ABSTRACT
Introduction
We aimed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of orforglipron in Japanese participants with type 2 diabetes.
Materials and Methods
This was a double‐blind, placebo‐controlled, randomized, phase 1 study. In Part A, participants received single doses of orforglipron (2 or 3 mg) or placebo. In Part B, participants received multiple ascending doses of daily oral orforglipron (final target doses: 12, 24, and 45 mg) or placebo for 12 weeks.
Results
Parts A and B enrolled 23 and 60 participants, respectively. The most common treatment‐emergent adverse events were gastrointestinal events of mild severity. No severe or serious adverse events were reported. At week 12, median t max was 5.92–8.00 h, and mean terminal half‐life was 51.8–76.1 h. Following multiple ascending doses, orforglipron groups had greater mean reductions from baseline to week 12 in glycemic parameters (fasting glucose: orforglipron 12 mg −64.8 mg/dL, 24 mg −61.1 mg/dL, 45 mg −65.6 mg/dL, placebo 7.4 mg/dL; glycated hemoglobin: orforglipron 12 mg −2.16%, 24 mg −2.17%, 45 mg −2.28%, placebo 0.67%) and body weight (orforglipron 12 mg −2.9 kg, 24 mg −6.3 kg, 45 mg −4.8 kg, placebo 0.3 kg) compared with placebo.
Discussion
In Japanese participants, safety, pharmacokinetic, and pharmacodynamic results were similar to those of previous orforglipron studies. The safety and tolerability of orforglipron were also consistent with those of other glucagon‐like peptide‐1 receptor agonists. Orforglipron is a potential new treatment option for Japanese patients with type 2 diabetes.
Keywords: Body Weight Loss, Orforglipron, Type 2 diabetes mellitus
Orforglipron, a novel oral non‐peptide GLP‐1 receptor agonist, was evaluated in a Phase 1, double‐blind, placebo‐controlled, randomized, single and multiple ascending dose study in Japanese participants with type 2 diabetes. The safety and tolerability profile of orforglipron was consistent with those of other GLP‐1 receptor agonists, and pharmacokinetic and pharmacodynamic results were similar to those of previous orforglipron studies.
INTRODUCTION
Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are highly effective therapeutics for type 2 diabetes (T2D), providing glycemic control primarily by increasing insulin secretion and inhibiting glucagon release 1 . However, established treatment options in this class are limited to injectable therapies or oral peptides with complex dosing regimens, including water and food restrictions, which may reduce treatment adherence and compliance 2 . Therefore, providing alternative oral GLP‐1RA options without restrictive administration conditions remains an unmet need.
Orforglipron is a novel, highly potent, oral, non‐peptide GLP‐1RA being developed to treat T2D and obesity in adults as an adjunct to diet and exercise 3 . Orforglipron is a partial agonist of the glucagon‐like peptide‐1 receptor, which primarily activates G‐protein coupled signaling pathways over beta‐arrestin recruitment 3 . In global phase 1 and 2 studies conducted in healthy participants and participants with T2D or obesity, orforglipron demonstrated safety and pharmacodynamic (PD) profiles consistent with the GLP‐1RA class and pharmacokinetics (PK) supporting once‐daily dosing 4 , 5 , 6 , 7 . Notably, two global phase 2 clinical trials showed that orforglipron treatment, without food or water restrictions, resulted in clinically relevant improvements in glycemic control and body weight at 26 weeks in participants with T2D 4 and at 36 weeks in participants with obesity 7 .
Patients with T2D from Japan and other East Asian countries exhibit different clinical features compared to non‐East Asian patients, including the development of T2D at a lower body mass index (BMI), earlier onset of T2D, earlier impairment of pancreatic beta cell function, and reduced insulin secretory capacity 8 , 9 , 10 , 11 . Given the potential ethnic differences in treatment response, the primary objective of the current study was to evaluate the safety and tolerability of single and multiple doses of orforglipron in Japanese patients with T2D over 12 weeks. Secondary and tertiary objectives were to assess orforglipron PK and PD parameters, including glycated hemoglobin (HbA1c), fasting glucose, body weight, and fasting lipids. This is the first study to administer orforglipron to Japanese patients with T2D. It is anticipated that data from this study will aid the future clinical development of orforglipron in Japan.
MATERIALS AND METHODS
Study design and treatment
This was a phase 1, double‐blinded, placebo‐controlled, randomized study conducted at five study sites in Japan (ClinicalTrials.gov: NCT05086445). The study design comprised a 28‐day screening period, followed by a 15‐day treatment period in Part A, an 84‐day treatment period in Part B, and a 2‐week follow‐up period (Figure S1). Part A assessed a single ascending dose (SAD) of orforglipron (2 or 3 mg) or placebo. Part B assessed multiple ascending doses (MADs) of orforglipron or placebo over 12 weeks (final target doses of 12, 24, or 45 mg).
The protocol was approved by ethical review boards at each study site. The study was conducted in accordance with consensus ethical principles derived from the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines. Participants provided written informed consent prior to entering the study.
Participants
The study was conducted from November 12, 2021, to September 5, 2022. It enrolled Japanese adults with T2D for ≥1 year who managed their T2D with diet and exercise only or were on stable oral antihyperglycemic medication (OAM) monotherapy (metformin, dipeptidyl peptidase‐4 inhibitor [other than omarigliptin or trelagliptin], or sodium‐glucose cotransporter‐2 inhibitors) for ≥3 months prior to screening and were willing to discontinue the OAM ≥28 days prior to dosing. Full enrollment criteria are included in the Data S1 section.
Randomization and masking
Each cohort comprised participants randomized to receive either orforglipron or a corresponding placebo. Participants were randomly assigned to treatment via a computer‐generated random sequence using a central interactive web response system. All participants, investigators, and study site personnel were blinded to treatment allocation.
Procedures
After screening, participants were admitted for baseline assessments and treatment. Participants were advised to maintain their regular dietary regimen and physical activities throughout the study. Treatment was administered in the fasted state. Orforglipron or placebo in capsule form was orally administered with approximately 200 mL of water in the morning before breakfast. On Day 1, participants in Part A received a single dose of orforglipron or placebo. PK sampling and safety monitoring procedures were conducted until discharge on Day 5. Concentrations of orforglipron in blood plasma were assayed using a validated liquid chromatography mass spectrometry method (Data S1). Outpatient visits occurred on Days 8 and 15. After completing Part A, participants were enrolled in Part B (Cohorts 1a and 2a; Figure S1). Safety data through Day 8 following the SAD in Part A were reviewed before initiating the corresponding dose group in Part B.
In Part B, the study intervention was administered orally once daily as MADs for up to 12 weeks. Participants were assigned to three cohorts, each divided into two subgroups (‘a’ and ‘b’) for a staggered dosing approach. Doses were escalated from a starting dose of 2 or 3 mg to maintenance doses of 12, 24, and 45 mg (Figure S1). Safety data review was required for dose escalation decisions in Part B.
Meal intake and appetite were assessed on Days −1, 28, and 84 of treatment. Participants were provided standardized mixed meals of approximately 600 calories (20% protein, 25% fat, 55% carbohydrate) for morning, midday, and evening meals, administered 2, 6, and 10 h after the study drug. Following each meal, the individual nutrient and total caloric intake were evaluated. One hour before each meal, participants were asked to rate their subjective appetite sensations using a validated tool consisting of four 100‐mm visual analog scales (VAS) measuring hunger, fullness, satiety, and prospective food consumption 12 . Ratings ranged from 0 (‘extremely’) to 100 (“not at all”) on each scale. Morning and evening meals for the meal intake test were also used for a mixed meal tolerance test (MMTT). Blood samples were collected at 0 (pre‐meal), 0.5, 1.0, 1.5, and 2.0 h after the start of each meal to measure fasting and post‐meal glucose, insulin, and glucagon levels, which were evaluated using validated analytical assays (immunochemiluminometric assay for insulin and electrochemiluminescence immunoassay for glucagon).
Outcomes
Safety endpoints included treatment‐emergent adverse events (TEAEs) and serious adverse events (SAEs), as reported by the participant (or their caregiver or legal representative). Investigators recorded the events at each site and determined if there was a reasonable possibility that the events were related to study treatment. Adverse events of special interest (AESIs) for this study included cardiovascular events, gastrointestinal events, and hypoglycemia. Additional safety monitoring was conducted to assess pancreatic and liver health throughout the study (see Data S1). Blood pressure and pulse rate were measured in the sitting position.
PK endpoints included the maximum observed drug concentration (C max) and area under the concentration curve (AUC). PD endpoints included changes from baseline in fasting glucose, HbA1c, and body weight. Exploratory endpoints included changes from baseline in the fasting lipid profile, MMTT parameters, meal intake, and appetite VAS.
Statistical analysis
The sample size is typical of phase 1 studies and was selected to ensure sufficient data for evaluating the primary safety endpoints. Up to 65 participants were planned for enrollment to ensure that approximately 15 evaluable participants in each cohort completed Part B. It was assumed that the dropout rate would be greater in higher‐dose cohorts due to gastrointestinal tolerability. Accordingly, approximately 18, 20, and 22 participants were to be randomized to cohorts 1, 2, and 3, respectively.
Baseline demographic and clinical characteristics were summarized separately for Parts A and B using descriptive statistics. Continuous measures are presented as numbers and mean (standard deviation [SD]), while categorical measures are presented as frequency (percentage). Safety was evaluated in the safety population, which included all randomized participants who received at least one dose of the study drug. Safety data were summarized descriptively as the number of events and the number (percentage) of participants experiencing an event. TEAEs are shown by study part, treatment, severity, relationship to study intervention, and type, based on the Medical Dictionary for Regulatory Activities version 24.1 system organ class and preferred terms. Vital signs were summarized as changes from baseline (Day 1, predose) using descriptive statistics. For change‐from‐baseline values, a mixed model for repeated measures (MMRM) was used, with treatment, time point, and treatment‐by‐time point interaction as fixed effects, participant as a random effect, and baseline as a covariate.
PK was assessed in all patients who received at least one dose of orforglipron and had evaluable PK data. PK parameters were estimated using noncompartmental methods and summarized by dose group with descriptive statistics. PD was assessed in all patients who received at least one dose of orforglipron or placebo and had evaluable PD data. PD data were collected in Part B only. Changes from baseline in glycemic parameters and body weight were analyzed using an MMRM, with the same fixed effects and covariates as the analysis model for vital signs. Treatment differences between orforglipron and placebo were estimated as least‐squares means (90% confidence intervals [CIs]). Participants who received a placebo were pooled across all cohorts.
Meal intake, appetite VAS, and MMTT data were summarized descriptively as means with standard error for meal intake and mean (SD) for MMTT parameters. Baseline was defined as the meal‐matched Day ‐1 observation. Correlations between appetite VAS components and meal intake and between meal intake and body weight change at week 12 were examined. R‐squared and P‐values are presented, with P < 0.05 considered statistically significant.
For all analyses, participants were analyzed according to the assigned treatment group. Statistical analyses were conducted using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).
RESULTS
Participant disposition
Twenty‐three participants were enrolled in Part A (Figure S2). All were randomized (n = 4 to placebo; n = 10 to orforglipron 2 mg; n = 9 to orforglipron 3 mg) and received at least one dose of the study drug. Twenty‐one participants (91.3%) completed Part A and moved on to Part B. The two participants who discontinued in Part A were in the orforglipron 2 mg group: one discontinued due to an adverse event (AE) of nausea, and the other due to a physician decision.
Sixty participants were enrolled in Part B and received at least one dose of the study drug. Of these, 11, 14, 17, and 18 participants were randomized to the placebo, orforglipron 12, 24, and 45 mg cohorts, respectively. Overall, 54 (90.0%) participants completed Part B. Two participants discontinued due to an AE: one (5.9%) from the orforglipron 24 mg group, who reported a moderate AE of decreased appetite after receiving a 2 mg dose, and one (7.1%) from the orforglipron 12 mg group, who reported a mild AE of nausea after receiving a 3 mg dose.
Baseline demographic and clinical characteristics
In Part A, all 23 (100%) participants were male, with an overall mean age of 55.3 years, BMI of 26.0 kg/m2, HbA1c of 7.8%, and duration of T2D of 9.3 years (Table 1). In Part B, 58 (96.7%) participants were male, with an overall mean age of 56.1 years, BMI of 27.2 kg/m2, HbA1c of 7.9%, and duration of T2D of 7.4 years (Table 1). Baseline demographics and clinical characteristics were generally similar across treatment regimens.
Table 1.
Demographics and baseline clinical characteristics
| Part A – SAD N = 23 | Part B – MAD N = 60 | ||||||
|---|---|---|---|---|---|---|---|
| Placebo N = 4 | OFG 2 mg N = 10 | OFG 3 mg N = 9 | Placebo N = 11 | OFG 12 mg N = 14 | OFG 24 mg N = 17 | OFG 45 mg N = 18 | |
| Age, years | 55.5 (1.7) | 53.1 (11.7) | 57.6 (5.5) | 57.7 (5.8) | 56.3 (8.6) | 53.4 (10.0) | 57.6 (6.2) |
| Male, n (%) | 4 (100%) | 10 (100%) | 9 (100%) | 10 (90.9%) | 13 (92.9%) | 17 (100%) | 18 (100%) |
| Weight, kg | 74.0 (9.2) | 77.5 (13.1) | 74.7 (14.0) | 79.4 (10.1) | 82.8 (9.5) | 80.8 (15.2) | 74.7 (16.3) |
| BMI, kg/m2 | 26.2 (3.6) | 25.9 (3.6) | 25.9 (4.4) | 27.6 (3.7) | 28.3 (3.3) | 27.2 (4.5) | 26.1 (4.7) |
| Duration of diabetes, years | |||||||
| Mean (SD) | 13.0 (8.4) | 5.4 (4.4) | 12.0 (9.6) | 9.4 (6.3) | 6.1 (5.5) | 5.5 (3.9) | 8.9 (7.8) |
| Range | 6.0–24.0 | 2.0–17.0 | 2.0–32.0 | 2.0–24.0 | 2.0–20.0 | 2.0–17.0 | 1.0–32.0 |
| HbA1c, mmol/mol | 66.4 (13.2) | 59.5 (8.0) | 62.8 (9.8) | 61.9 (11.7) | 63.9 (8.2) | 62.8 (7.8) | 61.6 (9.8) |
| HbA1c, % | 8.2 (1.2) | 7.6 (0.7) | 7.9 (0.9) | 7.8 (1.1) | 8.0 (0.8) | 7.9 (0.7) | 7.8 (0.9) |
| Fasting glucose, mmol/L | 11.1 (3.2) | 9.1 (1.2) | 10.6 (2.8) | 10.2 (3.1) | 9.8 (1.9) | 9.6 (1.7) | 10.4 (2.6) |
| Fasting glucose, mg/dL | 199.1 (56.8) | 163.5 (22.0) | 190.2 (50.1) | 184.0 (55.3) | 175.9 (33.7) | 173.8 (29.8) | 188.0 (47.3) |
| Use of OAM † n (%) | |||||||
| None | 2 (50.0%) | 7 (70.0%) | 6 (66.7%) | 4 (36.4%) | 12 (85.7%) | 10 (58.8%) | 10 (55.6%) |
| Metformin | 2 (50.0%) | 0 | 2 (22.2%) | 4 (36.4%) | 0 | 0 | 2 (11.1%) |
| DPP4 inhibitor | 0 | 2 (20.0%) | 1 (11.1%) | 1 (9.1%) | 1 (7.1%) | 4 (23.5%) | 4 (22.2%) |
| SGLT2 inhibitor | 0 | 1 (10.0%) | 0 | 2 (18.2%) | 1 (7.1%) | 3 (17.6%) | 2 (11.1%) |
Mean (SD) shown unless otherwise indicated. BMI, body mass index; DPP4, dipeptidyl peptidase‐4; HbA1c, glycated hemoglobin; MAD, multiple ascending dose; OAM, oral antihyperglycemic medication; OFG, orforglipron; SAD, single ascending dose; SGLT2, sodium‐glucose cotransporter‐2.
All participants withdrew from OAM treatment at least 28 days prior to the first dose of treatment.
Safety
In Part A, two participants (50.0%) in the placebo group, five participants (50.0%) in the orforglipron 2 mg group, and six participants (66.7%) in the orforglipron 3 mg group reported TEAEs (Table 2). In Part B, a higher proportion of participants in the orforglipron groups (12 mg: 11 [78.6%]; 24 mg: 13 [76.5%]; 45 mg: 9 [50.0%]) reported TEAEs compared with the placebo group (5 [45.5%]). Most TEAEs were mild, with none rated as severe. No deaths or SAEs were reported in this study.
Table 2.
Safety summary
| n (%) | Part A – SAD N = 23 | Part B – MAD N = 60 | |||||
|---|---|---|---|---|---|---|---|
| Placebo N = 4 | OFG 2 mg N = 10 | OFG 3 mg N = 9 | Placebo N = 11 | OFG 12 mg N = 14 | OFG 24 mg N = 17 | OFG 45 mg N = 18 | |
| TEAEs | 2 (50.0%) | 5 (50.0%) | 6 (66.7%) | 5 (45.5%) | 11 (78.6%) | 13 (76.5%) | 9 (50.0%) |
| Mild | 2 (50.0%) | 3 (30.0%) | 6 (66.7%) | 5 (45.5%) | 11 (78.6%) | 12 (70.6%) | 9 (50.0%) |
| Moderate | 0 | 2 (20.0%) | 1 (11.1%) | 1 (9.1%) | 0 | 3 (17.6%) | 0 |
| Severe | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| SAEs | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Deaths | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TRAEs | 2 (50.0%) | 5 (50.0%) | 5 (55.6%) | 4 (36.4%) | 11 (78.6%) | 12 (70.6%) | 9 (50.0%) |
| AESIs | |||||||
| Gastrointestinal | 1 (25.0%) | 5 (50.0%) | 6 (66.7%) | 4 (36.4%) | 11 (85.7%) | 11 (64.7%) | 8 (44.4%) |
| Cardiovascular | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hypoglycemia | 0 | 0 | 0 | 0 | 0 | 1 (5.9%) † | 0 |
| TEAEs with ≥5% frequency ‡ | |||||||
| Nausea | 1 (25.0%) | 3 (30.0%) | 5 (55.6%) | 2 (18.2%) | 9 (64.3%) | 4 (23.5%) | 6 (33.3%) |
| Constipation | 0 (0) | 0 (0) | 3 (33.3%) | 1 (9.1%) | 2 (14.3%) | 3 (17.6%) | 5 (27.8%) |
| Decreased appetite | 0 (0) | 1 (10.0%) | 0 (0) | 1 (9.1% | 5 (35.7%) | 3 (17.6%) | 3 (16.7%) |
| Vomiting | 1 (25.0%) | 4 (40.0%) | 2 (22.2%) | 1 (9.1%) | 3 (21.4%) | 2 (11.8%) | 1 (5.6%) |
| Headache | 1 (25.0%) | 0 (0) | 1 (11.1%) | 1 (9.1%) | 3 (21.4%) | 0 (0) | 2 (11.1%) |
| Abdominal discomfort | 1 (25.0%) | 1 (10.0%) | 0 (0) | 0 (0) | 1 (7.1%) | 3 (17.6%) | 0 (0) |
| Hyperaesthesia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (11.8%) | 2 (11.1%) |
| Diarrhea | 0 (0) | 0 (0) | 0 (0) | 2 (18.2%) | 1 (7.1%) | 2 (11.8%) | 0 (0) |
| Abdominal distension | 0 (0) | 2 (20.0%) | 0 (0) | 0 (0) | 1 (7.1%) | 1 (5.9%) | 0 (0) |
| Dyspepsia | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (7.1%) | 1 (5.9%) | 1 (5.6%) |
| Early satiety | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 1 (5.9%) | 2 (11.1%) |
| Eruction | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 2 (14.3%) | 0 (0) | 1 (5.6%) |
| Pancreas‐ and liver‐related TEAEs | |||||||
| Pancreatitis or other pancreatic disease | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Liver or biliary tract disease | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| Lipase increased | 0 (0) | 0 (0) | 0 (0) | 1 (9.1%) § | 1 (7.1%) ¶ | 0 (0) | 0 (0) |
| GGT increased | 0 (0) | 0 (0) | 0 (0) | 1 (9.1%) †† | 0 (0) | 0 (0) | 0 (0) |
MedDRA v.24.0. Data shown as n (%) participants with events. AESI, adverse event of special interest; GGT, gamma‐glutamyltransferase; MAD, multiple ascending dose; OFG, orforglipron; PBO, placebo; SAD, single ascending dose; SAE, serious adverse event; TEAE, treatment‐emergent adverse event; TRAE, treatment‐related adverse event.
There was one hypoglycemic event with a glucose value of 69 mg/dL in the OFG 24 mg group.
TEAEs shown if ≥5% frequency overall in either Part A or B.
Participant reported a TEAE of lipase increased on Day 43, which resolved after approximately 14 days. The participant had a baseline lipase value of 35.0 U/L at Day 1 predose (reference range: 0–100 U/L) and 48.0 U/L on Day 36, which increased to 186.0 U/L on Day 43, before decreasing to 62.0 U/L on Day 57.
Participant reported a TEAE of lipase increased on Day 57, approximately 1 day and 2 h after receiving 12 mg OFG. The TEAE resolved after approximately 28 days. The participant had a baseline lipase value of 66.0 U/L at Day 1 predose (reference range: 0 to 120 U/L) and 119.0 U/L on Day 43, which increased to 349.0 U/L on Day 57, before decreasing to 324.0 U/L on Day 71 and 56.0 U/L on Day 85 (186.0 U/L at follow‐up).
Participant reported a TEAE of GGT increased on Day 71, which had not recovered at the end of the study. The participant had a baseline GGT value of 69.0 U/L at Day 1 predose (reference range: 10–61 U/L). The participant had a GGT value of 140.0 U/L on Day 57, which increased to 232.0 U/L on Day 71, before decreasing to 201.0 U/L on Day 85 (160.0 U/L at follow‐up).
Gastrointestinal AEs and decreased appetite were the most common TEAEs in all treatment groups and occurred more commonly in the orforglipron groups compared with placebo (Part A: placebo 25.0%, orforglipron 50.0–66.7%; Part B: placebo 36.4%, orforglipron 44.4–85.7%; Table 2). Nausea was the most commonly reported gastrointestinal TEAE in the orforglipron groups (Part A: placebo 25.0%, orforglipron 30.0–55.6%; Part B: placebo 18.2%, orforglipron 23.5–64.3%; Table 2). The majority of gastrointestinal TEAEs occurred during the first week of treatment and during dose escalation. All gastrointestinal TEAEs had resolved by the end of the study, except for one ongoing TEAE of mild constipation. The majority of gastrointestinal TEAEs were considered related to study treatment by the investigator.
No cardiovascular events were reported in the study. One participant each in the placebo (9.1%) and orforglipron 12 mg (7.1%) groups had transiently increased lipase levels during Part B (Table 2). One participant (5.9%) in the orforglipron 24 mg group in Part B experienced an event of nocturnal hypoglycemia on Day 19, following a dose of orforglipron 6 mg. The event resolved without treatment within 40 min, with the lowest blood glucose level recorded at 69 mg/dL.
Changes in systolic blood pressure and diastolic blood pressure were similar across treatment groups in Parts A and B (Figure S3). Pulse rate was increased in all orforglipron MAD groups (Figure S3), with mean change from baseline in pulse rate at week 12 (predose) ranging from 9.3 to 11.7 beats per minute (bpm) in the orforglipron groups, compared with a −1.5‐bpm change in the placebo group.
PK
PK findings are summarized in Figure S4. On Day 1 in Part A, following a single orforglipron dose of 2 or 3 mg, the median time of maximum observed drug concentration (t max) of orforglipron was 8.00 h, with individual t max values ranging from 4.00 to 12.00 h. Plasma concentrations of orforglipron declined after t max in a generally biphasic manner, with geometric mean terminal half‐life (t 1/2) values of 35.1 h following a 2 mg dose and 28.4 h following a 3 mg dose.
On Day 84 in Part B, following MADs of orforglipron, the mean plasma concentration‐time profiles generally showed a dose‐dependent increase in plasma concentrations. Median t max values ranged from 5.92 to 8.00 h following administration of 12, 24, and 45 mg of orforglipron. Plasma concentrations of orforglipron declined in a generally biphasic manner after t max, with the geometric mean t 1/2 values ranging from 51.8 to 76.1 h following the last dose of orforglipron on Day 84. On Day 84, AUC(0–24) and C max increased less than proportionally with increasing dose.
PD
Following MADs of orforglipron, fasting glucose, HbA1c, and body weight were lower in the orforglipron groups compared to placebo at most time points after week 4 (Figure 1). For glycemic parameters, similar decreases from baseline were observed in all orforglipron groups, whereas no decrease from baseline was observed in the placebo group (week 12 mean change in fasting glucose: orforglipron −61.1 to −65.6 mg/dL vs placebo 7.4 mg/dL; mean change in HbA1c: −2.16% to −2.28% vs placebo 0.67%; Figures 1a and 1b). For body weight, all orforglipron dose groups showed weight reduction compared to placebo over the treatment period, with greater weight loss observed in the 24 and 45 mg dose groups compared with the 12 mg dose group (week 12 mean change in body weight: orforglipron 12 mg −2.9 kg; 24 mg −6.3 kg; 45 mg −4.8 kg; placebo 0.3 kg; Figure 1c). Lipid levels also trended downward in all orforglipron dose groups compared with placebo (Figure S5).
Figure 1.
Body weight and glycemic parameters over 12 weeks of orforglipron treatment. Change from baseline in (a) fasting glucose, (b) HbA1c %, and (c) body weight following MADs of orforglipron in Part B. Plotted data represent least‐squares mean change from baseline with 90% CIs. ETDs shown for orforglipron vs placebo as estimated mean differences (90% CIs). CI, confidence intervals; ETD, estimated treatment difference; HbA1c, glycated hemoglobin; MAD, multiple ascending dose; OFG, orforglipron; PBO, placebo.
Orforglipron dose groups showed decreases in meal intake at weeks 4 and 12, whereas the placebo group showed no change (Figure S6). Orforglipron groups generally reported decreased hunger and prospective food consumption scores and increased fullness scores on the appetite VAS (Figure S7). Satiety scores did not change from baseline in any treatment group. Among the appetite VAS components, hunger, fullness, and prospective food consumption were correlated with meal intake at week 12, but no correlation was observed between satiety and meal intake (Figure S8). Additionally, meal intake and body weight loss at week 12 were positively correlated with each other (Figure S9).
In the MMTT, postprandial glucose and glucagon levels were decreased at week 12 in all orforglipron groups compared to placebo, while postprandial insulin levels showed no clear trend (Figure S10). Week 12 MMTT glucose parameters were generally reduced from baseline in the orforglipron groups but remained unchanged in the placebo group.
DISCUSSION
In this phase 1 study, orforglipron demonstrated an acceptable safety profile and clinically meaningful improvements in glucose levels and body weight over 12 weeks compared with placebo in Japanese participants with T2D. A key aspect of the study design was the use of different dose escalation schemes across the orforglipron cohorts. This is important to consider when interpreting the data, as changes from baseline do not simply reflect the dose–response of the target maintenance doses. For example, the 24 mg orforglipron group received higher doses from weeks 0 to 6 compared to the 45 mg dose group, which had higher doses from 8 weeks onward.
Overall, TEAEs occurred more frequently with orforglipron (up to 78.6%) than with placebo (up to 50.0%). The most common TEAEs were mild gastrointestinal‐related events and decreased appetite, which are consistent with the safety profiles of other GLP‐1RA therapies 13 , 14 , 15 , 16 . PK data were supportive of once‐daily dosing in Japanese adults, with t1/2 ranging from 52 to 76 h at week 12. After 12 weeks of orforglipron treatment, participants experienced up to 6.3 kg (−7.8%) of weight loss and a 2.28% reduction in HbA1c. Clinically relevant reductions in fasting and postprandial glucose levels were observed, with similar magnitudes of change in glycemic parameters across the orforglipron dose groups. Improvements in glycemic parameters and body weight loss were accompanied by several changes in appetite sensations in the orforglipron groups, including reduced hunger and prospective food consumption and increased fullness. These changes in appetite sensations were correlated with decreased meal intake, which, in turn, correlated with body weight reductions, suggesting that appetite changes may contribute to orforglipron‐mediated weight loss.
The overall safety, efficacy, PK, and PD profiles were comparable to those previously reported in global phase 1 and 2 studies on orforglipron 4 , 5 , 6 , 7 . In a phase 1b trial conducted in participants with T2D, the mean t 1/2 ranged from 29 to 49 h at week 12, with mean improvements in HbA1c from −1.5% to −1.8% and body weight from −0.24 to −5.8 kg following MADs of orforglipron escalated up to 45 mg5. Additionally, in a phase 2 study in participants with T2D, orforglipron treatment resulted in a mean change in HbA1c from baseline of up to −2.1% and weight loss of up to 10.1 kg at week 26 following MADs of orforglipron up to 45 mg 4 . Currently, ongoing phase 3 clinical programs are further clarifying the efficacy and safety of orforglipron for the treatment of T2D (ACHIEVE program) and obesity or overweight (ATTAIN program).
The safety and tolerability of orforglipron in Japanese participants were also comparable to those of other GLP‐1RAs in early‐phase studies, including other oral compounds. In participants with T2D who received oral semaglutide, 31–61% reported gastrointestinal TEAEs, with higher incidences seen at higher doses (2.5–40 mg) and faster dose escalation (77%) 17 . Gastrointestinal AEs were also the most common TEAEs in participants with T2D or obesity without T2D treated with danuglipron, an oral small‐molecule GLP‐1RA administered twice daily. However, treatment discontinuation rates were much higher with danuglipron (up to 54.5%) 15 . The elevations in pulse rate observed in the current study (9.3–11.7 bpm at 12 weeks following MADs of orforglipron) were similar to those reported in global phase 1 orforglipron studies and typical of early‐phase studies of GLP‐1RAs 5 , 6 .
A strength of this study was the use of a staggered dosing approach, escalating from low starting doses, and the review of safety data prior to each dose escalation step, which was expected to minimize safety risks to participants and improve gastrointestinal tolerability. Additionally, enrolling participants with T2D, rather than healthy participants, allowed for a more accurate assessment of orforglipron in the target patient population. The limitations of this study include those inherent in phase 1 study designs, such as the small sample size per treatment group. When interpreting the results, it is important to note that the study population included a high proportion of males (91–100%), which may limit the generalizability of the results. Differences in the baseline duration of diabetes across treatment groups were also observed.
The safety profile and pharmacological characteristics of orforglipron in Japanese participants were similar to those observed in previous orforglipron studies. Safety and tolerability were also consistent with those of other GLP‐1RAs. Orforglipron is a potential new alternative to injectable GLP‐1RAs and oral peptide formulations for Japanese patients with T2D.
DISCLOSURE
CN reports no disclosures. KO, RN, KT, and TH are employees of Eli Lilly Japan K.K. and minor shareholders of Eli Lilly and Company.
Research protocol approval: The protocol was approved by the ethical review boards at each study site. This study was conducted in accordance with consensus ethical principles derived from the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice guidelines.
Informed consent: All participants provided written informed consent prior to trial participation.
Registry approval date and registration number: October 20, 2021; ClinicalTrials.gov, NCT05086445.
Animal studies: N/A.
Supporting information
Figure S1 | Schematic of study design for multiple ascending doses of orforglipron or placebo (Part B). Doses were escalated from a starting dose of 2 mg or 3 mg up to maintenance doses of 12 mg, 24 mg, or 45 mg. Each cohort was divided into two subgroups (‘a’ and ‘b’) for a staggered dosing approach. In Cohorts 1a and 1b, participants received dose levels of 2, 3, 6, 8, and 12 mg (with weekly escalation), followed by 24 mg for 7 weeks. In Cohort 2a, participants received dose levels of 3, 6, 12, 24, and 36 mg (with two‐weekly escalation), followed by 45 mg for 2 weeks. In Cohort 2b, participants received dose levels of 2 and 3 mg (with weekly escalation), followed by 6, 12, 24, and 36 mg (with two‐weekly escalation) and then 45 mg for 2 weeks. In Cohort 3a, participants received dose levels of 3 and 6 mg (with two‐weekly escalation), followed by 12 mg for 8 weeks. In Cohort 3b, participants received dose levels of 2 and 3 mg (with weekly escalation), followed by 6 mg for 2 weeks and then 12 mg for 8 weeks. If the investigator decided not to increase the dose level as planned, the participant was discontinued for doses ≤12 mg or was permitted to continue in the study dosing at the current dose level for doses ≥24 mg. No dose reductions were permitted for doses of ≤24 mg. Doses could be reduced to 24 or 36 mg if a participant was unable to tolerate a higher dose, with the reduced dose level maintained through to the last planned dosing on Day 84. OFG, orforglipron.
Figure S2 | Participant disposition.
Figure S3 | Vital parameters over time. (a, d) SBP, (b, e) DBP, and (c, f) pulse rate following SADs of orforglipron or placebo in Part A and MADs of orforglipron (escalating up to 12, 24, and 45 mg) or placebo in Part B. Data are shown as the least‐squares mean change from baseline with 90% confidence intervals. DBP, diastolic blood pressure; MAD, multiple ascending dose; OFG, orforglipron; SAD, single ascending dose; SBP, systolic blood pressure.
Figure S4 | Pharmacokinetics summary. Mean plasma concentration of orforglipron (a) following administration of single oral doses on Day 1 and (b) following multiple once‐daily doses with titration up to 45 mg on Day 84. Arithmetic mean (+standard deviation) plasma concentration profiles of OFG (linear scale) are shown. AUC(0‐∞), area under the concentration vs time curve from time zero to infinity; AUC(0‐t last), area under the concentration vs time curve from time zero to time t, where t is the last time point with a measurable concentration; C max, maximum observed drug concentration; CV, coefficient of variation; min‐max, minimum‐maximum range; N, number of participants; n, number of observations; OFG, orforglipron; t ½, half‐life associated with the terminal rate constant in noncompartmental analysis; t max, time of maximum observed drug concentration.
Figure S5 | Change from baseline in the lipid profile over 12 weeks (Part B). Participants received multiple ascending doses of orforglipron or placebo. Data are shown as the least‐squares mean change from baseline with 90% CIs. CI, confidence intervals; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; OFG, orforglipron; VLDL, very low‐density lipoprotein.
Figure S6 | Meal intake assessment (Part B). Meal intake assessments following a standardized mixed meal at baseline (meal‐matched Day −1) and at weeks 4 and 12 at 2, 6, and 10 h after administration of study drug in participants who received multiple ascending doses of orforglipron or placebo. Data are shown for mean (±SE) caloric intake as (a) morning, (b) midday, (c) evening, and (d) daily means. OFG, orforglipron.
Figure S7 | Appetite VAS assessments (Part B). Pre‐meal appetite VAS assessments of (a) hunger, (b) satiety, (c) fullness, and (d) prospective food consumption following standardized mixed meals in participants who received multiple ascending doses of orforglipron or placebo. Baseline was defined as meal‐matched Day −1. The average of three meals (breakfast, lunch, dinner) is shown per day. OFG, orforglipron; VAS, visual analog scale.
Figure S8 | Scatterplots of appetite VAS components vs meal intake at week 12 (Part B). Correlations between pre‐meal appetite VAS assessments of (a) hunger, (b) satiety, (c) fullness, and (d) prospective food consumption vs meal intake after a standardized mixed meal in participants who received multiple ascending doses of orforglipron or placebo. OFG, orforglipron; VAS, visual analog scale.
Figure S9 | Scatterplot of percentage change in body weight vs percentage change in meal intake at week 12 (Part B). Correlation between percentage change from baseline at 12 weeks in body weight vs meal intake following a standardized mixed meal in participants who received multiple ascending doses of orforglipron or placebo. Data were pooled across all treatment groups.
Figure S10 | Mean change from baseline in MMTT parameters (Part B). Mean (±SD) change from baseline in fasting and postprandial levels of (a) glucose, (b) insulin, and (c) glucagon over 2 h following a standardized mixed meal in the morning and evening. The time courses of MMTT parameters are shown for multiple ascending doses of OFG (final target doses of 12, 24, and 45 mg) or placebo at baseline (meal‐matched Day −1) and at week 12. MMTT, mixed meal tolerance test; OFG, orforglipron.
Data S1 | Supplemental methods.
ACKNOWLEDGMENTS
The authors thank the participants and medical institutions for their participation in this trial. Medical writing (Kaye Stenvers) and editing (Abbas Kassem, Raena Fernandes, Alyssa Luck, and Aruna Colaco Clemente) were provided by Syneos Health. This study was sponsored by Eli Lilly and Company. The manuscript was funded by Eli Lilly Japan K.K.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figure S1 | Schematic of study design for multiple ascending doses of orforglipron or placebo (Part B). Doses were escalated from a starting dose of 2 mg or 3 mg up to maintenance doses of 12 mg, 24 mg, or 45 mg. Each cohort was divided into two subgroups (‘a’ and ‘b’) for a staggered dosing approach. In Cohorts 1a and 1b, participants received dose levels of 2, 3, 6, 8, and 12 mg (with weekly escalation), followed by 24 mg for 7 weeks. In Cohort 2a, participants received dose levels of 3, 6, 12, 24, and 36 mg (with two‐weekly escalation), followed by 45 mg for 2 weeks. In Cohort 2b, participants received dose levels of 2 and 3 mg (with weekly escalation), followed by 6, 12, 24, and 36 mg (with two‐weekly escalation) and then 45 mg for 2 weeks. In Cohort 3a, participants received dose levels of 3 and 6 mg (with two‐weekly escalation), followed by 12 mg for 8 weeks. In Cohort 3b, participants received dose levels of 2 and 3 mg (with weekly escalation), followed by 6 mg for 2 weeks and then 12 mg for 8 weeks. If the investigator decided not to increase the dose level as planned, the participant was discontinued for doses ≤12 mg or was permitted to continue in the study dosing at the current dose level for doses ≥24 mg. No dose reductions were permitted for doses of ≤24 mg. Doses could be reduced to 24 or 36 mg if a participant was unable to tolerate a higher dose, with the reduced dose level maintained through to the last planned dosing on Day 84. OFG, orforglipron.
Figure S2 | Participant disposition.
Figure S3 | Vital parameters over time. (a, d) SBP, (b, e) DBP, and (c, f) pulse rate following SADs of orforglipron or placebo in Part A and MADs of orforglipron (escalating up to 12, 24, and 45 mg) or placebo in Part B. Data are shown as the least‐squares mean change from baseline with 90% confidence intervals. DBP, diastolic blood pressure; MAD, multiple ascending dose; OFG, orforglipron; SAD, single ascending dose; SBP, systolic blood pressure.
Figure S4 | Pharmacokinetics summary. Mean plasma concentration of orforglipron (a) following administration of single oral doses on Day 1 and (b) following multiple once‐daily doses with titration up to 45 mg on Day 84. Arithmetic mean (+standard deviation) plasma concentration profiles of OFG (linear scale) are shown. AUC(0‐∞), area under the concentration vs time curve from time zero to infinity; AUC(0‐t last), area under the concentration vs time curve from time zero to time t, where t is the last time point with a measurable concentration; C max, maximum observed drug concentration; CV, coefficient of variation; min‐max, minimum‐maximum range; N, number of participants; n, number of observations; OFG, orforglipron; t ½, half‐life associated with the terminal rate constant in noncompartmental analysis; t max, time of maximum observed drug concentration.
Figure S5 | Change from baseline in the lipid profile over 12 weeks (Part B). Participants received multiple ascending doses of orforglipron or placebo. Data are shown as the least‐squares mean change from baseline with 90% CIs. CI, confidence intervals; HDL, high‐density lipoprotein; LDL, low‐density lipoprotein; OFG, orforglipron; VLDL, very low‐density lipoprotein.
Figure S6 | Meal intake assessment (Part B). Meal intake assessments following a standardized mixed meal at baseline (meal‐matched Day −1) and at weeks 4 and 12 at 2, 6, and 10 h after administration of study drug in participants who received multiple ascending doses of orforglipron or placebo. Data are shown for mean (±SE) caloric intake as (a) morning, (b) midday, (c) evening, and (d) daily means. OFG, orforglipron.
Figure S7 | Appetite VAS assessments (Part B). Pre‐meal appetite VAS assessments of (a) hunger, (b) satiety, (c) fullness, and (d) prospective food consumption following standardized mixed meals in participants who received multiple ascending doses of orforglipron or placebo. Baseline was defined as meal‐matched Day −1. The average of three meals (breakfast, lunch, dinner) is shown per day. OFG, orforglipron; VAS, visual analog scale.
Figure S8 | Scatterplots of appetite VAS components vs meal intake at week 12 (Part B). Correlations between pre‐meal appetite VAS assessments of (a) hunger, (b) satiety, (c) fullness, and (d) prospective food consumption vs meal intake after a standardized mixed meal in participants who received multiple ascending doses of orforglipron or placebo. OFG, orforglipron; VAS, visual analog scale.
Figure S9 | Scatterplot of percentage change in body weight vs percentage change in meal intake at week 12 (Part B). Correlation between percentage change from baseline at 12 weeks in body weight vs meal intake following a standardized mixed meal in participants who received multiple ascending doses of orforglipron or placebo. Data were pooled across all treatment groups.
Figure S10 | Mean change from baseline in MMTT parameters (Part B). Mean (±SD) change from baseline in fasting and postprandial levels of (a) glucose, (b) insulin, and (c) glucagon over 2 h following a standardized mixed meal in the morning and evening. The time courses of MMTT parameters are shown for multiple ascending doses of OFG (final target doses of 12, 24, and 45 mg) or placebo at baseline (meal‐matched Day −1) and at week 12. MMTT, mixed meal tolerance test; OFG, orforglipron.
Data S1 | Supplemental methods.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.