Clinical trials and drug discovery
Table 2 Overview of compliance and TEAEs by treatment group Pooled
Mezagitamab 45mg (N=6)
Mezagitamab 90mg (N=6)
Mezagitamab 135mg (N=5)
placebo (N=5)
Treatment compliance (%)* Mean (SD)
80.0 (20.9)
79.2 (18.8)
62.5 (34.5)
70.0 (20.9)
Median
75.0
75.0
62.5
75.0
Min, Max
50, 100
50, 100
25, 100
50, 100
TEAE Any TEAE (% of patients) Grade 3 or higher TEAE
3 (60.0)
4 (66.7)
6 (100.0)
2 (40.0)
0
0
0
0
Drug-related TEAE (% of patients) Drug-related grade 3 or higher TEAE Treatment-emergent SAEs (% of patients) Drug-related treatment-emergent SAEs TEAEs resulting in study drug dose modification† (% of patients) TEAEs resulting in study drug discontinuation (% of patients)
1 (20.0)
1 (16.7)
1 (16.7)
1 (20.0)
0 0 0 0
0
0 0 0 0
0
1 (16.7)
1 (20.0)
0
0
1 (16.7)
1 (20.0)
0
0
0
1 (20.0)
Deaths
0
0
0
0
*Treatment compliance (%) was calculated as (actual number of doses taken)/(planned number of doses) × 100. †Dose modification includes dose interrupted and drug withdrawn. SAE, serious adverse event; TEAE, treatment-emergent adverse event.
mezagitamab 45mg (9.7), mezagitamab 90mg (9.7) and mezagitamab 135 mg (8.8) groups (table 1). Mild to moderate improvement in SLEDAI-2K total scores was observed with mezagitamab treatment through the end of treatment without observable differences between treatment groups (online supplemental table 1). At the end of treatment on day 85, the changes from baseline in total scores (LS mean) were comparable in the placebo group (−5.2) and the mezagitamab treatment groups (mezagitamab 45 mg: −3.1; mezagitamab 90 mg: −2.5; mezagitamab 135 mg: −4.2). The numbers of responders, defined as patients whose disease activity score decreased from baseline by at least four points, were similar across treatment groups at day 85. No trends were observed in individual SLEDAI-2K total scores. At baseline, the mean CLASI total activity scores were lower in the placebo (4.8), mezagitamab 45 mg (7.2) and mezagitamab 90mg (5.2) groups compared with the mezagitamab 135mg (11.8) group. There was moderate improvement from baseline to the end of treatment in the CLASI total activity score but with no observable differences between the treatment groups (online supple- mental table 1). At the end of treatment on day 85, the change from baseline in total activity score (LS mean) was similar in the placebo group (−3.7) compared with the mezagitamab treatment groups (mezagitamab 45mg: −4.3; mezagitamab 90 mg: −3.9; mezagitamab 135 mg: −3.6). The numbers of responders, defined as patients whose score decreased from baseline either by at least 4 points or by at least 20%, were also similar across treat- ment groups at this time point. However, there was a
trend for clinically meaningful improvement for patients with more severe skin disease at baseline: all patients with a baseline CLASI score of >10 met responder criteria at end of treatment (online supplemental figure 2). Of these, only one patient was a responder in the placebo group while there were five responders in mezagitamab- treated groups. Pharmacokinetics and pharmacodynamics Serum concentrations of mezagitamab were detectable in all patients at all dose levels, but below the LLOQ post- dose in several patients, particularly in the 45 mg dose group. Peak exposure was greater than dose proportional over the dose range tested (online supplemental figure 3). After the first administration, a threefold increase in dose resulted in an approximately 100-fold increase in mean C max from 57.5 ng/mL to 6130ng/mL. Most patients reached maximum drug concentrations at 108 hours after the first and second doses of mezagitamab. The NK cell population is an abundant CD38-expressing cell population in peripheral blood 18 and, therefore, can be used as a surrogate marker for CD38 engagement on target cells. Mezagitamab engaged the CD38 target on CD38+ NK cells in a dose-dependent manner, with median receptor occupancy increasing from 43.8% to 88.4% in the study dose range of 45–135 mg 1 day after the first dose. Corresponding reductions in NK cells were approximately similar for all mezagitamab dose groups, with −71.5%, −65.5% and −90.0% median changes from baseline observed for 45 mg, 90 mg and 135 mg, respec- tively (figure 1A). Placebo-treated patients showed no
5
McDonnell SRP, et al . Lupus Science & Medicine 2024; 11 :e001112. doi:10.1136/lupus-2023-001112
Powered by FlippingBook