FormalPara Key Points

CM-101, a humanized monoclonal antibody, successfully neutralizes C-C motif chemokine ligand 24 (CCL24), a key factor linked to inflammatory and fibrotic diseases.

Phase 1a studies involving both intravenous (IV) and subcutaneous (SC) administration of CM-101 in healthy participants demonstrated rare and mild adverse events.

In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), both IV and SC CM-101 exhibited good tolerability, with a notable reduction in serum levels of inflammatory, fibrotic, and collagen turnover biomarkers, suggesting its therapeutic potential in addressing inflammatory and fibrotic conditions.

1 Introduction

Chemokines are a family of proteins that signal through cell surface G protein-coupled receptors and induce migration of cells, particularly immune cells [1]. Chemokine C-C motif ligand 24 (CCL24) signals through C-C chemokine receptor type 3 (CCR3), promoting cell trafficking and regulating proinflammatory and profibrotic activities [2, 3]. Expression of CCL24 is low in healthy sera but high in inflamed or fibrotic tissue [2, 3]. In particular, the dysregulation of the CCL24/CCR3 axis is implicated in a variety of inflammatory and fibrotic diseases, including primary sclerosing cholangitis (PSC) [4], metabolic dysfunction-associated steatotic liver disease (MASLD) [3], (MASH) [3], and systemic sclerosis (SSc) [2].

Serum levels of CCL24 are higher in patients with MASLD than in healthy individuals; moreover, CCL24 levels are highest among patients with more severe fibrosis [3]. In PSC, inflammation and fibrosis affect the biliary epithelial cells. C-C motif ligand 24 is highly expressed in recruited immune cells and bile duct epithelium, as identified in liver biopsy specimens from patients with PSC [4].

Serum CCL24 levels are also higher in patients with SSc than in healthy volunteers, with more elevated CCL24 levels in patients with diffuse SSc versus limited SSc, indicating an association between CCL24 expression and extent of disease [2].

Currently, the treatment for hepatic inflammatory and fibrotic diseases focuses on reducing the complications of cirrhosis and liver transplantation, due to a lack of effective anti-inflammatory and anti-fibrotic treatments [5, 6].

CM-101 is a humanized immunoglobulin G1 monoclonal antibody that neutralizes CCL24 and prevents it from interacting with CCR3. Findings from broad and diverse preclinical studies employing a variety of models have demonstrated anti-inflammatory and anti-fibrotic activities with administration of CM-101, resulting from attenuation of CCL24, particularly in MASLD-, MASH-, PSC- and SSc-related models (Fig. 1) [2,3,4]. In a diet-induced MASH mouse model, CM-101 improved histologic scoring (decreased steatosis, inflammation, and hepatocyte ballooning) [3]. Elevated levels of aspartate aminotransferase (AST), alanine transaminase, and total bilirubin were also reduced following CM-101 treatment in mice with diet-induced liver damage. Accordingly, the inflammation characteristic of MASH was reduced in the STAMTM mouse model treated with CM-101 compared with controls. In rats with thioacetamide-induced liver fibrosis, those treated with CM-101 had histologic improvements compared with controls and displayed minimal macroscopically visible features of fibrosis [3].

Fig. 1
figure 1

Preclinical activity of CM-101 and rationale for in-human studies. *Findings reported by [2]. †Findings reported by [3]. ‡Findings reported by [4]. CCL24 C-C motif chemokine ligand 24, HSC hepatic stellate cells, HUVEC human umbilical vein endothelial cells, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, MCD methionine-choline deficient, NHDF normal human dermal fibroblasts, PSC primary sclerosing cholangitis, SSc systemic sclerosis, STAMTM MASH-derived hepatocellular carcinoma model, TAA thioacetamide

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Human hepatic stellate cells are the key contributors to liver fibrosis following injury through their activation into contractile myofibroblasts. A scratch assay determined that hepatic stellate cell motility was enhanced by incubation with CCL24, and completely reversed by treatment with CM-101 [3].

Inflammation in SSc is marked by endothelial cell activation, for which expression of vascular cell adhesion molecule 1, an adhesion molecule highly expressed on activated endothelial cells, is an effective measure. Human umbilical vein endothelial cells activated with sera from patients with SSc that were pretreated with CM-101 had reduced vascular cell adhesion molecule 1 expression relative to human umbilical vein endothelial cells treated with SSc sera alone [2]. In SSc, the migration and activation of dermal fibroblasts can be induced by CCL24 overexpression; in normal human dermal fibroblasts, incubation of CM-101 with CCL24 led to a dose-dependent reduction of normal human dermal fibroblast migration compared with normal human dermal fibroblasts incubated with CCL24 alone [2]. Conversion of fibroblasts into myofibroblasts is a hallmark of disease progression in SSc, for which the expression of alpha smooth muscle actin is an effective surrogate measurement. Findings from a preclinical study showed that CM-101 significantly attenuated cell activation and alpha smooth muscle actin expression in normal human dermal fibroblast cells incubated with sera from patients with SSc (p < 0.05) [2]. In a SSc bleomycin-induced dermal fibrosis mouse model, treatment with CM-101 prevented the increases in dermal thickness and skin collagen levels observed in mice exposed to CCL24 [2]. Moreover, in a bleomycin-induced pulmonary fibrosis mouse model, CM-101 significantly reduced pulmonary inflammation and fibrosis in bleomycin-exposed mice compared with controls (p < 0.05) [2]. Taken together, results from preclinical studies support the clinical investigation of CM-101 as a potential therapeutic agent for these inflammatory and fibrotic diseases.

Here, we report the first-in-human safety, pharmacokinetic, pharmacodynamic, and biomarker outcomes of intravenous (IV) and subcutaneous (SC) administration of CM-101 from three Phase 1 studies (two in healthy volunteer participants [NCT06025851 and NCT06037577], and one in patients with MASLD without evidence of MASH [NCT06044467]) that were designed to support clinical development of CM-101 in disease driven by inflammation and fibrosis.

2 Methods

2.1 Patients

Participants enrolled in the two Phase 1a studies were healthy male volunteers aged 18–45 years who had received no biological treatment with recombinant antibodies, immunological therapy, or anti-cancer treatment. Patients enrolled in the Phase 1b MASLD study were male or female, aged 18–75 years, with normal liver function, and ultrasound-confirmed (FibroScan®; Echosens, Paris, France) MASLD without evidence of MASH. Patients with diabetes type 1 or 2 (if uncontrolled at the time of screening or being treated with insulin), chronic viral hepatitis B or C infection, a history of substance abuse, or significant alcohol consumption (defined as an average >20 g/day in females and >30 g/day in males), or those who had an MASLD activity score of 3 or greater were excluded from the Phase 1b MASLD study. All studies were conducted in accordance with the Good Clinical Practice Guideline as defined by the International Conference on Harmonization and the Declaration of Helsinki. All study participants provided written informed consent prior to any study activity. The protocol, amendments, and informed consent forms for the Phase 1a studies were approved by the Tel Aviv Souraski Medical Center ethics committee; for the Phase 1b MASLD study, informed consent forms, protocol, and amendments were approved by the Hadassah Medical Center institutional review board.

2.2 Study Design and Treatment

The Phase 1a, first-in-human, single-center, randomized, double-blind, placebo-controlled, single-dose, dose-escalation IV study (Phase 1a IV study) investigated the safety, tolerability, and pharmacokinetics of CM-101 administered via IV infusion. Participants were randomized 3:1 to receive a single dose of either CM-101 or placebo via a 60-min IV infusion within one of four dose groups (0.75 mg/kg, 2.5 mg/kg, 5.0 mg/kg, and 10.0 mg/kg) (Fig. 2). For safety considerations, the first two participants in each dose group—one receiving CM-101 and one receiving placebo—were dosed initially, followed by the remaining participants within the group.

Fig. 2
figure 2

Study designs for the Phase 1a studies and the Phase 1b study. IV intravenous, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, SC subcutaneous

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The Phase 1a, single-center, randomized, double-blind, placebo-controlled, single-dose SC study (Phase 1a SC study) investigated the safety, tolerability, and pharmacokinetics of CM-101 administered via SC injection. Participants were randomized 3:1 to receive a single SC injection of either CM-101 5.0 mg/kg or placebo in the lower abdomen (Fig. 2).

The Phase 1b MASLD study was a double-blind, randomized, placebo-controlled, single-center, repeated-dose, two-cohort study that investigated the safety, tolerability, and pharmacokinetics of CM-101 in patients with MASLD without evidence of MASH. In cohort 1, patients were randomized 3:1 to receive CM-101 2.5 mg/kg or matching placebo via a 60-min IV infusion once every 3 weeks for 12 weeks (Fig. 2). In cohort 2, patients were randomized 3:1 to receive CM-101 5.0 mg/kg or matching placebo via a 30-sec slow SC injection into the abdominal wall once every 3 weeks for 12 weeks.

2.3 Assessments

2.3.1 Safety

The primary safety assessment for the two Phase 1a studies was the incidence, severity, and duration of adverse events (AEs) following a single dose of CM-101 in healthy volunteers. Adverse events were reported by the participants or observed by the investigator and included changes from baseline in vital sign measurements; electrocardiogram tracings; physical examination findings; concomitant medication concerns; and laboratory assessment findings that included hematology tests, blood chemistry tests, and urinalysis. Participants were monitored for AEs and remained under medical supervision for approximately 24 h post-dose. Adverse events were assessed throughout the entire 42 days of follow-up. Adverse event severity was recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, and coded into the database according to the Medical Dictionary for Regulatory Activities (MedDRA) version 21.0. Causality assessment involved a comprehensive review of factors such as known pharmacological effects, concurrent medications or medical conditions, and any relevant laboratory findings.

The primary safety assessment for the Phase 1b MASLD study was the incidence, severity, and duration of AEs that included clinically significant laboratory abnormalities following administration of CM-101 in patients with MASLD without evidence of MASH throughout 12 weeks of treatment and 6 weeks of follow-up. Results of vital sign measurements, physical examination findings, 12-lead electrocardiogram tracings, laboratory findings on hematology tests, blood chemistry tests, urinalysis, and injection-site reactions were assessed.

A data monitoring board reviewed severe or serious drug-related AEs and determined if events were to be considered dose-limiting toxicities. A dose-limiting toxicity was defined as a clinically significant drug-related AE or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medication use and occurring up to 14 days of dosing in the Phase 1a single-dose studies and up to 3 days after receiving any of the first three doses (Day 45) in the Phase 1b MASLD study.

2.3.2 Pharmacokinetics

In the Phase 1a studies, fasting blood samples were drawn pre-dose (within 90 min before dosing) and at various predefined time points after IV infusion or SC injection. Total CM-101 blood concentrations (free, partially free, and bound antibody) were quantified using an enzyme-linked immunosorbent assay. Pharmacokinetic analyses of participant concentration versus time data were performed using non-compartmental and compartmental pharmacokinetic approaches. Pharmacokinetic parameters included maximum serum concentration (Cmax), time to maximum serum concentration (Tmax), area under the concentration-time curve from time 0 to time t (AUC0–t), area under the concentration-time curve from time 0 extrapolated to infinity (AUC0–∞), elimination rate constant during the terminal phase (kterminal), terminal elimination half-life (t1/2), apparent volume of distribution during the terminal phase (Vz), apparent volume of distribution at steady state (Vss), and clearance (CL).

In the Phase 1b MASLD study, blood samples were collected before and immediately after each infusion, and at 2, 4 and 6 h after doses 1 (Day 1) and 5 (Day 84). CM-101 serum concentrations were determined using an enzyme-linked immunosorbent-based assay with values below the lower limit of quantification imputed as zero. Compartmental pharmacokinetic analyses were performed; parameters included pre-dose serum concentration (C0), Cmax, Tmax, area under the serum concentration-time curve from time of administration up to the last time point with a measurable concentration post-dosing (AUClast), AUC0−∞, elimination rate constant (λz), and t1/2.

2.3.3 Pharmacodynamics

An exploratory objective for all three studies was to investigate the effect of different doses on serum CCL24 levels pre- and post-treatment. Serum samples were collected pre-dose and at various predefined time points after IV infusion or SC injection. A human CCL24/Eotaxin-2/MPIF-2 Quantikine ELISA kit (DCC240B; R&D Systems, Minneapolis, MN, USA) was used to quantitate levels of CCL24 across time points.

In the Phase 1b MASLD study, the effect of CM-101 on fibrotic process was evaluated using serum fibrotic and collagen turnover biomarkers. The change from baseline at Week 15 (after five doses) in tissue inhibitor of metalloproteinase-1 (TIMP1), tissue inhibitor of metalloproteinase-2 (TIMP2), platelet-derived growth factor AA (PDGF-AA), N-terminal type III collagen propeptide (Pro-C3), N-terminal type IV collagen propeptide (Pro-C4) and type III collagen fragment (C3M) was calculated. Serum levels of soluble fibrotic biomarkers, such as TIMP1, TIMP2, and PDGF-AA were tested using Milliplex® (Merck KGaA, Darmstadt, Germany) multiplex analysis. Serum levels of Pro-C3, Pro-C4, and C3M were analyzed by a contract laboratory (Nordic Bioscience Laboratory, Copenhagen, Denmark) according to their protocols.

2.4 Statistical Analysis

All measured variables and derived parameters were tabulated by descriptive statistics. For categorical variables, summary tables were provided giving sample size and absolute and relative frequency by individual treatment (CM-101 or placebo). For continuous variables, summary tables were provided giving sample size; arithmetic mean; standard deviation; and minimum, median, and maximum values by individual treatment (CM-101 or placebo). Data were analyzed using SAS software version 9.3 or higher (SAS Institute, Cary, NC, USA). No formal sample size calculation was performed for these studies, as they were designed to assess preliminary safety and pharmacokinetic data. No data imputation for missing data was applied. In the Phase 1a studies, non-compartmental and compartmental pharmacokinetic analyses were performed using PK Solver version 2.0 software [7] validated with SAS version 9.4 (SAS Institute) and STATA SE version 13.0 (StataCorp, LLC, College Station, TX, USA). In the Phase 1b MASLD study, compartmental pharmacokinetic analyses were performed using MONOLIX 2018 R2 software (Lixoft, Antony, France).

3 Results

3.1 Phase 1a Studies in Healthy Volunteer Participants

A total of 32 healthy male participants were enrolled in the Phase 1a IV study with six participants in each CM-101 dose group and eight participants in the placebo group. The mean (standard deviation [SD]) age across all groups was 25.2 (5.2) years and the mean (SD) body mass index was 24.5 (2.0) kg/m2; all treatment groups had similar baseline demographics. A total of eight healthy male participants were enrolled in the Phase 1a SC study with six participants receiving CM-101 5.0 mg/kg and two participants receiving placebo. The mean (SD) age was 27.6 (5.1) years, and the mean (SD) body mass index was 26.0 (1.7) kg/m2.

3.1.1 Safety

In the Phase 1a IV study, 84 AEs were reported in 23 (71.9 %) participants, with 20 AEs considered possibly related to study drug. All AEs except for one (moderate myalgia in a participant receiving placebo) were mild. No serious AEs were reported in any treatment group. The most common AEs were headache, diastolic blood pressure decrease, and rhinitis (Table 1). There was no difference in the incidence of AEs across treatment groups. Four participants receiving CM-101 had injection-site reactions (three with mild pain, tenderness, or erythema and one with moderate erythema).

Table 1 Adverse events among healthy volunteers receiving a single dose of either intravenous or subcutaneous CM-101
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In the Phase 1a SC study, six AEs were reported in two of the eight participants with one AE considered possibly related to study drug (mild diastolic blood pressure decrease). No serious AEs were reported. No injection-site reactions were observed in participants receiving SC CM-101. No deaths were reported, and no participants withdrew due to an AE in either study.

3.1.2 CM-101 Pharmacokinetics

Following IV infusion, CM-101 serum concentrations demonstrated a rapid distribution phase followed by a slow elimination phase (Fig. 3). Serum concentrations were directly proportional to dose; higher maximum concentrations were observed with higher doses (Table 2). The mean elimination half-life ranged from 18.7 days to 19.5 days for each dose. Following SC injection, the serum concentration of CM-101 gradually increased over several days and reached maximum serum concentration in a mean of 4.5 days, and then slowly declined, with a mean elimination half-life of 20.8 days (Table 2 and Fig. 3). Based on the CM-101 serum concentration versus time data, the most appropriate model for CM-101 pharmacokinetics was a two-compartmental mammillary pharmacokinetics model with first-order kinetics.

Fig. 3
figure 3

Mean serum concentration versus time following a single dose of CM-101 in healthy volunteers. Error bars represent standard deviation; error bars not visible are smaller than the data point symbols

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Table 2 Pharmacokinetic parameters for a single dose of CM-101 in healthy volunteers (non-compartmental)
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3.1.3 Effect of CM-101 on CCL24 Serum Levels

Following IV administration of CM-101, total (free and bound) CCL24 serum levels markedly increased due to the binding of CM-101 to CCL24 in the circulation and the intravascular space (Fig. 4). For soluble chemokines, antibody treatment is known to increase circulating levels of a chemokine due to the formation of antibody-target complexes and sequestration of the chemokine from the intravascular space [8]. Total CCL24 serum levels increased in a dose-dependent manner and reached an average peak change from baseline after 8 h.

Fig. 4
figure 4

Serum CCL24 levels following a single IV or SC dose of CM-101 in healthy volunteers. Mean values are plotted. Error bars represent standard deviation; error bars not visible are smaller than the data point symbols. CCL24 C-C motif chemokine ligand 24, IV intravenous, PBO placebo, SC subcutaneous

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Similarly, following SC administration of CM-101, total CCL24 serum levels increased and reached a maximum increase from baseline 4 days post-treatment. Total CCL24 levels gradually decreased from Day 7 through Day 42.

3.2 Phase 1b MASLD Study

A total of 16 patients with ultrasound-confirmed MASLD without evidence of MASH were enrolled in the Phase 1b MASLD study. Baseline demographics and disease characteristics were balanced between treatment groups (Table 3). Patient ages ranged from 26 and 61 years. Most patients reported that they did not use tobacco products or consume alcohol. The most common comorbidity was obesity.

Table 3 Demographics and baseline disease characteristics of patients with MASLD without evidence of MASH in the Phase 1b MASLD study
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3.2.1 Safety

Repeated IV (2.5 mg/kg; n = 6) or SC (5.0 mg/kg; n = 6) administrations of CM-101 were generally well tolerated; AEs were rare with eight patients reporting 11 AEs during the 18-week study (Table 4). No single AE (e.g., fatigue or headache) was reported in more than one patient, and all reported AEs were mild or moderate. There were two AEs reported among patients receiving CM-101 in each cohort that were considered possibly related to study drug (2.5 mg/kg: conjunctivitis and vaginal discharge; 5.0 mg/kg: moderate alanine aminotransferase increased and mild AST increased, both experienced by the same patient who reported a previous episode of elevated liver enzyme levels 4 years earlier). One serious incident of blurred vision was reported in a patient receiving SC 5.0 mg/kg CM-101; the patient was hospitalized and subsequently diagnosed with a meningioma involving the optic chiasm and discontinued the study. This patient had serum levels of CCL24 within the average range of the cohort (the patient’s CCL24 levels were 523 pg/mg, while the median levels of CCL24 in this cohort was 488 pg/mL). The serious AE of blurred vision was deemed to be unrelated to study drug. No injection-site reactions or clinically significant trends in laboratory tests, vital sign measurements, electrocardiographic findings, or physical examinations were observed. No patients tested positive for anti-drug antibodies. There were no deaths or severe AEs reported throughout the study.

Table 4 Adverse events among patients with MASLD without evidence of MASH receiving either intravenous or subcutaneous CM-101
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3.2.2 Repeated Dosing Pharmacokinetics

Serum CM-101 levels over time demonstrated relatively lower pharmacokinetic variability among patients with MASLD without evidence of MASH who were receiving repeated IV CM-101 2.5 mg/kg infusions (Fig. 5). Overall, IV CM-101 exhibited biphasic pharmacokinetic behavior with gradual distribution kinetics and slower elimination kinetics. The average terminal half-life following repeated IV infusions was 20.3 days. Serum CM-101 levels over time in patients with MASLD without evidence of MASH receiving repeated SC CM-101 5.0 mg/kg injections demonstrated moderate to substantial pharmacokinetic variability between patients (Fig. 5). From the shape of the concentration-time curves, accumulation of CM-101 had not reached steady state after the fifth SC injection. The average terminal half-life following repeated SC administration was 16.2 days.

Fig. 5
figure 5

CM-101 mean concentration versus time curve following multiple administrations of CM-101 in patients with MASLD without evidence of MASH. For IV administrations, blood samples were collected pre-dose and at the end of infusion on Days 1, 21, 42, 63 and 84, and 2-, 4-, and 6-h post-dose on Days 1 and 84. For SC administrations, blood samples were collected pre-dose on Days 1, 21, 42, 63 and 84, and 6 h post-dose on Days 1 and 84. Both cohorts had additional sampling time points on Days 105 and 126 during follow-up. IV intravenous, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, Q3W every 3 weeks, SC subcutaneous

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3.2.3 Effect of Repeated CM-101 Dosing on CCL24 Serum Levels

Treatment with either IV or SC CM-101 led to a dose-dependent increase in serum total CCL24 (free and bound to CM-101) levels relative to baseline (Fig. 6). Total CCL24 levels were increased 1.4-fold by the third administration of IV CM-101 2.5 mg/kg. Similarly, total CCL24 levels were increased two-fold by the fourth administration of SC CM-101 5.0 mg/kg. Elevated total CCL24 levels were maintained until the end of treatment for both routes of administration. Matching placebo had no effect on serum CCL24 levels.

Fig. 6
figure 6

Serum CCL24 levels following multiple administrations of IV or SC CM-101 in patients with MASLD without evidence of MASH. Mean values are plotted. Error bars represent standard deviation. CCL24 C-C motif chemokine ligand 24, IV intravenous, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, PBO placebo Q3W every 3 weeks, SC subcutaneous

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3.2.4 Fibrotic Biomarkers and MASLD Parameters

Because patients enrolled in the study had MASLD without evidence of MASH, one patient with a low transient elastography (liver stiffness) score (2.6 kPa) was excluded. Among patients who received CM-101 via either IV or SC (n = 10), CM-101 treatment decreased serum levels of fibrotic biomarkers including TIMP1, TIMP2, and PDGF-AA, and collagen turnover markers including Pro-C3, Pro-C4, and C3M from baseline levels (Fig. 7). In contrast, among patients who received placebo (n = 3), the levels of these fibrotic and collagen turnover biomarkers increased or stayed near baseline levels.

Fig. 7
figure 7

Changes in serum levels of fibrotic and collagen turnover biomarkers in patients with MASLD without evidence of MASH (median, interquartile range [IQR]). Median, Min, Max and IQR values are summarized in a table. C3M type III collagen fragment, MASH metabolic dysfunction-associated steatohepatitis, MASLD metabolic dysfunction-associated steatotic liver disease, PBO placebo, PDGF-AA platelet-derived growth factor AA, Pro-C3 N-terminal type III collagen propeptide, Pro-C4 N-terminal type IV collagen propeptide, TIMP tissue inhibitor of metalloproteinase

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4 Discussion

Elevated CCL24 levels and the resulting dysregulation of the CCL24-CCR3 axis have been implicated in a variety of inflammatory and fibrotic diseases [2, 3]. Herein, we report on findings from the first-in-human study and two subsequent Phase 1 studies investigating CM-101, a monoclonal antibody that targets CCL24. A total of 42 patients received CM-101 in these three Phase 1 studies. CM-101 was well tolerated up to the highest administered dose in healthy volunteers (IV single dose, 10.0 mg/kg). Adverse events were generally uncommon and mild to moderate, and all resolved without sequalae; no severe AEs were reported. Only one non–drug-related serious AE (meningioma) was reported; a patient receiving four doses of CM-101 had blurred vision and was subsequently diagnosed with meningioma.

Administration of a single IV infusion of CM-101 exhibited a biphasic serum concentration versus time curve with a rapid distribution phase and a slow elimination phase. Following a single-dose SC injection, CM-101 was absorbed gradually, with a gradual decline over several weeks. With repeated IV infusions or SC injections, CM-101 accumulated over time, potentially reaching steady state and, with SC administration, exhibiting interpatient variability. Overall, the pharmacokinetic profile of CM-101 was dose-proportional, emblematic for each route of administration and typical for IgG1 monoclonal antibodies that undergo neonatal fragment crystallizable receptor-mediated recycling [9,10,11].

CM-101 exhibited efficient dose-dependent binding to CCL24, with an expected increase in total CCL24 serum levels (free CCL24 and soluble CM-101:CCL24 complexes). The generation of the antibody-target complexes block chemokine activity, and generally follow the kinetic pattern of antibody elimination, reducing target availability over time [11]. As with a single dose, multiple doses of CM-101 in patients with MASLD without evidence of MASH increased CCL24 levels in circulation dose dependently. CCL24 levels were increased 1.4-fold by the third IV dose and by two-fold by the fourth SC dose. C-C motif ligand 24 levels reached steady-state levels with IV infusions (after three administrations) more quickly than with SC injections (after four administrations), likely attributed to a rapid exposure after IV infusion compared with a more sustained exposure of CCL24 to CM-101 via SC injections.

Although patients enrolled in the Phase 1b MASLD study had normal liver function with only limited fibrotic (or disease) activity, CM-101 administration in these patients decreased liver inflammatory and fibrotic-related biomarkers. Serum levels of fibrosis markers (TIMP1, TIMP2, and PDGF-AA) and collagen turnover (Pro-C3, Pro-C4, and C3M) were decreased relative to baseline after 15 weeks (five doses) of CM-101. A similar reduction in TIMP1, which increases during liver fibrosis development, was observed with CM-101 in preclinical animal models [3]. Overall, the exploratory biomarker results provide the first evidence in patients with MASLD that CM-101 treatment may improve liver damage by interfering with fibrotic-related processes. Additional clinical trials are needed to determine whether CM-101 has robust anti-inflammatory and anti-fibrotic effects in patients with more severe disease (e.g., in patients with PSC, stage F2-F3 MASH, or SSc).

Specific targeting of the CCL24-CCR3 axis via CM-101 is a promising therapeutic option to treat diseases driven by the inflammation and fibrosis cycle [3]. In a variety of preclinical models, the vicious cycle of inflammation and fibrosis induced by the overexpression of CCL24 in MASLD, MASH, PSC, and SSc was interrupted by treatment with CM-101; in these preclinical models, CM-101 was able to reverse markers of inflammation and fibrosis [2,3,4]. By reducing inflammation and fibrosis through the targeting of CCL24, CM-101 targets the pathophysiology of these diseases and has the potential to be a disease-modifying therapy.

These studies were not without limitations. Results presented herein are from a first-in-human study and two other Phase 1 studies, and, accordingly, the sample size for each study was small, and variable doses and routes of administration were employed to allow for comprehensive evaluation of the pharmacokinetics of CM-101 and in identifying the optimal dosing regimens for future clinical studies. Additionally, liver biopsies were not performed. These studies were performed in healthy volunteers or patients with MASLD without evidence of MASH, rather than in patients with more advanced disease. Additionally, collectively, these Phase 1 studies were conducted in mostly White males. Longer, larger studies are needed to characterize the safety of CM-101 administered for more than 15 weeks.

5 Conclusion

These results demonstrate the favorable safety and pharmacokinetic profiles of CM-101 in healthy volunteers and patients with MASLD without evidence of MASH. Additionally, the exploratory biomarker results in patients with MASLD without evidence of MASH indicate early therapeutic potential. These results support the further study of CM-101 as a treatment option for patients with inflammatory and fibrotic diseases, including PSC, for which a Phase 2a clinical trial is ongoing (NCT04595825).