Efsitora Alfa

Lilly's once-weekly basal insulin LY3209590, a single-chain insulin fused to a human IgG2 Fc domain, approved by the FDA on September 23, 2026 as Onswik for adults with type 2 diabetes after the QWINT phase 3 trials.

Also referenced as: LY3209590, Insulin efsitora alfa, Insulin efsitora alfa-gobe, BIF, Onswik

Also appears in: Hormone

COA Public product evidence No certificate records are bound to a tracked Efsitora Alfa product page A record counts here only when a vendor publishes a certificate against one of its own tracked Efsitora Alfa product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

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What is Efsitora Alfa?

Efsitora alfa, developed by Eli Lilly as LY3209590 and called Basal Insulin Fc (BIF) in its early papers, is a once-weekly basal insulin for adults with type 2 diabetes. It is a fusion protein, not a peptide: each monomer is a single-chain insulin, an insulin B-chain analog joined by a short peptide linker to an insulin A-chain analog, fused through a second linker to a human IgG2 Fc region. Two monomers pair through the Fc domain into a divalent dimer of 299 amino acids per chain, with 24 cysteines forming 2 interchain and 10 intrachain disulfide bonds, N-linked glycosylation at Asn150 and a molecular weight of about 64 kDa. It is produced in Chinese hamster ovary cells by recombinant DNA technology, and the US nonproprietary name carries the biologic suffix as insulin efsitora alfa-gobe.

Native insulin and its daily analogs rely on depot or albumin-binding modifications to stretch their action to about a day; efsitora instead borrows the long circulation of an antibody. The FDA approved it as Onswik on September 23, 2026 under BLA 761408 for adults with type 2 diabetes, making it the second once-weekly basal insulin approved in the US after insulin icodec (BLA 761326, approved March 26, 2026). It has no presence in the research-peptide market.

How it works

• Same receptor, deliberately weaker binding. Efsitora binds the human insulin receptor with an affinity about two orders of magnitude lower than human insulin and activates it with reduced potency but full agonism, with faster receptor dephosphorylation; binding to the IGF-1 receptor was too weak to measure definitively, and mitogenic activity in SAOS-2 and H4IIE cells was at least 70-fold weaker than human insulin (Moyers et al., Journal of Pharmacology and Experimental Therapeutics, 2022;382(3):346–355). Once bound, it produces the same effects as human insulin: peripheral glucose uptake in muscle and fat, suppression of hepatic glucose output, and inhibition of lipolysis and proteolysis, as the Onswik label states.
• Three mechanisms of protraction. The label attributes the weekly profile to reduced renal clearance from the molecule’s size, protection from degradation through binding to the neonatal Fc receptor (FcRn), and lower insulin receptor affinity, which reduces receptor-mediated clearance, so agents that block FcRn can lower its exposure. In streptozotocin-diabetic rats a single subcutaneous dose lowered glucose from 24 through 336 hours, with peak concentration at 48 hours and a terminal half-life of about 120 hours (Moyers et al., Journal of Pharmacology and Experimental Therapeutics, 2022;382(3):346–355).
• A 17-day half-life and a flat weekly profile in humans. Single ascending doses in 16 healthy adults and 57 people with type 2 diabetes gave a half-life of about 17 days and a dose-dependent fall in fasting glucose lasting 5 days or longer; after 6 weeks of weekly dosing in 33 people with type 2 diabetes the steady-state peak-to-trough ratio was 1.14 (Heise et al., Diabetes, Obesity and Metabolism, 2023;25(4):1080–1090). The label gives a steady-state half-life of about 17 days, peak concentration at 2.5 days, a peak-to-trough ratio of 1.16, week-to-week exposure variability of 5% and subcutaneous bioavailability of about 86%; in a euglycemic clamp study in 53 adults with type 2 diabetes the glucose-lowering effect covered the whole weekly interval.

Research status

Phase 2. Two 26-week, open-label, treat-to-target trials against once-daily insulin degludec came first. In 278 insulin-naive adults with type 2 diabetes, weekly BIF was noninferior for HbA1c change (treatment difference 0.06%; 90% CI −0.11 to 0.24) with no severe hypoglycemia (Bue-Valleskey et al., Diabetes Care, 2023;46(5):1060–1067). In 265 adults with type 1 diabetes, BIF was noninferior but with a statistically significant 0.17% difference favoring degludec (Kazda et al., Diabetes Care, 2023;46(5):1052–1059). The phase 3 program, QWINT, comprised five open-label, treat-to-target trials against glargine U100 or degludec with HbA1c change at week 26 or 52 as the primary endpoint (Bergenstal et al., Diabetes, Obesity and Metabolism, 2024;26(8):3020–3030), each with a 0.4 percentage point noninferiority margin.

QWINT-1 (NCT05662332). A 52-week trial in 795 insulin-naive adults with type 2 diabetes tested a fixed-dose regimen, with efsitora stepped up at 4-week intervals through fixed levels as needed, against glargine U100 adjusted weekly. HbA1c fell from 8.20% to 7.05% with efsitora and from 8.28% to 7.08% with glargine, a difference of −0.03 percentage points (95% CI −0.18 to 0.12), confirming noninferiority without superiority (p=0.68). Combined clinically significant or severe hypoglycemia was lower with efsitora at 0.50 versus 0.88 events per participant-year (rate ratio 0.57; 95% CI 0.39 to 0.84), and the median number of dose adjustments was 2 versus 8 (Rosenstock et al., New England Journal of Medicine, 2025;393(4):325–335).

QWINT-2 (NCT05362058). A 52-week trial randomized 928 insulin-naive adults with type 2 diabetes, with and without GLP-1 receptor agonists, to efsitora or degludec. HbA1c fell from 8.21% to 6.97% with efsitora and from 8.24% to 7.05% with degludec (difference −0.09 percentage points; 95% CI −0.22 to 0.04), noninferior overall and in both GLP-1 subgroups. Combined clinically significant or severe hypoglycemia was 0.58 versus 0.45 events per participant-year (rate ratio 1.30; 95% CI 0.94 to 1.78), with no severe episodes on efsitora and six on degludec (Wysham et al., New England Journal of Medicine, 2024;391(23):2201–2211).

QWINT-3 (NCT05275400). The longest trial, 78 weeks at 127 sites in nine countries, randomized 986 adults with type 2 diabetes already on basal insulin 2:1 to efsitora (655) or degludec (331). The week 26 HbA1c change was −0.81 versus −0.72 percentage points (difference −0.09; 95% CI −0.19 to 0.01), establishing noninferiority. Through week 78, combined level 2 or 3 hypoglycemia occurred at 0.84 versus 0.74 events per patient-year (rate ratio 1.14; 95% CI 0.83 to 1.56); serious adverse events were reported in 16% versus 11%, and nine deaths occurred (seven and two), none judged treatment-related (Philis-Tsimikas et al., Lancet, 2025;405(10497):2279–2289).

QWINT-4 (NCT05462756). A 26-week trial at 78 sites randomized 730 adults with type 2 diabetes on basal plus prandial insulin to efsitora or glargine U100, both with insulin lispro. From a baseline HbA1c of 8.18% in both groups, the change was −1.01 versus −1.00 percentage points, noninferior; overall level 2 or 3 hypoglycemia was 6.6 versus 5.9 events per patient-year (rate ratio 1.11; 95% CI 0.85 to 1.44) and serious adverse events 7% versus 6% (Blevins et al., Lancet, 2025;405(10497):2290–2301).

QWINT-5 (NCT05463744), the type 1 diabetes trial. A 52-week trial at 82 centers randomized 692 adults with type 1 diabetes to efsitora (343) or degludec (349), both with insulin lispro. The week 26 HbA1c change was −0.51% versus −0.56% (difference 0.052%; 95% CI −0.077 to 0.181), meeting noninferiority. Hypoglycemia was worse with efsitora: combined level 2 or 3 events were 14.03 versus 11.59 per patient-year (rate ratio 1.21; 95% CI 1.04 to 1.41; p=0.016), highest in the first 12 weeks, and severe hypoglycemia occurred in 10% of efsitora participants (35 of 343) versus 3% (11 of 349) on degludec; the authors concluded that dose initiation and optimization in type 1 diabetes needed further evaluation (Bergenstal et al., Lancet, 2024;404(10458):1132–1142). No type 1 diabetes indication was sought, and the US label states that Onswik is not recommended in type 1 diabetes because of the increased risk of severe hypoglycemia.

Immunogenicity. Across the four type 2 diabetes trials, treatment-emergent anti-efsitora antibodies developed in 7% of insulin-naive and 3% of insulin-experienced adults, with no clinically significant safety effect identified.

Comparative analyses. Matching-adjusted indirect comparisons of QWINT-3 against ONWARDS 2 and QWINT-4 against ONWARDS 4 found efsitora comparable to insulin icodec for HbA1c change, with lower level 2 or 3 hypoglycemia event rates (rate ratio 0.436; 95% CI 0.241 to 0.786) and less weight gain in the basal-insulin-experienced comparison only (Bajaj et al., Diabetes, Obesity and Metabolism, 2026;28(11):10725–10735); no head-to-head trial of the two weekly insulins has been reported.

Regulatory path. The FDA received the BLA on September 23, 2025 and approved BLA 761408 on September 23, 2026 for Onswik in two concentrations without an advisory committee. The approval letter waives pediatric studies below age 10 and defers a required pharmacokinetic and safety study in patients aged 10 to under 18 with type 2 diabetes as a postmarketing requirement. In the European Union, the CHMP adopted a positive opinion on June 25, 2026 recommending marketing authorization for Onswik (EMEA/H/C/006388) in type 2 diabetes. As of November 2026, all 19 efsitora studies on ClinicalTrials.gov, including the pediatric pharmacokinetic study (NCT06362265), are listed as completed, and none is recruiting.

Common dosage forms

• Onswik U-500 KwikPen. A 3 mL single-patient-use prefilled pen containing 1,500 units of insulin efsitora alfa-gobe at 500 units/mL, for subcutaneous self-injection.
• Onswik U-1,000 KwikPen. The same 3 mL prefilled pen containing 3,000 units at 1,000 units/mL.
• European presentation. The CHMP opinion covers Onswik as 500 unit/mL and 1,000 unit/mL solutions for injection in a prefilled pen.
• No other presentation. No vial, cartridge, pump-compatible or compounded form exists.

Key considerations

• Regulatory status. The FDA Approved status reflects the September 23, 2026 approval of Onswik (insulin efsitora alfa-gobe) injection under BLA 761408 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is not approved for type 1 diabetes, and the EMA’s CHMP adopted a positive opinion for the same indication on June 25, 2026.
• A fusion protein, not a peptide. At about 64 kDa, with an IgG2 Fc domain and FcRn recycling, efsitora is an antibody-scale biologic that carries insulin; its interaction with FcRn inhibitors and its potential for placental transfer follow from that structure rather than from insulin biology.
• Noninferior, not superior, glycemic control. All five QWINT trials met their noninferiority margin and none showed superiority on HbA1c; the measurable advantages were fewer injections, fewer dose adjustments and lower hypoglycemia in the fixed-dose QWINT-1 design, while QWINT-2 and QWINT-3 showed numerically higher, nonsignificant hypoglycemia rates against degludec.
• Type 1 diabetes is a labeled limitation. QWINT-5 produced a significant 21% excess of clinically significant hypoglycemia and a threefold higher incidence of severe hypoglycemia versus degludec, and the US label advises against use in type 1 diabetes for that reason.
• Long tail of action. With a 17-day half-life, steady state takes 4 to 10 weeks and glucose lowering persists 4 to 6 weeks after the last injection, so the effects of any regimen change resolve more slowly than with daily insulins.