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Pharmacological Management of Alzheimer’s Disease
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Rakesh Kumar, Rajan Kumar, Abhinav Anand, Neha Sharma, Navneet Khurana
Solanezumab is an anti-Aβ monoclonal antibody and neuroprotector that is under the clinical trial for the remedy of the AD (McCartney, 2015). Solanezumab is investigated by Eli Lilly. In a clinical study of 24 months old PDAPP, transgenic mice observed the antibody ‘m266’ with a rapid normalization of the cognitive deficits (Dodart et al., 2002).
Alzheimer's Disease
Published in Marc E. Agronin, Alzheimer's Disease and Other Dementias, 2014
There are several monoclonal antibodies in large clinical trials, listed in Table 4.6. Bapineuzumab was the first of this group, but although it showed reductions in CSF levels of Ab42 and phosphylated tau protein, it failed to demonstrate significant benefit over placebo in individuals with mild to moderate AD (Tayeb, Murray, Price, & Tarazi, 2013). All clinical trials have since been stopped. Solanezumab also failed to showed improvement in cognitive outcome measures in mildly impaired AD patients, but pooled data revealed a slowing of cognitive decline by around 34% (Eli Lilly, 2012). As a result, solanezumab remains in active trials. Both agents have shown a low but clinically relevant incidence of vasogenic edema and cerebral microhemorrhages, believed to be related to the mobilization of Ab proteins in the brain, particularly in small blood vessels. These occurrences are visualized on MRI scans and typically not associated with clinical symptoms (Tayeb et al., 2013). Vasogenic edema appears to resolve with interruption of treatment and is not usually recurrent when treatment is later resumed. Several other monoclonal antibodies are being studied, listed in Table 4.6. Recently, the FDA has modified its take on these studies, indicating that slowing cognitive decline is a reasonable endpoint in early-stage AD patients as opposed to considering only cognitive improvement (Kozauer & Katz, 2013).
Drug development for Alzheimer’s disease: review
Published in Journal of Drug Targeting, 2019
Kejing Lao, Naichun Ji, Xiaohua Zhang, Wenwei Qiao, Zhishu Tang, Xingchun Gou
Solanezumab is a newer monoclonal antibody, which targets an epitope in the central region of Aβ and preferentially binds to soluble Aβ oligomers. Preclinical study in mice demonstrated that m266 (the murine precursor of solanezumab) rapidly increases plasma Aβ which is highly correlated with amyloid burden in the hippocampus and cortex [62]. Phase II trials revealed dose-dependent increase in the levels of Aβ in the plasma and CSF, which indicated that insoluble species were cleaved from senile plaques [63]. Thus, Lilly funded two prior phase III randomised trials, Expedition1 and Expedition2, comparing solanezumab with placebo in patients with mild-to-moderate AD. These findings, announced in 2012 and later published, showed that the drug failed to improve cognitive or functional outcomes [64]. However, in a pre-specified analysis combining the two trials, there appeared to be a statistically significant benefit for the subgroup of patients with mild dementia. In a 2012 press release, Lilly reported a 34% reduction in cognitive deterioration in this population. Lilly then launched Expedition3, a new randomised trial comparing solanezumab with placebo in patients with mild dementia. More than 2100 patients with mild dementia underwent randomisation and were followed for 18 months, with a longer open-label extension. Unfortunately, in November 2016, Eli Lilly announced that solanezumab did not meet the primary endpoint in the EXPEDITION3 clinical trial [65]. Now, solanezumab is being tested in a prevention study in asymptomatic older subjects, who have positive positron emission tomography (PET) scans for brain amyloid deposits.
A review of therapeutic failures in late-stage clinical trials
Published in Expert Opinion on Pharmacotherapy, 2023
Ritu Jain, Janakiraman Subramanian, Anurag S. Rathore
Solanezumab (LY2062430) is an example of failed drug candidates due to lack of knowledge about the disease and the drug pathways. It was developed by Eli Lilly & Co. to prevent amyloid beta (Aβ) protein build up in the brain, often associated with Alzheimer’s. Since 2003, not a single Alzheimer’s drug has been approved by FDA and more than 200 therapeutic candidates have failed or abandoned for a variety of reasons [32]. Till now, there are only five FDA-approved symptomatic treatment drugs in the market, and nothing to treat the disease itself [33]. Major shortcoming for the failures is the inadequate understanding of the disease pathophysiology. Solanezumab is a humanized monoclonal antibody which targets the soluble monomeric Aβ protein instead of the fibrillar form. The preclinical studies using the murine isoform (m266) of solanezumab were performed in transgenic mice expressing the Aβ precursor protein. M266 was found to interact with free Aβ protein in the plasma, changing the protein equilibrium between plasma and brain. The amount of free Aβ protein in brain plaque was significantly reduced with single dose administration [34]. Phase I and phase II clinical trials were conducted simultaneously, both on mildly and moderately affected patients. These patients exhibited satisfactory tolerance, and no adverse reactions were recorded after single dose. However, unfortunately, there was also no change in cognitive behavior or memory. In the multiple dose study, increased level of Aβ protein in plasma and cerebrospinal fluid (CSF) was observed with no clinical benefit [35]. Three phase III trials were then conducted (EXPEDITION-1, -2, and -3) with more than 4000 patients. EXPEDITION-1 and -2 also failed to show significant cognitive changes between the treated and placebo groups, but a subgroup of patients with mild disease showed minor improvement of cognition, i.e. the disease progression slowed. Mild condition patients enrolled in EXPEDITION-1 and -2 studies were not screened for Aβ plaque [36], and therefore the data collected were insufficient. This is also an example of failures due to use of same subjective rating scales as endpoints for a variety of diseases that may vary in terms of their mechanism of action. Neurological disease is one such example for which minimum scientific knowledge is available about the disease progression and is dynamic in nature, yet similar endpoints are used. Not following the correct procedure and improper inclusion criteria led to the failure of this drug candidate against Alzheimer’s disease. Later, EXPEDITION-3 was conducted with proper testing of plaque in mild disease patients. Still, it failed to reach the primary endpoint [37]. The preclinical results of this drug did not translate to clinical trials on humans.
Recent advancements toward therapeutic vaccines against Alzheimer’s disease
Published in Expert Review of Vaccines, 2018
Krystal Herline, Eleanor Drummond, Thomas Wisniewski
Solanezumab (Eli Lilly & Co.) is a humanized monoclonal antibody that targets the mid-domain of the Aβ peptide, recognizing soluble monomeric Aβ and not fibrillar Aβ. It is hypothesized that Solanezumab works by binding to Aβ in the periphery, which then draws Aβ out from the CNS [41–43]. Disappointingly, Phase III trial results (EXPEDITION-1 and -2 trials) showed no overall significant cognitive improvement in the treatment group as measured by ADAS-Cog11 and ADCS-ADL scores [44]. However, subgroup-specific analysis of individuals with mild AD compared to placebo suggested a slowing in cognitive decline (~34%) as measured by ADAS-Cog14 and MMSE, and a slowing in functional decline (~18%) as measured by ADCS-iADL [45]. As a result, the EXPEDITION-3 trial was initiated in 2013 that repeated the same treatment regime in 2121 individuals with mild dementia due to AD. Patients received 400 mg of Solanezumab intravenously every 4 weeks for 18 months. Additionally, EXPEDITION-3 required participants to have biomarker confirmation of amyloid accumulation by PET scan or measurement of Aβ42 levels in the CSF [46]. This additional requirement was made because approximately 25% of participants in the EXPEDITION-1 and -2 trials were shown to be amyloid-negative, which could have been a significant confounding factor in the initial studies. The primary outcome from the EXPEDITION-3 trial showed that Solanezumab marginally slowed the rate of cognitive decline; there was 11% difference (p = 0.10) in the change from baseline in ADAS-Cog14 score between the Solanezumab group and placebo group [47]. This failure to reach significance in the primary outcome leads investigators to report the results of the secondary outcomes qualitatively and without significance testing. There were small treatment effects evident in the MMSE score in change from baseline (Solanezumab: −3.17 and placebo: −3.66). ARIA was present in one individual receiving Solanezumab and in two participants in the placebo group. Investigators have suggested a number of reasons why this trial failed to show clinical efficacy and why EXPEDITION-3 trial found less robust effects on ADAS-Cog decline (−11%) than EXPEDITION-1 and -2 studies (−34%) despite having enrolled patients who were biomarker positive for AD pathology: (1) the high level of peripheral engagement leading to a reduction in peripheral-free Aβ by 90% was not sufficient to see a cognitive benefit and/or (2) the minimal amount of antibody that entered the brain, which is 0.1–0.3% of that found in plasma, was unable to reduce fibrillar Aβ [47]. (3) Antibodies targeting soluble Aβ in mild AD may not be effective at such a late stage of the disease process and/or (4) the Aβ hypothesis of AD does not fully encompass the complexity of AD and therefore an Aβ targeting therapeutic would not be expected to slow disease progression. (5) The percentage of APOE ε4-positive patients was higher in the EXPEDITION-3 trial (69.3% in the Solanezumab group and 66.3% in the placebo group) than in the EXPEDITION-1 and EXPEDITION-2 trials (57.6% overall) [45,47].