The two phase 1 studies, Study A and Study B, were both randomized, crossover studies conducted in healthy adults (Orforglipron Phase 1 Study A Design and Orforglipron Phase 1 Study B Design).3

In Study A, a total of 12 participants received a single dose of oral orforglipron (3 mg) (treatment period 1) followed by another single dose of orforglipron after a washout period of at least 5 days (treatment period 2). In each treatment period, participants were assigned to either fasted or fed treatment arms. In both studies, orforglipron was taken with approximately 240 mL of water.3,7

In Study B, a total of 34 participants received a single daily dose of orforglipron, escalating the dose weekly to 2 mg, 4 mg, 8 mg, and to 16 mg on day 22. There were no food or water restrictions during this escalation period.3

On day 21, Study B participants were randomized to either fasted or fed treatment.3

For both studies, fasted treatment was defined as receiving the orforglipron dose following an overnight fast of at least 10 hours and no food was allowed for at least 4 hours postdose.3

In Study A, fed (eg, food effect) treatment was defined as receiving the orforglipron dose following a standardized high-calorie meal consumed after an overnight fast of at least 10 hours. This meal consisted of about 500 kcal with approximately

• 30% fat
• 50% carbohydrates, and
• 20% protein.3 

In Study B, fed treatment was defined as receiving a predose meal on days 1 to 6, with a standardized high-fat, high-calorie meal predose on day 7. This meal consisted of 800 to 1000 kcal with approximately

• 50% fat
• 25%-30% carbohydrates, and
• 15%-19% protein.3

Blood samples for PK measurements were collected at specified intervals pre- and postdose to assess

• area under the concentration-time curve (AUC)
• maximum serum concentration (C_max),
• time to maximum concentration (t_max), and
• half-life (t_1/2) associated with terminal rate constant.3

For Study A, AUC_0-∞ was evaluated after a single dose of orforglipron 3 mg. For Study B, steady-state AUC_0-24 was evaluated after multiple doses of orforglipron 16 mg.3

In these phase 1 studies, the overall mean exposure to orforglipron (AUC and C_max) was 18%-24% lower when administered with food. The effect on t_max and half-life was comparable between fed and fasted states. See Study A: Profile in Participants Taking Orforglipron 3 mg Daily and Study B: Profile in Participants Taking Orforglipron 16 mg Daily for the concentration-time curve for Study A and Study B, respectively.3

Considering the exposure-response relationship of orforglipron, the noted PK differences attributable to the prandial state are not expected to lead to clinically meaningful differences in orforglipron's safety and efficacy.3

In both studies, the majority of treatment-emergent adverse events (TEAEs) were related to gastrointestinal events and were mild to moderate in severity. No serious adverse events or deaths were reported in either study.3

In Study A, all TEAEs occurred under the fasted condition. Of the 12 participants who received at least one dose of orforglipron 3 mg, 2 (16.7%) reported at least 1 TEAE. Reported adverse events of special interest (AESI) included

• nausea (n=2), and
• vomiting (n=1).3

In Study B, under the fasted condition, 18 of 28 participants (64.3%) reported at least 1 TEAE. Reported AESI under the fasted condition were

• nausea (n=4)
• vomiting (n=2), and
• diarrhea (n=2).3

Under the fed condition, 12 of 27 participants (44.4%) reported at least 1 TEAE. Reported AESI under the fed condition were

• nausea (n=5)
• vomiting (n=2), and
• diarrhea (n=2).3
  

There were no reported cases of acute pancreatitis in either study.3

There were no food or water restrictions for orforglipron administration in the phase 2 study evaluating efficacy and safety in adult participants with T2D.2

Phase 3 studies included in the ACHIEVE program are ongoing and aim to further investigate safety and efficacy of orforglipron without food or water restrictions in participants with T2D.3