Explore the vast range of titles available.

Background We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-β by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-β plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer’s disease (AD). Methods A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-β plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Results Sixty-seven of the 89 patients initially enrolled had ≥ 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-β plaque levels below the amyloid-β positivity threshold. Conclusion Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-β plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-β plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. Trial registration ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD).

Endogenously formed prostacyclin (PGI2) and synthetic PGI2 analogues have recently been shown to regulate cell survival in various cell lines. To elucidate the significance of PGI2 in human breast cancer, we performed immunohistochemistry to analyze expression of prostacyclin-synthase (PGIS) in 248 human breast cancer specimens obtained from surgical pathology files. We examined patients’ 10-year survival retrospectively by sending a questionnaire to their general practitioners and performed univariate analysis to determine whether PGIS expression correlated with patient survival. Lastly, the effects of PGI2 and its analogues on cell death were examined in a human breast cancer cell line (MCF-7) and a human T-cell leukemia cell line (CCRF-CEM). PGIS expression was observed in tumor cells in 48.7% of samples and was associated with a statistically significant reduction in 10-year survival (P=0.038; n=193). Transient transfection of PGIS into MCF-7 cells exposed to sulindac increased cell viability by 50% and exposure to carbaprostacyclin protected against sulindac sulfone induced apoptosis in CCRF-CEM cells. Expression of PGIS is correlated with a reduced patient survival and protects against cell death in vitro, suggesting that PGIS is a potential therapeutic target in breast cancer.

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Amyloid plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab. The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure 11C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with ClinicalTrials.gov. Of 74 participants who were recruited into the OLE study between June 3, 2020, and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons; 13 people completed 3 years of treatment. The mITT group for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0·79 (n=53 [95% CI 0·47 to 1·32]) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0·53 (n=22 [0·27 to 1·03]) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was –0·71 SUVR (95% CI –0·88 to –0·53, p<0·0001). Amyloid-related imaging abnormalities occurred in 53% (39 of 73) of participants: 47% (34 of 73) with microhaemorrhages, 30% (22 of 73) with oedema, and 6% (five of 73) were associated with superficial siderosis. No treatment-associated macrohaemorrhages or deaths occurred. Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Our conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long-term trials. National Institute on Aging, Alzheimer's Association, GHR Foundation, and F Hoffmann-La Roche/Genentech.

Background Anti‐amyloid monoclonal antibody therapies have successfully removed amyloid plaque as measured using imaging techniques. However, the characteristic fluid biomarker trajectories following plaque removal remains understudied, particularly during the preclinical phases of disease. We investigated biomarker trajectories in the context of the gantenerumab open label extension (OLE) of the Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN‐TU) secondary prevention trial (DIAN‐TU‐001) in Autosomal Dominant Alzheimer’s disease (ADAD) mutation carriers. Method Cerebrospinal fluid (CSF) amyloid beta 1‐42/40 (ABeta 42/40) ratio, total tau, phosphorylated Tau 217 (pTau217) and microtubule‐binding region of tau containing residue 243 (MTBR‐Tau243) were measured using Immuno‐Precipitation followed by Mass Spectrometry (IP‐MS) in all participants. Linear mixed‐effects models assessed temporal changes in biomarker levels. Correlations between biomarker measurements, clinical data, and imaging parameters were evaluated, considering estimated age at onset (EYO), and dosage. Result During both the DIAN‐TU‐001 double‐blind and OLE phases, we observed a significant increase in the CSF ABeta 42/40 ratio, notably among presymptomatic individuals. This change approached the levels considered to be healthy (11.58%), even in participants beyond their EYO. In addition, CSF pTau 217 levels declined in the participants treated with gantenerumab compared to the placebo group during the double blind and OLE phases in both asymptomatic and symptomatic groups. Higher doses were associated with faster rates of change for both biomarkers. A significant decrease in total tau was observed across treatment groups (gantenerumab and placebo) during the OLE phase. No changes were observed for MTBR243. Conclusion Treatment with amyloid‐removing therapy induced changes in biomarker measurements consistent with a healthier state. Improvement in biomarker levels in individuals receiving treatment prior to their EYO supports the potential of early amyloid‐removal therapy to mitigate the risk of progression. Importantly, the rate of biomarker change was directly proportional to dosage, suggesting potential dose‐dependent benefits. Additional trials are warranted to elucidate the progression of both biomarkers and clinical symptoms after effective brain amyloid removal.

Background Amyloid‐plaque removal by monoclonal antibody therapies slows progression in symptomatic Alzheimer’s disease (AD), but effects on preventing the onset of symptoms and dementia in asymptomatic people with amyloid plaques are unknown. We report the final primary and secondary outcomes of the Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) trial to evaluate amyloid‐plaque removal in delaying disease progression, including symptom onset, in symptomatic and asymptomatic dominantly inherited Alzheimer’s disease (DIAD) individuals treated for up to a decade. Method This double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg subcutaneous q2 weeks [NCT01760005]. The primary outcome was assessed for time to symptom onset and progression with the Cox proportional hazards model, comparing the treatment cohort to controls (double‐blind placebo participants who didn’t enter OLE, plus external controls). Estimated years to symptom onset (EYO) was included as a covariate and the average year of symptom onset relative to EYO was calculated. Other clinical and cognitive measures will be reported per the statistical analysis plan. Result In asymptomatic participants at baseline treated with gantenerumab (n = 53), the overall HR (95% CI) was 1.00 (0.47, 2.14) for time to first Clinical Dementia Rating (CDR) global progression, and 0.76 (0.45, 1.29) for recurrent CDR‐Sum of Boxes (CDR‐SB) progression. In the longest‐treated group (n = 22, average 8 years), the HR (95% CI) was 0.50 (0.17, 1.47) for CDR global and 0.50 (0.25, 0.99) for CDR‐SB. The average age of dementia symptom onset for the longest gantenerumab exposure was 3 to 6 years later when compared to placebo or external controls. Conclusion While no clinical effect was observed in the total group, results suggest potential delayed symptom onset and 50% dementia progression reduction in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab treatment. Exploratory evaluation indicates that years of dementia free survival may be achieved with prevention. However, this analysis included a small cohort in an OLE with external controls, limiting conclusions. Ongoing follow‐up of this cohort will continue to inform future prevention trial designs and these results may represent the first clinical evidence of AD prevention with amyloid removal.

Background Amyloid‐related Imaging Abnormalities (ARIA) are side effects of beta‐amyloid plaque‐lowering monoclonal antibody drugs (APLmAbs). Understanding of ARIA mechanisms, risks, nature, evolution and optimal approaches to mitigation and management remains incomplete. Sporadic Alzheimer’s Disease (AD) trials support ARIA risk factors including higher APLmAb doses/exposures, ApoE4‐carrier status, and presence/severity of microhemorrhages (MCH)/superficial siderosis. ARIA can present and evolve across a wide spectrum of radiographic and clinical profiles and be mitigated through patient selection, clinical/MRI surveillance/detection, monitoring and management practices. Through atypical cases selected from participants with dominantly‐inherited AD (Cognitively unimpaired/CU or MCI stages) treated with an APLmAb, insights are shared into unusual manifestations or high‐risk ARIA (e.g. multiple recurrences, multifocal or radiologically severe) and approaches to participant‐centered shared decision‐making and individualized management. Method Clinical and imaging course, management and insights from 5 selected cases with unusual profiles or high‐risk ARIA‐E (± ARIA‐H) from the DIAN‐TU Gantenerumab Open‐label trial will be presented. Result Case#1: “Recurrent ARIA‐E over 6 years” with 6 asymptomatic unifocal/multifocal ARIA‐E events over six‐years in CU participant (CDR 0.0, MMSE 29, Expected‐Year‐of‐Onset AD symptoms [EYO]+2.5 years, e4‐heterozygous). Case#2: “Recurrent ARIA‐E with accumulating +32 MCHs” in participant with MCI (CDR 0.5, MMSE 28, EYO+6 years, e4‐heterozygous) treated with oral steroids. Case#3 and Case#4: “Late‐Onset” ARIA‐E with development of ARIA‐E late in the course of treatment with high‐dose gantenerumab (e.g. years into treatment initiation/titration and tolerance of 1500mg Q2W for >6 months) in two CU participants (CDR 0.0, MMSE 30, ∼EYO‐6 years) with no previous history of ARIA‐E. Case#3 (e4‐heterozygous) developed unifocal (13mm) asymptomatic ARIA‐E, continued on treatment with resolution of ARIA‐E. Case#4 (e4‐non‐carrier) developed radiographically severe multifocal and multilobar, mildly symptomatic ARIA‐E (+1 ARIA‐H superficial siderosis); gantenrumab was held but ARIA increased, and then resolved after IV pulse‐steroids with oral taper. Case#5 “Recurrent ARIA‐E in same area in CU participant with EYO+10 years (CDR 0.0, MMSE 29, e4‐heterozygous). Conclusion These illustrative cases may provide insights into unusual profiles (e.g. Late‐onset/“delayed” or CU with +EYO) or high‐risk ARIA‐E and suggest potential approaches and considerations for clinicians and trialists to individualize APLmAb treatment and ARIA detection, monitoring and management.

Background Anti‐amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN‐TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study. Method This double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005]. We report long‐term amyloid‐plaque removal by PET and findings for metabolic FDG PET and tau PET, and additionally changes of atrophy on volumetric MRI. Imaging measures were secondary outcome analyses. Comparison is made between the treatment cohort and controls (DB placebo participants who didn’t enter OLE, plus external controls from the DIAN OBS). Estimated years to onset was included as a covariate. The gap period of ∼1 year is specifically analyzed to estimate any “rebound” effect on amyloid or tau accumulation or neurodegeneration. Volumetric MRI measures include hippocampal volumes, lateral ventricular volumes, and white matter hyperintensities. Result In participants who were asymptomatic at baseline and treated with gantenerumab (n = 53), amyloid‐plaque removal measured by PIB‐PET in Centiloids was dose‐dependent. Few participants had reached completely negative levels (below 24). No statistical significance was found for FDG PET, tau PET, or volumetric MRI, including hippocampal volumes. Impact of the gap period of ∼1 year (gap in treatment) on the rate of amyloid accumulation compared to the rate of accumulation predicted in observational studies of this cohort is under evaluation, as are the other imaging measures. Conclusion While no overall effect was observed in the total group for non‐amyloid measures, results suggest dose dependent clearance of amyloid plaque in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab. The potential “rebound effect” of elevated amyloid accumulation for participants for whom there was a significant gap in therapy between the trial and the OLE is under evaluation and will be presented, as will the variables for FDG PET, tau PET, and volumetric MRI.

Gantenerumab is a fully human anti-amyloid beta (Aβ) monoclonal immunoglobulin G1 antibody in devel- opment for the treatment of Alzheimer’s disease (AD). Two ongoing multicentre, randomised, double-blind, placebo-controlled, Phase III studies, GRADUATE I (NCT03444870) and GRADUATE II (NCT03443973), are assessing the efficacy and safety of subcutaneous gantenerumab in early AD for 27 months.Eligible participants had prodromal AD or probable AD dementia; demonstrated abnormal memory using the Free and Cued Selective Recall Test; met criteria for the Mini-Mental State Examination (≥22) and Clinical Dementia Rating – Global Score (0.5-1); and had confirmed Aβ pathology. Participants were randomised 1:1 to receive subcutaneous gantenerumab or placebo, administered at study site or via home nursing. The study drug is titrated in three up-titration steps (120 mg, 225 mg, 510 mg monthly) over 9-months to the target 1,020 mg monthly dosage. All participants receive the same titration and target dose, regardless of apolipoprotein E β4 status.The GRADUATE primary endpoint is change from baseline to Week 116 in Clinical Dementia Rating scale – Sum of Boxes. Secondary efficacy measures, fluid and imaging biomarkers, and safety are also being assessed.Recruitment is complete. Participants were enrolled from 32 countries across 5 continents. Detailed baseline characteristics will be presented.

Background We previously investigated low doses (105 or 225 mg) of gantenerumab, a fully human monoclonal antibody that binds and removes aggregated amyloid-[beta] by Fc receptor-mediated phagocytosis, in the SCarlet RoAD (SR) and Marguerite RoAD (MR) phase 3 trials. Several lines of evidence suggested that higher doses may be necessary to achieve clinical efficacy. We therefore designed a positron emission tomography (PET) substudy to evaluate the effect of gantenerumab uptitrated to 1200 mg every 4 weeks on amyloid-[beta] plaques as measured using florbetapir PET in patients with prodromal to moderate Alzheimer's disease (AD). Methods A subset of patients enrolled in the SR and MR studies who subsequently entered the open-label extensions (OLEs) were included in this substudy. Patients were aged 50 to 90 years with a clinical diagnosis of probable prodromal to moderate AD and were included based on a visual read of the original screening scan in the double-blind phase. Patients were assigned to 1 of 5 titration schedules (ranging from 2 to 10 months) with a target gantenerumab dose of 1200 mg every 4 weeks. The main endpoint of this substudy was change in amyloid-[beta] plaque burden from OLE baseline to week 52 and week 104, assessed using florbetapir PET. Florbetapir global cortical signal was calculated using a prespecified standard uptake value ratio method converted to the Centiloid scale. Results Sixty-seven of the 89 patients initially enrolled had [greater than or equai to] 1 follow-up scan by August 15, 2018. Mean amyloid levels were reduced by 39 Centiloids by the first year and 59 Centiloids by year 2, a 3.5-times greater reduction than was seen after 2 years at 225 mg in SR. At years 1 and 2, 37% and 51% of patients, respectively, had amyloid-[beta] plaque levels below the amyloid-[beta] positivity threshold. Conclusion Results from this exploratory interim analysis of the PET substudy suggest that gantenerumab doses up to 1200 mg resulted in robust amyloid-[beta] plaque removal at 2 years. PET amyloid levels were consistent with sparse-to-no neuritic amyloid-[beta] plaques in 51% of patients after 2 years of therapy. Amyloid reductions were similar to those observed in other placebo-controlled studies that have suggested potential clinical benefit. Trial registration ClinicalTrials.gov, NCT01224106 (SCarlet RoAD) and NCT02051608 (Marguerite RoAD). Keywords: Alzheimer's disease, Amyloid-[beta] plaque, Centiloid, Disease-modification therapies, Gantenerumab, Florbetapir, Open-label extension, Positron emission tomography