A milestone in the push for improved access and affordability of life-saving medications in approval of first insulin biosimilar, Semglee.
On March 23, 2020, insulin was officially moved to the biologic regulatory classification by the Food and Drug Administration (FDA). Biologics are complex macromolecules composed of sugars, proteins, nucleic acids, or a combination of these. Biologics may be living entities such as cells and tissues that can be isolated from various human, animal, or microbial sources. With insulins classified as biologics, drug companies can now begin manufacturing their own “generic” insulins. These “generics” are referred to as biosimilars. The “brand-name” biological product can be referred to as the reference biologic because it provides a reference or framework for the approval of biosimilars. Congress developed the Biologics Price Competition and Innovation Act (BPCI Act) of 2009 to create an abbreviated licensure pathway for biological products that are proven to be biosimilar to or interchangeable with an FDA-approved biological product. This pathway was established in an attempt to provide more treatment options, increase access to life-saving medications, and lower health care costs through competition. Just a few months after insulin was deemed a biologic, Mylan and Biocon have announced the approval of Semglee, a new insulin glargine injection, to be offered in vial and pen delivery systems. This FDA approval marks a significant milestone in the push for improved access and affordability of insulin products in the United States.
Semglee, co-developed by Mylan Pharmaceuticals and Biocon Biologic, was deemed a biologic under section 351(a) by the Public Health Service (PHS) Act. The new drug application (NDA) was approved under the 505(b)(2) pathway. A 505(b)(2) NDA contains full safety and effectiveness reports but allows at least some of the information required for NDA approval, such as safety and efficacy of the active ingredient, to come from studies that were conducted neither by nor for the applicant. To put it simply, it is a hybrid between an NDA and an abbreviated new drug application (ANDA), offering a unique opportunity for rapid and less costly approval. Drugs approved under the 505(b)(2) pathway will usually contain well-understood active ingredients to be used as reference drugs. All the company must do is to create a bridge between what is already known about the previously approved reference drug and the novel drug product. As the amino acid sequence of Semglee is identical to that of Lantus® (insulin glargine), it was necessary to link the information of the two. In doing so, manufacturers have successfully made Semglee the first insulin “biosimilar” approved in the United States.
The approval of Semglee was based on two randomized clinical trials – INSTRIDE1 and INSTRIDE2. They compared Semglee (MYL-1501D) to Lantus, the branded insulin glargine. INSTRIDE1, a 52-week, open-label, randomized trial, tested the safety and efficacy of once-daily Semglee injections administered with mealtime insulin lispro in patients with type 1 diabetes mellitus (T1DM). The outcome of interest was the change in glycated hemoglobin (HbA1c) from baseline to week 24. Changes in fasting plasma glucose, insulin dose, self-monitored blood-glucose, immunogenicity, overnight hypoglycemic episodes, and adverse effects up to week 52 were also considered. Mean HbA1c change at week 24 was 0.14% (SE 0.054; 95% CI 0.033, 0.244) for Semglee and 0.11% (SE 0.054; 95% CI 0.007, 0.220) for reference insulin glargine. Safety profiles were similar between both biologics, and the results showed no clinically meaningful differences in terms of efficacy between Semglee and the reference insulin glargine.
The INSTRIDE2 trial was a 52-week, multi-centered, open-label, randomized, parallel-group, non-inferiority study that compared the safety and efficacy of Semglee with reference insulin glargine in T2DM patients that were insulin-naïve and on oral antidiabetic agents. Change in HbA1c was measured at baseline and week 24. Secondary endpoints were the same as in the INSTRIDE1 study. Mean change in HbA1c from baseline at week 24 was −0.60% (95% CI −0.78, −0.41) for Semglee and − 0.66% (95% CI −0.84, −0.48) for reference insulin glargine. Safety and tolerability profiles were assessed up to week 52. They were determined to be similar among both products. The trial showed the non-inferiority of Semglee to the reference insulin.
Leaders at Mylan Pharmaceuticals express a desire to seek for interchangeable status between Semglee and Lantus soon. Interchangeable biologics can be automatically substituted for the original medication at the pharmacy counter. To be approved for substitution, the manufacturers must also prove that the biosimilar will have the same clinical results in any patient if they switch back and forth between the original brand and the biosimilar medication. A switch-study, INSTRIDE3, was thus conducted. This study aimed to determine the efficacy, safety, and immunogenicity when switching between Semglee and reference insulin glargine in patients with T1DM. Patients from INSTRIDE1 were selected to participate in the INSTRIDE3 trial. The same outcomes were measured as in the previous two trials. Results were comparable between the reference sequence and the treatment switching sequence in all outcomes. We can expect to see the interchangeability status very soon.
- Semglee was deemed non-inferior to Lantus® insulin glargine in terms of safety and efficacy.
- The recommended starting dose is approximately one-third of the total daily insulin requirement.
- For those with type 2 diabetes, the starting dose is 0.2 units/kg or up to 10 units once daily.
Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020. Atlanta, GA: Centers for Disease Control and Prevention, US Department of Health and Human Services; 2020.
Blevins TC, Barve A, Sun B, Ankersen M. Efficacy and safety of MYL-1501D vs. insulin glargine in patients with type 1 diabetes after 52 weeks: Results of the INSTRIDE 1 phase III study. Diabetes Obes Metab. 2018;20(8):1944-1950. doi:10.1111/dom.13322
Blevins TC, Barve A, Sun B, et al. Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 2 diabetes after 24 weeks: Results of the phase III INSTRIDE 2 study. Diabetes Obes Metab. 2019;21(1):129-135. doi:10.1111/dom.13495
Blevins TC, Barve A, Raiter Y, et al. Efficacy and safety of MYL-1501D versus insulin glargine in people with type 1 diabetes mellitus: Results of the INSTRIDE 3 phase 3 switch study. Diabetes Obes Metab. 2020;22(3):365-372. doi:10.1111/dom.13904
Melinda Rodriguez, PharmD Candidate 2021, Lake Erie College of Osteopathic Medicine – L|E|C|O|M School of Pharmacy