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2024-05-23-Novo Nordisk好***

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Insulin Icodec: A Novel Once-Weekly Basal Insulin for Diabetes Management

Overview

Purpose: Novo Nordisk is seeking approval for insulin icodec, a basal insulin designed for once-weekly subcutaneous administration, to improve glycemic control in adults with diabetes mellitus.

Target Indication: The primary focus is on type 1 diabetes (T1D), with supporting data from type 2 diabetes (T2D) studies.

Diabetes Overview and Unmet Medical Needs

Diabetes Prevalence:

Global prediction: 783 million people with diabetes by 2045.
U.S. statistics: 37.3 million people (11.3% of the population) affected by diabetes.
Chronic hyperglycemia leads to significant long-term complications such as macrovascular and microvascular disorders, affecting quality of life.

Current Treatment Challenges:

T1D: Absolute insulin deficiency treated with multiple daily injections or continuous subcutaneous insulin infusion.
T2D: Stepwise treatment starting with lifestyle changes and progressing to oral medications, eventually leading to basal insulins.
Hypoglycemia Risk: All insulins carry a risk of hypoglycemia, which can be managed by balancing benefits against risks.
Treatment Adherence: Frequent injections are a barrier to initiating and adhering to insulin therapy.

Insulin icodec Benefits:

Simplified and more convenient once-weekly basal insulin treatment for T2D and T1D.

Product Description and Molecular Mechanism

Insulin icodec:

Design: A novel long-acting human insulin analogue with an extended half-life covering a full week.
Structure: Comprises a modified insulin peptide backbone and a fatty acid-containing sidechain.
Mechanism:
- Albumin Binding: Strong but reversible binding to albumin forms a depot of essentially inactive insulin icodec, which is slowly and continuously released.
- Amino Acid Substitutions: Three substitutions in the peptide backbone contribute to molecular stability and reduced insulin receptor binding, extending the half-life.

Clinical Pharmacology

Pharmacokinetics:

Steady State: Reached after 2-4 weeks of once-weekly administration.
Exposure: Exposure increases proportionally with dose, with low within-subject variability.
Half-Life: Terminal half-life of approximately 1 week.
Weight Effect: Increased body weight reduces insulin icodec exposure, mitigated by individual dose titration.
Renal and Hepatic Impairment: No clinically meaningful impact on pharmacokinetics.

Pharmacodynamics:

Glucose-Lowering Effect: Covers the full weekly dosing interval in both T1D and T2D, with the greatest effect on Days 2-4.
Day-to-Day Differences: Larger in T1D compared to T2D, similar to daily basal insulin products.

Population Pharmacokinetics:

Comparable exposure across age, sex, race, ethnicity, anti-insulin icodec antibody level, albumin level, and diabetes population (T2D vs. T1D).

Clinical Development Program

Phase 3 Program:

Consists of 18 clinical trials, including six phase 3a trials (referred to as 'ONWARDS' trials).
Trials cover both T1D and T2D populations.

Hypoglycemia Monitoring:

Utilized continuous glucose monitoring (CGM) in selected ONWARDS trials.
CGM-based hypoglycemia detection provides a more unbiased assessment, classifying episodes based on interstitial glucose levels.

This summary highlights the key aspects of insulin icodec, its design, clinical benefits, and the comprehensive clinical development program supporting its approval.

InsulinIcodec TreatmenttoImproveGlycemicControlinAdultswithDiabetesMellitus BLA761326 BriefingDocument EndocrinologicandMetabolicDrugsAdvisoryCommitteeMay24,2024 AdvisoryCommitteeBriefingMaterials:AvailableforPublicRelease 1ExecutiveSummary NovoNordiskisseekingapprovalforinsulinicodec,abasalinsulinforonce-weeklysubcutaneousadministration.Insulinicodecisaonce-weeklylong-actinghumaninsulinanaloguewhichwasdevelopedtoprovideglycemiccontrolinadultswithdiabetes(BLA761326). ThepurposeoftheEMDACmeetingistodiscussthebenefit-riskofinsulinicodecforthetreatmentofpeoplewithtype1diabetes(T1D).Therefore,thisdocumentwillfocusonT1Dbasedonthesinglerandomized,controlledpivotalstudyknownasONWARDS6.Inaddition,thisdocumentalsoincludesdatafromfiverandomized,controlledstudies(ONWARDS1to5)supportingapositivebenefit-riskinpatientswithtype2diabetes,sincethosedatainformtheoverallbenefitsandsafeuseofinsulinicodec. 1.1Diabetesoverviewandunmetmedicalneed(Section2) Diabetesmellitusisametabolicdisordercharacterizedbythepresenceofhyperglycemiaduetodefectiveinsulinsecretion,defectiveinsulinactionorboth.Diabetesmellitusisgenerallyclassifiedaccordingtoetiologicalfactors,wheretype1diabetes(T1D)andtype2diabetes(T2D)constitutethevastmajorityofcases.Thenumberofpeoplelivingwithdiabetesworldwideispredictedtoincreaseto783millionby2045.IntheUnitedStates,37.3millionpeople(11.3%ofthepopulation)areaffectedbydiabeteswhichrepresentsasignificantmedical,socialandeconomicburden.1,2 Thechronichyperglycemiaofdiabetesmellitusisassociatedwithclinicallysignificantlong-termcomplicationsthatentailmacrovascularandmicrovascularcomplicationsandmaygreatlyaffectpeople’squalityoflife.Themicrovasculardisordersassociatedwithdiabetesaretypicallyretinopathy,nephropathy,andneuropathy.Maintainingtightglycemiccontrol(70–180mg/dL)reducestheriskoflong-termcomplicationsassociatedwithdiabetes.3 Givenitsprogressivenature,thecurrenttreatmentcascadeforT2Dfollowsastepwiseapproachcomprisinglifestylechangesincombinationwithpharmacologicalinterventionthatmayeventuallyleadtomoreintensivetherapies,includingbasalinsulins.SinceT1Discharacterizedbyabsoluteinsulindeficiency,thecurrentgoldstandardofcareisinsulintherapyinvolvingmultipledailyinjectionsofbolusandbasalinsulinorcontinuoussubcutaneousinsulininfusion4,5,6. Insulinishighlyeffectiveinloweringbloodglucose,anddifferentinsulinformulationsarecurrentlyapprovedforthetreatmentofT2DandT1D.Hypoglycemiaisaninherentriskofallinsulinsandthechoiceofinsulinshouldbebalancedagainstthebenefitsforeachindividualperson.Inaddition,thecomplicatedtreatmentrequirementsareconsideredbybothpeoplelivingwithdiabetesandphysicianstobeabarriertoinsulintherapyinitiationandadherence,asinsulintherapymayrequirefrequentinjectionstomaintainglycemiccontrol.7,8Importantly,thedegreeofadherencetoinsulintreatmenthasbeenshowntobeasignificantpredictorofreductionsinHbA1c9,10anddecreasedadherenceisassociatedwiththedevelopmentofmicrovasculardisorders. Incurrentpractice,cliniciansandpeoplelivingwithdiabetescanchoosefromarangeofinsulinsthatcanbeemployedinvariousregimenstosuitanindividual’sneeds,basedonthepathology,individualrequirements,lifestyle,andpersonalpreferences.11Insulinicodec,asaonce-weeklybasalinsulin,wouldrepresentanalternativeoptionforpeoplewithT2DorT1D,conferringtheadditionalbenefitofasimplifiedandmoreconvenientbasalinsulintreatment. 1.2Productdescriptionandmolecularmechanism(Section4) Insulinicodecisanovellong-actinghumaninsulinanalogue,whichhasbeendesignedtoretainthesame,well-establishedbiological/metaboliceffectsofhumaninsulinwhileextendingthehalf-lifetocoverthebasalinsulinrequirementsforafullweekallowingforaonce-weeklysubcutaneousinjection. Theinsulinicodecmoleculeconsistsofamodifiedinsulinpeptidebackboneandafattyacid-containingsidechain.TheadditionoftheC20fatty-diacid-containingchainimpartsastrongbutreversiblebindingtoalbuminwhichleadstotheformationofadepotofessentiallyinactiveinsulinicodec,fromwhichinsulinicodecisslowlyandcontinuouslyreleased.Inaddition,threeaminoacidsubstitutionsinthepeptidebackboneofinsulinicodecprovidemolecularstabilityandcontributetoattenuatinginsulinreceptorbindingandclearance,resultinginaconsiderablyextendedhalf-life(Figure4-1). 1.3Clinicalpharmacology(Section6) Pharmacokineticassessmentsdemonstratedthatsteadystateforinsulinicodecwasreachedafter2-4weeksofonce-weeklyadministration.Atsteadystate,theconcentration-timeprofileshowedthatinsulinicodecexposurecoveredtheone-weekdosinginterval(Figure6-1).Theterminal half-lifeofinsulinicodecatsteadystatewasapproximately1week.Totalexposureandmaximumconcentrationincreasedproportionallywithincreasingdose.Thewithin-subjectvariabilityininsulinicodecexposurefromweektoweekatsteadystatewasfoundtobelow(Section6.2). Pharmacodynamicassessmentsdemonstratedthat,atsteadystate,theglucose-loweringeffectofinsulinicodeccoveredthefullweeklydosingintervalbothinT2DandT1D,withthegreatestglucoselowering-effectoccurringonDays2-4aftertheweeklyadministration(Figure6-2andFigure6-3).Theday-to-daydifferencesinglucose-loweringeffectover

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