2024胰岛素治疗可改善成人糖尿病患者的血糖控制报告

Briefing Document Endocrinologic and Metabolic DrugsAdvisory CommitteeMay 24,2024 Advisory Committee BriefingMaterials: Available for Public Release 1Executive Summary Novo Nordisk is seeking approval for insulin icodec, a basal insulin for once-weekly subcutaneousadministration. Insulin icodecis a once-weekly long-acting human insulinanaloguewhichwasdevelopedtoprovideglycemic control in adults with diabetes(BLA 761326). The purpose of the EMDAC meetingis todiscussthebenefit-risk of insulin icodec for thetreatmentofpeoplewithtype 1diabetes (T1D). Therefore, thisdocumentwill focus onT1Dbased on thesinglerandomized, controlledpivotal study known as ONWARDS6. In addition,this documentalso includesdatafrom fiverandomized, controlled studies (ONWARDS1to5)supportingapositive benefit-risk inpatients withtype2 diabetes,since those data inform the overall benefits andsafe use ofinsulin icodec. 1.1Diabetes overview and unmet medical need(Section2) Diabetes mellitus is a metabolic disordercharacterizedby the presence of hyperglycemia due todefective insulin secretion,defectiveinsulin action or both. Diabetes mellitus is generally classifiedaccording toetiologicalfactors, where type 1 diabetes (T1D) and type 2 diabetes (T2D) constitutethe vast majority of cases. The number of peoplelivingwith diabetes worldwideis predicted toincrease to 783 million by 2045. In the United States,37.3 million people (11.3% of the population)are affected by diabeteswhichrepresents a significant medical, social and economic burden.1, 2 The chronic hyperglycemia of diabetes mellitus is associated with clinically significant long-termcomplications that entail macrovascular and microvascular complications and may greatly affectpeople’squality of life. The microvascular disorders associated with diabetes are typicallyretinopathy, nephropathy,and neuropathy. Maintaining tight glycemic control(70–180 mg/dL)reduces the risk of long-term complications associated with diabetes.3 Givenitsprogressive nature,the current treatment cascadeforT2Dfollows a stepwise approachcomprising lifestyle changes in combination with pharmacological intervention thatmayeventuallylead tomore intensivetherapies,includingbasal insulins.Since T1D ischaracterizedby absoluteinsulin deficiency, the current gold standard of care isinsulin therapy involving multiple dailyinjections of bolus and basal insulin or continuous subcutaneous insulin infusion4,5, 6. Insulin is highly effective in lowering blood glucose, and different insulin formulations arecurrently approved for the treatment of T2D and T1D. Hypoglycemia is an inherent risk of allinsulins andthe choice of insulinshould be balanced against the benefitsfor each individual person.In addition, the complicated treatment requirements are consideredby both people living withdiabetes and physiciansto be a barrier to insulin therapy initiation and adherence, as insulin therapymay require frequent injections to maintain glycemic control.7, 8Importantly, the degree ofadherence to insulin treatment has been shown to be a significant predictor of reductions in HbA1c9,10anddecreasedadherence isassociated with the development of microvascular disorders. In current practice, clinicians andpeople living with diabetescan choose from a range of insulinsthat can be employed in various regimens to suit an individual’s needs, based on the pathology,individual requirements, lifestyle,and personal preferences.11Insulin icodec,as a once-weeklybasal insulin,would represent analternativeoptionforpeople with T2D or T1D,conferringtheadditional benefit of a simplified and more convenient basal insulin treatment. 1.2Product descriptionandmolecular mechanism(Section4) Insulin icodec is a novel long-acting human insulin analogue, which has been designed toretain thesame,well-established biological/metabolic effectsofhuman insulin while extending the half-life tocover the basal insulin requirements for a full weekallowing fora once-weekly subcutaneousinjection. Theinsulin icodecmoleculeconsists of a modifiedinsulinpeptide backbone and a fatty acid-containing sidechain.The addition of the C20 fatty-diacid-containing chain imparts a strong butreversible binding to albumin which leads to the formation of a depot of essentially inactive insulinicodec,from which insulin icodec is slowly and continuouslyreleased.In addition, three amino acidsubstitutions in the peptide backbone of insulin icodec provide molecular stability and contribute toattenuating insulin receptor binding and clearance,resultinginaconsiderably extended half-life(Figure4-1). 1.3Clinical pharmacology(Section6) Pharmacokinetic assessments demonstrated that steady state for insulin icodec was reached after2-4weeks of once-weekly administration. At steady state, the concentration-time profile showedthat insulin icodec exposure covered the one-week dosing interval (Figure6-1). The terminalhalf-life of insulin icodec at steady state was approximately 1 week. Total exposure and