Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as [¹⁴C]-LY3502970, Orforglipron
LY3502970 · 37 trials · 34 indications
Obesity related complications defined as type 2 diabetes, hypertension, or dyslipidemia; Class 1 obesity defined as body mass index (BMI) ≥30 kilograms per square meter (kg/m2) or an equivalent region-specific threshold
Composite endpoint includes nonfatal myocardial infarction, nonfatal stroke, hospitalization or urgent visit due to heart failure, coronary revascularization, or all-cause death
On a constant load treadmill test
* Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A, measured to reflect average plasma glucose concentration over a prolonged period of time. * Values represented under "Least Squares (LS) Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE were calculated using a mixed-model repeated measures (MMRM) analysis for post-baseline measures, with country, baseline by time by treatment, and strata by time by treatment in the model. Strata were defined by joint levels of HbA1c level (\<= \[less than or equal to\] 8.0% ,\> \[greater than\] 8.0%). Variance-covariance structure for change from baseline was unstructured.
A TEAE was defined as any adverse event that began on or after the first dose of study drug or began before the first dose of study drug and worsened on or after the first dose of study drug.
* HbA1c is the glycosylated fraction of hemoglobin A. It is measured to identify average plasma glucose concentration over prolonged periods of time. * LS mean was analysed by mixed model repeated measures (MMRM) model with Country + Baseline\*Time\*Treatment + Strata\*Time\*Treatment as variables. Strata is defined by joint levels of HbA1c level (\<=8.0%, \>8.0%).
* Hemoglobin A1c (HbA1c) is the glycosylated fraction of hemoglobin A, measured to reflect average plasma glucose concentration over prolonged periods of time. * Values represented under "Least Squares (LS) Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) with analysis country, treatment by time, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of baseline HbA1c (≤ \[less than or equal to\] 8.0%, \> \[greater than\] 8.0%) and prior use of any antihyperglycemic medication (yes or no). Variance-covariance structure for change from baseline was unstructured.
Values reported as "LS Mean" are model-based estimates (MBE) of the adjusted (unconditional) treatment effect. MBEs was calculated using an analysis of covariance (ANCOVA) model with the following variables: treatment group, baseline value, baseline Body Mass Index (BMI) category (\<35 kilogram per meter square \[kg/m²\] or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Strata were defined by joint levels of sex (female, male) and baseline type 2 diabetes status (yes, no).
Percentage of participants with ≥5% body weight reduction was analysed by Logistic regression with the following variables: treatment group, baseline value, baseline BMI category (\<35 kg/m² or ≥35 kg/m²), and stratification factors (sex and baseline type 2 diabetes status). Stratification factors were defined by the combination of sex (female, male) and baseline type 2 diabetes status (yes, no). The model also allowed the treatment effect to vary across baseline values and stratification factors.
Values represented under "Least Squares (LS) Mean" are model-based estimates (MBE) of the unconditional average treatment effect. MBE was calculated using a mixed-model repeated measures (MMRM) for post-baseline measures with geographic region, baseline by time by treatment, and strata by time by treatment in the model. Strata was defined by joint levels of Sex (female, male) and prediabetes status (yes, no). Variance-covariance structure for change from baseline was unstructured.
Time to First Occurrence of Any MACE-4 (Myocardial Infarction (MI), Stroke, Hospitalization for Unstable Angina, or Cardiovascular \[CV\] Death)
Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with Baseline + Baseline BMI Group + Sex + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables. Variance-Covariance structure (Actual Value) = Unstructured. Variance-Covariance structure (Percent Change from Baseline) = Unstructured.
HbA1c is the glycosylated fraction of hemoglobin A. HbA1c is measured to identify average plasma glucose concentration over prolonged periods of time. Least Squares (LS) mean was determined by mixed model repeated measures (MMRM) model with Baseline + Country + Baseline HbA1c Group (\<=8.0%, \>8.0%) + Treatment + Time + Treatment\*Time (Type III sum of squares) as variables.
PK: Area under the concentration versus time curve from time 0 to the end of the once daily dosing interval at steady state AUC\[0-tau\] on Day 7.
PK: Maximum concentration of LY3502970 during a once daily dosing interval at steady state on Day 7.
AUC \[0-∞\] of simvastatin and its active acid metabolite (simvastatin acid) following simultaneous administration with or without Orforglipron capsule were reported in this outcome measure.
AUC \[0-∞\] of simvastatin and its active acid metabolite (simvastatin acid) following staggered administration with or without Orforglipron capsule were reported in this outcome measure. Simvastatin was administered \~2h (±10 min) after Orforglipron capsule administration (Staggered dosing).
AUC \[0-∞\] of simvastatin and its active acid metabolite (simvastatin acid) following simultaneous administration with or without sodium bicarbonate administration were reported in this outcome measure.
AUC \[0-∞\] of acetaminophen following staggered administration with or without either 1 mg or 36 mg Orforglipron capsule were reported in this outcome measure. Acetaminophen was administered \~2h (±10 min) after Orforglipron capsule administration (Staggered dosing).
AUC \[0-∞\] of midazolam and its metabolite (1'-Hydroxymidazolam) following simultaneous administration with or without Orforglipron capsule were reported in this outcome measure.
Cmax of simvastatin and its active acid metabolite (simvastatin acid) following simultaneous administration with or without Orforglipron capsule were reported in this outcome measure.
Cmax of simvastatin and its active acid metabolite (simvastatin acid) following staggered administration with or without Orforglipron capsule were reported in this outcome measure. Simvastatin was administered \~2h (±10 min) after Orforglipron capsule administration (Staggered dosing).
Cmax of simvastatin and its active acid metabolite (simvastatin acid) following simultaneous administration with or without sodium bicarbonate administration were reported in this outcome measure.
Cmax of acetaminophen following staggered administration with or without either 1 mg or 36 mg Orforglipron capsule were reported in this outcome measure. Acetaminophen was administered \~2h (±10 min) after Orforglipron capsule administration (Staggered dosing).
Cmax of Midazolam and its metabolite (1'-Hydroxymidazolam) following simultaneous administration with or without Orforglipron capsule is reported in this outcome measure.
A summary of TEAEs, SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the Reported Adverse Events module
PK: AUC\[0-24\] of LY3502970 in fasted state
PK: Cmax of LY3502970 in fasted state
PK: Tmax of LY3502970 in fasted state
An SAE is defined as any untoward medical occurrence that, at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other situations based on medical judgement. A summary of SAEs and other non-serious adverse events (AEs), regardless of causality, will be reported in the Reported Adverse Events module.
| Arm | Type | Description |
|---|---|---|
| Orforglipron | EXPERIMENTAL | Participants will receive orforglipron orally. |
| Placebo | PLACEBO_COMPARATOR | Participants will receive placebo orally. |
| Orforglipron to Placebo | EXPERIMENTAL | Participants will receive orforglipron orally followed by placebo orally |
| Placebo to Orforglipron | EXPERIMENTAL | Participants will receive placebo orally followed by orforglipron orally |
| Dulaglutide | ACTIVE_COMPARATOR | Participants will receive dulaglutide subcutaneously (SC) |
| Orforglipron (GZS1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (GZS1) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron (GZS2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (GZS2) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron (GZT1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (GZT1) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron (GZT2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (GZT2) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron Dose 1 | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 2 | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 3 | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 4 | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 1 (Study GZP1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 2 (Study GZP1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 3 (Study GZP1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 4 (Study GZP1) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (Study GZP1) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron Dose 1 (Study GZP2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 2 (Study GZP2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 3 (Study GZP2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Orforglipron Dose 4 (Study GZP2) | EXPERIMENTAL | Participants will receive orforglipron orally |
| Placebo (Study GZP2) | PLACEBO_COMPARATOR | Participants will receive placebo orally |
| Orforglipron (GZL1) | EXPERIMENTAL | Participants will receive orforglipron orally or placebo. |
| Orforglipron (GZL2) | EXPERIMENTAL | Participants will receive orforglipron orally or placebo. |
| Orforglipron (ISA PW01) | EXPERIMENTAL | Participants will receive orforglipron or placebo orally. Each ISA will detail the intervention specific. |
| Orforglipron 3 mg | EXPERIMENTAL | Participants received orforglipron, administered orally once daily (QD), starting at a dose of 1 milligram (mg) and escalated at week 4 to a dose of 3 mg, which was then maintained up to week 40. |
| Orforglipron 12 mg | EXPERIMENTAL | Participants received orforglipron, administered orally QD, starting at a dose of 1 mg and escalated every 4 weeks (to 3 mg at week 4 and 6 mg at week 8) until reaching a dose of 12 mg at week 12, which was then maintained up to week 40. |
| Orforglipron 36 mg | EXPERIMENTAL | Participants received orforglipron, administered orally QD, starting at a dose of 1 mg and escalated every 4 weeks (to 3 mg at week 4, 6 mg at week 8, 12 mg at week 12, and 24 mg at week 16) until reaching a dose of 36 mg at week 20, which was then maintained up to week 40. |
| Dapagliflozin 10 mg | ACTIVE_COMPARATOR | Participants received dapagliflozin, administered orally QD, at a fixed dose of 10 mg starting at randomization, which was maintained up to week 40. |
| 3 mg Orforglipron QD | EXPERIMENTAL | Participants received oral orforglipron, initiated at 1 milligram (mg) and increased every 4 weeks until reaching to a maintenance dose of 3 mg QD and insulin glargine therapy 100 U/mL administered SC QD, over a period of 40 weeks. |
| 12 mg Orforglipron QD | EXPERIMENTAL | Participants received oral orforglipron, initiated at 1 mg and increasing every 4 weeks until reaching to a maintenance dose of 12 mg QD and insulin glargine therapy 100 U/mL administered SC QD, over a period of 40 weeks. |
| 36 mg Orforglipron QD | EXPERIMENTAL | Participants received oral orforglipron, initiated at 1 mg and increasing every 4 weeks until reaching to a maintenance dose of 36 mg QD and insulin glargine therapy 100 U/mL administered SC QD, over a period of 40 weeks. |
| 3 mg Orforglipron | EXPERIMENTAL | Participants received once-daily oral orforglipron for 52 weeks. Treatment began with a 1-mg loading dose for the first 4 weeks, followed by the maintenance dose of 3 mg for the remainder of the duration. |
| 12 mg Orforglipron | EXPERIMENTAL | Participants received once-daily oral orforglipron for 52 weeks. Treatment began with a 1-mg loading dose for the first 4 weeks, followed by dose escalations every 4 weeks to reach the maintenance dose of 12 mg at week 12, which was then continued for the remainder of the duration. |
| 36 mg Orforglipron | EXPERIMENTAL | Participants received once-daily oral orforglipron for 52 weeks. Treatment began with a 1-mg loading dose for the first 4 weeks, followed by dose escalations every 4 weeks to reach the maintenance dose of 36 mg at week 20, which was then continued for the remainder of the duration. |
| 7 mg Semaglutide | ACTIVE_COMPARATOR | Participants initiated treatment with a 3 mg once-daily oral dose of semaglutide and increased the dose every 4 weeks until the targeted dose of 7 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period. |
| 14 mg Semaglutide | ACTIVE_COMPARATOR | Participants initiated treatment with a 3 mg once-daily oral dose of semaglutide and increased the dose every 4 weeks until the targeted dose of 14 mg once-daily was reached, after which this dose was to be continued for the remainder of the 52-week treatment period. |
| Placebo QD | PLACEBO_COMPARATOR | Participants received matching placebo capsule orally once daily (QD). Treatment was initiated with placebo corresponding to 1 mg equivalent to Orforglipron, with dose escalation every 4 weeks to maintain blinding, and was continued through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity. |
| 6 mg Orforglipron QD | EXPERIMENTAL | Participants received oral orforglipron capsule once daily. Treatment was initiated at 1 mg once daily, with dose escalation every 4 weeks to a target dose of 6 mg, which was maintained through Week 72, unless dose interruption or modification was required. Treatment was administered as an adjunct to a reduced-calorie diet and increased physical activity. |
| 6 mg Orforglipron | EXPERIMENTAL | Primary Treatment Period (Week 0-Week 72): Participants with normoglycemia or prediabetes at the time of randomization received orforglipron, administered orally QD, starting at a dose of 1 milligrams (mg) and escalated every 4 weeks until reaching a dose of 6 mg at week 8, which was then maintained up to week 72. |
| Insulin Glargine | ACTIVE_COMPARATOR | Participants will receive insulin glargine subcutaneously (SC). Doses will be individualized and titrated according to a treat-to-target algorithm. |
| 12 milligram (mg) LY3502970 | EXPERIMENTAL | Participants received maintenance dose 12 mg with dose escalation starting from 3 mg,6 mg and then 12 mg LY3502970 administered orally once daily until 36 weeks. |
| 24 mg LY3502970 | EXPERIMENTAL | Participants received maintenance dose 24 mg with dose escalation starting from 3 mg, 6 mg, 8 mg,12 mg and then 24 mg LY3502970 administered orally once daily until 36 weeks. |
| 36 mg-1 LY3502970 | EXPERIMENTAL | Participants received maintenance dose 36 mg with dose escalation starting from 2 mg, 3 mg, 6 mg, 8 mg, 12 mg, 24 mg and then 36 mg LY3502970 administered orally once daily until 36 weeks. |
| 36 mg-2 LY3502970 | EXPERIMENTAL | Participants received maintenance dose 36 mg with dose escalation starting from 3 mg, 6 mg,12 mg, 24 mg and then 36 mg LY3502970 administered orally once daily until 36 weeks. |
| 45 mg-1 LY3502970 | EXPERIMENTAL | Participants received maintenance dose 45 mg with dose escalation starting from 3 mg, 6 mg, 8 mg, 12 mg, 24 mg, 36 mg and then 45 mg LY3502970 administered orally once daily until 36 weeks. |
| 45 mg-2 LY3502970 | EXPERIMENTAL | Participants received maintenance dose 45 mg with dose escalation starting from 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg and then 45 mg LY3502970 administered orally once daily until 36 weeks. |
| 3 milligrams (mg) LY3502970 | EXPERIMENTAL | Participants received maintenance dose of 3 mg with dose escalation starting from 2 mg LY3502970 administered orally once daily (QD). |
| 12 mg LY3502970 | EXPERIMENTAL | Participants received maintenance dose 12 mg with dose escalation starting from 2 mg, 6 mg and then 12 mg LY3502970 administered orally QD. |
| 36 mg LY3502970 - 1 | EXPERIMENTAL | Participants received maintenance dose 36 mg with dose escalation starting from 2 mg, 3 mg, 6 mg, 8 mg, 12 mg, 24 mg and then 36 mg LY3502970 administered orally QD. |
| 36 mg LY3502970 - 2 | EXPERIMENTAL | Participants received maintenance dose 36 mg with dose escalation starting from 3 mg, 6 mg,12 mg, 24 mg and then 36 mg LY3502970 administered orally QD. |
| 45 mg LY3502970 - 1 | EXPERIMENTAL | Participants received maintenance dose 45 mg with dose escalation starting from 3 mg, 6 mg, 8 mg, 12 mg, 24 mg, 36 mg and then 45 mg LY3502970 administered orally QD. |
| 45 mg LY3502970 - 2 | EXPERIMENTAL | Participants received maintenance dose 45 mg with dose escalation starting from 2 mg, 3 mg, 6 mg, 12 mg, 24 mg, 36 mg and then 45 mg LY3502970 administered orally QD. |
| 1.5 mg Dulaglutide | ACTIVE_COMPARATOR | Participants received 1.5 mg Dulaglutide administered subcutaneously (SC) once weekly (QW). |
| Part A: LY3502970 QD Oral Administration (Cohort 1A, Sequence 1) | EXPERIMENTAL | Participants received LY3502970 orally once daily (QD) across inpatient Treatment Periods 1-12 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: 1 mg (Capsule) * Period 2: Dose Level 2 (Tablet) * Period 3: Dose Level 1 (Tablet) * Period 4: Dose Level 3 (Tablet) * Period 5: 3 mg (Capsule) * Period 6: Dose Level 5 (Tablet) * Period 7: Dose Level 4 (Tablet) * Period 8: Dose Level 6 (Tablet) * Period 9: 6 mg (Capsule) * Period 10: Dose Level 8 (Tablet) * Period 11: Dose Level 7 (Tablet) * Period 12: Dose Level 9 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 1A, Sequence 2) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-12 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: Dose Level 2 (Tablet) * Period 2: 1 mg (Capsule) * Period 3: Dose Level 3 (Tablet) * Period 4: Dose Level 1 (Tablet) * Period 5: Dose Level 5 (Tablet) * Period 6: 3 mg (Capsule) * Period 7: Dose Level 6 (Tablet) * Period 8: Dose Level 4 (Tablet) * Period 9: Dose Level 8 (Tablet) * Period 10: 6 mg (Capsule) * Period 11: Dose Level 9 (Tablet) * Period 12: Dose Level 7 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 1A, Sequence 3) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-12 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: Dose Level 1 (Tablet) * Period 2: Dose Level 3 (Tablet) * Period 3: 1 mg (Capsule) * Period 4: Dose Level 2 (Tablet) * Period 5: Dose Level 4 (Tablet) * Period 6: Dose Level 6 (Tablet) * Period 7: 3 mg (Capsule) * Period 8: Dose Level 5 (Tablet) * Period 9: Dose Level 7 (Tablet) * Period 10: Dose Level 9 (Tablet) * Period 11: 6 mg (Capsule) * Period 12: Dose Level 8 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 1A, Sequence 4) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-12 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: Dose Level 3 (Tablet) * Period 2: Dose Level 1 (Tablet) * Period 3: Dose Level 2 (Tablet) * Period 4: 1 mg (Capsule) * Period 5: Dose Level 6 (Tablet) * Period 6: Dose Level 4 (Tablet) * Period 7: Dose Level 5 (Tablet) * Period 8: 3 mg (Capsule) * Period 9: Dose Level 9 (Tablet) * Period 10: Dose Level 7 (Tablet) * Period 11: Dose Level 8 (Tablet) * Period 12: 6 mg (Capsule) |
| Part A: LY3502970 Oral Administration (Cohort 2A, Sequence 1) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg and 6 mg; Capsule), followed by inpatient Treatment Periods 7-18 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: 12 mg (Capsule) * Period 8: Dose Level 11 (Tablet) * Period 9: Dose Level 10 (Tablet) * Period 10: Dose Level 12 (Tablet) * Period 11: 24 mg (Capsule) * Period 12: Dose Level 14 (Tablet) * Period 13: Dose Level 13 (Tablet) * Period 14: Dose Level 16 (Tablet) * Period 15: 36 mg (Capsule) * Period 16: Dose Level 17 (Tablet) * Period 17: Dose Level 15 (Tablet) * Period 18: Dose Level 18 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 2A, Sequence 2) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg, and 6 mg; Capsule), followed by inpatient Treatment Periods 7-18 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: Dose Level 11 (Tablet) * Period 8: 12 mg (Capsule) * Period 9: Dose Level 12 (Tablet) * Period 10: Dose Level 10 (Tablet) * Period 11: Dose Level 14 (Tablet) * Period 12: 24 mg (Capsule) * Period 13: Dose Level 16 (Tablet) * Period 14: Dose Level 13 (Tablet) * Period 15: Dose Level 17 (Tablet) * Period 16: 36 mg (Capsule) * Period 17: Dose Level 18 (Tablet) * Period 18: Dose Level 15 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 2A, Sequence 3) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg and 6 mg; Capsule), followed by inpatient Treatment Periods 7-18 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: Dose Level 10 (Tablet) * Period 8: Dose Level 12 (Tablet) * Period 9: 12 mg (Capsule) * Period 10: Dose Level 11 (Tablet) * Period 11: Dose Level 13 (Tablet) * Period 12: Dose Level 16 (Tablet) * Period 13: 24 mg (Capsule) * Period 14: Dose Level 14 (Tablet) * Period 15: Dose Level 15 (Tablet) * Period 16: Dose Level 18 (Tablet) * Period 17: 36 mg (Capsule) * Period 18: Dose Level 17 (Tablet) |
| Part A: LY3502970 Oral Administration (Cohort 2A, Sequence 4) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg, and 6 mg; Capsule), followed by inpatient Treatment Periods 7-18 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: Dose Level 12 (Tablet) * Period 8: Dose Level 10 (Tablet) * Period 9: Dose Level 11 (Tablet) * Period 10: 12 mg (Capsule) * Period 11: Dose Level 16 (Tablet) * Period 12: Dose Level 13 (Tablet) * Period 13: Dose Level 14 (Tablet) * Period 14: 24 mg (Capsule) * Period 15: Dose Level 18 (Tablet) * Period 16: Dose Level 15 (Tablet) * Period 17: Dose Level 17 (Tablet) * Period 18: 36 mg (Capsule) |
| Part B: LY3502970 Oral Administration (Cohort 1B, Sequence 1) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-9 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: 1 mg (Capsule- First Treatment) * Period 2: 1 mg (Capsule- Second Treatment) * Period 3: 0.8 mg (Tablet) * Period 4: 3 mg (Capsule- First Treatment) * Period 5: 3 mg (Capsule- Second Treatment) * Period 6: 2.5 mg (Tablet) * Period 7: 6 mg (Capsule- First Treatment) * Period 8: 6 mg (Capsule- Second Treatment) * Period 9: 5.5 mg (Tablet) |
| Part B: LY3502970 Oral Administration (Cohort 1B, Sequence 2) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-9 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: 1 mg (Capsule- First Treatment) * Period 2: 0.8 mg (Tablet) * Period 3: 1 mg (Capsule- Second Treatment) * Period 4: 3 mg (Capsule- First Treatment) * Period 5: 2.5 mg (Tablet) * Period 6: 3 mg (Capsule- Second Treatment) * Period 7: 6 mg (Capsule- First Treatment) * Period 8: 5.5 mg (Tablet) * Period 9: 6 mg (Capsule- Second Treatment) |
| Part B: LY3502970 Oral Administration (Cohort 1B, Sequence 3) | EXPERIMENTAL | Participants received LY3502970 orally QD across inpatient Treatment Periods 1-9 (7 days per period), followed by a follow-up visit approximately 7 days after the last dose. Doses were administered as follows: * Period 1: 0.8 mg (Tablet) * Period 2: 1 mg (Capsule- First Treatment) * Period 3: 1 mg (Capsule- Second Treatment) * Period 4: 2.5 mg (Tablet) * Period 5: 3 mg (Capsule- First Treatment) * Period 6: 3 mg (Capsule- Second Treatment) * Period 7: 5.5 mg (Tablet) * Period 8: 6 mg (Capsule- First Treatment) * Period 9: 6 mg (Capsule- Second Treatment) |
| Part B: LY3502970 Oral Administration (Cohort 2B, Sequence 1) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg, and 6 mg \[Capsule\]), followed by inpatient Treatment Periods 7-15 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: 12 mg (Capsule- First Treatment) * Period 8: 12 mg (Capsule- Second Treatment) * Period 9: 9 mg (Tablet) * Period 10: 24 mg (Capsule- First Treatment) * Period 11: 24 mg (Capsule- Second Treatment) * Period 12: 14.5 mg (Tablet) * Period 13: 36 mg (Capsule- First Treatment) * Period 14: 36 mg (Capsule- Second Treatment) * Period 15: 17.2 mg (Tablet) |
| Part B: LY3502970 Oral Administration (Cohort 2B, Sequence 2) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg, and 6 mg \[Capsule\]), followed by inpatient Treatment Periods 7-15 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: 12 mg (Capsule- First Treatment) * Period 8: 9 mg (Tablet) * Period 9: 12 mg (Capsule- Second Treatment) * Period 10: 24 mg (Capsule- First Treatment) * Period 11: 14.5 mg (Tablet) * Period 12: 24 mg (Capsule- Second Treatment) * Period 13: 36 mg (Capsule- First Treatment) * Period 14: 17.2 mg (Tablet) * Period 15: 36 mg (Capsule- Second Treatment) |
| Part B: LY3502970 Oral Administration (Cohort 2B, Sequence 3) | EXPERIMENTAL | Participants received LY3502970 orally QD during home dosing Treatment Periods 1-6 (1 mg, 3 mg, and 6 mg \[Capsule\]), followed by inpatient Treatment Periods 7-15 (7 days per period) and a follow-up visit approximately 7 days after the last dose. Doses during inpatient periods were administered as follows: * Period 7: 9 mg (Tablet) * Period 8: 12 mg (Capsule- First Treatment) * Period 9: 12 mg (Capsule- Second Treatment) * Period 10: 14.5 mg (Tablet) * Period 11: 24 mg (Capsule- First Treatment) * Period 12: 24 mg (Capsule- Second Treatment) * Period 13: 17.2 mg (Tablet) * Period 14: 36 mg (Capsule- First Treatment) * Period 15: 36 mg (Capsule- Second Treatment) |
| Cohort 1: Oral Drug Dosing With or Without Orforglipron Co-Administration | EXPERIMENTAL | Participants received single oral doses as follows:Day 1: 20 milligram(mg) simvastatin; Day 2: 0.25 mg digoxin; Day 7:20 mg simvastatin + 600 mg sodium bicarbonate; Day 8: 20 mg rosuvastatin; Day 10: 1000 mg acetaminophen; Day 12: 0.2 mg midazolam;Day 14: 1 mg Orforglipron, followed by 1000 mg acetaminophen administered 2 hours (±10 minutes) later (staggered); Day 15: 1 mg Orforglipron; Days 16-97: Orforglipron administered once daily with dose escalation every 14 days:1 mg (Days 16-27), 3 mg (Days 28-41),6 mg (Days 42-55),12 mg (Days 56-69),24 mg (Days 70-83),36 mg (Days 84-97). Days 98-110: 36 mg Orforglipron administered once daily with co administration as follows:Day 98: 20 mg simvastatin (simultaneous); Day 99: 0.25 mg digoxin (simultaneous); Day 104: 20 mg simvastatin (staggered); Day 105:20 mg rosuvastatin (simultaneous); Day 107: 1000 mg acetaminophen (staggered); Day 109:0.2 mg midazolam (simultaneous); Day 111: 20 mg Orforglipron tablet + 20 mg simvastatin (simultaneous). |
| Cohort 2: Oral Drug Dosing With or Without Orforglipron Co-Administration | EXPERIMENTAL | Participants received single oral doses as follows: Day 1: 20 mg Simvastatin; Day 2: 0.25 mg Digoxin; Day 7: 20 mg Simvastatin + 600 mg Sodium Bicarbonate; Day 9: 1 mg Orforglipron capsule; Days 10-90: Participants received orforglipron capsule orally QD for 12 weeks, beginning at 1 mg QD. The dose was escalated every 14 days as follows: 1 mg (Days 10-22), 3 mg (Days 23-36), 6 mg (Days 37-50), 12 mg (Days 51-64), 24 mg (Days 65-78), and 36 mg (Days 79-90). Participants continued 36 mg Orforglipron QD until Day 100, with co-administration of the following drugs; Day 93: 20 mg Simvastatin (simultaneous); Day 94: 0.25 mg Digoxin (simultaneous); Day 99: 20 mg Simvastatin administered 2 hours ±10 minutes after Orforglipron administration (staggered dosing); Day 101: 20 mg Orforglipron tablet + 20 mg Simvastatin (simultaneous) |
| LY3502970 (Cohort 1) | EXPERIMENTAL | Participants received LY3502970 with dose escalation every 4 weeks, starting from 1 milligram (mg), 3 mg, 6 mg and then 12 mg LY3502970 administered orally once daily (QD) from Day 1 for 16 weeks. |
| LY3502970 (Cohort 2) | EXPERIMENTAL | Participants received LY3502970 with dose escalation every 4 weeks, starting from 1 mg, 3 mg, 6 mg, 12 mg, 24 mg and then 36 mg LY3502970 administered orally QD from Day 1 for 24 weeks. |
| Part A: LY3502970 (Periods 1 to 11) | EXPERIMENTAL | Participants received a once daily (QD) oral dose of LY3502970 in the tablet or capsule formulation, depending on the period of the study, throughout Periods 1 to 11 as follows: * Period 1 (Day 1-7): 0.8 milligram (mg) LY3502970 tablet (fasted state) * Period 2 (Day 8-14): 2 mg LY3502970 capsule (fasted state) * Period 3 (Day 15-21): 2.5 mg LY3502970 tablet (fasted state) * Period 4 (Day 22-28): 5 mg LY3502970 tablet (fasted state) * Period 5 (Day 29-35): 8 mg LY3502970 capsule (fasted state) * Period 6 (Day 36-42): 10 mg LY3502970 tablet (fasted state) * Period 7 (Day 43-49): 16 mg LY3502970 capsule (fasted state) * Period 8 (Day 50-56): 20 mg LY3502970 tablet (fasted state) * Period 9 (Day 57-63): 36 mg LY3502970 capsule (fasted state) * Period 10 (Day 64-70): 36 mg LY3502970 capsule or 37.5 mg LY3502970 tablet (fed state) * Period 11 (Day 71-77): 37.5 mg LY3502970 tablet (fasted state) |
| Part B: 45 mg LY3502970 / 60 mg LY3502970 (Periods 12 to 13) | EXPERIMENTAL | Participants after completion of Part A (Periods 1-11), in Part B received a QD oral dose of LY3502970 as follows: * Period 12 (Day 78-84): 45 mg LY3502970 tablet (fasted state) * Period 13 (Day 85-91): 60 mg LY3502970 tablet (fasted state) |
| Part B: 35 mg LY3502970 / 35 mg LY3502970 (Periods 12 to 13) | EXPERIMENTAL | Participants after completion of Part A (Periods 1-11), in Part B received a QD oral dose of LY3502970 as follows: * Period 12 (Day 78-84): 35 mg LY3502970 tablet (fasted state) * Period 13 (Day 85-91): 35 mg LY3502970 tablet (fasted state) |
| Part B: 36 mg LY3502970 DF / 36 mg LY3502970 EPB (Periods 12 to 13) | EXPERIMENTAL | Participants after completion of Part A (Periods 1-11), in Part B received a QD oral dose of LY3502970 as follows: * Period 12 (Day 78-84): 36 mg LY3502970 dual-fill (DF) capsule (fasted state) * Period 13 (Day 85-91): 36 mg LY3502970 extemporaneously prepared blended (EPB) capsule (fasted state) |
| LY3502970 Cohort 1 | EXPERIMENTAL | Participants received oral doses of 2 milligrams (mg) LY3502970 from days 1-14 and 3 mg LY3502970 from days 15-28 once daily (QD). |
| LY3502970 Cohort 2 | EXPERIMENTAL | Participants received oral doses of 1 mg LY3502970 from days 1-7, 2 mg LY3502970 from days 8-21 and 3 mg LY3502970 from days 22-28 QD. |
| LY3502970 Cohort 3 | EXPERIMENTAL | Participants received oral doses of 1 mg LY3502970 from days 1-14, 2 mg LY3502970 from days 15-21 and 3 mg LY3502970 from days 22-28 QD. |
| LY3502970 (Part A) | EXPERIMENTAL | Participants received single doses of LY3502970 administered orally. |
| LY3502970 (Part B) | EXPERIMENTAL | Participants received multiple doses of LY3502970 administered orally. |
| Placebo (Part A) | PLACEBO_COMPARATOR | Participants received placebo administered orally. |
| Placebo (Part B) | PLACEBO_COMPARATOR | Participants received placebo administered orally. |
| LY3502970 | EXPERIMENTAL | 3, 6, 9, 12, 15, 21, 27, 36 and 45 milligrams (mg) LY3502970 administered orally. |
| Name | Type | Description |
|---|---|---|
| Orforglipron | DRUG | Administered orally. |
| Placebo | DRUG | Administered orally. |
| Dulaglutide | DRUG | Administered SC |
| Dapagliflozin | DRUG | Administered orally |
| Semaglutide | DRUG | Administered orally |
| Insulin Glargine | DRUG | Administered SC once daily |
| LY3502970 | DRUG | Administered orally |
| Simvastatin | DRUG | Administered orally. |
| Digoxin | DRUG | Administered orally. |
| Rosuvastatin | DRUG | Administered orally. |
| Acetaminophen | DRUG | Administered orally. |
| Midazolam | DRUG | Administered orally. |
| Sodium Bicarbonate | DRUG | Administered orally. |
Inclusion Criteria: * Have body mass index (BMI) ≥28.0 kilograms per square meter (kg/m2) and \<30 kg/m2 or ≥24.0 kg/m2 and \<28 kg/m2, and at least 1 of the following weight-related comorbidities at screening: * hypertension * dyslipidemia * obstructive sleep apnea * Fatty liver * cardi...
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LY3502970 is an investigational small molecule developed by Eli Lilly and Company for the treatment of type 2 diabetes, obesity, and overweight. It is being studied in Phase 1 clinical trials and has not been approved for any indication. The drug is designed to act on the GLP-1 receptor, a target involved in metabolic regulation.
LY3502970 is being studied for type 2 diabetes mellitus, obesity, and overweight, including overweight with weight-related comorbidities. It is an investigational therapy in Phase 1 development and is not approved for any use. Clinical trials have enrolled participants with type 2 diabetes as well as healthy overweight and obese volunteers.
LY3502970 targets the GLP-1 receptor, a cell surface receptor in the target class of receptors. GLP-1 receptor activity is relevant to glucose regulation and body weight, which aligns with the metabolic indications under study: type 2 diabetes, obesity, and overweight. The drug is a small molecule rather than a peptide-based GLP-1 agent.
LY3502970 is developed by Eli Lilly and Company, which trades on the New York Stock Exchange under the ticker LLY. Lilly is the sponsor of the Phase 1 clinical program evaluating the drug in type 2 diabetes, obesity, and overweight. The compound is a small molecule directed at the GLP-1 receptor.
LY3502970 is in Phase 1 clinical development. It is investigational and has not been approved by the FDA or any other regulatory agency. The completed Phase 1 trials have evaluated the drug in healthy overweight and obese participants, in Chinese participants with obesity or overweight with weight-related comorbidities, and in Japanese participants with type 2 diabetes.
Four completed Phase 1 trials have studied LY3502970: NCT06023095 in Chinese participants with obesity or overweight with weight-related comorbidities, NCT05841238 and NCT05313802 in healthy overweight and obese participants in the United States, and NCT05086445 in Japanese participants with type 2 diabetes. These trials enrolled a combined total of 210 participants across the studies listed.
[¹⁴C]-LY3502970 is an alternative name for LY3502970. The carbon-14 label is used in study settings, typically for absorption, metabolism, and excretion research, while the underlying compound is the same GLP-1 receptor small molecule developed by Eli Lilly and Company for type 2 diabetes, obesity, and overweight.