The IVIG results are very disappointing, as this means we are likely at least two to three years away from an approved disease-modifying therapy for AD dementia patients, as large-scale trials for other agents are still enrolling. The finding of a somewhat better response among ApoE4 carriers may reflect the higher likelihood of these patients harboring amyloid pathology, based on results from other Phase 3 trials, and thus potentially more likely to respond to immunotherapy. It is unclear how to interpret the trend level effects seen in a small subgroup of moderate AD dementia, but this might also reflect higher likelihood of amyloid pathology in more impaired patients or possibly effects of antibodies in IVIG targeting other aggregated proteins, such as tau, that may be more dynamic later in the disease process. The biomarker and imaging data to be presented in July may be helpful in interpreting the pattern of clinical effects, but overall the results were not encouraging for IVIG as a therapeutic avenue for AD.

View all comments by Reisa Sperling

The topline results were announced today to satisfy SEC requirements and Baxter's obligation to its investors to report material findings in a timely fashion. However, analysis of data from the GAP study is very much ongoing. It is too soon to talk about the overall findings or the long-term implications. All we can really say right now is that the primary endpoints of the study were not met, and there are some positive findings in the preplanned subgroup analyses that are encouraging. In my opinion, the future of the approach hinges on how robust those subgroup results prove to be and whether there are additional signals in the remainder of the clinical, imaging, and biomarker datasets. I think we stand to learn a lot from this study, and I look forward to presenting a more complete picture at the AAIC meeting on 16 July 2013.

View all comments by Norman Relkin

Prior to commenting, I need to disclose that I am the principal investigator of an ongoing IVIG study for mild cognitive impairment due to Alzheimer's disease, which is supported by Sutter Institute for Medical Research and Octapharma.

While the GAP trial did not demonstrate statistical significance for its primary endpoints, it does provide us with informative data about IVIG for Alzheimer's disease. First, there was a trend of improved cognitive function in the IVIG 0.4 g/kg every two weeks dosage arm, which has also been the optimal and most effective IVIG dosing in prior investigations. Second, this positive trend occurred in those subjects with more evidence of having dementia truly caused by Alzheimer's disease, i.e., genetic marker (ApoE4) or more clinically evident symptoms (moderate disease). Third, this larger trial supports the safety data of prior studies confirming that IVIG appears to be a relatively safe immunotherapeutic strategy for AD without any new safety concerns.

I believe the GAP study will help us to hone our approach and design of future...  Read more

Prior to commenting, I need to disclose that I am the principal investigator of an ongoing IVIG study for mild cognitive impairment due to Alzheimer's disease, which is supported by Sutter Institute for Medical Research and Octapharma.

While the GAP trial did not demonstrate statistical significance for its primary endpoints, it does provide us with informative data about IVIG for Alzheimer's disease. First, there was a trend of improved cognitive function in the IVIG 0.4 g/kg every two weeks dosage arm, which has also been the optimal and most effective IVIG dosing in prior investigations. Second, this positive trend occurred in those subjects with more evidence of having dementia truly caused by Alzheimer's disease, i.e., genetic marker (ApoE4) or more clinically evident symptoms (moderate disease). Third, this larger trial supports the safety data of prior studies confirming that IVIG appears to be a relatively safe immunotherapeutic strategy for AD without any new safety concerns.

I believe the GAP study will help us to hone our approach and design of future investigations using IVIG, which still remains a potential treatment for Alzheimer's disease.

View all comments by Shawn Kile

We clearly need to wait until the release of the complete data before drawing conclusions. However, what clearly strikes me here is the difference between the interpretations made from clinical versus basic science data. On the one hand, randomized clinical trial results are considered negative when primary endpoints are not reached. We all understand the purpose of this rule, which may, however, be a little stringent for multifactorial heterogeneous diseases. How can we expect to find one single drug that will benefit all subtypes of AD patients? This “one size fits all” approach cannot apply to a complex, elusive disease such as AD.

On the other hand, I can’t help thinking that similar results from a preclinical study performed in animal models would have been twisted into a big “positive” publication. Indeed, the difference in response between ApoE4 carriers and non-carriers is so striking that it clearly deserves the attention of the AD research community. When in most clinical studies, mildly symptomatic ApoE4 non-carriers tend to respond better to treatments, the...  Read more

We clearly need to wait until the release of the complete data before drawing conclusions. However, what clearly strikes me here is the difference between the interpretations made from clinical versus basic science data. On the one hand, randomized clinical trial results are considered negative when primary endpoints are not reached. We all understand the purpose of this rule, which may, however, be a little stringent for multifactorial heterogeneous diseases. How can we expect to find one single drug that will benefit all subtypes of AD patients? This “one size fits all” approach cannot apply to a complex, elusive disease such as AD.

On the other hand, I can’t help thinking that similar results from a preclinical study performed in animal models would have been twisted into a big “positive” publication. Indeed, the difference in response between ApoE4 carriers and non-carriers is so striking that it clearly deserves the attention of the AD research community. When in most clinical studies, mildly symptomatic ApoE4 non-carriers tend to respond better to treatments, the preliminary data from the GAP study suggest the opposite: Cognitive benefits after IVIg treatment were detected in patients with moderate ApoE4-positive AD. Again, we’ll have to wait until the full disclosure of the data because chance may have played a role here. Nevertheless, this looks like a very promising pharmacogenetic finding, which could have important mechanistic implications on how we should treat AD relative to ApoE status.

Disclosure: I have been involved in preclinical research in IVIg supported by private and public funds.

View all comments by Frederic Calon

With every AD clinical trial having missed primary endpoints and therefore being deemed as "failed," one wonders whether the fundamental design of AD trials is such that they are destined to fail?

Most human AD trials run for approximately an 18-month period, which is roughly equivalent to a two-week treatment in mice (based on their average lifespans). In AD mouse models, not many two-week treatments have resulted in statistically significant improvement in memory performance. Most successful treatments need two to three months to show memory improvements, which, one could argue, is equivalent to seven to 10 years in humans. So, are preclinical strategies failing in humans because we do not test them long enough?

Second, the Assessment Score numbers (ADAS-COG, ADCS-ADL, and 3M) in the GAP study show a large variation—the standard deviation numbers are bigger than the mean values, which could be concealing positive effects. The use of biomarkers in place of assessment scores is not a good alternative since changes in biomarkers and cognitive performance are not always...  Read more

With every AD clinical trial having missed primary endpoints and therefore being deemed as "failed," one wonders whether the fundamental design of AD trials is such that they are destined to fail?

Most human AD trials run for approximately an 18-month period, which is roughly equivalent to a two-week treatment in mice (based on their average lifespans). In AD mouse models, not many two-week treatments have resulted in statistically significant improvement in memory performance. Most successful treatments need two to three months to show memory improvements, which, one could argue, is equivalent to seven to 10 years in humans. So, are preclinical strategies failing in humans because we do not test them long enough?

Second, the Assessment Score numbers (ADAS-COG, ADCS-ADL, and 3M) in the GAP study show a large variation—the standard deviation numbers are bigger than the mean values, which could be concealing positive effects. The use of biomarkers in place of assessment scores is not a good alternative since changes in biomarkers and cognitive performance are not always correlated. So, unless we can refine testing protocols to drastically reduce the variability, future trials will be similarly handicapped.

One final point—as expected the mild AD cohort in the GAP study deteriorated much more slowly than the moderate AD patients during the 18-month period. However, the deterioration in the mild cohort was so small that IVIg-treated patients’ numbers were worse than the placebo group. We might face the same problem in prevention trials, where the treatment starts at presymptomatic stages of the disease. These are formidable but soluble challenges that will require considerable debate.

View all comments by Sanjay W. Pimplikar