‐administered with rHuPH20

“…SC PK data from these programs, as well as several other antibodies in clinical development with rHuPH20, were leveraged in this work. [10][11][12][13][14][15][16][17][18] Other drug modalities commercialized with rHuPH20, that is, polyclonal IgG…”

“…rHuPH20 is approved in several commercial SC products, five of which are monoclonal antibodies: daratumumab (Darzalex FASPRO®/DARZALEX® SC), trastuzumab (Herceptin Hylecta™/Herceptin® SC), pertuzumab/trastuzumab (Phesgo®), and rituximab (Rituxan Hycela®/MabThera®) in the United States, and atezolizumab (Tecentriq® SC) in Great Britain. SC PK data from these programs, as well as several other antibodies in clinical development with rHuPH20, were leveraged in this work 10–18 . Other drug modalities commercialized with rHuPH20, that is, polyclonal IgG (HyQvia®) and efgartigimod alfa (antibody fragment) (VYVGART® HYTRULO), were not included in the analysis.…”

“…SC PK data from these programs, as well as several other antibodies in clinical development with rHuPH20, were leveraged in this work. 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 Other drug modalities commercialized with rHuPH20, that is, polyclonal IgG (HyQvia®) and efgartigimod alfa (antibody fragment) (VYVGART® HYTRULO), were not included in the analysis.…”