8 February 2013. Aside from a reasonable safety profile, the first published Phase 2 study of a blood-derived antibody preparation to treat Alzheimer’s disease looks inconclusive at best. The six-month dose-finding trial of Octapharma AG’s intravenous immunoglobulin (IVIg) missed its primary endpoint, failing to change plasma Aβ. The IVIg product also showed no signs of cognitive or functional benefit.
If there was a glimmer of hope, it came from brain scans showing better glucose metabolism in parietal and frontal cortical areas of treated patients relative to those on placebo. Some researchers said poor trial design and short timeframe made the results hard to interpret. “These findings are not what the Alzheimer’s disease research community was hoping for, and echo the largely negative results of the other recent immunotherapy studies,” wrote Clive Holmes, University of Southampton, U.K., in an editorial accompanying the January 31 Lancet Neurology report (see ARF related news story on bapineuzumab) and ARF related news story on solanezumab). Richard Dodel of Philipps University, Marburg, Germany, led the Phase 2 study.
Intravenous immunoglobulin is a human blood preparation that contains natural antibodies, including some against Aβ. Researchers believe it lowers brain Aβ through a peripheral sink mechanism, shifting Aβ from the cerebrospinal fluid (CSF) to the blood. Two small, open-label studies support this idea, showing increased serum Aβ in AD patients treated with IVIg for six months (Dodel et al., 2004; Relkin et al., 2009). In a Phase 2 trial of 24 AD patients reported at the 2008 International Conference on Alzheimer’s Disease (ICAD), those receiving Gammagard®, an IVIg preparation developed by Baxter Healthcare, improved on cognitive and global measures at three-, six-, and nine-month time points (see ARF related conference story). At 18 months, magnetic resonance imaging (MRI) data indicated that IVIg may have protected against brain atrophy (see ARF related conference story). Of the 16 patients who completed the open-label three-year follow-up, the four receiving the most effective dose (0.4 g/kg every two weeks) “were essentially unchanged from baseline,” Norman Relkin of Weill Cornell Medical College, New York, told Alzforum. On this last finding, other scientists cautioned that a number as small as four means little because it might also represent outlier patients whose disease progresses slowly.
Besides effects on Aβ, some researchers believe the mixture of natural antibodies in IVIg may treat AD via other effects on innate immunity.
For the current Phase 2 trial, Dodel’s team enrolled 58 people with probable AD from 12 sites—seven in the U.S. and five in Germany. For six months, participants received saline placebo or one of six IVIg doses: 0.2 g/kg, 0.5 g/kg, or 0.8 g/kg every four weeks, or half those doses every two weeks. Five of the six treatment arms showed no change in plasma Aβ compared to placebo. One subgroup (0.4 g/kg every two weeks) did separate from placebo, but in the wrong direction—plasma Aβ1-42 levels dropped, instead of rising as in prior IVIg studies. There was no cognitive signal on ADAS-cog, Mini-Mental State Examination, or CDR Sum of Boxes, or functional improvement on ADCS Activities of Daily Living. Hippocampal and whole brain volumes on MRI also did not respond to IVIg treatment.
Dodel confessed he was “not happy” about the trial design. There were only five to seven participants per arm. “[That is] not enough to make a conclusion about whether [the treatment] is effective,” Dodel said. Relkin agreed, calling this an “underpowered study with a lot of variance.” With fewer sites and more standardized raters, “the results could have been different,” he told Alzforum.
Perhaps the only credible finding from this trial, Relkin said, was the improved cerebral metabolism in treated patients—a secondary outcome measured by fluorodeoxyglucose positron emission tomography (FDG-PET). Because it is a standardized, semi-quantitative measure, inter-site and inter-subject variability may be less of an issue, Relkin noted, adding, “That may be why this one particular measure did show the expected effect.” The Gammagard Phase 2 study found similar metabolic benefits by FDG-PET, he said.
The IVIg story is far from over. Results of the Phase 3 Gammagard trial are due for release in the second quarter of 2013. Despite the present Phase 2 result, Octapharma and several other companies “are ready to go into Phase 3 trials if Baxter sees a positive effect,” Dodel told Alzforum. Other companies that have IVIg programs include Grifols Biologicals, Inc.; CSL Behring; and Sutter Health (see ARF related conference story).—Esther Landhuis.
Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Förster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Hagg S, Wietek S, Farlow M, Jessen F. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer’s disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurology. 31 Jan 2013. Abstract
Holmes C. Intravenous immunoglobulin for Alzheimer’s disease. Lancet Neurology. 31 Jan 2013. Abstract