Our data support a greater focus on the impact of pre-existing, drug-reactive autoantibodies on the development of antibody fragments and biotherapeutics targeting cell surface receptors.
Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4 + and CD8 + T cells. We describe the engineering and first-inhuman clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3 + cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/ kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3 + and CD3 + T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.
The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.
PC945 is a novel antifungal triazole formulated for nebulized delivery to treat lung
Aspergillus
infections. Pharmacokinetic and safety profiles from nonclinical studies and clinical trials in healthy subjects, and subjects with mild asthma were characterized. Toxicokinetics were assessed following daily 2‐hour inhalation for 14 days. Potential for drug‐drug interactions was evaluated using pooled human liver microsomes. Clinical safety and pharmacokinetics were assessed following (a) single inhaled doses (0.5‐10 mg), (b) 7‐day repeat doses (5 mg daily) in healthy subjects; (c) a single dose (5 mg) in subjects with mild asthma.
C
max
occurred 4 hours (rats) or immediately (dogs) after a single dose. PC945 lung concentrations were substantially higher (>2000‐fold) than those in plasma. PC945 only inhibited CYP3A4/5 substrate metabolism (IC
50
: 1.33 µM [testosterone] and 0.085 µM [midazolam]). Geometric mean
C
max
was 322 pg/mL (healthy subjects) and 335 pg/mL (subjects with mild asthma) 4‐5 hours (median t
max
) after a single inhalation (5 mg). Following repeat, once daily inhalation (5 mg), Day 7
C
max
was 951 pg/mL (0.0016 µM) 45 minutes after dosing. Increases in
C
max
and AUC
0–24h
were approximately dose‐proportional (0.5‐10 mg). PC945 administration was well tolerated in both healthy subjects and subjects with mild asthma. Treatment‐emergent adverse events were mild/moderate and resolved before the study ended. No clinically significant lung function changes were observed. PC945 pharmacokinetics translated from nonclinical species to humans showed slow absorption from lungs and low systemic exposure, thereby limiting the potential for adverse side effects and drug interactions commonly seen with systemically delivered azoles.
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