3.1 Participant Disposition and Characteristics

The study period was from 4 October, 2021 to 9 August, 2022. Seventy participants were randomized across cohorts (Table 1 of the Electronic Supplementary Material [ESM]); baseline demographics and clinical characteristics are shown in Table 1. Sixty-four participants completed treatment, while six participants discontinued treatment after receiving one of more doses of the study drug. Three study drug discontinuations were due to AEs, including two participants who received batoclimab 170 mg qw (cohort 3; COVID-19–related AEs; considered not related to the study drug by the investigator) and one participant who received batoclimab 340 mg qw coadministered with atorvastatin 10 mg qd (cohort 6; upper abdominal pain on day 23 of batoclimab treatment; considered probably related to the study drug). Two participants withdrew consent, and one was lost to follow-up.

Table 1 Demographics and baseline characteristics3.2 Change in Serum Lipids

Dose-dependent increases were observed in total cholesterol and LDL-C from baseline to 6 weeks post-baseline with weekly dosing of batoclimab ≥ 255 mg (cohorts 2, 3, 4, 5, and 7; Fig. 2; Table 2 of the ESM), although differences between batoclimab-treated and placebo-treated participants did not achieve statistical significance because of the small number of participants in each cohort. The mean percent change (minimum, maximum) in total cholesterol from baseline to 6 weeks post-baseline was − 0.2% (− 34.0%, 22.4%), 9.3% (− 18.0%, 41.2%), 13.2% (− 7.3%, 26.7%), 17.5% (− 17.3%, 84.0%), and 18.9% (2.7%, 41.5%) with batoclimab 170 mg qw (cohort 3), 255 mg qw (cohort 4), 340 mg qw (cohort 5), 340 mg q2w (cohort 7), and 680 mg qw (cohort 2), respectively. Corresponding results for LDL-C were − 0.2% (− 44.1%, 34.1%), 17.4% (− 20.5%, 56.8%), 27.6% (− 8.2%, 82.2%), 27.9% (− 17.4%, 123.2%), and 28.8% (1.8%, 65.9%), respectively. Low-density lipoprotein-cholesterol increased after 2 weeks of treatment with batoclimab, plateaued by approximately 4 weeks post-baseline, and returned to near-baseline levels by week 10 (5 weeks after the last dose of the study drug; Table 3 of the ESM). Changes from baseline levels to week 6 in HDL-C and TGs did not show any consistent dose-related trends (Fig. 2; Table 2 of the ESM).

Fig. 2

Absolute change from baseline to 6 weeks post-baseline in fasting lipids: a total cholesterol, b low-density lipoprotein cholesterol (LDL-C), c high-density lipoprotein cholesterol (HDL-C), and d triglycerides. CFB change from baseline, q2w every 2 weeks, qw weekly, SE standard error

Coadministration of atorvastatin reduced the increases in total cholesterol and LDL-C that were observed with batoclimab-only administration at doses of 680 mg qw and 340 mg qw (cohorts 2 and 5; Fig. 3). In fact, both cholesterol and LDL-C decreased from atorvastatin baseline (week − 2) to week 0 in cohorts 1 and 6. Increases in LDL-C following initiation of batoclimab treatment were mitigated by approximately 80% and 70% with atorvastatin coadministration compared with treatment with batoclimab alone in the batoclimab 340-mg qw and 680-mg qw groups, respectively (Table 4 of the ESM). The least-squares mean (95% CI) difference in total cholesterol change from week − 2 (atorvastatin baseline) to week 6 in participants receiving batoclimab 680 mg qw with atorvastatin 40 mg qd versus without (cohorts 1 and 2) was − 2.60 mmol/L (− 3.50 to − 1.71; P < 0.0001). Similarly, the least-squares mean (95% CI) difference in the LDL-C change was − 2.26 mmol/L (− 2.96 to − 1.56; P < 0.0001). Corresponding differences in participants receiving batoclimab 340 mg qw with atorvastatin 10 mg qd versus without (cohorts 5 and 6) were − 1.40 mmol/L (− 2.11 to − 0.68; P = 0.0011) for total cholesterol and − 1.51 mmol/L (− 2.09 to − 0.92; P = 0.0001) for LDL-C.

Fig. 3

Absolute change from atorvastatin baseline in a fasting total cholesterol and b low-density lipoprotein cholesterol (LDL-C) with and without atorvastatin. Gray arrows indicate the time of batoclimab or placebo dosing. CFB change from baseline, qw weekly, SE standard error

Participant LDL-C levels were categorized as one of the following: optimal (< 2.59 mmol/L), near/above optimal (≥ 2.59 mmol/L and < 3.36 mmol/L), borderline high (≥ 3.36 mmol/L and < 4.14 mmol/L), high (≥ 4.14 mmol/L and < 4.91 mmol/L), or very high (≥ 4.91 mmol/L). In the batoclimab 680-mg group (cohort 2), one participant with near/above optimal levels of LDL-C at baseline had a worst post-baseline level of high LDL-C, and two patients with high baseline levels had a worst post-baseline level of very high LDL-C (Table 5 of the ESM). In contrast, no participants receiving atorvastatin were observed to shift to high or very high LDL-C (Table 5 of the ESM).

Consistent with findings for total cholesterol and LDL-C, a dose-dependent increase in ApoB was observed with batoclimab administration. From baseline to 6 weeks post-baseline, the mean percent change (minimum, maximum) in ApoB was − 0.2% (− 35.7%, 45.2%), 7.5% (− 15.6%, 27.0%), 31.5% (− 3.5%, 78.6%), 15.8% (− 12.9%, 82.7%), and 27.2% (5.7%, 54.0%) with batoclimab 170 mg qw (cohort 3), 255 mg qw (cohort 4), 340 mg qw (cohort 5), 340 mg q2w (cohort 7), and 680 mg qw (cohort 2), respectively. No clear or consistent treatment-related changes were observed for ApoA1, lipoprotein (a), LDL particle size or particle number, or any other parameters measured by the NMR LipoProfile® test. There were also no apparent treatment- or dose-related effects of batoclimab on high-sensitivity C-reactive protein.

3.3 Change in Serum Albumin

A dose-dependent decrease in the serum albumin level was observed with repeated administration of batoclimab at doses ≥ 255 mg qw (cohorts 2, 4, 5, and 7), but this returned to near-baseline levels by 4 weeks after the last dose (Fig. 4). Results in the batoclimab 170-mg qw and 340-mg q2w cohorts (cohorts 3 and 7) remained comparable to those in placebo participants. Coadministration of atorvastatin with batoclimab did not result in any meaningful differences from the decrease in albumin levels compared to those observed with batoclimab alone (Fig. 1 of the ESM). Shifts to low albumin levels during treatment were primarily observed in cohorts 1 (batoclimab 680 mg qw with atorvastatin 40 mg qd) and 2 (batoclimab 680 mg qw alone), reported in five participants each.

Fig. 4

Absolute change from baseline in serum albumin. Gray arrows indicate the time of batoclimab or placebo dosing. CFB change from baseline, q2w every 2 weeks, qw weekly, SE standard error

3.4 Correlation Between Changes in Albumin and Changes in Lipids

Regression analyses did not find a correlation between the change in serum albumin and the change in LDL-C from baseline to 6 weeks, even after adjusting for batoclimab dose and baseline LDL-C value (R2 < 0.1; Fig. 2 of the ESM). Similarly, no correlations were observed between changes in serum albumin and any other lipid parameters in this small dataset. Numerically, the 680-mg qw dose of batoclimab (cohort 2) was associated with the largest mean albumin decrease and the largest mean LDL-C increase relative to other doses.

3.5 Atorvastatin Pharmacokinetics

Measures of atorvastatin exposure (AUCtau and maximum plasma concentration) were similar with and without coadministration of batoclimab. Geometric mean ratios comparing exposure data after 6 weeks of atorvastatin and batoclimab coadministration versus administration of atorvastatin alone ranged from 1.10 to 1.19 (Table 2), suggesting that there were no important DDIs. Although a statistically significant difference in AUCtau was observed in patients receiving atorvastatin 10 mg qd with versus without batoclimab 340 mg qw (cohorts 5 and 6), this was not considered clinically important, and it was not seen in the cohort receiving top-dose batoclimab (cohort 2). Exposure data for ortho-hydroxylated atorvastatin metabolites were similar with and without coadministration of batoclimab 680 mg qw or 340 mg qw. Exposure data for para-hydroxylated atorvastatin metabolites were similar when administered with and without batoclimab 680 mg qw (cohorts 1 and 2); however, comparisons of exposures to atorvastatin metabolites in the atorvastatin 10-mg qd/batoclimab 340-mg qw cohort (cohort 6) could not be obtained because of the large proportion of samples that were below the lower limit of quantification. Finally, dosage and coadministration with batoclimab had no clear or consistent effect on the half-life and clearance of atorvastatin (Table 6 of the ESM).

Table 2 Descriptive statistics for atorvastatin pharmacokinetics parameters3.6 Safety

The overall incidences of treatment-emergent AEs were similar across all cohorts except for the batoclimab 340-mg q2w cohort (cohort 7), in which a lower incidence was observed (Table 3). The majority of AEs were grade 1 or grade 2 in severity. A higher incidence of treatment-related AEs was observed in the batoclimab 340-mg qw group (cohort 5), mainly driven by injection-site reactions (primarily induration). Five participants had treatment-emergent AEs leading to study discontinuation: two participants with COVID-19 (both receiving batoclimab 170 mg qw; cohort 3), judged by the investigator as not related to the study drug; two participants with upper abdominal pain (batoclimab 340 mg qw with atorvastatin 10 mg qd [cohort 6; n = 1], batoclimab 170 mg qw [cohort 3; n = 1]), judged by the investigator as probably related to the study drug; and one participant with acute drug intoxication (atorvastatin 10 mg qd with placebo [cohort 6]), judged by the investigator as not related to the study drug.

Table 3 Summary of AEs across cohorts

The occurrence of upper abdominal pain in the participant receiving batoclimab 170-mg qw (cohort 3) was reported as a grade 3 serious AE occurring 1 day after the last dose of batoclimab. The participant was hospitalized and received treatment with narcotic analgesics, ondansetron, melatonin, and intravenous fluids. An evaluation demonstrated a hiatal hernia, erosive esophagitis, and a corpus luteum cyst with a mild pelvic fluid collection, suggesting a possible cyst rupture. The investigator assessed the serious adverse event as probably related to the study drug; however, the sponsor assessed the event as unrelated to treatment given multiple other potential contributing factors.