2 Studies Show Similar PK, PD for MK-1293 and Originator Insulin Glargine

A new paper, accepted for publication in Diabetes, Obesity and Metabolism, describes 2 recent studies that demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293, an insulin glargine follow-on being developed by Merck (who funded the studies), and the originator insulin glargine (Lantus).
The Center for Biosimilars Staff
August 22, 2017
A new paper, accepted for publication in Diabetes, Obesity and Metabolism, describes 2 recent studies that demonstrate pharmacokinetic (PK) and pharmacodynamic (PD) similarity between MK-1293, an insulin glargine follow-on being developed by Merck (who funded the studies), and the originator insulin glargine (Lantus).

The euglycemic clamp studies—1 in patients with type 1 diabetes (T1D) and 1 in healthy volunteers—were conducted to demonstrate PK and PD similarity between MK-1293 and both European Union (EU)- and US-sourced Lantus. The PK assessment was based on the liquid chromatography–mass spectrometry-based measurement of the major insulin glargine metabolite (MI), while PD was characterized using the euglycemic clamp platform.

Study A, a double-blind, randomized, single-center, 2-treatment, 4-period replicate crossover study in patients with T1D, compared MK-1293 with EU-sourced insulin glargine. The 70 patients who completed this study had been diagnosed with T1D for at least 12 months, and had a total daily insulin dose (basal plus prandial) of no more than 1.2 units/kg per day, and were stable for 2 weeks prior to screening. During each period, patients received either the follow-on or the originator insulin glargine in one of 2 alternating treatment sequences. All subject received both treatments twice.

Patients in study A who were taking insulin glargine at the screening were transitioned to insulin detemir for the duration of the study. Within 36 hours of dosing, the only basal insulin permitted was neutral protamine Hagedorn. Approximately 10 hours before dosing, after the evening snack, an overnight infusion of insulin aspart was given to stabilize plasma glucose concentration at approximately the clamp target of 130 mg/dL (7.22 mmol/L) by the dosing time.

Study B compared MK-1293 with the reference insulin glargine in a double-blind, randomized, single-center, 3-period, complete crossover study in healthy volunteers. In each period, subjects received 1 of 3 single-dose treatments (MK-1293, US-sourced Lantus, or EU-sourced Lantus) in a randomized order. All subjects received each treatment once. The plasma glucose concentration clamp target for study B was 80 mg/dL (4.4 mmol/L).

In study A, the researchers found that the mean PK profiles for the M1 glargine metabolite were similar between MK-1293 and the EU-sourced Lantus. The 90% confidence interval (CI) for the geometric mean ratios fell within the predetermined margin of 0.80 to 1.25 for both primary PK endpoints (AUC0-24 hr and Cmax). Both secondary PK endpoints (AUC0-12 and AUC12-24) fell within the same range (though no margins were predefined for the secondary endpoints).

In the study A patients, between the time of dosing and end of action, the mean plasma glucose concentration was 129.5 mg/dL. The 95% CIs for the ratios of arithmetic means for all 4 primary PD endpoints (GIR-AUC0-24, GIR-AUC0-12, GIR-AUC12-24, and GIRmax) were within 0.80 and 1.25, meeting the pre-specified criteria for statistical similarity.

Ninety-six healthy volunteers completed study B. The mean PK profiles for the ML glargine metabolite were similar between all 3 treatments, and the 90% CIs for the geometric mean ratios for all 3 treatments were within the pre-defined margin of 0.08 to 1.25 for both primary PK endpoints (AUC0-24 hr and Cmax). For both secondary PK endpoints (AUC0-12 and AUC12-24), the 90% CIs for the geometric mean ratios also fell within the same margin, though, as with study A, no margins were predefined for the secondary PK endpoints.

Mean plasma glucose concentration in study B was 80.6 mg/dL. The 90% CIs for the arithmetic mean rations for all 3 treatments were within same pre-specified range as study A, for the same 4 primary endpoints as study A.

MK-1293 was well tolerated in both studies. No serious adverse events, deaths, or discontinuations for safety or tolerability reasons occurred in either cohort.

The researchers concluded that, in both studies, the pre-specified similarity criteria between MK-1293 and the reference product for the comparison of PK and PD met their primary endpoints, and that all treatments were well tolerated. The researchers concluded that the PK and PD properties of MK-1293 are highly similar to those of the originator product.

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