“Real world” eligibility for aducanumab

On June 7, 2021, the U.S. Food and Drug Administration (FDA) approved aducanumab, an amyloid beta-directed monoclonal antibody, as a new treatment for Alzheimer's disease (AD),1 taking advantage of Accelerated Approval program. The aducanumab effect on beta plaques2 was deemed to predict benefits patients and, thus, considered approvable surrogate endpoint. Nevertheless, there are residual uncertainties concerning clinical effectiveness drug3-5 that has be confirmed via post-approval phase 4 studies. As often happening in design randomized controlled trials (RCTs), relatively rigid eligibility criteria were adopted EMERGE [NCT02484547] ENGAGE [NCT02477800] 3 studies render more homogeneous sampled populations. choice aimed at reducing established biological heterogeneity target conditions (i.e., mild cognitive impairment [MCI] AD dementia) reduce safety/tolerability concerns. At same time, stringent may result recruitment who not adequately representative overall population, consequently generalizability findings.6 A poor external validity already documented leading approval pharmacological compounds currently marketed symptomatic AD.7, 8 To identify proportion would potentially eligible receive “real world”, we systematically applied pre-approval research protocols population referring geriatric outpatient unit tertiary university hospital Milan (Italy). total 911 consecutively attending complaints considered. Patients underwent comprehensive assessment, including neuropsychological evaluation, frailty assessment (using 40-item Frailty Index [FI]), routine blood tests, neuroimaging, part standard care. In addition, minority these 11.4%) lumbar puncture measure cerebrospinal fluid (CSF) biomarkers Aβ1–42, total-tau, phospho-tau). diagnoses MCI, dementia, non-AD dementias formulated according current international diagnostic criteria. local Ethics Committee authorized data collection use registry. Written informed consent obtained from (or proxies appropriate). inclusion exclusion retrieved information registered clinicaltrials.org database. These then operationalized our database sequentially test their potential aducanumab. About half (n = 423) resulted ineligible due age >85, <6 years education, absence formal caregiver (Figure 1). Another relevant 389) excluded because meeting prespecified (e.g., diagnosis Mini-Mental State Examination score <24, and/or evident functional impairment). Most remaining subjects 99) probably selected they frail FI >0.25,9 thus “good health” required), presenting major laboratory abnormality, underweight/obesity, or significant brain vascular neuroimaging. Finally, given nearly one-third with MCI did exhibit CSF positive status Aß1–42 < 600 pg/ml10), assumed three additional possibly negative amyloid-beta measurement. Thus, only six 0.66%) study candidates Our findings should cautiously interpreted since derived single center experience by adapting routinely collected activities. Moreover, analyses those clinicaltrial.gov. We cannot sure some modifications have been used conduction no article yet published peer-reviewed journal. results suggest marginal disorders “real-world” services benefit low This observation, together unanswered questions efficacy cost-effectiveness,11, 12 before planning any reorganization redistribution care resources. this context, final indications provided FDA will critical. original version prescribing (marketed Aduhelm), limit its cases but included all stages.13 different RCTs, criterion based age, concomitant diseases, therapies mentioned. revised indication, limited dementia.14 If registry, two make 392 43.0%) 311 34.1%) patients, respectively. other words, determine 65-fold 52-fold increase number compared what designed trials. It is clear how resulting gap between world” fields massive, exemplifying once again “evidence-based medicine issue” challenging decisions care.7 Authors competing interest disclose present study. Marco Canevelli supported grant Italian Ministry Health (GR-2016-02364975) project “Dementia immigrants ethnic minorities living Italy: clinical-epidemiological aspects public health perspectives” (ImmiDem). Matteo Cesari received honoraria presentations scientific meetings funding Nestlé Pfizer. He involved coordination Innovative Medicines Initiative-funded (including partners European Federation Pharmaceutical Industries Associates [Sanofi, Novartis, Servier, GSK, Lilly]). Canevelli: conception design, writing manuscript. Paolo Dionigi Rossi: collection, interpretation data, drafting Astrone: collection. Ernesto Consorti: Nicola Vanacore: Cesari: conception, None.