Donanemab in Early Symptomatic Alzheimer Disease
Authors: Sims John R. , Zimmer Jennifer A. , Evans Cynthia D. , Lu Ming , Ardayfio Paul , Sparks JonDavid , Wessels Alette M. , Shcherbinin Sergey , Wang Hong , Monkul Nery Emel Serap , Collins Emily C. , Solomon Paul , Salloway Stephen , Apostolova Liana G. , Hansson Oskar , Ritchie Craig , Brooks Dawn A. , Mintun Mark , Skovronsky Daniel M. ,   TRAILBLAZER-ALZ 2 Investigators, Abreu Rafael , Agarwal Pinky , Aggarwal Puja , Agronin Marc , Allen Alison , Altamirano Dario , Alva Gustavo , Andersen James , Anderson Allan , Anderson Donald , Arnold Jennifer , Asada Takashi , Aso Yasuhiro , Atit Vikram , Ayala Ricardo , Badruddoja Michael , Badzio-jagiello Hanna , Bajacek Michal , Barton David , Bear David , Benjamin Sabrina , Bergeron Richard , Bhatia Perminder , Black Sandra , Block Allan , Bolouri Mohammad , Bond Wendy , Bouthillier Jean , Brangman Sharon , Brew Bruce , Brisbin Sarah , Brisken Toby , Brodtmann Amy , Brody Mark , Brosch Jared , Brown Celia , Brownstone Paul , Bukowczan Sylwia , Burns Jeffrey , Cabrera Alicia , Capote Horace , Carrasco Angel , Cevallos Yepez Jose , Chavez Eric , Chertkow Howard , Chyrchel-paszkiewicz Urszula , Ciabarra Anthony , Clemmons Edward , Cohen Daniel , Cohen Robert , Cohen Ian , Concha Mauricio , Costell Brian , Crimmins Denis , Cruz-pagan Yvette , Cueli Adolfo , Cupelo Robert , Czarnecki Maciej , Darby David , Dautzenberg P.l.j. , De Deyn Peter , De La Gandara Jose , Deck Kenneth , Dibenedetto David , Dibuono Mark , Dinnerstein Eric , Dirican Ahmet , Dixit Shanker , Dobryniewski Jacek , Drake Ryan , Drysdale Peter , Duara Ranjan , Duffy John , Ellenbogen Aaron , Faradji Victor , Feinberg Marc , Feldman Robert , Fishman Simon , Flitman Stephen , Forchetti Concetta , Fraga Ivonne , Frank Andrew , Frishberg Benjamin , Fujigasaki Hiroto , Fukase Hiroyuki , Fumero Ileana , Furihata Kenichi , Galloway Christopher , Gandhi Rekha , George Kristi , Germain Marcel , Gitelman Darren , Goetsch Nicholas , Goldfarb Danielle , Goldstein Mark , Goldstick Lawrence , Gonzalez Rojas Yaneicy , Goodman Ira , Greeley David , Griffin Carl , Grigsby Eric , Grosz Daniel , Hafner Karl , Hart David , Henein Sam , Herskowitz Brad , Higashi Shinji , Higashi Yasuto , Ho Gilbert , Hodgson Jonathan , Hohenberg Mark , Hollenbeck Larry , Holub Richard , Hori Tomokatsu , Hort Jakub , Ilkowski Jan , Ingram K. Jennifer , Isaac Mitchell , Ishikawa Mitsunori , Janu Lubos , Johnston Mark , Julio William , Justiz William , Kaga Tomotsugu , Kakigi Tatsuya , Kalafer Marvin , Kamijo Mikiko , Kaplan Jeffrey , Karathanos Michael , Katayama Sadao , Kaul Siddharth , Keegan Andrew , Kerwin Diana , Khan Uzma , Khan Arifulla , Kimura Noriyuki , Kirk Gregory , Klodowska Gabriela , Kowa Hisatomo , Kutz Christen , Kwentus Joseph , Lai Rosalyn , Lall Ayesha , Lawrence Mary , Lee Elly , Leon Ramon , Linker Gary , Lisewski Pawel , Liss Jonathan , Liu Collins , Losk Scott , Lukaszyk Ewelina , Lynch Jennifer , Macfarlane Stephen , Macsweeney Josephine , Mannering Nicholas , Markovic Oto , Marks Donald , Masdeu Joseph , Matsui Yutaka , Matsuishi Kunitaka , Mcallister Peter , Mcconnehey Brock , Mcelveen Alvin , Mcgill Lora , Mecca Adam , Mega Michael , Mensah Jason , Mickielewicz Anatol , Minaeian Artin , Mocherla Bharat , Murphy Cynthia , Murphy Paul , Nagashima Hirotaka , Nair Anil , Nair Malini , Nardandrea John , Nash Marshall , Nasreddine Ziad , Nishida Yoshihiko , Norton Jeffrey , Nunez Lazaro , Ochiai Jun , Ohkubo Takuya , Okamura Yasuyuki , Okorie Eugene , Olivera Esteban , O'mahony John , Omidvar Omid , Ortiz-Cruz Desiree , Osowa Alexander , Papka Michelle , Parker Alicia , Patel Paayal , Patel Ashok , Patel Meenakshi , Patry Claude , Peckham Elizabeth , Pfeffer Michael , Pietras Alison , Plopper Michael , Porsteinsson Anton , Poulin Robitaille Raphael , Prins Niels , Puente Orlando , Ratajczak Marcin , Rhee Margaret , Ritter Angela , Rodriguez Ramon , Rodriguez Ables Lilia , Rojas Julio , Ross Jeffrey , Royer Paule , Rubin Jay , Russell David , Rutgers Sterre Malou , Rutrick Stephanie , Sadowski Martin , Safirstein Beth , Sagisaka Takafumi , Scharre Douglas , Schneider Lon , Schreiber Curtis , Schrift Michael , Schulz Paul , Schwartz Harvey , Schwartzbard Julie , Scott John , Selem Lissette , Sethi Pramod , Sha Sharon , Sharlin Kenneth , Sharma Sanjiv , Shiovitz Thomas , Shiwach Rajinder , Sladek Martin , Sloan Bart , Smith Amanda , Solomon Paul , Sorial Ehab , Sosa Evelio , Stedman Mary , Steen Susan , Stein Lee , Stolyar Arkadiy , Stoukides John , Sudoh Shinji , Sutton James , Syed Junaid , Szigeti Kinga , Tachibana Hisatsugu , Takahashi Yuichi , Tateno Amane , Taylor James Dale , Taylor Kelly , Tcheremissine Oleg , Thebaud Adly , Thein Stephen , Thurman Louise , Toenjes Steven , Toji Hiromasa , Toma Misaki , Tran Duc , Trueba Pilar , Tsujimoto Masashi , Turner Raymond , Uchiyama Akiyoshi , Ussorowska Dorota , Vaishnavi Sanjeev , Valor Elena , Vandersluis Joel , Vasquez Alberto , Velez Juan , Verghese Cherian , Vodickova-borzova Klaudia , Watson David , Weidman David , Weisman David , White Alexander , Willingham Katherine , Winkel Izabela , Winner Paul , Winston Jaron , Wolff Adam , Yagi Hideo , Yamamoto Hideki , Yathiraj Sanjay , Yoshiyama Yasumasa , Zboch Marzena 
Published: July 2023

Importance

There are limited efficacious treatments for Alzheimer disease.

Objective

To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.

Design, Setting, and Participants

Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).

Interventions

Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.

Main Outcomes and Measures

The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.

Results

Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P &amp;lt; .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P &amp;lt; .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P &amp;lt; .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P &amp;lt; .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.

Conclusions and Relevance

Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.

Trial Registration

ClinicalTrials.gov Identifier: NCT04437511