Background

NewGam/Octagam® is an intravenous immunoglobulin preparation by the Switzerland-based company Octapharma. It is a marketed product. The rationale of evaluating it in Alzheimer's disease, as for other intravenous immunoglobulin preparations such as Gammagard® and Flebogamma (as Gamunex), is that naturally occurring polyclonal autoantibodies against Aβ may be protective and are reduced in Alzheimer's disease (see Weksler et al., 2002).

Findings

The first trial of this IVIG preparation in Alzheimer's evaluated six different doses of Octagam 10 percent against two placebo comparators in a six-month trial of 58 people with mild to moderate AD. This multicenter Phase 2 trial has been completed. This trial missed its primary endpoint of change in plasma Aβ levels, and was negative for most of its secondary biomarker outcomes with the exception of a signal suggesting a benefit for cerebral metabolism. None of the doses tested showed any benefit for cognition or function (see Dodel et al, 2013; Feb 2013 news).

A second, single-center Phase 2 study conducted at Sutter Institute for Medical Research in Sacramento, California, investigated the long-term effects of a short course of this IVIG preparation. Octagam 10 percent (0.4 g/kg) or saline placebo was infused every other week for two months in 50 people with amnestic MCI due to AD, with two years of follow-up. Initial results on 28 patients assessed one year after treatment indicated possible effects on the Clinical Dementia Rating Sum of Boxes and brain atrophy as seen on MRI (see Mar 2013 conference story). Full publication of the data reported less brain atrophy and a treatment benefit on ADAS-cog13 and MMSE in the IVIG group compared to the placebo group at 12 months; these differences disappeared by 24 months. The paper also reported a trend toward fewer progressions to AD dementia in the treated group at 12 months, and argued for additional research on this approach (Kile et al., 2015). In additional follow up of 27 participants, treatment did not change brain volume, cognition, or conversion to dementia at five years (Kile et al., 2021).

A single center, proof of mechanism study in five people with MCI due to AD measured brain amyloid by florbetapir PET and retinal amyloid by autofluorescent imaging. All received five infusions of 0.4 g/kg Octagam 10 percent over two months. In three of the five participants, brain amyloid was reduced one month after the last infusion; all five had lowering of amyloid in at least one eye (Kile et al., 2020).

A metanalysis of five clinical trials of intravenous immunoglobulin formulations found no evidence for improved cognition or disease modification in people with Alzheimer’s disease or MCI (Liu and Wang, 2019).

Clinical Trial Timeline