Toronto: In Small Trial, IVIg Slows Brain Shrinkage
There may be a new reason to support your local phlebotomist—if data from an extension trial of 24 people hold up in Phase 3, that is. A preparation of human blood immunoglobulins slows clinical decline in Alzheimer patients and protects their brains against shrinkage over 18 months, according to data presented at the 62nd annual American Academy of Neurology meeting, held last week in Toronto, Canada. Norman Relkin, Weill Cornell Medical Center, New York, presented results from the Gammagard Phase 2 clinical trial. The data extend nine-month findings shown last July at the International Conference on Alzheimer’s Disease (see ARF related news story), which suggested benefit in the primary endpoints of cognition (ADAS-cog) and global change (ADCS-CGIC). The 18-month data, which include MRI results, indicate that IVIg also protects against brain atrophy. “The results were certainly a surprise,” said Relkin, who told ARF that the brain volumetric analysis was neither a primary nor secondary outcome in the trial, but simply an exploratory outcome. “It was only because the effect size was so large that we saw the differences,” he said. The findings support the idea that immunotherapy might become an effective treatment for AD.
Relkin said that the original analysis of the MRI data, conducted by his collaborator Jim Brewer at University of California, San Diego, were so impressive that he found it hard to believe. But independent analysis of the data by Dana Moore at Weill Cornell, using different software, essentially told the same story: that patients on IVIg had rates of brain atrophy consistent with those of age-matched normal individuals.
That atrophy was normal in treated patients would be suggestive of a disease-modifying (DM) effect. In fact, as luck would have it, this Phase 2 trial of IVIg used a delayed start design, which is one potential way of demonstrating disease modification. By comparing the rate of progression of disease in groups of patients starting the therapy at different times, DM effects can be revealed, the theory goes. In this case, however, the delayed start was not designed from the outset to prove disease modification. It was more a case of how the study evolved—funding agencies initially required a six-month proof-of-concept trial, said Relkin, and the trial was later extended to 18 months. As a result, eight patients received placebo for six months and then IVIg for 12 months (the delayed start), while 16 patients received the treatment from the beginning of the trial. “The hope of having something which is disease modifying has eluded us in so many clinical trials. I’m reluctant to say that we found something that is disease modifying, but in terms of trajectory and biological changes, things seem to point in that direction,” said Relkin. The patients who received the optimal dose of IVIg had an initial symptomatic improvement that was maintained over the 18 months of the study. MR measurements showed that they also had less atrophy than patients who had the delayed start.
Patients received 0.2 g IVIg per kg body weight twice a month, 0.4 g/Kg twice a month, or 0.8 g/Kg once a month. The trial was blinded during the first six months and open-label afterwards. Patients knew they were receiving treatment, though not which dose; raters stayed blinded to who had initially been on placebo. Overall, the MRIs measured 46 percent reduction in annual brain atrophy in patients who received continuous treatment compared to those who initially received placebo, said Relkin. There was significantly less ventricular enlargement in the continuous treatment group as well (6.7 percent a year versus 12.7 percent a year). There appears to have been a dose-dependent effect, whereby patients on the optimal dose (0.4 g/Kg biweekly) had annual rates of atrophy similar to those seen in normal patients in the ADNI cohort, according to Relkin. “What makes the data exciting is a tight correlation between brain volumetric data and primary outcome measures of cognition (ADAS-cog) and global change (ADCS-CGIC),” said Relkin. At baseline no correlation was apparent between brain volumes and the primary measures, but the changes over the course of 18 months were highly correlated.
IVIg is a mixture of immunoglobulins, some of which Relkin believes target Aβ. He told ARF that these antibodies may differ from others currently being tested in that they recognize epitopes formed when Aβ aggregates. IVIg also has documented immunomodulatory effects, Relkin added, noting that this may convert pro-inflammatory microglia into phagocytic, non-inflammatory cell types that can mop up Aβ. Amyloid imaging with PIB-PET may be able to address the question of Aβ removal. Half the patients in this Phase 2 trial were scanned for PIB at six months and again at 18 to 24 months. Those data are currently being analyzed, Relkin said.
A Phase 3, multicenter trial of IVIg enrolling 360 AD patients is underway. It is sponsored by an NIA grant through the Alzheimer’s Disease Cooperative Study (ADCS) and is jointly funded by Baxter BioScience, who make the IVIg preparations. This non-patentable therapy is FDA approved and has been used for decades for certain life-threatening immunodeficiency disorders, including congenital pediatric immunodeficiency. The rising interest in an Alzheimer’s indication has certain patient groups worried that a successful Phase 3 trial could result in intense demand for the immunoglobulin mix, noted Relkin. He stressed that IVIg should not be used off-label and mentioned that there is an industry initiative afoot to guarantee IVIg to those patients who cannot live without it. Ultimately, if the ADCS Phase 3 trial is successful, then an analysis of the mixture could identify specific components that could be used to make more targeted immunotherapies, said Relkin.—Tom Fagan.
Universities of Manchester and Oxford
The trial of IVIg (Gammagard) for treating AD patients was done with the aim of augmenting their relatively low level of anti-Aβ antibodies, thereby enhancing the clearance of Aβ. We wonder if, instead, the beneficial effect of IVIg might have been through its anti-HSV1 action, particularly in view of the apparent paradox that monoclonal Aβ treatments have not had the same beneficial effect (1).
IVIg products are derived from the pooled plasma of thousands of people, so they contain large amounts of neutralizing antibodies to a number of microbes, including HSV1. IVIg is able not only to neutralize any extracellular virus, but also to help destroy cells acutely infected with HSV1 (2)—a useful feature, as the virus can be transferred from cell to cell without release of extracellular virus. In murine models of herpes simplex encephalitis, IVIg was found to protect against death and it reduced the number of trigeminal ganglia containing latent HSV1 (3). Further, a study of genital herpes in humans showed that the reduction in recurrence frequency and duration was far greater, and the lesion severity less, with IVIg treatment than with acyclovir (ACV), and there was a trend towards IVIg causing a greater reduction in viral load (4).
Whether in this and previous studies (5-7) there was indeed an IVIg-induced anti-HSV1 action (especially in ApoE-ε4 carriers, as it is the combination of HSV1 in brain and ApoE-ε4 that confers risk of AD) is unknown as, unfortunately, no data on ApoE genotypes are mentioned.
If the mechanism operating in the IVIg-induced improvement of AD patients does indeed involve HSV1, this suggests that treatment of patients with IVIg in combination with the very safe antiviral agent ACV would be particularly beneficial, as ACV acts in a completely different way—by stopping HSV1 DNA replication. Thus, the combined action could well be synergistic.
Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer's disease: hope for the future?. Ther Adv Neurol Disord. 2010 May;3(3):141-52. PubMed.
Kohl S, Loo LS. In vitro and in vivo antibody-dependent cellular cytotoxicity of intravenous immunoglobulin G preparations against herpes simplex virus. Rev Infect Dis. 1986 Jul-Aug;8 Suppl 4:S446-8. PubMed.
Erlich KS, Mills J. Passive immunotherapy for encephalitis caused by herpes simplex virus. Rev Infect Dis. 1986 Jul-Aug;8 Suppl 4:S439-45. PubMed.
Masci S, De Simone C, Famularo G, Gravante M, Ciancarelli M, Andreassi M, Amerio P, Santini G. Intravenous immunoglobulins suppress the recurrences of genital herpes simplex virus: a clinical and immunological study. Immunopharmacol Immunotoxicol. 1995 Feb;17(1):33-47. PubMed.
Devi G, Schultz S, Khosrowshahi L, Agnew A, Olali E. A retrospective chart review of the tolerability and efficacy of intravenous immunoglobulin in the treatment of Alzheimer's disease. J Am Geriatr Soc. 2008 Apr;56(4):772-4. PubMed.
Fillit H, Hess G, Hill J, Bonnet P, Toso C. IV immunoglobulin is associated with a reduced risk of Alzheimer disease and related disorders. Neurology. 2009 Jul 21;73(3):180-5. PubMed.
Relkin NR, Szabo P, Adamiak B, Burgut T, Monthe C, Lent RW, Younkin S, Younkin L, Schiff R, Weksler ME. 18-Month study of intravenous immunoglobulin for treatment of mild Alzheimer disease. Neurobiol Aging. 2009 Nov;30(11):1728-36. PubMed.
Make a Comment
To make a comment you must login or register.