Background

Gammagard® is a preparation of pooled human plasma antibodies from blood donations. It has an established safety record from human use in immunodeficiency and certain autoimmune conditions. Gammagard® has been used off-label for the treatment of a small number of Alzheimer's disease patients for years. The proposed treatment rationale is twofold. Intravenous immunoglobulin mixtures contain a small fraction of polyclonal antibodies directed against Aβ that are thought to effect clearance or counteract synaptic toxicity caused by Aβ (Szabo et al., 2010). The concentration of natural Aβ antibodies is lower in IVIg preparations than in engineered monoclonal Aβ immunotherapies. In addition, IVIg has immunomodulatory effects, which are proposed to change patients' cytokine profiles to induce a noninflammatory, phagocytic microglial phenotype (see Aug 2011 news story).

Findings

An open-label dose-finding study in eight patients with mild AD reported increases of Aβ antibodies in serum, decreases of Aβ in CSF, and stabilization of MMSE scores over 18 months (see Relkin et al., 2009).

A blinded Phase 2 trial of 24 people with mild to moderate AD tested two doses of Gammagard®, at two treatment regimens each, for six months against placebo. Each treatment group had four patients. This trial reported a benefit on the Clinical Global Impression of Change primary outcome that persisted at three years of follow up, beneficial changes in plasma cytokine concentrations, and reduced ventricular enlargement on MRI scans (see Jul 2013 conference story; Apr 2010 conference story). 

Two pivotal Phase 3 trials were run. The first, run by the Alzheimer's Disease Cooperative Study at 45 sites in the United States and Canada, compared 18-month treatment with 400 mg/kg and 200 mg/kg of Gammagard® to placebo in 390 patients with mild to moderate Alzheimer's disease against cognitive and global function as assessed by the Alzheimer's Disease Assessment Scale-Cognitive Subscale and the Alzheimer's Disease Cooperative Study Activities of Daily Living. Substudies measured CSF, cerebral metabolism by FDG-PET, and brain amyloid load by PET. This trial was completed. Primary endpoints showed no difference between study drug and placebo.  Prespecified subgroup analysis showed a trend toward benefit for the higher dose, but only in moderate AD and with insufficient power to be statistically significant (see May 2013 news story, see full results on clinicaltrials.gov). 

Baxter subsequently terminated a second pivotal trial, which started in 2012 and was to have run until 2015 in 530 patients with mild to moderate AD in countries around the world. A long-term follow-up extension to the first pivotal trial was also terminated.

For all trials on this treatment, see clinicaltrials.gov.