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Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18‐month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified. [ABSTRACT FROM AUTHOR]

Background: Clinical trials are essential for testing safety and efficacy of potential treatments for Alzheimer's disease (AD), but recruitment is often difficult due to a variety of factors. Recruitment tactics in AD clinical trials may include media advertising, physician referrals, patient registries, and referral campaigns. Newer strategies such as social media and community outreach have also been successful in increasing recruitment. However, not all recruitment tactics are successful for every study site and a multi‐faceted approach tailored to each site may be more successful. Method: INTERCEPT‐AD is a phase 1 randomized, double‐blind study of ACU193 in mild cognitive impairment or mild dementia due to AD. Seventeen study sites in the U.S. screened potential participants identified through multiple recruitment tactics which were grouped post hoc into seven categories: site database, external referral, physician referral, site campaign, and three sponsor‐initiated campaigns. Recruitment efforts were tailored to each site's patient population, community, and staff availability. Result: INTERCEPT‐AD screened 260 participants and 70 were eligible for study participation. Recruitment was completed in January 2023. The sponsor worked directly with individual sites to develop a tailored recruitment plan that considered each site's target population, historically successful recruitment tactics, and current ability to screen patients from outside sources. Comparisons of the seven types of recruitment sources showed site databases were used most frequently (12/17 sites, 71%) and accounted for the most screenings and eligible participants (107 [41%] and 32 [46%], respectively). Additional data from all recruitment sources and success rates will be presented. Conclusion: Study sites found success using a combination of tactics specifically tailored to their enrollment goals. Sites with robust internal patient databases had higher rates of screening and enrollment. A combination of site‐led and sponsor‐driven recruitment initiatives likely maximized enrollment rates. These findings suggest a strategy using diverse recruitment tactics customized to a study site's capabilities and patient population may be more successful than a one‐size‐fits‐all approach. [ABSTRACT FROM AUTHOR]

Background: PET tracers enable the in‐vivo measurement of amyloid in the brain and have been incorporated in eligibility criteria for clinical trials. Automated quantitative image analysis enables the calculation of a standardised uptake value ratio (SUVr) which can enable a rapid amyloid classification without requiring a visual read. However, quantitative analysis may have an equivocal range where amyloid classification does require a visual read. The range of SUVrs that is equivocal is not well understood. Method: Participants in the INTERCEPT‐AD trial of ACU193 (Siemers et al., J Prev Alzheimers Dis. 2023;10(1):19‐24) underwent an amyloid [18F] Florbetapir PET scan and T1‐weighted MRI scans. MRIs were segmented using the LEAP algorithm (Wolz et al., NeuroImage. 2010;49(2):1316‐1325), registered to the PET image, and the global cortical average (GCA) SUVr based on brain regions typically with high amyloid load in Alzheimer's disease (Klunk et al., Alzheimers Dement. 2015;11(1):1‐15) was calculated, using the whole cerebellum as the reference region. SUVrs greater than 1.2 were classified as amyloid positive, SUVrs less than 1.0 were classified as amyloid negative, and SUVrs in the equivocal range were assessed by visual read by trained central radiologists. Results: Of 194 participants who underwent screening, 188 had an SUVr available from automated analysis. Of these, 64 were within the equivocal range (SUVr 1.0 – 1.2) and had a visual read performed. For PET scans in the equivocal range, 53 (83%) were classified as amyloid negative and 11 (17%) were classified as amyloid positive by visual read. Within the equivocal range, there was no difference in SUVrs between the images classified by visual read as amyloid negative or positive. Conclusion: SUVrs may be used as an objective quantitative amyloid classification method at values > 1.2 for trial inclusion; however, in the equivocal range, the GCA SUVr did not correspond with amyloid classification based on a visual read. Further study is required to investigate the equivocal range and the use of combined quantitative measures and visual reads. [ABSTRACT FROM AUTHOR]

Background: ACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer's disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD. Method: INTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers. Result: Sixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented. Conclusion: We will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder affecting approximately 40 million people worldwide. There are few treatments available that affect the underlying degenerative process, making AD one of the largest unmet medical needs. ACU193 is a humanized, IgG2 subclass monoclonal antibody that targets soluble amyloid beta oligomers (sAβOs). Evidence supports the view that sAβOs are one of the primary instigators of AD neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 may be a promising approach for the treatment of AD. Method: INTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐dose study investigating the safety, tolerability, and pharmacokinetics of intravenous ACU193 in mild cognitive impairment or mild dementia due to AD. The SAD portion includes four cohorts with 2 mg/kg, 10 mg/kg, 25 mg/kg, and 60 mg/kg ACU193 or placebo. The MAD portion includes three cohorts receiving three doses of ACU193 or placebo: 10 mg/kg once every four weeks (Q4W), 60 mg/kg Q4W and 25 mg/kg once every 2 weeks (Q2W). Key inclusion criteria are 55‐90 years of age, PET scan positive for brain amyloid, MMSE 18‐30 and CDR‐Global score 0.5 or 1.0. The INTERCEPT‐AD trial is fully enrolled. Result: At 17 sites in the U.S., 260 participants were screened, 65 were randomized, and 62 received at least one dose of ACU193 or placebo, including 33 females (53%) and 29 males (47%). Negative PET (61%) was the most common reason for screen failure. Baseline age was 72.1 ± 7.8 years (mean ± SD), CDR Sum of Boxes score was 3.5 ± 1.8, ADAS‐Cog‐13 was 24.2 ± 9.0 and screening MMSE was 24.2 ± 3.6. ApoE e4 homozygotes accounted for 13% of the study population and ApoE e4 heterozygotes for 46.7%. Traditionally underrepresented ethnoracial populations comprised 23% of the study (5% Black/African American, 16% Hispanic/Latino, 2% Other). Additional baseline measures including demographics, clinical characteristics, AD medication, and imaging data will be presented. Conclusion: We describe key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. Data generated from this trial will guide further development of ACU193 for the treatment of early AD. [ABSTRACT FROM AUTHOR]

Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population. [ABSTRACT FROM AUTHOR]

Background: Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin B1 and plexin B2 receptors. SEMA4D is upregulated in neurons and oligodendrocytes in response to stress and triggers inflammatory activation of plexin B1/B2 positive astrocytes with concomitant loss of some normal astrocyte functions. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington's disease (HD) and Alzheimer's disease (AD). SIGNAL‐HD is a double‐blind, placebo‐controlled study of pepinemab in HD. Given previous studies of fluorodeoxyglucose (FDG) positron emission tomography (PET) loss in HD and the mechanism of action of pepinemab, FDG‐PET imaging was included in the SIGNAL‐HD study. Method: Transgenic mouse models for HD (Q175) and AD (CVN) as well as human pathological tissue was used for immunohistochemistry. The SIGNAL‐HD study includes participants with late prodromal and early manifest HD. Results from 36 subjects in Cohort A informed group size and treatment duration in Cohort B. A subset of participants in Cohort A underwent PET scanning using FDG at baseline, at the end of the 6‐month placebo‐controlled period and at 12 months at the end of the open‐label treatment period. Result: SEMA4D was upregulated and astrocyte activation was present for HD and AD based on samples from transgenic models and staged patient autopsy samples. SIGNAL‐HD Cohort A (n=36) has been completed and Cohort B (n=265) is fully enrolled. For participants in Cohort A undergoing FDG‐PET imaging (n=19), those in the pepinemab group showed increases in FDG uptake compared to baseline (median 8.6%, range: 0.5‐20.4%) while participants taking placebo showed the expected decrease after 6 months. Nominal statistical significance (p<0.05) pepinemab compared to placebo was achieved for 11/14 frontal and parietal brain regions. Conclusion: Transgenic mouse models and human neuropathological analyses are consistent with an upregulation of SEMA4D in HD and AD. The increase in FDG‐PET signal in SIGNAL‐HD Cohort A suggests central target engagement and improvement in brain metabolic activity. SIGNAL‐AD, a randomized, placebo‐controlled, phase 1b/2 study of pepinemab in early AD, will also incorporate FDG‐PET and is planned to begin mid‐2020. [ABSTRACT FROM AUTHOR]

Abstract: Drug discovery has traditionally been almost exclusively the purview of pharmaceutical and biotechnology companies, whereas universities have focused on basic research. However, given the challenges involved in discovering and developing truly effective, symptomatic treatments and disease-modifying drugs for Alzheimer’s disease, there is a need to reassess this simple division of labor. Whereas each sector is likely to retain a core interest and expertise at either end of the drug discovery spectrum, there is room for closer cooperation at the intersection of the for-profit and not-for-profit sectors. The Alzheimer’s Association Research Roundtable convened a meeting of senior industry researchers and academic investigators to discuss this intersection and to assess the opportunity for closer partnership on Alzheimer’s disease drug discovery and development. [Copyright &y& Elsevier]