Abstract
Background and Objectives
Cagrilintide is a long-acting amylin agonist under development as monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and treatment of type 2 diabetes. Two studies were conducted to assess the effects of renal or hepatic impairment on pharmacokinetics, safety and tolerability following single doses of cagrilintide.
Methods
In both studies, adult participants were categorised into four groups on the basis of renal or hepatic function (normal function and mild, moderate or severe impairment) and received a single dose of cagrilintide 0.6 or 0.9 mg, respectively. The primary endpoint was area under the cagrilintide plasma concentration curve from time zero extrapolated to infinity (AUC0–∞) from baseline (day 1) to day 36 (renal impairment study) or day 39 (hepatic impairment study). Other pharmacokinetic parameters included maximum observed cagrilintide plasma concentration (Cmax), time to Cmax (tmax) and safety.
Results
The renal impairment study included 33 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 5) and the hepatic impairment study included 32 participants (normal function, n = 14; mild impairment, n = 7; moderate impairment, n = 7; severe impairment, n = 4). In both studies, total cagrilintide exposure (AUC0–∞), Cmax and other pharmacokinetic parameters were similar across groups with no consistent patterns observed with renal or hepatic impairment. Compared with normal renal function, the estimated ratio of the mean AUC0–∞ was 1.23 (90% confidence interval [CI], 0.91–1.66) in mild impairment, 1.18 (0.87–1.59) in moderate impairment and 1.21 (0.87–1.68) in severe impairment. Compared with normal hepatic function, the estimated ratio of the mean AUC0–∞ was 0.99 (0.89–1.11) in mild impairment, 1.01 (0.91–1.12) in moderate impairment and 1.11 (0.96–1.30) in severe impairment.
Overall, 21 and 16 treatment-emergent adverse events (TEAEs) were reported in 11 and 9 participants in the renal and hepatic studies, respectively. In both studies, no serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No increase in number of adverse events with increasing renal or hepatic impairment was observed, and no new safety or tolerability findings with cagrilintide were identified with renal or hepatic impairment.
Conclusions
In these studies, within the limitations of small sample sizes, no clinically relevant differences in cagrilintide pharmacokinetics were observed in participants with renal or hepatic impairment compared with those with normal function, suggesting that dose adjustment is not warranted for these populations. Cagrilintide was well-tolerated and there were no unexpected safety issues.
Trial Registration
Studies are registered at ClinicalTrials.gov (NCT04209049 registered 23 December 2019 and NCT05564104 registered 3 October 2022).
Supplementary Information
The online version contains supplementary material available at 10.1007/s40262-026-01654-0.
Key Points
| Two clinical studies were conducted to assess the effects of renal or hepatic impairment on the pharmacokinetics, safety and tolerability of cagrilintide, a long-acting amylin agonist under development as a monotherapy for weight management and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for weight management and type 2 diabetes. | |
| In both studies, cagrilintide pharmacokinetic parameters were similar across the groups with normal function and renal or hepatic impairment with no new safety or tolerability concerns. | |
| Renal or hepatic impairment had no clinically relevant effect on cagrilintide pharmacokinetics, suggesting that dose adjustment is not warranted in these populations. | |
| Cagrilintide was well-tolerated and there were no unexpected safety issues. |
Introduction
Amylin is a peptide hormone co-secreted with insulin from pancreatic beta-cells in response to food intake [1–4]. Amylin is involved in the central regulation of food intake, body weight and glycaemia [5], leading to decreased food intake, reduced body weight and improved glycaemic control [1–3]. Cagrilintide is a long-acting amylin agonist that has 84% homology to native human amylin with several amino acid substitutions and other chemical alterations to enhance stability, potency and biological half-life [3, 6]. Cagrilintide binds to the calcitonin receptor and all three amylin receptors (AMY1, AMY2 and AMY3 receptors) [6]. Cagrilintide has pharmacokinetic properties compatible with once-weekly administration, with an elimination terminal half-life (t1/2) of approximately 180 h (7.5 days) [7]. Cagrilintide is under development as a monotherapy for the treatment of overweight and obesity and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist semaglutide (CagriSema) for the treatment of overweight, obesity and type 2 diabetes [4] with the rationale that the two molecules may have complementary effects on appetite and glucose regulation. Cagrilintide efficacy, safety and tolerability have been assessed in several clinical studies. As a fixed-dose combination, CagriSema was assessed in two phase 3 studies (REDEFINE 1 and 2), resulting in significant and clinically relevant reductions in body weight compared with placebo in adults with overweight or obesity, with [8] or without type 2 diabetes [9]. In both of these studies, CagriSema was well-tolerated with an acceptable safety profile, with similar results reported in a phase 1b study in participants with overweight or obesity [7] and a phase 2 study in participants with type 2 diabetes [4]. As monotherapy, in a phase 2 study, cagrilintide led to significant reductions in body weight and was well-tolerated in participants with overweight or obesity [10]. Furthermore, in a post hoc analysis of the cagrilintide monotherapy arm in REDEFINE 1, cagrilintide led to clinically meaningful reductions in body weight and waist circumference versus placebo and presented a favourable safety profile [11].
Regulatory authorities advise assessing how renal and hepatic impairment affects the pharmacokinetics of new drugs, as this evaluation may indicate the need for dose adjustment in these populations [12–15]. Understanding the impact of renal or hepatic impairment on the pharmacokinetic properties of cagrilintide is crucial for managing overweight and obesity in individuals with these conditions, particularly as chronic kidney disease and liver disease including metabolic dysfunction-associated steatotic liver disease are common comorbidities of obesity.
Here, we report two separate clinical studies that investigated the pharmacokinetic properties, safety and tolerability of cagrilintide in people with renal impairment and in people with hepatic impairment.
Methods
A two-centre, open-label, parallel-group study investigated the pharmacokinetics, safety and tolerability of a single subcutaneous (SC) dose of cagrilintide 0.6 mg in participants with varying degrees of renal function (NCT04209049). A three-centre, open-label, parallel-group study investigated the pharmacokinetics, safety and tolerability of a single SC dose of cagrilintide 0.9 mg in participants with varying degrees of hepatic function (NCT05564104). The difference in cagrilintide doses used between the two studies was based on the available evidence at the time the studies were planned. At the time of the hepatic impairment study, which was conducted after the renal impairment study, the available evidence supported a higher cagrilintide dose of 0.9 mg. Study designs are shown in Fig. 1.
Fig. 1.
Study designs of renal and hepatic impairment studies where participants were grouped according to renal or hepatic function and assessed following a single dose of cagrilintide 0.6 or 0.9 mg, respectively. BMI body mass index, eGFR estimated glomerular filtration rate, NCBP non-childbearing potential, PK pharmacokinetics, SC subcutaneous
Relevant ethics committees approved both study protocols. All participants provided written, informed consent. Both studies were conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and US Food and Drug Administration/European Medicines Agency guidelines for studies in people with renal or hepatic impairment [12–15].
Renal Impairment Study
Study Population
Male and female participants of non-childbearing potential were eligible for inclusion in the renal impairment study if they were aged between 18 and 80 years with a body mass index (BMI) between 20 and 39.9 kg/m2 and a body weight ≥ 60 kg at screening. Participants were allocated into four groups on the basis of renal function estimated using the Chronic Kidney Disease Epidemiology Collaboration formula as per the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines at the time [16]: normal renal function (estimated glomerular filtration rate [eGFR] ≥ 90 mL/min), mild renal impairment (eGFR ≥ 60–< 90 mL/min), moderate renal impairment (eGFR ≥ 30–< 60 mL/min) and severe renal impairment (eGFR < 30 mL/min, not requiring dialysis). Participants with renal impairment were recruited before those with normal renal function to help ensure similarity across groups in age and body weight.
Participants with renal impairment were excluded if they had previously undergone renal transplantation or had unstable renal function or acute exacerbation of renal disease within 14 days of baseline, as indicated by recent history or worsening of clinical or laboratory signs. Participants with normal renal function were eligible for inclusion if they were judged to be of general good health by the investigator, on the basis of a medical examination (including physical examination, medical history, vital signs and electrocardiogram [ECG]) with laboratory parameters within normal limits.
Study Design
Participants received a single dose of SC cagrilintide 0.6 mg on day 1 after fasting overnight for at least 6 h, with water intake allowed. Cagrilintide was administered in a skinfold in the abdomen using a NovoPen® 4 by qualified site staff at the clinic. Blood samples for pharmacokinetic analysis were collected up to 15 min pre-dose (day 1), and at 4, 8, 12, 18, 24, 30, 36, 48, 54, 60, 72, 84, 96 and 120 h post-dose. This was followed by a 35-day pharmacokinetic blood sampling and safety assessment period (i.e., 4–5 times the estimated cagrilintide t1/2), with blood samples collected on days 8, 15, 22, 29 and 36.
Endpoints and Statistical Analysis
A sample size of 35 (14 with normal renal function and 7 in each of the renal impairment groups) was chosen. This was not based on a formal power calculation but was within the standard range of participants in pharmacokinetic studies of people with renal impairment [13]. SAS v9.4 (TS1M5) pharmacokinetic software was used to calculate pharmacokinetic values.
The primary endpoint was area under the cagrilintide plasma concentration curve from time zero extrapolated to infinity (AUC0–∞) from baseline (day 1) to day 36 (end of study). Secondary endpoints were the maximum observed cagrilintide plasma concentration (Cmax) and time to Cmax (tmax). The number of treatment-emergent adverse events (TEAEs) was a secondary safety endpoint. T1/2 for cagrilintide, apparent total body clearance of cagrilintide from plasma (CL/F) and apparent volume of distribution (Vz/F) of cagrilintide based on plasma concentration values were exploratory pharmacokinetic endpoints.
AUC0–∞ was log-transformed and analysed using a normal linear model and an analysis of covariance (ANCOVA) with renal status as factor and log-transformed body weight at baseline as covariate. Residual variance was allowed to depend on the renal function group. Geometric mean ratios between renal impairment groups and the normal renal function group were estimated with 90% CIs. Cmax was analysed using the same approach, whereas tmax and all exploratory pharmacokinetic endpoints were summarised by renal function group using descriptive statistics.
Other assessments included changes in laboratory parameters (including but not limited to haematology and biochemistry), and physical examination, vital signs and ECG.
Hepatic Impairment Study
Study Population
Male and female participants of non-childbearing potential aged between 18 and 80 years with a BMI between 18.5 and 39.9 kg/m2 were eligible for inclusion in the hepatic impairment study. Participants were allocated into four groups on the basis of hepatic function (normal or impaired) with hepatic impairment being defined as a diagnosis of cirrhosis due to parenchymal liver disease, which is confirmed and documented by at least one of the following: medical history, physical examination, hepatic ultrasound, computed axial tomography scan, magnetic resonance imaging or liver biopsy. Hepatic function had to be stable, defined as no clinically significant change in disease status, as judged by the investigator. Participants with hepatic impairment were allocated into three groups, with the degree of impairment categorised by the investigator according to Child–Pugh criteria: mild (Grade A; 5–6 points), moderate (Grade B; 7–9 points) or severe (Grade C; 10–15 points) [12]. Participants with hepatic impairment were recruited before those with normal hepatic function to help ensure similarity across groups in age and body weight.
Participants with hepatic impairment must have been on a stable dose of medication or treatment regimen (e.g., no new medications and no changes to current medications within 14 days of screening) and were excluded if they had clinical signs of acute hepatitis, records of biliary obstruction or other causes of hepatic impairment not related to parenchymal disorders or diseases, a history of hepatic encephalopathy ≥ Grade 3 or presence of hepatic encephalopathy ≥ Grade 2, gastroesophageal varices not managed according to standard of care for patients with cirrhosis or with bleeding within 90 days prior to screening, acute or exacerbation of chronic liver failure or history of liver transplantation.
Participants with normal hepatic function were eligible for inclusion if they were judged to be of general good health by the investigator, based on a medical examination (including physical examination, medical history, vital signs and ECG) and had liver enzyme levels within prespecified limits (alanine aminotransferase ≤ upper limit of normal [ULN] + 10%, aspartate aminotransferase ≤ ULN + 20% and total bilirubin ≤ ULN + 20%).
Study Design
Participants received a single dose of SC cagrilintide 0.9 mg on day 1. Study product was administered in a skinfold in the abdomen using a NovoPen® 4 by qualified site staff delegated to this task at the clinic. Blood samples for pharmacokinetic analysis were collected up to 15 min pre-dose (day 1), and at 4, 8, 12, 18, 24, 30, 36, 48, 54, 60, 72, 84, 96 and 120 h post-dose. This was followed by a 38-day pharmacokinetic blood sampling and safety assessment period (i.e., 4–5 times the estimated cagrilintide t1/2), with blood samples collected on days 8, 15, 22, 29 and 39.
Endpoints and Statistical Analysis
A sample size of 35 (14 in the normal hepatic function and 7 in each of the hepatic impairment groups) was chosen. This was not based on a formal power calculation but was within the standard range of participants in pharmacokinetic studies of people with hepatic impairment [12, 14]. SAS v9.4 (TS1M5) pharmacokinetic software was used to calculate pharmacokinetic values.
The primary endpoint was AUC0–∞ for plasma cagrilintide from baseline (day 1) to day 39 (end of study). Supportive secondary endpoints were Cmax, tmax, t1/2 and CL/F. Vz/F was an exploratory pharmacokinetic endpoint. The number of TEAEs was reported but was not specified as a study endpoint.
The primary endpoint was log-transformed and analysed using a normal linear model and an ANCOVA with hepatic status as factor and log body weight at baseline as covariate. Residual variance was allowed to depend on the hepatic function group. Treatment ratios between hepatic impairment groups and the normal group were estimated with 90% CIs. Cmax was analysed using the same approach as for the primary endpoint, whereas tmax, t½, CL/F and Vz/F were summarised by hepatic function group using descriptive statistics.
Other assessments included changes in laboratory parameters (including but not limited to haematology and biochemistry), and physical examination, vital signs and ECG.
Plasma Bioanalysis
The bioanalysis of cagrilintide pharmacokinetic samples was performed by Celerion Switzerland AG (Fehraltorf, Switzerland) for both studies using a liquid chromatography–tandem mass spectrometry (LC-MS/MS) detection assay following plasma protein precipitation. The assay was validated according to local procedures: the FDA 2018 guideline on validation of bioanalytical methods [17], the EMA 2011 guideline on validation of bioanalytical methods [18] and current practice. Venous blood samples were stored at −20 °C in polypropylene tubes until analysed, 80 µL of ethylenediaminetetraacetic acid (EDTA) plasma was used to assess cagrilintide pharmacokinetics at each timepoint, thus 16 mL EDTA plasma from each participant was used. The analysis was carried out on an AB Sciex Triple Quad 6500+ LC-MS/MS system using TurboIonSpray and SelexION interface. The LC system was a Waters Acquity UPLC® system (Waters, Elstree, UK). Quantification was performed by peak area ratios of cagrilintide versus internal standard. The calibration curve fitting was done by weighted linear regression (1/concentration2). The lower limit of quantification for cagrilintide was 0.425 nmol/L.
Results
Renal Impairment Study
A total of 199 participants were screened and 33 were exposed to cagrilintide (full analysis set and safety analysis set: normal renal function, n = 14; mild renal impairment, n = 7; moderate renal impairment, n = 7; severe renal impairment, n = 5) at two sites in the USA between 15 January 2020 and 5 January 2021 (Supplementary Table S1). Only five participants were recruited for the severe renal impairment group instead of the seven that were planned because of recruitment being paused due to restrictions imposed by the coronavirus 2019 (COVID-19) pandemic. A total of 32 participants completed the study; one participant in the normal renal function group withdrew after exposure (lost to follow-up). Demographics and baseline characteristics were generally similar among the renal function groups (Table 1).
Table 1.
Demographic and baseline characteristics by renal function group
| Normal renal function (n = 14) | Mild renal impairment (n = 7) | Moderate renal impairment (n = 7) | Severe renal impairment (n = 5) | |
|---|---|---|---|---|
| Female, n | 5 | 2 | 3 | 0 |
| Age, years | 64.4 (4.3) | 67.1 (9.1) | 70.3 (8.1) | 68.4 (9.8) |
| Race, n | ||||
| White | 12 | 6 | 6 | 4 |
| Black or African American | 2 | 1 | 1 | 1 |
| Ethnicity, n | ||||
| Hispanic or Latino | 14 | 0 | 2 | 1 |
| Body weight, kg | 77.0 (7.2) | 76.8 (5.4) | 81.9 (20.1) | 91.5 (9.4) |
| Body mass index, kg/m2 | 28.0 (3.2) | 27.6 (2.6) | 28.4 (4.7) | 30.5 (4.1) |
| eGFR, mL/min/1.73 m2 | 97 (7) | 73 (7) | 48 (7) | 19 (6) |
All data are mean (SD) unless otherwise stated. eGFR calculated using CKD-EPI formula
CKD-EPI Chronic Kidney Disease Epidemiology Collaboration, eGFR estimated glomerular filtration rate, SD standard deviation
Pharmacokinetics
Geometric mean concentration–time profiles of plasma cagrilintide appeared to be similar across the four renal function groups (Fig. 2). In line with the concentration–time profiles, total cagrilintide exposure was similar across the different renal function groups (Table 2 and Fig. 2). Participants with normal renal function had a slightly lower total cagrilintide exposure (AUC0–∞) compared with participants with renal impairment, but without a trend across the different renal impairment groups. The estimated treatment ratios of the mean AUC0–∞ of cagrilintide in each of the renal impairment groups to the normal renal function group were 1.23 (90% CI, 0.91–1.66) for the mild renal impairment group, 1.18 (90% CI, 0.87–1.59) for the moderate renal impairment group and 1.21 (90% CI, 0.87–1.68) for the severe renal impairment group.
Fig. 2.
a Geometric mean cagrilintide plasma concentration (nmol/L) over time on a linear scale by renal function after a single dose of cagrilintide 0.6 mg. b Individual participant profiles for each renal function group on a linear scale. Study period was from dosing at baseline (day 1, 0 hours) to day 36
Table 2.
Pharmacokinetic endpoints by renal function group after a single dose of cagrilintide 0.6 mg
| Normal renal function (n = 14) | Mild renal impairment (n = 7) | Moderate renal impairment (n = 7) | Severe renal impairment (n = 5) | |
|---|---|---|---|---|
| AUC0–∞, h*nmol/L | 2622 (63) | 3207 (20) | 2969 (24) | 2766 (20) |
| AUC0–∞ estimated treatment ratio (90% CI) versus normal function | – | 1.23 (0.91–1.66) | 1.18 (0.87–1.59) | 1.21 (0.87–1.68) |
| Cmax, nmol/L | 7.15 (79.8) | 9.04 (34.9) | 8.02 (28.8) | 7.52 (30.9) |
| Cmax estimated treatment ratio (90% CI) versus normal function | – | 1.27 (0.86–1.88) | 1.17 (0.81–1.70) | 1.22 (0.79–1.86) |
| tmax, h | 72 (24, 120) | 48 (24, 120) | 48 (18, 168) | 60 (24, 84) |
| t1/2, h | 186 (13.2) | 194 (10.8) | 204 (13.2) | 211 (9.4) |
| CL/F, L/h | 0.052 (63.2) | 0.042 (20.4) | 0.046 (23.6) | 0.049 (20.2) |
| Vz/F, L | 13.9 (72.3) | 11.9 (19.5) | 13.5 (20.2) | 15.0 (17.8) |
All data are geometric mean (coefficient of variation, %), except for tmax, for which median (minimum, maximum) values are presented
AUC area under the plasma concentration–time curve, CI confidence interval, CL/F total apparent clearance, Cmax maximum concentration, tmax time to reach maximum plasma concentration, t½ terminal half‐life, Vz/F apparent volume of distribution
Cmax was also similar in the renal impairment groups versus the normal renal function group. The variation in Cmax was larger within the normal renal function group, which had a small number of outlying profiles. No consistent pattern was seen with the median tmax across the groups (72, 48, 48 and 60 h for normal renal function and mild, moderate and severe renal impairment, respectively). The geometric mean of the t1/2 of cagrilintide in the renal function groups was 186 h for people with normal renal function (range 149–244 h), 194 h (range 160–221 h) for participants with mild renal impairment, 204 h (range 166–237 h for participants with moderate renal impairment and 211 h (range 187–232 h) for participants with severe renal impairment. CL/F and Vz/F showed no consistent pattern across groups.
Safety
In total, 21 TEAEs were reported in 11 participants: 14 events were reported in eight participants (57.1%) with normal renal function, two in one participant (14.3%) with mild renal impairment, and five in two participants (28.6%) with moderate renal impairment (Table 3). No TEAEs were reported in the severe renal impairment group. The most frequent TEAEs were injection site erythema, nausea, vomiting and decreased appetite. All events were mild or moderate in severity, and all were resolved or resolving. No serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No clinically relevant changes were observed for laboratory parameters or physical examination. In the normal renal function group, one participant had a clinically significant vital sign abnormality (increased blood pressure) and one had a clinically significant ECG abnormality, with both reported as resolved mild TEAEs.
Table 3.
Adverse events by renal function group assessed from baseline (day 1) to day 36 after a single dose of cagrilintide 0.6 mg
| Normal renal function (n = 14) | Mild renal impairment (n = 7) | Moderate renal impairment (n = 7) | Severe renal impairment (n = 5) | |
|---|---|---|---|---|
| n, E | n, E | n, E | n, E | |
| Adverse events | 8, 14 | 1, 2 | 2, 5 | 0 |
| Serious adverse events | 0 | 0 | 0 | 0 |
| Severity | ||||
| Severe | 0 | 0 | 0 | 0 |
| Moderate | 0 | 0 | 1, 2 | 0 |
| Mild | 8, 14 | 1, 2 | 1, 3 | 0 |
| Injection site reaction | 4, 4 | 0 | 0 | 0 |
| Deaths | 0 | 0 | 0 | 0 |
| Adverse events by preferred term (≥ 2 events in any group) | ||||
| Injection site erythema | 3, 3 | 0 | 0 | 0 |
| Nausea | 0 | 1, 1 | 2, 2 | 0 |
| Vomiting | 0 | 1, 1 | 2, 2 | 0 |
| Decreased appetite | 2, 2 | 0 | 0 | 0 |
n number of participants, E number of events
Hepatic Impairment Study
A total of 57 participants were screened and 32 were exposed to cagrilintide (full analysis set and safety analysis set: normal hepatic function, n = 14; mild hepatic impairment, n = 7; moderate hepatic impairment, n = 7; severe hepatic impairment, n = 4) at two sites in Slovakia and one in Germany between 5 April 2023 and 19 December 2024 (Supplementary Table S1). Only four participants were recruited for the severe hepatic impairment group because of recruitment difficulties. All 32 participants completed the study. Demographics and baseline characteristics were generally similar among the hepatic function groups (Table 4).
Table 4.
Demographic and baseline characteristics by hepatic function group
| Normal hepatic function (n = 14) | Mild hepatic impairment (n = 7) | Moderate hepatic impairment (n = 7) | Severe hepatic impairment (n = 4) | |
|---|---|---|---|---|
| Female, n | 7 | 5 | 3 | 1 |
| Age, years | 62.4 | 65.6 | 58.6 | 58.0 |
| Race, n | ||||
| White | 14 | 7 | 7 | 4 |
| Ethnicity, n | ||||
| Hispanic or Latino | 0 | 0 | 0 | 0 |
| Body weight, kg | 86.4 (16.6) | 79.8 (19.6) | 86.3 (22.3) | 85.9 (17.4) |
| Body mass index, kg/m2 | 30.0 (4.2) | 29.9 (6.4) | 29.3 (5.8) | 28.5 (2.8) |
| Serum albumin, g/dL | 4.5 (0.3) | 4.3 (0.2) | 4.1 (0.3) | 3.7 (0.9) |
| Bilirubin (µmol/L) | 6.4 (2.9) | 11.0 (5.9) | 22.2 (6.8) | 48.4 (18.8) |
All data are mean (SD) unless otherwise stated.
SD standard deviation
Pharmacokinetics
Geometric mean concentration–time profiles of plasma cagrilintide appeared to be similar across the four hepatic function groups (Fig. 3). In line with the concentration–time profiles, total cagrilintide exposure (AUC0–∞) was similar across the four groups (Table 5 and Fig. 3). The estimated treatment ratios of the mean AUC0–∞ of cagrilintide compared with the normal hepatic function group were 0.99 (90% CI, 0.89–1.11) for the mild hepatic impairment group, 1.01 (90% CI, 0.91–1.12) for the moderate hepatic impairment group and 1.11 (90% CI, 0.96–1.30) for the severe hepatic impairment group.
Fig. 3.
a Geometric mean cagrilintide plasma concentration (nmol/L) over time on a linear scale by hepatic function after a single dose of cagrilintide 0.9 mg. b Individual participant profiles for each hepatic function group on a linear scale. Study period was from dosing at baseline (day 1, 0 hours) to day 39
Table 5.
Pharmacokinetic endpoints by hepatic function group after a single dose of cagrilintide 0.9 mg
| Normal hepatic function (n = 14) | Mild hepatic impairment (n = 7) | Moderate hepatic impairment (n = 7) | Severe hepatic impairment (n = 4) | |
|---|---|---|---|---|
| AUC0–∞, h*nmol/L | 5056 (18.6) | 5437 (19.5) | 5193 (31.1) | 5668 (28.3) |
| AUC0–∞ estimated treatment ratio (90% CI) versus normal function | – | 0.99 (0.89–1.11) | 1.01 (0.91–1.12) | 1.11 (0.96–1.30) |
| Cmax, nmol/L | 15.11 (21.7) | 16.33 (28.4) | 13.44 (42.0) | 14.85 (47.2) |
| Cmax estimated treatment ratio (90% CI) versus normal function | – | 1.00 (0.82–1.22) | 0.88 (0.73–1.06) | 0.98 (0.69–1.38) |
| tmax, h | 45 (24, 120) | 36 (24, 96) | 84 (30, 168) | 45 (30, 168) |
| t1/2, h | 174 (10.0) | 176 (8.7) | 188 (5.4) | 199 (7.5) |
| CL/F, L/h | 0.040 (18.6) | 0.038 (19.5) | 0.039 (31.1) | 0.036 (28.3) |
| Vz/F, L | 10.1 (17.9) | 9.5 (17.9) | 10.7 (25.7) | 10.4 (21.1) |
All data are geometric mean (coefficient of variation, %), except for tmax, for which median (minimum, maximum) values are presented.
AUC area under the plasma concentration–time curve, CI confidence interval, Cmax maximum concentration, tmax time to reach maximum plasma concentration, t½ terminal half‐life, CL/F total apparent clearance, Vz/F apparent volume of distribution
Cmax was also similar in the hepatic impairment groups versus the normal hepatic function group. A variation in tmax was observed across the groups but with no apparent association with increasing hepatic impairment (45, 36, 84 and 45 h for normal hepatic function and mild, moderate and severe hepatic impairment, respectively). There was a tendency toward higher t1/2 with increasing hepatic impairment ranging from 174 h (range 144–204 h) in the group with normal hepatic function to 199 h (range 184–214 h) in the group with severe hepatic impairment. CL/F and Vz/F were similar across the groups with no consistent pattern.
Safety
A total of 16 TEAEs were reported in nine participants. A total of 12 events were reported in five participants (35.7%) in the normal hepatic function group, three events in three participants (42.9%) in the mild hepatic impairment group and one event in one participant (14.3%) in the moderate hepatic impairment group. No TEAEs were reported in the severe hepatic impairment group (Table 6). The most frequent TEAE was decreased appetite (n = 5). All events were mild or moderate in severity with no severe TEAEs reported, and all were resolved. No serious TEAEs, TEAEs leading to study withdrawal or deaths were reported. No clinically relevant findings were observed for laboratory parameters, vital signs or ECG.
Table 6.
Adverse events by hepatic function group assessed from baseline (day 1) to day 39 after a single dose of cagrilintide 0.9 mg
| Normal hepatic function (n = 14) | Mild hepatic impairment (n = 7) | Moderate hepatic impairment (n = 7) | Severe hepatic impairment (n = 4) | |
|---|---|---|---|---|
| n, E | n, E | n, E | n, E | |
| Adverse events | 5, 12 | 3, 3 | 1, 1 | 0 |
| Serious adverse events | 0 | 0 | 0 | 0 |
| Severity | ||||
| Severe | 0 | 0 | 0 | 0 |
| Moderate | 1, 1 | 0 | 0 | 0 |
| Mild | 5,11 | 3, 3 | 1, 1 | 0 |
| Injection site reaction | 0 | 1, 1 | 0 | 0 |
| Deaths | 0 | 0 | 0 | 0 |
| Adverse events by preferred term (≥ 2 events in any group) | ||||
| Decreased appetite | 3, 3 | 2, 2 | 0 | 0 |
| Nausea | 1, 2 | 0 | 1, 1 | 0 |
| Vomiting | 1, 2 | 0 | 0 | 0 |
n number of participants, E number of events
Discussion
The results of these two studies found no clinically relevant differences in cagrilintide pharmacokinetics in people with renal or hepatic impairment, regardless of severity. In addition, there were no safety or tolerability issues identified regarding the use of cagrilintide in participants with renal or hepatic impairment. These findings indicate that dose adjustment of cagrilintide is not warranted in people with renal or hepatic impairment.
Renal impairment affects not only the renal excretion of a drug but may also alter metabolism and active transport in the kidney, liver or gut and affect absorption, tissue distribution and plasma protein binding [13]. Preclinical studies have shown that cagrilintide is extensively metabolised and subsequently excreted as metabolites in bile and urine [data on file]. In this study, cagrilintide exposure (AUC0–∞ and Cmax) over a 35-day period after a single 0.6 mg dose was similar in participants with renal impairment and normal renal function. However, participants with normal renal function had a slightly lower total exposure and rate of absorption than participants with renal impairment, but without a trend across the different renal impairment groups. The variation in Cmax within the normal renal function group was larger than the renal impairment groups owing to outlying profiles with low exposure. Median tmax appeared to be reduced in participants with renal impairment, while t1/2 increased. The tendency for increased t1/2 with increasing renal impairment was not considered clinically relevant, as exposure was similar between groups, and results supported once-weekly SC administration of cagrilintide. The derived pharmacokinetic parameters, CL/F and Vz/F also varied across the renal function groups with no apparent pattern. These data indicate that the pharmacokinetics of cagrilintide are unaffected by renal impairment.
The primary concern with hepatic impairment is a potential change in exposure to a drug that is extensively cleared by hepatic metabolism or biliary excretion via the liver, that could impact on the pharmacodynamic action or lead to adverse effects [19]. In this study, hepatic impairment did not affect cagrilintide exposure over a 38-day period after a single 0.9 mg dose. Variability was observed in tmax across the groups but with no apparent association with increasing hepatic impairment. There was a tendency toward higher t1/2 with increasing hepatic impairment, but applying the same rationale as stated above for participants with renal impairment, this was not considered clinically relevant. Overall, these data indicate that there is no clinically relevant effect of hepatic impairment on cagrilintide pharmacokinetics.
Our results suggest that dose adjustment of cagrilintide is not warranted in people with renal or hepatic impairment. This is consistent with previous studies of the amylin analogue, pramlintide. Similar to cagrilintide, pramlintide is primarily eliminated via the kidneys and, in a pharmacokinetic study in participants with type 1 diabetes, no statistically significant differences were noted in total (AUC0-∞) and peak (Cmax) exposure after administration of a single pramlintide 60 μg dose in participants with mild, moderate or severe renal impairment compared with those with normal renal function, although inter-patient variability was high [20]. Based on these data, no dose adjustment of pramlintide is required in people with renal impairment, although studies have not been conducted in people on dialysis. Pharmacokinetic studies have also not been conducted in people with hepatic impairment. However, based on the large degree of renal metabolism of pramlintide, hepatic dysfunction is not expected to affect exposure.
In both current studies, the safety data with cagrilintide were consistent with data from previous studies with no new safety or tolerability issues observed [4, 7, 10]. The most frequent TEAEs across the two studies were nausea, vomiting, decreased appetite and injection site erythema. No severe TEAEs or serious TEAEs were observed in either study. There was no indication of increased frequency of TEAEs with increasing renal or hepatic impairment. Indeed, in both studies, the highest frequency of TEAEs was in the normal function groups, possibly owing to the smaller sample sizes in the more severe impairment groups, or alternatively because participants with more serious health concerns, such as those with severe renal or hepatic impairment, may be less likely to notice or report mild or moderate TEAEs, as observed in populations with cancer [21].
Cagrilintide is in development as a monotherapy for the treatment of overweight and obesity and as a fixed-dose combination with the glucagon-like peptide-1 receptor agonist, semaglutide (CagriSema) for the treatment of overweight, obesity and type 2 diabetes. In previous studies, renal or hepatic impairment had no clinically relevant effect on the pharmacokinetics of SC semaglutide [22, 23]. Similar findings have also been reported for oral semaglutide [24, 25]. In a phase 1b study of co-administered SC semaglutide 2.4 mg with cagrilintide 0.16–4.5 mg (CagriSema) in participants with overweight or obesity, cagrilintide exposure was proportional to dose and did not affect semaglutide exposure or elimination [7]. Cagrilintide AUC0–168h ranged from 926–24,271 nmol × h/L, Cmax ranged from 6.14 to 170 nmol/L, t1/2 ranged between 159–195 h and median tmax was 24–72 h. CL/F and Vz/F for both semaglutide and cagrilintide were similar across treatment groups. These data, together with our findings, suggest that dose adjustment of CagriSema is unlikely to be needed in people with renal or hepatic impairment.
Potential limitations of both studies include the use of a single dose rather than multiple doses of cagrilintide and the use of doses (0.6 mg in the renal impairment study and 0.9 mg in the hepatic impairment study) lower than the 2.4 mg dose being evaluated in clinical development. The doses chosen were because higher doses of cagrilintide may be associated with gastrointestinal adverse effects, in particular nausea and vomiting, and require dose escalation to be attained. Multiple dosing with escalation to a higher dose was considered inappropriate for participants in these studies given their potential poor health status. However, the pharmacokinetics of cagrilintide are dose-proportional and linear, with exposure determined primarily by apparent clearance (CL/F) at any administered dose, and AUC defined as dose/(CL/F), thus allowing direct comparison across different dosing regimens. Based on this pharmacokinetic profile, administration of cagrilintide to participants with varying degrees of renal or hepatic impairment is expected to yield comparable exposure across dose levels and dosing frequencies, without compromising safety. Another limitation was that both studies had low numbers of participants, with the fewest in the groups with severe renal or hepatic impairment. In the renal impairment study, this was in part owing to disruption by the COVID-19 pandemic, with temporary closure of the two study centres. Although mitigation measures were implemented, this resulted in fewer participants than planned enrolled into the severe renal impairment group. Similarly, recruitment of participants with severe hepatic impairment into the hepatic impairment study was challenging and, despite a third study site being added and the recruitment period being prolonged, it was not possible to complete recruitment of seven participants into the severe hepatic impairment group. Again, this may have been, in part, owing to the effect of the COVID-19 pandemic, which resulted in high mortality among patients with severe hepatic disease [26, 27]. Participant numbers were, however, in accordance with the regulatory guidelines for these types of studies [12–15]. The renal impairment study excluded participants who required dialysis and while renal clearance is a focus of this study, this can be seen as a limitation. A further limitation was that there was a lack of racial or ethnic diversity in the hepatic impairment study. It should also be noted that there was a protocol deviation in the renal impairment study whereby participants were assigned to renal function groups using an eGFR value expressed in mL/min/1.73 m2 instead of mL/min. When classifying eGFR values as per protocol, the group allocations were as follows: normal renal function (mL/min/1.73 m2: n = 14; mL/min: n = 15), mild renal impairment (n = 7, unchanged), moderate renal impairment (n = 7, unchanged) and severe renal impairment (mL/min/1.73 m2: n = 5; mL/min: n = 4) (Supplementary Table S2). Data were re-analysed according to the per-protocol definitions and found only minor changes to AUC0–∞ and Cmax, with no effect on the conclusions.
Conclusions
In these studies, within the limitations of small sample sizes, no clinically relevant differences were observed in cagrilintide pharmacokinetics in people with renal or hepatic impairment compared with those with normal function. Cagrilintide was well-tolerated with no new safety findings and no increase in the number of TEAEs with increasing renal or hepatic impairment. These results indicate that no specific dose adjustment for cagrilintide is required for people with renal or hepatic impairment.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgments
The authors thank the study participants, the investigators and study site staff who conducted the study. The authors also thank Tine Aggerholm Bækdal and Ayna Baladi Nejad, former employees of Novo Nordisk A/S, for their contributions to both studies. Medical writing support was provided by Andy Bond, of Apollo, OPEN Health Communications, and funded by Novo Nordisk A/S, in accordance with Good Publication Practice (GPP) guidelines (www.ismpp.org/gpp-2022).
Funding
Both studies were funded by Novo Nordisk A/S and are registered with ClinicalTrials.gov (NCT04209049 and NCT05564104).
Declarations
Conflict of interest
Mette JF Nielsen, Helene H Hansen Duus, Katrine Kirkeby, Britt W Lauenborg, Benjamin Low and Louise Witten are employees and stockholders of Novo Nordisk A/S. Niels-Peter Becker is a former employee of Novo Nordisk A/S and a current employee of F. Hoffmann-La Roche Ltd. Viera Kupčová has no conflicts of interest to report. Olivia Svolgaard is an employee of Novo Nordisk A/S.
Ethical Approval
Relevant ethics committees approved both study protocols. All participants provided written, informed consent. Both studies were conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and US Food and Drug Administration/European Medicines Agency guidelines for studies in people with renal or hepatic impairment
Consent to Participate/Publish
All participants provided written, informed consent.
Availability of Data and Material
An authorised researcher can request access to clinical trial study data by submitting a research proposal for review and approval by Novo Nordisk and an internal independent review panel. Requests are usually considered after the research is finished and the main results have been published. If the research supports a regulatory application, requests will be considered after the product, and its intended use are approved in both the EU and the USA. Participants’ clinical data will be anonymised, following an approved internal process, before data are shared to external third parties. For details on how to request access to clinical data, visit novonordisk-trials.com.
Author Contributions
Mette JF Nielsen, Britt W Lauenborg and Viera Kupčová contributed to the design, protocol and conduct of the studies. Olivia Svolgaard contributed to protocol development, conduct of the studies and closing the studies. Helene H Hansen Duus and Katrine Kirkeby were responsible for the statistical analyses. All authors were responsible for data interpretation. All authors had full access to study data, contributed to the drafting and revision of the manuscript and approved the manuscript for submission.
References
- 1.Ludwig MQ, Coester B, Gordian D, et al. A cross-species atlas of the dorsal vagal complex reveals neural mediators of cagrilintide’s effects on energy balance. bioRxiv. 2025. 10.1101/2025.01.13.632726. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Boyle CN, Lutz TA, Le Foll C. Amylin - Its role in the homeostatic and hedonic control of eating and recent developments of amylin analogs to treat obesity. Mol Metab. 2018;8:203–10. 10.1016/j.molmet.2017.11.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183–94. 10.1021/acs.jmedchem.1c00565. [DOI] [PubMed] [Google Scholar]
- 4.Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402(10403):720–30. 10.1016/s0140-6736(23)01163-7. [DOI] [PubMed] [Google Scholar]
- 5.Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev. 2015;67(3):564–600. 10.1124/pr.115.010629. [DOI] [PubMed] [Google Scholar]
- 6.Cao J, Belousoff MJ, Johnson RM, et al. Structural and dynamic features of cagrilintide binding to calcitonin and amylin receptors. Nat Commun. 2025;16(1):3389. 10.1038/s41467-025-58680-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397(10286):1736–48. 10.1016/s0140-6736(21)00845-x. [DOI] [PubMed] [Google Scholar]
- 8.Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide-semaglutide in adults with overweight or obesity and type 2 diabetes. N Engl J Med. 2025. 10.1056/NEJMoa2502082. [DOI] [PubMed] [Google Scholar]
- 9.Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med. 2025. 10.1056/NEJMoa2502081. [DOI] [PubMed] [Google Scholar]
- 10.Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398(10317):2160–72. 10.1016/s0140-6736(21)01751-7. [DOI] [PubMed] [Google Scholar]
- 11.Garvey WT, Kuhlman AB, Rømer J, Pietiläinen KH, Tvermosegaard KB, Lau DCW. Efficacy and safety of cagrilintide 2.4 mg in adults with overweight/obesity: data from REDEFINE 1. Diabetologia. 2025;68(Suppl 1):S1–754. 10.1007/s00125-025-06497-1. [Google Scholar]
- 12.European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. (CPMP/EWP/2339/02). 2005. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-pharmacokinetics-medicinal-products-patients-impaired-hepatic-function_en.pdf. Accessed 6 Apr 2025.
- 13.European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function (EMA/CHMP/83874/2014). 2015. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-evaluation-pharmacokinetics-medicinal-products-patients-decreased-renal-function_en.pdf. Accessed 6 Apr 2025.
- 14.US Food and Drug Administration, Center for Drug Evaluation and Research. Guidance for industry. Pharmacokinetics in patients with impaired hepatic function – study design, data analysis and impact on dosing and labeling. 2003. https://www.fda.gov/media/71311/download. Accessed 6 Apr 2025.
- 15.US Food and Drug Administration, Center for Drug Evaluation and Research. Pharmacokinetics in patients with impaired renal function – study design, data analysis, and impact on dosing. Guidance for industry. 2024. https://www.fda.gov/media/78573/download. Accessed 6 Apr 2025.
- 16.KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3(1):1-150. [DOI] [PubMed]
- 17.US Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Bioanalytical method validation. Guidance for industry. 2018. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf. Accessed 6 Apr 2025.
- 18.European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009 rev. 1 Corr. 2**). 2011. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf. Accessed 6 Apr 2025.
- 19.Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61. 10.1007/s00228-008-0553-z. [DOI] [PubMed] [Google Scholar]
- 20.US Food and Drug Administration. SYMLIN® (pramlintide acetate) injection for subcutaneous use. Prescribing Information. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021332s028lbl.pdf. Accessed 6 May 2025.
- 21.Cleeland CS. Symptom burden: multiple symptoms and their impact as patient-reported outcomes. J Natl Cancer Inst Monogr. 2007;2007(37):16–21. 10.1093/jncimonographs/lgm005. [DOI] [PubMed] [Google Scholar]
- 22.Marbury TC, Flint A, Jacobsen JB, Derving Karsbøl J, Lasseter K. Pharmacokinetics and tolerability of a single dose of semaglutide, a human glucagon-like peptide-1 analog, in subjects with and without renal impairment. Clin Pharmacokinet. 2017;56(11):1381–90. 10.1007/s40262-017-0528-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Jensen L, Kupcova V, Arold G, Pettersson J, Hjerpsted JB. Pharmacokinetics and tolerability of semaglutide in people with hepatic impairment. Diabetes Obes Metab. 2018;20(4):998–1005. 10.1111/dom.13186. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Baekdal TA, Thomsen M, Kupčová V, Hansen CW, Anderson TW. Pharmacokinetics, safety, and tolerability of oral semaglutide in subjects with hepatic impairment. J Clin Pharmacol. 2018;58(10):1314–23. 10.1002/jcph.1131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Granhall C, Søndergaard FL, Thomsen M, Anderson TW. Pharmacokinetics, safety and tolerability of oral semaglutide in subjects with renal impairment. Clin Pharmacokinet. 2018;57(12):1571–80. 10.1007/s40262-018-0649-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hartl L, Semmler G, Hofer BS, et al. COVID-19-related downscaling of in-hospital liver care decreased patient satisfaction and increased liver-related mortality. Hepatol Commun. 2021;5(10):1660–75. 10.1002/hep4.1758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Fedeli U, Barbiellini Amidei C, Casotto V, et al. Mortality from chronic liver disease: recent trends and impact of the COVID-19 pandemic. World J Gastroenterol. 2023;29(26):4166–73. 10.3748/wjg.v29.i26.4166. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.