Background

Solanezumab is a humanized monoclonal IgG1 antibody directed against the mid-domain of the Aβ peptide. It recognizes soluble monomeric, not fibrillar, Aβ. The therapeutic rationale is that it may exert benefit by sequestering Aβ, shifting equilibria between different species of Aβ, and removing small soluble species of Aβ that are directly toxic to synaptic function. In preclinical research, a single injection of m266, the mouse version of solanezumab, reversed memory deficits in APP-transgenic mouse models while leaving amyloid plaques in place, raising the prospect of targeting the soluble pool of Aβ (Apr 2002 news story).

Findings

In Phase 1, single doses of 0.5, 1.5, 4.0, or 10.0 mg/kg of solanezumab were well-tolerated in healthy volunteers and 19 patients with mild to moderate AD. MRI showed no evidence of inflammation, vasogenic edema, or microhemorrhage. A multiple-dose study in Japan delivered a 400 mg dose to 33 patients with mild to moderate AD intravenously every one, four, or eight weeks, also without serious adverse events related to solanezumab. Pharmacodynamic biomarker studies found changes in plasma and CSF Aβ40, Aβ42, plasma pyro-Glu Aβ, and plasma and CSF N-terminally truncated Aβ, but not CSF total tau and phosphorylated tau.

In Phase 2, trials administering 100 to 1,600 mg per month of solanezumab for 12 weeks, and monitoring for safety and biomarker effects for one year, confirmed the antibody's safety and tolerability. Phase 2 showed dose-dependent increases of various Aβ species in plasma and CSF but no effects on the ADAS-Cog, i.e., no indication of clinical benefit.

In Phase 3, two trials, EXPEDITION-1 and -2, randomized 2,052 people with mild to moderate AD to receive infusions of 400 mg of solanezumab or placebo once a month for 80 weeks. Data analysis was conducted by the study sponsor and independently by the Alzheimer Disease Study Group. Solanezumab continued to be safe, but EXPEDITION overall showed no improvement on the primary outcome measures of ADAS-Cog11 and ADCS-ADL. However, a prespecified subgroup analysis of the EXPEDITION-1 trial showed that solanezumab reduced cognitive decline in mild AD when measured by ADAS-Cog 14, prompting the FDA to approve revision of the primary endpoint of EXPEDITION-2 to a single endpoint of cognition in patients with mild AD before the trial database was locked. That analysis saw a trend to improved cognition with solanezumab in people with mild AD, but it missed statistical significance. Statistically significant benefit was seen in a pooled analysis of patients with mild AD in both trials. Benefit for instrumental activities of daily living also was seen in the mild subpopulation. The benefit appeared late, grew over time, and thus is thought to be consistent with a disease-modifying effect. The effect size of the benefit is small, generally thought to be smaller than that of cholinesterase-inhibitor drugs (Doody et al., 2014).

In July 2013, Lilly started EXPEDITION-3, a 39-center Phase 3 trial in 2,100 patients with mild AD and demonstrated brain amyloid burden. In March 2016, Lilly announced that it would change the primary outcome for this trial. The original plan registered with regulatory agencies was to use a cognitive (ADAS-Cog 14) and a functional (ADCS-iADL) battery as co-primary outcomes; however, the new plan is to use ADAS-Cog as a single primary and ADCS-iADL as a secondary outcome. According to the company, this changed the trial's data analysis but not the conduct of the trial itself (see company release). On November 23, 2016, Lilly announced, based on top-line results, that solanezumab had missed its primary endpoint in this trial. Primary and secondary outcome results were trending in the direction of a treatment benefit, but effects were small and fell short of statistical significance. Lilly will not pursue FDA approval for solanezumab in mild AD (see company release). Trial results have been published  (Honig et al., 2018; Schwarz et al., 2019).

Solanezumab's safety record and indication of a small benefit in mild AD prompted its selection for two secondary prevention studies. In 2012, the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) began conducting a five-year Phase 2/3 trial to test solanezumab and Roche's therapeutic antibody gantenerumab in 210 asymptomatic and very mildly symptomatic carriers of autosomal-dominant mutations in the Alzheimer's genes APP, presenilin-1, and presenilin-2. This study began as a two-year, Phase 2 biomarker study, and evolved into a Phase 3 registration trial with a cognitive endpoint measured after at least four years of treatment. Dosing began at 400 mg every four weeks, and was increased to 1,600 mg midway through the trial. 

On February 10, 2020, study investigators announced the trial had failed to meet its primary endpoint, showing no statistically significant treatment-related change on the DIAN Multivariate Cognitive Endpoint, a composite developed for this trial (Feb 2020 news). The study followed 194 participants for up to seven years; 50 received solanezumab, and 36 completed four years of treatment.

According to biomarker data presented at the 2020 AAT-AD/PD Focus Meeting, solanezumab treatment caused a steep increase in CSF Aβ42, indicating target engagement. Solanezumab did not alter tau biomarkers, and changed CSF neurofilament light concentrations for the worse. Participants in the trial were offered an open-label extension with high-dose gantenerumab, based on that antibody’s positive effects on imaging and other biomarkers in the DIAN-TU trial (Apr 2020 conference news). Peer-reviewed results were subsequently published (Jun 2021 news).

In February 2014, the Alzheimer's Disease Cooperative Study began a three-year trial testing solanezumab in 1,150 asymptomatic or very mildly symptomatic people 65 and older who have biomarker evidence of brain amyloid deposition, i.e., who meet a diagnosis of Phases 2 or 3 of preclinical AD as proposed by the 2011 NIA-AA diagnostic research criteria (Sperling et al., 2011). Called A4, this secondary prevention trial uses the cognitive battery ADCS-PACC, which was developed to be sensitive at earlier clinical stages (Donohue et al., 2014). Amid a controversial leadership change, oversight of this trial has moved from ADCS to the new Alzheimer's Therapy Research Institute at the University of Southern California. In June 2017, the study directors announced a quadrupling of the dose from 400 to 1,600 mg solanezumab or placebo given by IV every four weeks, based on results of the EXPEDITION program. Moreover, the A4s study length also increased to 4½ years. The trial will run until the end of 2022.

In December 2015, Lilly began evaluating a subcutaneous formulation of solanezumab in a Phase 1 trial of 130 people. The trial was stopped in January 2017.

In June 2016, Lilly began a Phase 3 study in prodromal AD. Called ExpeditionPRO. It was to enroll 2,450 people with a clinical diagnosis of prodromal AD per IWG criteria, or of MCI due to AD per NAI-AA criteria, in up to 223 locations worldwide. Participants were to have a positive amyloid PET scan and score within a defined range on the MoCA and FCSRT tests. The trial started comparing a two-year course of a monthly infusion of solanezumab to placebo for change on the ADAS-Cog14 scale; 16 listed secondary outcomes ran the gamut from clinical, cognitive, functional, psychiatric, and global measures to biomarkers in blood, CSF, and PET scans for both amyloid and tau pathology. In January 2017, Lilly terminated this trial after enrolling only 26 participants.

For all solanezumab trials, see clinicaltrials.gov.

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