Therapeutics

Solanezumab

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Overview

Name: Solanezumab
Synonyms: LY2062430
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Eli Lilly & Co.
Approved for: None

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 (see 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 CSFAβ40, 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 was seen also in the mild subpopulation. The benefit appeared late, grew over time, and is thus 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. 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. It is expected to read out in December 2016. 

Solanezumab's safety record and indication of a small benefit in mild AD has prompted its selection for two secondary prevention studies. The Dominantly Inherited Alzheimer's Network (DIAN) is conducting a five-year Phase 2/3 trial to test solanezumab and Roche's passive immunotherapy 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 trial reads out biomarker effects at two years (Phase 2). Subsequently, it will advance promising drugs to a three-year (Phase 3) testing phase whose primary endpoint is a composite battery of cognitive tests shown to be sensitive at the earliest symptomatic stages.  The Alzheimer's Disease Cooperative Study is preparing in late 2013 to begin a three-year trial testing solanezumab in 1,000 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 (see Sperling et al., 2011).

For all solanezumab trials, see clinicaltrials.gov.

Clinical Trial Timeline

  • Phase 2
  • Phase 2/3
  • Phase 3
  • Study completed / Planned end date
  • Planned end date unavailable
  • Study aborted
Sponsor Clinical Trial 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024
Eli Lilly & Co. NCT00329082
N=25
Eli Lilly & Co. NCT00749216
N=33
Eli Lilly & Co. NCT00905372
N=1000
Eli Lilly & Co. NCT00904683
N=1000
Eli Lilly & Co. NCT01148498
N=55
Eli Lilly & Co. NCT01127633
N=1275
Eli Lilly & Co. NCT01760005
N=210
Eli Lilly & Co. NCT01900665
N=2100

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References

Therapeutics Citations

  1. Gantenerumab

News Citations

  1. One-Shot Deal? Mice Regain Memory Day After Vaccination, Plaques Stay Put

Paper Citations

  1. . Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):280-92. PubMed.

External Citations

  1. clinicaltrials.gov

Further Reading

Papers

  1. . Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol. 2010 Mar-Apr;33(2):67-73. PubMed.
  2. . Safety and biomarker effects of solanezumab in patients with Alzheimer's disease. Alzheimers Dement. 2012 Jul;8(4):261-71. PubMed.
  3. . Comparison of pharmacokinetics, pharmacodynamics, safety, and tolerability of the amyloid β monoclonal antibody solanezumab in Japanese and white patients with mild to moderate alzheimer disease. Clin Neuropharmacol. 2012 Jan;35(1):25-9. PubMed.