Result card

  • CUR17 / TEC3: What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?
English

What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?

Authors: Antonio Migliore, Tapani Keranen, Sinikka Sihvo, Jesús González-Enríquez, Nadine Berndt, Houria Mouas

Internal reviewers: Kristian Lampe, Romana Tandara Haček, Mirjana Huic, Anna-Theresa Renner

Acknowledgments: ,

Individual manufacturers are exploring the feasibility of developing IVIG therapy for Alzheimer’s disease including Mild Cognitive Impairment but, at time of writing, no manufacturers applied for market authorisation to EMA {Appendix CUR-3}. No data are available regarding the monitoring of off-label or compassionate use of IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

IVIG is presently very widely used for the treatment of a variety of immunologic disorders. IVIG is being used as a treatment in many different conditions, including mainly primary and secondary antibody deficiency states, haematology (acquired red cell aplasia, alloimmune thrombocytopenia, autoimmune haemolytic anaemia, haemolytic disease of the newborn, immune thrombocytopenic purpura), neurology (Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculneuropathy, inflammatory myopathy, Myastenia gravis, multifocal motor neuropaty) and other conditions (Kawasaki disease, transplantation, toxic epidermal necrolysis, staphylococcal or streptococcal toxic shock syndrome, autoimmune congenital heart block, autoimmune uveitis). See {TEC2}.

For more than thirty years, IVIG has been used for the treatment of post-exposure to infectious diseases, immune disorders and the management of patients with neurological conditions. IVIG treatment is used routinely for some immune-mediated neurological disorders such as Guillain-Barre syndrome, and recently IVIG has been investigated for the treatment of neurodegenerative disorders.

IVIG has not been approved for prevention or treatment of AD and mild cognitive impairment.

IVIG treatment of AD patients was first reported in a pilot study in 2004 {20}. Five patients with mild to moderate AD – Mini Mental State Examination (MMSE) mean score 19.4 – received Octagam (Octapharma; dose = 0.4 g/kg) on 3 successive days, every 4 weeks for 6 months. MMSE scores improved slightly in four of the AD patients and were unchanged in the fifth one, while their Alzheimer's Disease Assessment Scale-Cognitive sub-scale (ADAS-cog) scores decreased, suggesting increased cognitive functioning, in four patients and did not change in the fifth one. In 2009 results were published from a pilot study in which eight AD patients (mean MMSE score 23.5) were administered Gammagard S/D (Baxter Healthcare). After 6 months of treatment the mean MMSE score increased to 26.0, reflecting increased scores for six patients and no change in scores for two patients. After a 3-month washout period, the mean MMSE score returned to baseline (23.9). Following an additional 9 months of treatment, MMSE scores were essentially unchanged (mean 24.0).

Before publishing these results, in 2006 Baxter began a double-blind Phase II AD trial with Gammagard. Improved outcomes were noted in the Gammagard-treated subjects compared to those initially treated with placebo at 3, 6, and 9 months.

The results of a double-blind, placebo-controlled, 24- week phase II AD trial with Octagam were published in January 2013 {20}. Octagam had no apparent effects on cognitive or functional scores in the AD patients. No increase was found for plasma Aβ1-40; this had been reported in the pilot studies and suggested that IVIG products might increase efflux of Aβ from the brain. The only positive finding reported in this study, less reduction in glucose metabolism in some brain regions in the Octagam-treated individuals, was of uncertain significance. In conclusion, this trial showed favourable safety and tolerability of intravenous immunoglobulin and the absence of severe autoimmune reactions. Longer studies of larger populations are needed to assess effects on cognition and function in patients with Alzheimer’s disease.

In May 2013, the results of a placebo-controlled phase III AD trial with Gammagard were announced. Three hundred ninety patients had been treated every 2 weeks for 18 months with 200 mg/kg Gammagard, 400 mg/kg Gammagard, or placebo. No significant differences were found for the rate of cognitive decline between the Gammagard-treated group and placebo group.

Two AD-related IVIG trials are still in progress. Flebogamma (Grifols Biologicals) is being evaluated, together with albumin, in an AD phase III trial, and NewGam (Octapharma) is being investigated by Sutter Health in a phase II trial to determine its effects in patients with amnestic mild cognitive impairment (MCI) and its influence on the risk for these patients to develop AD. A possible reason for the failures in the most recent IVIG trials is that by the time AD’s clinical features become evident, its pathology, including extensive neuronal loss, is already well established. The trial with MCI patients should provide an indication of whether earlier IVIG treatment may be beneficial.

Newer research and developing human trials are becoming established for the use of intravenous immunoglobulins (IVIG) for the treatment and prevention of Alzheimer’s disease.

The IVIG trials reported to date in AD patients have produced conflicting findings. Because the most recent trials produced negative results, enthusiasm for IVIG as a treatment for AD has been reduced. Polyvalent antibody therapy for AD, as typified by IVIG, should have advantages over administration of individual monoclonal antibodies. To identify which antibodies should be included in an AD-specific IVIG preparation, more must be known about the range of anti-AD antibodies in IVIG and their effects on AD pathology in animal models. 

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Migliore A et al. Result Card CUR17 / TEC3 In: Migliore A et al. Health Problem and Current Use of the Technology In: Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 30 October 2020]. Available from: http://corehta.info/ViewCover.aspx?id=267

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