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Orforglipron-Obesity
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling.
What efficacy and safety data is available from the phase 2 study of orforglipron in people with obesity?
In adults with obesity or overweight, orforglipron was associated with weight reduction at 26 weeks when compared with placebo. Safety and tolerability were consistent with other GLP-1 receptor agonists in phase 2 trials.
Orforglipron Phase 2 Study Overview in Adults With Obesity or Overweight
Orforglipron is a novel, once-daily, oral, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist being developed for the treatment of adults with obesity or overweight and the treatment of type 2 diabetes.1
A phase 2, 36-week, multicenter, randomized, double-blind, parallel-group study evaluated the safety and efficacy of daily oral orforglipron compared with placebo in adults with obesity or overweight.1
Key Inclusion and Exclusion Criteria
Key inclusion and exclusion criteria for participation in this study are provided below (Key Inclusion and Exclusion Criteria in a Phase 2 Study of Orforglipron for Adults With Obesity).
Inclusion Criteria |
Exclusion Criteria |
|
|
Abbreviations: BMI = body mass index; eGFR = estimated glomerular filtration rate; HbA1c= glycated hemoglobin; MEN = multiple endocrine neoplasia; OSA= obstructive sleep apnea.
aExcluded liposuction or abdominoplasty, if performed >1 year prior to screening.
Study Design
This study randomized 272 adults with obesity or overweight in Canada, the United States, and Hungary to receive
- placebo, or
- orforglipron once per day to achieve maintenance doses of 12 mg, 24 mg, 36 mg (subdivided into subcohort-1 and -2), or 45 mg (subdivided into subcohort-1 and -2).1
Orforglipron was administered orally without food or water restrictions.2
Randomization was stratified by
- body mass index (BMI) (≤35, >35 kg/m2), and
- sex.1
Orforglipron Phase 2 Study Design in Adults With Obesity or Overweight presents an overview of the study design including various dosing schemes and dose escalations strategies for orforglipron.
Figure 1 description: After a 2-week screening and lead-in period, participants were randomly assigned in a 5:5:5:3:3:3:3 ratio to receive placebo or orforglipron at a maintenance dose of 12 mg, 24 mg, 36 mg, or 45 mg once daily for 36 weeks. The 36 mg and 45 mg dosing cohorts were each divided into 2 subcohorts that had different starting doses and dose-escalation schemes. The starting dose of each orforglipron treatment arm was either 2 mg or 3 mg, with differing dose escalation strategies of up to 16 weeks in length. The primary endpoint was percent change in body weight from baseline at 26 weeks. The 36-week treatment period was followed by 2-week safety follow-up period.
During the study, all participants received education on healthy eating and exercise.1
Study Endpoints
The primary endpoint of the study was to demonstrate the effect of Orforglipron-CWM on percent change from baseline in body weight at week 26.1
A secondary endpoint evaluated percent change from baseline in body weight at week 36.1
Other secondary endpoints evaluated at both week 26 and week 36 included, but were not limited to,
- absolute change from baseline in body weight,
- weight reductions of at least 5% and at least 10%,
- change from baseline in waist circumference, and
- safety and tolerability assessments.1
No multiplicity adjustments were made for control of type I error rate in this early phase study.1
Baseline Characteristics
Baseline demographics and clinical characteristics of randomized participants were generally balanced across treatment groups ( Baseline Demographics and Clinical Characteristics). Most participants were female (59%) and white (89%) and included a mean
- age of 54.2 years
- body weight of 108.7 kg, and
- BMI of 37.9 kg/m2.1
Parametera |
Placebo |
OFG 12 mg |
OFG 24 mg |
OFG 36 mg #1b |
OFG 36 mg #2b |
OFG 45 mg #1b |
OFG 45 mg #2b |
Age, years |
54.0±8.8 |
49.8±10.5 |
57.0±9.1 |
56.3±11.8 |
55.4±10.9 |
56.5±10.7 |
50.9±12.6 |
Sex, female, n(%) |
29 (58) |
31 (62) |
30 (57) |
18 (62) |
18 (62) |
19 (61) |
16 (53) |
Race or ethnicity, n(%)c |
|||||||
American Indian or Alaska Native |
0 |
0 |
1 (2) |
0 |
0 |
0 |
0 |
Asian |
2 (4) |
0 |
0 |
0 |
0 |
0 |
0 |
Black |
1 (2) |
3 (6) |
6 (11) |
4 (14) |
4 (14) |
1 (3) |
0 |
Multiple |
2 (4) |
0 |
0 |
0 |
0 |
0 |
0 |
White |
45 (90) |
47 (94) |
46 (87) |
25 (86) |
25 (86) |
29 (94) |
30 (100) |
Weight parameters |
|||||||
Body weight, kg |
107.6±25.2 |
107.5±25.3 |
112.1±30.2 |
107.8±22.5 |
108.8±28.5 |
105.2±20.4 |
110.9±28.1 |
BMI, kg/m2 |
37.8±6.5 |
37.7±7.7 |
38.1±7.7 |
38.0±6.4 |
38.0±6.3 |
36.8±5.5 |
38.7±7.6 |
Waist circumference, cm |
115.5±15.4 |
114.4±16.5 |
120.1±19.1 |
116.2±16.2 |
118.4±14.7 |
116.1±12.8 |
117.7±14.8 |
Glucose parameters |
|||||||
HbA1c, % |
5.6±0.4 |
5.5±0.4 |
5.7±0.3 |
5.7±0.4 |
5.6±0.4 |
5.7±0.3 |
5.6±0.4 |
Vital signs |
|||||||
Systolic blood pressure, mm Hg |
128.5±9.5 |
129.4±12.1 |
129.7±10.8 |
131.1±11.4 |
131.7±12.6 |
128.9±11.0 |
126.4±11.6 |
Diastolic blood pressure, mm Hg |
81.5±7.2 |
82.9±6.8 |
82.1±7.4 |
81.5±7.6 |
81.2±8.1 |
80.6±8.5 |
78.0±8.5 |
Pulse rate, bpm |
69.6±10.6 |
73.9±9.1 |
71.9±12.1 |
69.7±9.3 |
69.0±9.3 |
71.2±9.6 |
68.4±10.4 |
Abbreviations: BMI = body mass index; bpm = beats per minute; HbA1c = glycated hemoglobin; OFG = orforglipron.
aData presented as mean +/- SD unless otherwise noted.
bEach of the 36 and 45 mg cohorts was grouped into 2 subcohorts, with different starting doses and dose escalations.
cRace or ethnic group was reported by the participant. Missing data was reported for 1 patient in the OFG 45mg #1 group.
Results
Efficacy
Data from this phase 2 study were evaluated using the efficacy estimand. Efficacy estimand included data from all randomly assigned participants who were exposed to ≥1 dose of orforglipron, excluding data after the permanent discontinuation of orforglipron or placebo (efficacy analysis set).1
Treatment with orforglipron led to dose-dependent reduction in weight parameters as shown in Weight Parameter Changes Observed During Treatment with Orforglipron and Change in Body Weight at Week 36.
Parametera |
Timeframe |
Placebo |
OFG 12 mg |
OFG 24 mg |
OFG 36 mgb |
OFG 45 mgb |
||
Percent change from baseline in BW, % |
Week 26 |
-2.0 (-3.6 to -0.4) |
-8.6 (-10.2 to -6.9) |
-11.2 (-12.8 to -9.6) |
-12.3 (-13.8 to -10.7) |
-12.6 (-14.1 to -11.1) |
||
Week 36 |
-2.3 (-4.3 to -0.4) |
-9.4 (-11.5 to -7.4) |
-12.5 (-14.5 to -10.5) |
-13.5 (-15.3 to -11.6) |
-14.7 (-16.5 to -12.8) |
|||
Absolute change from baseline in BW, kg |
Week 26 |
-2.1 (-3.8 to -0.4) |
-9.0 (-10.7 to -7.2) |
-12.3 (-14.0 to -10.6) |
-12.9 (-14.5 to -11.3) |
-13.3 (-14.9 to -11.7) |
||
Week 36 |
-2.4 (-4.5 to -0.4) |
-9.8 (-11.9 to -7.6) |
-13.6 (-15.7 to -11.6) |
-14.2 (-16.2 to -12.3) |
-15.4 (-17.4 to -13.5) |
|||
Change from baseline in WC, cm |
Week 26 |
-3.6 (-5.5 to -1.7) |
-8.0 (-10.0 to -6.0) |
-8.8 (-10.8 to -6.8) |
-10.1 (-12.0 to -8.3) |
-12.2 (-14.1 to -10.4) |
||
Week 36 |
-4.0 (-6.2 to -1.8) |
-9.6 (-11.9 to -7.3) |
-11.2 (-13.4 to -8.9) |
-10.6 (-12.7 to -8.5) |
-13.6 (-15.7 to -11.5) |
|||
Abbreviations: BW = bodyweight; LSM = least squares mean; OFG = orforglipron; WC = waist circumference.
aData presented is LSM (95% CI) (efficacy estimand).
bFor the 36 mg and 45 mg dose cohorts, data were pooled across subcohorts for each dose.
Figure 2 description: After 26 weeks, treatment with orforglipron resulted in dose-dependent percent change in body weight and absolute reduction in weight. Further weight reduction was observed at 36 weeks, with no appearance of plateau.
Note: Data presented are LSM (I bars indicate standard errors).
Abbreviation: LSM = least squares mean.
Weight reductions of at least 5%, 10%, or 15% at week 26 were more common in orforglipron treatment arms compared with placebo (Proportion of Participants Achieving Weight Reduction at Week 26).1
Figure 3 description: At week 26, achievement of weight reduction targets (≥5%, ≥10%, ≥15%) were more likely to occur with orforglipron treatment than with placebo. Weight reductions of at least 10% by 26 weeks were observed in 71% of participants treated with orforglipron.
Note: Results were calculated by applying Rubin’s rule, wherein the percentages of participants who met the target were combined in imputed data sets. For the 36 and 45 mg dose cohorts, data were pooled across the subcohorts for each dose.
Vital Signs
Systolic blood pressure lowered in all orforglipron dosing cohorts, with reductions of up to 10.5 mm Hg at weeks 26 and 36, compared with reductions of up to 3.6 mm Hg and 1.6 mm Hg in the placebo group at the same time points, respectively.1
Mean pulse rate was increased in all orforglipron dose cohorts, with the greatest change from baseline occurring at approximately week 12. Change from baseline in mean pulse rate at week 36 ranged from 3.2 to 7.4 beats per minute across orforglipron dose cohorts and was -1.8 beats per minute in the placebo group.1
Observed changes in mean pulse rate were similar, in magnitude and time course, to those observed with other GLP-1 receptor agonists.1
Safety
Safety analyses were conducted in the safety analysis set from the treatment period plus safety follow-up. The safety analysis set included all randomly assigned participants exposed to ≥1 dose of orforglipron or placebo, regardless of adherence.1
An overview of AEs and treatment-emergent adverse events (TEAEs) that occurred in ≥5% of study participants are presented in Overview of Adverse Events and Adverse Events Occurring in ≥5% of Participants.
Participants treated with orforglipron compared with those receiving placebo reported
- higher rates of study treatment discontinuation due to AEs, and
- more frequent gastrointestinal AEs.1
Gastrointestinal events reported with orforglipron were generally
- mild to moderate in severity
- linked to rapid dose escalation and high starting dose (eg, 3 mg vs 2 mg), and
- were transient and resolved without permanent discontinuation.1
The highest incidence of these events were reported in the 24 mg dose cohort, which received a higher starting dose of 3 mg and a rapid weekly dose escalation scheme until the maintenance dose was reached. In this dose cohort, incidence of nausea and vomiting was higher within the first 2 weeks and then subsequently decreased.1
Similar effects were seen in phase 2 trials of GLP-1 receptor agonists, where the best starting dose, optimal titration approach, and dose for efficacy have not yet been determined.3-5 The short duration of phase 2 trials also limits the time available for dose escalation. The phase 3 studies will evaluate the dosing approaches intended for broad clinical use optimized for tolerability.5
Parameter |
Placebo |
OFG 12 mg |
OFG 24 mg |
OFG 36 mg #1a |
OFG 36 mg #2a |
OFG 45 mg #1a |
OFG 45 mg #2a |
Any TEAEs |
38 (76) |
43 (86) |
46 (87) |
24 (83) |
28 (97) |
28 (90) |
27 (90) |
Serious AEs |
0 |
0 |
2 (4) |
0 |
3 (10) |
2 (6) |
0 |
AEs leading to discontinuation of OFG or placebo |
1 (2) |
7 (14) |
10 (19) |
3 (10) |
6 (21) |
5 (16) |
4 (13) |
Abbreviations: AE = adverse event; OFG = orforglipron; TEAE = treatment-emergent adverse event.
aEach of the 36 and 45 mg cohorts was grouped into 2 subcohorts, with different starting doses and dose escalations.
AEs Occurring in ≥5% of Participants, n (%) |
Placebo |
OFG 12 mg |
OFG 24 mg |
OFG 36 mg #1a |
OFG 36 mg #2a |
OFG 45 mg #1a |
OFG 45 mg #2a |
Nausea |
5 (10) |
25 (50) |
31 (58) |
12 (41) |
14 (48) |
13 (42) |
11 (37) |
Vomiting |
3 (6) |
13 (26) |
17 (32) |
8 (28) |
4 (14) |
9 (29) |
8 (27) |
Constipation |
3 (6) |
12 (24) |
17 (32) |
8 (28) |
7 (24) |
6 (19) |
4 (13) |
Diarrhea |
5 (10) |
12 (24) |
19 (36) |
1 (3) |
4 (14) |
5 (16) |
10 (33) |
COVID-19 |
9 (18) |
9 (18) |
9 (17) |
4 (14) |
7 (24) |
5 (16) |
5 (17) |
Eructation |
0 |
9 (18) |
11 (21) |
5 (17) |
2 (7) |
2 (6) |
6 (20) |
Headache |
5 (10) |
4 (8) |
8 (15) |
3 (10) |
2 (7) |
4 (13) |
2 (7) |
Fatigue |
1 (2) |
2 (4) |
7 (13) |
4 (14) |
2 (7) |
4 (13) |
4 (13) |
Gastroesophageal reflux disease |
1 (2) |
4 (8) |
5 (9) |
3 (10) |
4 (14) |
4 (13) |
2 (7) |
Dyspepsia |
3 (6) |
8 (16) |
4 (8) |
1 (3) |
1 (3) |
3 (10) |
2 (7) |
Dizziness |
1 (2) |
5 (10) |
2 (4) |
1 (3) |
1 (3) |
2 (6) |
4 (13) |
Abdominal pain |
2 (4) |
4 (8) |
4 (8) |
0 |
2 (7) |
2 (6) |
1 (3) |
Decreased appetite |
1 (2) |
4 (8) |
4 (8) |
0 |
1 (3) |
3 (10) |
2 (7) |
Urinary tract infection |
3 (6) |
2 (4) |
3 (6) |
0 |
3 (10) |
1 (3) |
2 (7) |
Abbreviations: AE = adverse event; OFG = orforglipron.
aEach of the 36 and 45 mg cohorts was grouped into 2 subcohorts, with different starting doses and dose escalations.
One case of pancreatitis was reported in the 24 mg dose cohort, which after diagnostic follow-up and review by an independent adjudication committee was determined to not be pancreatitis.1
There were no clinically relevant changes in calcitonin level observed in orforglipron-treated participants.1
Discontinuation
Discontinuation of orforglipron or placebo occurred in 65 participants, 36 of whom discontinued due to adverse events (AEs).1
As shown in Study Treatment Discontinuation, the most common AEs leading to study treatment (orforglipron or placebo) discontinuation were gastrointestinal events (31 out of 36 cases), which mostly occurred during dose escalation.1
Parameter |
Placebo |
OFG 12 mg |
OFG 24 mg |
OFG 36 mg #1a |
OFG 36 mg #2a |
OFG 45 mg #1a |
OFG 45 mg #2a |
Discontinued treatment, n(%) |
8 (16.0) |
13 (26.0) |
14 (26.4) |
5 (17.2) |
6 (20.7) |
12 (38.7) |
7 (23.3) |
Discontinuation due to AEs, n(%) |
1 (2.0) |
7 (14.0) |
10 (18.9) |
3 (10.3) |
6 (20.7) |
5 (16.1) |
4 (13.3) |
Discontinuation due to GI AEsb, n(%) |
1 (2.0) |
7 (14.0) |
9 (17.0) |
3 (10.3) |
4 (13.8) |
4 (12.9) |
3 (10.0) |
Abbreviations: AE = adverse event; GI = gastrointestinal; OFG = orforglipron.
aEach of the 36 and 45 mg cohorts was grouped into 2 subcohorts, with different starting doses and dose escalations.
bGI AEs included vomiting, nausea, diarrhea, abdominal pain upper, constipation, abdominal discomfort, food poisoning, gastroesophageal reflux disease, regurgitation, and vomiting projectile.
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Wharton S, Blevins T, Connery L, et al; GZGI Investigators. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877-888. https://doi.org/10.1056/NEJMoa2302392
2Data on file, Eli Lilly and Company and/or one of its subsidiaries.
3Nauck MA, Petrie JR, Sesti G, et al; Study 1821 Investigators. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care. 2016;39(2):231-241. https://doi.org/10.2337/dc15-0165
4Frias JP, Wynne AG, Matyjaszek-Matuszek B, et al. Efficacy and safety of an expanded dulaglutide dose range: a phase 2, placebo-controlled trial in patients with type 2 diabetes using metformin. Diabetes Obes Metab. 2019;21(9):2048-2057. https://doi.org/10.1111/dom.13764
5Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023;402(10400):472-483. https://doi.org/10.1016/S0140-6736(23)01302-8
Date of Last Review: January 26, 2024