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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.).

In two phase 3 placebo-controlled, randomized trials in 1012 and 1040 patients with mild-to-moderate Alzheimer's disease, solanezumab, a humanized monoclonal antibody that preferentially binds soluble forms of amyloid, did not improve cognition or functional status. Alzheimer's disease is associated with the accumulation of aggregated amyloid-beta (Aβ) peptide in the cerebral cortex and hippocampus. One approach to reducing brain amyloid involves increasing the clearance of Aβ by means of prolonged treatment with monoclonal antibodies directed against this peptide. In preclinical studies, a murine antibody that targeted the central domain of Aβ and was selective for soluble forms slowed Aβ deposition in a transgenic mouse model 1 ; in another transgenic murine model, Aβ–antibody complexes were present in the cerebrospinal fluid (CSF) and plasma, and behavioral deficits were reversed without a decrease in amyloid plaques, as assessed by . . .

In this placebo-controlled trial, the γ-secretase inhibitor semagacestat did not improve cognitive status in patients with Alzheimer's disease and was associated with more adverse events than placebo, including skin cancers and infections. Alzheimer's disease begins decades before the appearance of clinical symptoms, with the deposition of aggregated amyloid-beta (Aβ) peptide plaques in the cortex and hippocampus. This protein is cleaved from the amyloid precursor protein (APP) by the sequential action of β- and γ-secretases, producing fragments that include Aβ1-40 and Aβ1-42. Since the accumulation of aggregated Aβ is associated with disease progression, both β-secretase and γ-secretase represent potential therapeutic targets. Multiple small molecules can inhibit γ-secretase in vitro, 1 – 4 but Notch and other transmembrane proteins are also substrates for γ-secretase, 1 – 4 and studies have raised concern that the inhibition of γ-secretase could . . .

Background This review describes the research and development process of gantenerumab, a fully human anti-amyloid monoclonal antibody in development to treat early symptomatic and asymptomatic Alzheimer’s disease (AD). Anti-amyloid monoclonal antibodies can substantially reverse amyloid plaque pathology and may modify the course of the disease by slowing or stopping its clinical progression. Several molecules targeting amyloid have failed in clinical development due to drug-related factors (e.g., treatment-limiting adverse events, low potency, poor brain penetration), study design/methodological issues (e.g., disease stage, lack of AD pathology confirmation), and other factors. The US Food and Drug Administration’s approval of aducanumab, an anti-amyloid monoclonal antibody as the first potential disease-modifying therapy for AD, signaled the value of more than 20 years of drug development, adding to the available therapies the first nominal success since cholinesterase inhibitors and memantine were approved. Body Here, we review over 2 decades of gantenerumab development in the context of scientific discoveries in the broader AD field. Key learnings from the field were incorporated into the gantenerumab phase 3 program, including confirmed amyloid positivity as an entry criterion, an enriched clinical trial population to ensure measurable clinical decline, data-driven exposure-response models to inform a safe and efficacious dosing regimen, and the use of several blood-based biomarkers. Subcutaneous formulation for more pragmatic implementation was prioritized as a key feature from the beginning of the gantenerumab development program. Conclusion The results from the gantenerumab phase 3 programs are expected by the end of 2022 and will add critical information to the collective knowledge on the search for effective AD treatments.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson’s disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab’s potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic–rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson’s disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings. An exploratory analysis of the 1-year clinical trial PASADENA in individuals with early-stage Parkinson’s disease suggests that prasinezumab might reduce motor signs progression to a greater extent in those with more rapidly progressing disease.

Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10–24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference −4·0 [95% CI −5·73 to −2·28]; p<0·0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference −1·9 [−2·92 to −0·85]; p=0·0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease. Medivation (USA).

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).

In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP. In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720. 313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (−0·20 [−0·20 to −0·17] vs −0·20 [−0·22 to −0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]). Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments. Allon Therapeutics.