Howard Feldman, MD, FRCPC, FAAN (Neurology)
Professor AdjunctAbout
Research
Overview
Medical Research Interests
Dementia; Information Science; Named Groups
Publications
2025
evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease
Cummings J, Atri A, Feldman H, Hansson O, Sano M, Knop F, Johannsen P, León T, Scheltens P. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alzheimer's Research & Therapy 2025, 17: 14. PMID: 39780249, PMCID: PMC11708093, DOI: 10.1186/s13195-024-01666-7.Peer-Reviewed Original ResearchConceptsSymptomatic ADAlzheimer's diseaseDouble-blindGlucagon-like peptide-1 receptor agonist semaglutidePlacebo-controlled phase 3 trialOnce-daily oral semaglutideClinical Dementia RatingMild cognitive impairmentAD-related processesAD biomarkersSafety of semaglutideDose-escalation regimenPhase 3 studyBaseline to weekEffect of semaglutidePhase 3 trialCognitive impairmentPathophysiology of Alzheimer's diseasePotential disease-modifying effectsDementia RatingSymptomatic Alzheimer's diseaseTreatment of type 2 diabetesPlacebo-controlledType 2 diabetesDisease-modifying potential
2024
Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease
Grill J, Tam S, Thai G, Vides B, Pierce A, Green K, Gillen D, Teng E, Kremen S, Beigi M, Rissman R, Léger G, Balasubramanian A, Revta C, Morrison R, Jennings R, Pa J, Zhang J, Jin S, Messer K, Feldman H. Phase 2A Proof-of-Concept Double-Blind, Randomized, Placebo-Controlled Trial of Nicotinamide in Early Alzheimer Disease. Neurology 2024, 104: e210152. PMID: 39671543, PMCID: PMC11655133, DOI: 10.1212/wnl.0000000000210152.Peer-Reviewed Original ResearchConceptsTau phosphorylationP-tau<sub>181</sub>Histone deacetylasesCDR-SBAlzheimer's diseaseCSF p-tauPrimary outcomeP-tauDiagnosis of mild cognitive impairmentAlzheimer's Disease Assessment ScaleAlzheimer's Disease Cooperative Study-ActivitiesClass III histone deacetylasePrespecified secondary outcomesCellular oxidation-reduction reactionsDisease Assessment ScaleLevels of tauAD biomarkersHolm-Bonferroni procedureMild cognitive impairmentControl type I errorThreonine 231Histone deacetylase inhibitionAcademic clinical centersAssessment ScaleAdverse eventsComparison of eligibility criteria and baseline characteristics between the patient populations of evoke and evoke+, Clarity AD, and TRAILBLAZER‐ALZ‐2
Feldman H, Scheltens P, Hansson O, Sano M, van der Flier W, Bardtrum L, Johannsen P, Jeppesen R, Leon T, Hansen C, Cummings J. Comparison of eligibility criteria and baseline characteristics between the patient populations of evoke and evoke+, Clarity AD, and TRAILBLAZER‐ALZ‐2. Alzheimer's & Dementia 2024, 20: e083684. PMCID: PMC11713343, DOI: 10.1002/alz.083684.Peer-Reviewed Original ResearchClinical Dementia RatingNon-white participantsPositron emission tomographyEarly-stage AD patientsAlzheimer's diseaseMini-Mental State ExaminationMild AD dementiaMild cognitive impairmentTau positron emission tomographyEpisodic memoryGlucagon-like peptide-1 receptor agonist semaglutidePlacebo-controlled trialInclusion criteriaTau pathologyCDR sumCognitive impairmentMini-MentalState ExaminationDementia RatingImpaired patientsAD patientsGlobal scoreAmyloid positivityTrial populationDisease-modifying therapiesReasons for screening failure in the evoke and evoke+ trials of semaglutide for early AD
Sano M, Cummings J, Feldman H, Hansson O, van der Flier W, Bardtrum L, Jeppesen R, Johannsen P, Léon T, Hansen C, Scheltens P. Reasons for screening failure in the evoke and evoke+ trials of semaglutide for early AD. Alzheimer's & Dementia 2024, 20: e088735. PMCID: PMC11713595, DOI: 10.1002/alz.088735.Peer-Reviewed Original ResearchMini-Mental State ExaminationAmyloid positivityStrategic infarctsMild AD dementiaRepeatable BatteryPsychiatric disordersCognitive Assessment scoreMild cognitive impairment due to ADInclusion of participantsCognitive impairment due to ADCognitive scoresMini-MentalState ExaminationCDR scoreNeurological disordersScreening failureDisordersEvidence of neurologic disordersAD dementiaScreening failure rateSmall vessel pathologyEvokedScoresCentral nervous systemHierarchical screening procedureRegional differences in baseline demographic and clinical characteristics from the evoke and evoke+ trials of semaglutide for early Alzheimer’s disease
van der Flier W, Scheltens P, Feldman H, Hansson O, Sano M, Bardtrum L, Johannsen P, Jeppesen R, Hansen C, Leon T, Cummings J. Regional differences in baseline demographic and clinical characteristics from the evoke and evoke+ trials of semaglutide for early Alzheimer’s disease. Alzheimer's & Dementia 2024, 20: e088793. PMCID: PMC11713752, DOI: 10.1002/alz.088793.Peer-Reviewed Original ResearchMini-Mental State Examination scoreBaseline dataCognitive scoresClinical Dementia Rating-SumAlzheimer's diseaseApolipoprotein E4 carrier statusClinical Dementia Rating-Sum of Boxes scoresInclusion of participantsMild cognitive impairmentScreening failure rateProportion of individualsMild dementiaGeographic regionsType 2 diabetesBox scoresAD medicationsClinical characteristicsInclusion criteriaCarrier statusNorth AmericaExamination scoresClinical trial populationsPatient characteristicsCognitive impairmentSmall vessel pathologyA Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods
Luchsinger J, Feldman H, Messer K, Edland S, Leger G, Jacobs D, Salmon D, Revta C, Lupo J, Durant J, Gibson G. A Seamless Phase 2A‐Phase 2B Multi‐Center Trial to Test the Benefits of Benfotiamine on the Progression of Alzheimer’s Disease‐Benfoteam: Design and Methods. Alzheimer's & Dementia 2024, 20: e091963. PMCID: PMC11714007, DOI: 10.1002/alz.091963.Peer-Reviewed Original ResearchPhase 2bDosing decisionsPerson-months of exposureLonger-term safetyWeeks of treatmentCo-primary endpointsClinically significant benefitBiomarker test resultsMulti-center trialTolerated doseDouble-blindEvaluate safetySmall molecule treatmentBlood levelsActive treatmentPhase 2aThiamine deficiencyPerson-monthsDoseCohen's d effect sizesPharmacological effectsTherapeutic directionsBenfotiamineGlucose metabolismMg/dayVaroglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Advances In Alzheimer's Disease 2024 DOI: 10.3233/aiad240007.Peer-Reviewed Original ResearchGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesPost hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer’s disease, positive for plasma p-tau217
Kovacech B, Cullen N, Novak P, Hanes J, Kontsekova E, Katina S, Parrak V, Fresser M, Vanbrabant J, Feldman H, Winblad B, Stoops E, Vanmechelen E, Zilka N. Post hoc analysis of ADAMANT, a phase 2 clinical trial of active tau immunotherapy with AADvac1 in patients with Alzheimer’s disease, positive for plasma p-tau217. Alzheimer's Research & Therapy 2024, 16: 254. PMID: 39580468, PMCID: PMC11585249, DOI: 10.1186/s13195-024-01620-7.Peer-Reviewed Original ResearchConceptsClinical Dementia Rating-Sum of BoxesPhase 2 clinical trialGlial fibrillary acidic proteinPost hoc analysisAlzheimer's diseaseAlzheimer's Disease Cooperative Study ActivitiesPlasma p-tau217Clinical Dementia Rating-SumClinical trialsWhole-brain volumeSpread of tau pathologyPlasma biomarkers of neurodegenerationPlasma P-tau217 levelsMicrotubule-binding regionSubgroup of participantsADAMS participantsTau pathologyAD-related neuropathological changesCognitive declineFibrillary acidic proteinActive immunotherapyDouble-blindPlacebo-controlledVolumetric MRITau immunotherapyVaroglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease
Feldman H, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner R, Lopez O, Smith A, Durant J, Lupo J, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs D, Salmon D, Léger G, DeMarco M, Weber F, Group F. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer’s Disease. Journal Of Alzheimer's Disease 2024, 101: s79-s93. PMID: 39422941, PMCID: PMC11494639, DOI: 10.3233/jad-231126.Peer-Reviewed Original ResearchConceptsGlutaminyl cyclasePost-translationallyAlzheimer's diseasePhase 2bEarly phase clinical trialsAmyloid-bCytokine monocyte chemoattractant protein-1Monocyte chemoattractant protein-1Highest tolerated doseLonger-term safetyPhase clinical trialsWeeks of treatmentFirst-in-classTarget of therapyUnique dual mechanismChemoattractant protein-1Interim futility analysisClinical efficacyDisease cascadeProtein 1Electroencephalogram changesOptimal doseClinical trialsAnalysis of cognitive functionHigh dosesA framework for translating tauopathy therapeutics: Drug discovery to clinical trials
Feldman H, Cummings J, Boxer A, Staffaroni A, Knopman D, Rizzo S, Territo P, Arnold S, Ballard C, Beher D, Boeve B, Dacks P, Diaz K, Ewen C, Fiske B, Gonzalez M, Harris G, Hoffman B, Martinez T, McDade E, Nisenbaum L, Palma J, Quintana M, Rabinovici G, Rohrer J, Rosen H, Troyer M, Kim D, Tanzi R, Zetterberg H, Ziogas N, May P, Rommel A. A framework for translating tauopathy therapeutics: Drug discovery to clinical trials. Alzheimer's & Dementia 2024, 20: 8129-8152. PMID: 39316411, PMCID: PMC11567863, DOI: 10.1002/alz.14250.Peer-Reviewed Original ResearchPrimary tauopathiesClinically heterogeneous neurodegenerative diseasesTau protein aggregationHeterogeneous neurodegenerative diseaseSurrogate disease biomarkersTauopathiesProtein aggregationDefinition of rare diseasesAlzheimer's diseaseNeurodegenerative diseasesClinical trialsEarly-phase clinical trialsEarly-phase trialsDisease biomarkersFrontotemporal degenerationDrug developmentProgressive supranuclear palsyDiscovery to clinical trialsSelection of targetsTherapeuticsPharmacodynamic biomarkers