Eli Lilly's Investigational Oral Pill Shows Weight Loss Benefits With Lingering Side Effect Concerns

Eli Lilly And Co LLY on Saturday announced detailed results from the ACHIEVE-1 Phase 3 trial of orforglipron compared to placebo in adults with type 2 diabetes and inadequate glycemic control with diet and exercise alone.

The company released its topline data from the trial in April.

At 40 weeks, all three doses (3 mg, 12 mg, 36 mg) of orforglipron achieved the primary endpoint of superior A1C reduction.

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In addition, the 12 mg and 36 mg doses showed clinically meaningful and statistically significant reductions in body weight vs. placebo.

In the study, orforglipron met the primary endpoint of superior A1C reduction compared to placebo at 40 weeks, lowering A1C by 1.3% to 1.6% from a baseline of 8.0% for the efficacy estimand.

In key secondary endpoints, up to 76.2% of participants taking orforglipron achieved the ADA treatment target A1C of <7%, 66.0% achieved an A1C of ≤6.5%, and 25.8% achieved <5.7%, defined as a normal A1C value.

Improvements in A1C were observed as early as four weeks and were accompanied by similar reductions in fasting serum glucose.

In another key secondary endpoint, participants taking the highest dose of orforglipron lost an average of 16.0 lbs (7.9%).

While participants in ACHIEVE-1 did not appear to reach a weight plateau, longer-duration trials, such as the ATTAIN trials, will provide a comprehensive evaluation of the safety and efficacy of orforglipron for obesity.

While the tolerability profile was in line with the incretin class, William Blair highlights that at the highest dose, nausea, vomiting, and constipation did not appear to subside over time, in contrast with its peptide GLP-1 receptor agonist counterparts.

“We are less bullish about the prospects of orforglipron in this setting for two reasons: early plateauing and persistent side effects,” said analyst Andy Hsieh.

Once-Weekly Insulin Efsitora

In addition to the orforglipron data, Eli Lilly also shared promising results for its investigational once-weekly insulin, efsitora.

On Sunday, Eli Lilly announced detailed results from QWINT-1, QWINT-3, and QWINT-4 Phase 3 trials evaluating the safety and efficacy of investigational once-weekly insulin efsitora alfa (efsitora) in adults with type 2 diabetes who used insulin for the first time, previously used daily basal insulin, and previously used daily basal insulin and mealtime insulin, respectively.

Eli Lilly released topline results from the QWINT-1 and QWINT-3 trials in September 2024.

In each trial, once-weekly efsitora met the primary endpoint of non-inferior A1C reduction compared to daily basal insulin.

In QWINT-1, efsitora reduced A1C by 1.31% compared to 1.27% for insulin glargine at week 52 for the efficacy estimand.

In the trial, efsitora was titrated to four fixed doses at four-week intervals, as needed for blood glucose control.

In QWINT-3, efsitora reduced A1C by 0.86% compared to 0.75% for insulin degludec at week 26 for the efficacy estimand. In QWINT-4, efsitora reduced A1C by 1.07% compared to 1.07% for insulin glargine.

Lilly plans to submit efsitora for adults with type 2 diabetes to global regulatory agencies by the end of this year.

In QWINT-1, efsitora resulted in approximately 40% fewer hypoglycemic events compared to insulin glargine, with estimated combined rates of severe or clinically significant hypoglycemic events per patient-year of exposure of 0.50 with efsitora vs. 0.88 with insulin glargine at 52 weeks. In QWINT-3, these rates were 0.84 with efsitora vs. 0.74 with insulin degludec at 78 weeks.

In QWINT-4, estimated combined rates of severe or clinically significant hypoglycemic events per patient-year of exposure were 6.6 with efsitora vs. 5.9 with insulin glargine at 26 weeks.

Across the three trials, efsitora demonstrated an overall safety profile similar to two of the most commonly used daily basal insulin therapies for type 2 diabetes.

Price Action: LLY stock is trading lower by 0.19% to $761.25 premarket at last check Monday.

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