Phase 2 results for diabetes drug LY3298176 published in The Lancet
The publication moved a dual GIP/GLP-1 drug into late-stage testing, but the human data reported so far come from small, short studies.
Results from a Phase 2 trial of the experimental diabetes drug LY3298176 in type 2 diabetes were published Oct. 4, 2018 in The Lancet by Frias and colleagues. The study was randomized and controlled against both placebo and an active comparator. The dose-by-dose results of that Phase 2 trial have not been reported.
LY3298176 — the molecule now named tirzepatide — is a fatty acid modified peptide designed to activate two gut-hormone receptors at once, GIP and GLP-1, and to be given once a week by subcutaneous injection [1]. The aim was to learn whether adding GIP activity to the established benefits of a selective GLP-1 receptor agonist would improve metabolic results in type 2 diabetes [1].
A separate paper in Molecular Metabolism (Volume 18, December 2018, pages 3–14) laid out the drug's path from laboratory work to first-in-human testing [1]. In cell assays and in mice, LY3298176 activated both receptors, produced glucose-dependent insulin secretion and improved glucose tolerance through both receptors. Given over time to mice, it lowered body weight and food intake more than a GLP-1 receptor agonist did [1].
The human data in that paper came from a three-part Phase 1 program: single-ascending doses of 0.25–8 mg and four-week multiple-ascending doses of 0.5–10 mg in healthy subjects, then a four-week, multiple-dose proof-of-concept study of 0.5–15 mg in patients with type 2 diabetes [1]. Doses above 5 mg were reached by titration, and dulaglutide was used as a positive control [1]. A total of 142 people received at least one dose of LY3298176, dulaglutide or placebo, and the primary objective was safety and tolerability [1]. The trial was registered as NCT02759107 [1].
In the proof-of-concept portion, the 10 mg and 15 mg doses of LY3298176 reduced fasting serum glucose compared with placebo. The least-squares mean difference was −49.12 mg/dL (95% CI −78.14 to −20.12) for 10 mg and −43.15 mg/dL (95% CI −73.06 to −13.21) for 15 mg [1].
Body-weight reductions were also significantly greater than placebo in the healthy-volunteer multiple-dose part for the 1.5 mg, 4.5 mg and 10 mg groups: −1.75 kg (95% CI −3.38 to −0.12), −5.09 kg (−6.72 to −3.46) and −4.61 kg (−6.21 to −3.01) [1]. In patients with type 2 diabetes, the 10 mg and 15 mg doses produced least-squares mean differences of −2.62 kg (−3.79 to −1.45) and −2.07 kg (−3.25 to −0.88) versus placebo [1].
The most frequent side effects were gastrointestinal — vomiting, nausea, decreased appetite, diarrhea and abdominal distension — in both healthy subjects and patients with type 2 diabetes. All were dose-dependent and considered mild to moderate in severity [1]. Weight loss was greater with LY3298176 than with the selective GLP-1 receptor agonist dulaglutide in healthy humans, according to the paper [1].
Why it matters for patients
The results matter mainly as a signal about a mechanism. Activating GIP and GLP-1 together is different from the selective GLP-1 receptor agonists already used in type 2 diabetes, and this program was an early test in people of whether the combination adds anything [1].
The blood sugar and weight changes reported so far come from small, short studies. The largest human dataset described involved 142 people across all dose groups and control arms, with four weeks of dosing at most [1]. That is not long enough, or large enough, to show whether the drug reduces complications of diabetes, or whether its benefits and risks change with longer use.
Tolerability is the other practical question. The gastrointestinal side effects that appeared here are in the same category that GLP-1 receptor agonists produce, they rose with dose, and the paper describes the drug's tolerability as comparable to GLP-1 receptor agonists [1].
What happens next
The authors concluded that the data warrant further clinical evaluation of LY3298176 for type 2 diabetes and potentially for obesity [1]. The Phase 2 trial published in The Lancet was the step that moved the drug into Phase 3 testing in type 2 diabetes. Results from those larger trials, and any regulatory decisions, had not been reported at that point.
Sources
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