A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists ...in type 2 diabetes mellitus (T2DM).
LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice.
A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25–8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5–10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5–15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.
LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist.
A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25–15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean LSM difference 95% CI: −49.12 mg/dL −78.14, −20.12 and −43.15 mg/dL −73.06, −13.21, respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference 95% CI: −1.75 kg −3.38, −0.12, −5.09 kg −6.72, −3.46 and −4.61 kg −6.21, −3.01, respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference 95% CI: −2.62 kg −3.79, −1.45 and −2.07 kg −3.25, −0.88, respectively.
The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.
Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.
•LY3298176 activates both GIP and GLP-1 receptor signaling in vitro.•LY3298176 lowers blood glucose in mice through actions on both incretin receptors.•LY3298176 reduced fasting glucose in humans with type 2 diabetes.•Weight loss was greater with LY3298176 than the selective GLP-1 receptor agonist, dulaglutide in healthy humans.•Tolerability of LY3298176 was comparable to GLP-1 receptor agonists.
With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to ...fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.
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•LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors•LY3437943 caused greater body weight loss in obese mice than tirzepatide•LY3437943 increased energy expenditure through glucagon receptor activation•Safety and tolerability of LY3437943 were similar to other incretin-based drugs
Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies.
The effect of dual glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) receptor agonist (RA) tirzepatide on gastric emptying (GE) was compared to that of GLP‐1RAs ...in non‐clinical and clinical studies. GE was assessed following acute and chronic treatment with tirzepatide in diet‐induced obese mice versus semaglutide or long‐acting GIP analogue alone. Participants with and without type 2 diabetes (T2DM) from a phase 1, 4‐week multiple dose study received tirzepatide, dulaglutide or placebo. GE was assessed by acetaminophen absorption. In mice, tirzepatide delayed GE to a similar degree to that achieved with semaglutide; however, these acute inhibitory effects were abolished after 2 weeks of treatment. GIP analogue alone had no effect on GE or on GLP‐1's effect on GE. In participants with and without T2DM, once‐weekly tirzepatide (≥5 and ≥4.5 mg, respectively) delayed GE after a single dose. This effect diminished after multiple doses of tirzepatide or dulaglutide in healthy participants. In participants with T2DM treated with an escalation schedule of tirzepatide 5/5/10/10 or 5/5/10/15 mg, a residual GE delay was still observed after multiple doses. These data suggest that tirzepatide's activity on GE is comparable to that of selective GLP‐1RAs.
Background and Aims
The pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being ...developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function.
Methods
Forty-five subjects, categorized by baseline renal status, i.e. mild (
n
= 8, estimated glomerular filtration rate eGFR 60–89 mL/min/1.73m
2
), moderate (
n
= 8, eGFR 30–59 mL/min/1.73m
2
), severe renal impairment (
n
= 7, eGFR < 30 mL/min/1.73m
2
), end-stage renal disease requiring dialysis (
n
= 8), and normal renal function (
n
= 14, eGFR ≥ 90 mL/min/1.73m
2
), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration–time curves (AUCs) and maximum plasma drug concentration (
C
max
) of renal impairment versus the normal renal function group (90% confidence interval CI). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression.
Results
Tirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and
C
max
comparing each renal impairment group versus normal renal function spanned unity, except for a 25–29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups.
Conclusion
There were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment.
Clinical Trial Registration
ClinicalTrials.gov NCT03482024.
Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. This ...study evaluated the pharmacokinetics (PK) and tolerability of TZP in subjects with renal impairment (with or without T2DM) vs. healthy subjects with normal renal function. Subjects in this single-dose study were categorized by renal impairment defined by baseline estimated glomerular filtration rate (eGFR, MDRD equation): 14 with normal renal function (≥90 mL/min/1.73m2), 8 with mild impairment (60-89 mL/min/1.73m2), 8 with moderate impairment (30-59 mL/min/1.73m2), 7 with severe impairment (<30 mL/min/1.73m2) and 8 with end stage renal disease (ESRD) requiring dialysis. All subjects received a single subcutaneous dose of 5 mg TZP. Blood samples were collected to determine TZP plasma concentrations to estimate PK parameters. Adverse events were monitored to assess safety and tolerability. Log-transformed AUC0-∞, AUC0-tlast, and Cmax were evaluated by analysis of variance and 90% CI of the ratio between groups was estimated. Additionally, relationship between TZP PK parameters and eGFR (MDRD and CKD-EPI) and creatinine clearance (Cockcroft-Gault) was assessed by regression analysis. PK parameters were similar between subjects with severe renal impairment and healthy subjects (geometric LSM ratios 90% CI of 1.03 0.836, 1.27, 1.04 0.841, 1.28 and 1.23 0.966, 1.56 for AUC∞, AUC0-tlast, and Cmax, respectively). Similar results were observed when comparing the PK parameters of mild, moderate and ESRD groups vs. healthy subjects. There was no statistically significant relationship at the two-sided 10% significance level between exposure and eGFR. No notable differences in safety profiles were observed. There were no clinically relevant effects of renal impairment on TZP PK. Thus, patients with renal impairment treated with tirzepatide may not require dose adjustments.
Disclosure
S. Urva: None. T. Quinlan: None. J. Landry: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Martin: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
Multi-receptor incretin agonists are being developed for several metabolic disorders. LY is an investigational triple agonist with potent activity on glucose-dependent insulinotropic polypeptide ...(GIP) , glucagon-like polypeptide-1 (GLP-1) , and glucagon receptors. LY was safely studied in a prior first-in-human study and pharmacokinetics properties supported once weekly dosing. The primary objective of this randomized, double-blind, placebo-controlled, Phase 1 proof-of-concept study was to assess the safety and tolerability of multiple ascending doses of LY in patients with type 2 diabetes (T2D) . Seventy-two patients were randomized (9:3:1) to 5 rising dose cohorts of subcutaneous LY, placebo, and dulaglutide 1.5mg, respectively. Within cohort, dose-escalation was implemented at highest 2 cohorts. Vital signs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. Efficacy was assessed by monitoring change in glycated hemoglobin (HbA1c) and body weight at week 12. The most common treatment-emergent AEs were gastrointestinal (nausea and diarrhea) , which were mostly mild in severity. By week 12, mean systolic and diastolic blood pressure decreased from baseline in LY compared to placebo group, while pulse and heart rate increased from baseline within most LY cohorts and dulaglutide, but not with placebo. By week 12, mean HbA1c decreased from baseline in all groups, with higher doses of LY showing statistically significant placebo-adjusted decreases of up to 1.56%. Except at the initial cohort, dose-dependent decreases in mean placebo-adjusted body weight of up to 8.96 kg were observed with LY. LY3437943 exhibits safety and tolerability profile similar to other incretins. Promising glycemic and body weight loss efficacy within this study highlights the potential for LY to provide additional benefit versus existing therapies in treatment of T2D and obesity.
Disclosure
S. Urva: Employee; Eli Lilly and Company. M. Loh: Employee; Eli Lilly and Company. T. Coskun: Employee; Eli Lilly and Company. Y. Du: None. C. Loghin: Employee; Eli Lilly and Company. A. Haupt: Employee; Lilly. Stock/Shareholder; Lilly. Z. Milicevic: Employee; Eli Lilly and Company.
Funding
Eli Lilly and Company
Multifunctional incretins are in clinical development for several metabolic conditions. Novel LY3437943 has potent agonist activity on glucose-dependent insulinotropic polypeptide (GIP), ...glucagon-like peptide-1 (GLP-1) and glucagon receptors. The primary objective of this randomized, double-blind, placebo (PBO)-controlled, Phase 1, first in human study was to assess safety and tolerability of single-ascending doses of LY3437943. Forty-five healthy subjects were randomized (6:2) to subcutaneous LY3437943 (6 rising dose levels) or PBO. Vital signs, ECGs, laboratory data and adverse events (AEs) were monitored to assess safety and tolerability. LY3437943 pharmacokinetics (PK) as well as change from baseline (BL) in fasting insulin, C-peptide and weight were measured. Appetite was assessed using a visual analog scale (VAS). The most common treatment-emergent AEs were gastrointestinal, including vomiting (with higher doses), abdominal distention and nausea, which were dose-dependent, mostly mild in severity, occurred within 4 days of dosing and resolved within a week of onset. Dose-dependent increases in heart rate and decreases in systolic blood pressure were observed, which returned to near BL by Day 29. Mean terminal half-life of LY3437943 ranged from 134-165 h (∼7 days) across the 6 doses, supporting once-weekly dosing. Dose-dependent increases in mean fasting insulin and C-peptide, with maximum levels observed at 24 and 48 h, returned to near BL by Day 15. Dose-dependent weight loss was statistically significant with the 3 highest doses vs. PBO (up to 3.5 kg at the highest dose). Weight loss was maintained up to Day 43 following single administration of the two highest doses. Overall VAS score significantly increased with higher doses vs. PBO, reflecting decreased appetite. Triple-agonist peptide LY3437943 had a safety and tolerability profile similar to other incretins in Phase 1 trials with PK and pharmacodynamic outcomes that support further clinical evaluation.
Disclosure
S. Urva: Employee; Self; Eli Lilly and Company. Y. Du: None. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. T. Coskun: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
LY3305677 (LY) is an acylated single chain peptide analog of mammalian oxyntomodulin designed for once weekly dosing. It has dual pharmacology of GLP-1 and glucagon and has therapeutic potential for ...T2D, obesity and NASH. This randomized, double blind, placebo-controlled phase 1 study assessed safety and tolerability of single ascending doses of LY. Healthy subjects (N=48) were randomized (6:2) and 47 received subcutaneous LY (6 doses: 0.03 mg to 5.0 mg) or placebo. Safety biomarkers, LY pharmacokinetics (PK), and key exploratory pharmacodynamic (PD) biomarkers were assessed including fasting insulin, glucagon, triglyceride levels, and body weight. Most common LY-related AEs were gastrointestinal events. Dose-dependent increase in nausea, decreased appetite, and vomiting were seen. Most of the events were mild and transient. Increase in heart rate was noted, which returned to baseline for most groups at follow-up visit. No injection site reactions were seen. Median time to maximum LY concentration ranged from 18.2 to 72.1 h, and geometric mean half-life ranged from 7.5 to 9.8 days. Generally, mean fasting insulin level increased within 24 h and lasted over 8 days. At Day 8, LY 2.5 mg and 5.0 mg reduced mean fasting glucagon levels by 2.33 pmol/L and 2.67 pmol/L, respectively as compared with placebo. At Day 5, mean fasting triglyceride levels reduced from baseline by 0.5 mmol/L with LY 5.0 mg as compared to 0.1 mmol/L with placebo. Change from baseline in body weight reached a maximum -2.4 kg with the 5 mg dose, versus -0.5 kg for placebo at Day 8 and this effect was sustained through Day 29 at 5 mg.
LY3305677 PK properties are suitable for once-weekly dosing with a safety and tolerability profile similar to other incretins in Phase 1 trials, supporting future clinical evaluation.
Disclosure
L. Tham: Employee; Self; Eli Lilly and Company. M. K. Thomas: Employee; Self; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: None. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. C. Loghin: Employee; Self; Eli Lilly and Company.
Funding
Eli Lilly and Company
Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of ...dulaglutide were characterized in patients with T2D and healthy subjects.
The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models.
Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration-time curve and the maximum concentration were both <17% coefficient of variation (CV). There was no difference in pharmacokinetics between injection sites (arm, thigh or abdomen). Dulaglutide pharmacokinetics were well described by a two-compartment model with first-order absorption and elimination. The population clearance was estimated at 0.126 L/h inter-individual variability (CV) 33.8%. Age, body weight, sex, race and ethnicity did not influence dulaglutide pharmacokinetics to any clinically relevant degree.
The pharmacokinetics of dulaglutide support once-weekly administration in patients with T2D. The pharmacokinetic findings suggest that dose adjustment is not necessary on the basis of body weight, sex, age, race or ethnicity or site of injection.
A long-acting GLP-1 receptor agonist (RA) transiently delays gastric emptying (GE). We investigated the GE effect of a novel dual GIP and GLP-1 RA, tirzepatide (TZP), compared to that of a selective ...GLP-1 RA in nonclinical and clinical studies. No effect on GE was seen with GIP RA alone in mice. Combination of GIP RA with GLP-1 RA or a dual agonist, TZP, did not delay GE more than GLP-1 RA alone. The effect of TZP on GE was evaluated in a Phase 1 study, comprising 4 week multiple ascending dose (MAD; N=35) QW in healthy subjects and 4-week proof of concept (PoC) (N=53) in patients with T2DM. In MAD, TZP was administered QW at fixed doses of 0.5, 1.5, 4.5 mg, and a titration dose of 5-5-8-10 mg. A selective GLP-1 RA, dulaglutide (dula), 1.5 mg QW was also included. In PoC, TZP was administered QW at fixed doses of 0.5 mg and 5 mg, and at titration doses of 5-5-10-10 mg and 5-5-10-15 mg. Acetaminophen (APAP) was administered on Day -1 (prior to TZP or dula), at 24 hours after the first (Day 2) and fourth (Day 23) doses to coincide with peak TZP or dula exposure. Impact of TZP on GE was evaluated using APAP Cmax, AUC, and tmax, compared to placebo (PL). Baseline adjusted Cmax of APAP (ratio to Day -1) was used to compare the GE effect of TZP with that of dula. APAP Cmax decreased by approximately 50% and tmax was delayed by an hour after the first TZP dose (doses >1.5 mg), suggesting a delay in GE while AUC was not notably altered. Evaluation of APAP PK after the first and fourth doses of the fixed dose regimen of TZP showed that impact of TZP on GE was maximized after first dose (Day 2 vs. PL), and showed complete tachyphylaxis after repeated dosing (Day 23 vs. PL). Similarly, in the titration cohort, impact of TZP on GE was significant after the first dose. However, incomplete tachyphylaxis was observed after 4 weeks of TZP administration due to the titration regimen. Impact of the fixed doses of TZP on GE was comparable to that of a selective GLP 1 RA (dula).
Disclosure
S. Urva: None. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sun Pharma. T. Coskun: Employee; Self; Eli Lilly and Company. X. Cui: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. C. Benson: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company.
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