January 22, 2013 7:33 pm
This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com
Baxter International’s (NYSE:BAX) Phase III Gammagard clinical trial has been met with reservation from experts, who cited the mild-to-moderate patient population as problematic for success in treating Alzheimer’s disease (AD).
Gammagard, an immune globulin infusion (IVIg) that is produced from pooled plasma of healthy human blood donors, lacks good scientific rationale in AD, added two of the experts interviewed by BioPharm Insight. The therapy is currently approved as a replacement therapy for primary humoral immunodeficiency, a genetic condition where a patient’s immune system is often unable to make proteins called antibodies. Antibodies help stave off infection from bacteria or viruses.
The large, well-controlled Phase III Gammaglobulin Alzheimer’s Partnership (GAP) study will help Baxter better understand the therapeutic potential of immune globulin therapy, a Baxter spokesperson commented. “We look forward to seeing those results this year, and until then it is premature to comment,” he added.
The 390-patient GAP trial has a January 2013 primary completion date, as per ClinicalTrials.gov. A second 402-patient Phase III study in the same mild-to-moderate population is ongoing, with a December 2014 primary completion date. GAP evaluates the use of 400mg/kg and 200mg/kg Gammagard liquid 10% doses administered every two weeks in mild-to-moderate AD. The study will measure cognitive and global functional change using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Alzheimer´s Disease Cooperative Study-Activities of Daily Living scale.
Last summer, Phase II 36-month extension results demonstrated no decline on several scales of cognition including the ADAS-Cog in four patients. The study assessed 11 patients given 400mg/kg Gammagard every two weeks. Because of the small sample size, the extension trial findings may not be completely extendable to the GAP study, BioPharm Insight previously reported.
Gammagard intends to replace missing antibodies in those who are deficient, however, in AD, the rationale is less clear. The therapy contains several antibodies and is therefore known as a “polyclonal” antibody. Theoretically, these antibodies would target proteins like amyloid, tau and other toxins that contribute to AD pathology.
Mild-to-moderate population a cause for concern
Considering so many failures in the mild-to-moderate AD population, pursuing another anti-amyloid strategy in the same population is risky, said Dr Ziad Nasreddine, founder and director, Memory Clinic, Quebec, Canada.
Mild-to-moderate is too late, as we have already seen several trials fail in this patient population, agreed Robert Vassar, professor of cell and molecular biology, Feinberg School of Medicine, Chicago, Illinois. By the time individuals have progressed to mild-to-moderate AD, they are likely to have brain amyloid levels that are too high to be effectively cleared by anti-amyloid drugs.
Experts referred to the most recent failures of Pfizer (NYSE:PFE)/Johnson & Johnson (NYSE:JNJ)/Elan’s (NYSE:ELN) bapineuzumab and Eli Lilly’s (NYSE:LLY) solanezumab in mild-to-moderate AD. Both drugs are known as monoclonal antibodies (mAbs), as they each are a single antibody against amyloid protein.
While Gammagard could demonstrate a positive signal in early AD, the effects on cognition are unlikely to be statistically significant in mild-to-moderate AD, added Yansheng Du, associate professor of neurology, Indiana University School of Medicine. This sentiment was echoed by David Teplow, professor of neurology, David Geffen School of Medicine at University of California, Los Angeles.
Rationale in AD debated
IVIg for AD is lacking scientific rationale, according to Vassar. The therapy’s anti-inflammatory properties are unlikely to be specific for AD, he said. There is no good theoretical reason for using IVIg in AD, agreed Teplow. While inflammation is a real phenomenon in AD, Teplow said he is not confident IVIg will be a good way to treat it.
The bulk of IVIg, a polyclonal antibody, is not going to have anti-amyloid properties, Vassar explained. The fraction of anti-amyloid antibodies will be “miniscule,” he said.
Furthermore, only a small percentage of the therapy will even penetrate the blood brain barrier (BBB) and reach the brain, he added. BioPharm Insight previously cited Dr Bengt Winblad, director, Karolinska Institutet-Alzheimer Disease Research Center, Stockholm, Sweden, indicating there are so many different types of antibodies in IVIg that the question is whether the antibodies are in high enough concentrations to have a significant effect on the brain. The low antibody concentrations are unlikely to match the high production of amyloid in mild-to-moderate AD brains, he said.
Gammagard is disadvantaged because the concentration of anti-amyloid antibodies is diluted, such that the ratio of anti-amyloid antibodies to other antibodies is 1:1,000, Du said. Yet, he noted, the small concentration might be sufficient to pull amyloid out of the brain and into the periphery as explained by the “peripheral sink” hypothesis. Through this mechanism, it is not necessary for anti-amyloid antibodies to get into the brain, Du explained. He added, though, this mechanism is not clearly defined.
Moreover, Du noted, the highest 400mg/kg dose being assessed in GAP might be too low. He indicated 1g/kg to 2g/kg doses might be better; these doses are tolerated by patients but have drawbacks - for example, patients would have to undergo intravenous infusion all day to get the dose, Du said.
IVIg does sound potentially useful since immunoglobulins probably contain antibodies directed at multiple types of amyloid forms, Nasreddine said. In comparison, mAbs used in most trials are targeting only a specific part of the amyloid protein, which may not be pathogenic, he added.
However, since immunoglobulins come from multiple donors, each treatment batch might contain various amounts of antibodies and thus confer variable clinical response, Nasreddine said.
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