Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, Mathis CA, Blennow K, Barakos J, Okello AA, Rodriguez Martinez de Liano S, Liu E, Koller M, Gregg KM, Schenk D, Black R, Grundman M. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer's disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010 Apr;9(4):363-72. Epub 2010 Feb 26 PubMed.

Comments

- P. Murali Doraiswamy
- Posted: 05 Mar 2010
- News: PIB-PET Biomarker Study Confirms Bapineuzumab Lowers Amyloid
This is a very impressive study. It is the kind of pilot biomarker study that every top investigator dreams of doing, and kudos to the team that did it.

I noticed some 15 percent of AD patients were dropped from entering the trial because the scan showed they did not have sufficient amyloid in the brain. Without dropping these people, the study would likely have had no chance of showing a positive result and might have also exposed more people to risks. This shows the power of PET amyloid imaging to select people who have pathology in order to maximize your chance of a drug effect. Prior to this, we were treating AD patients blindly without knowing how much amyloid they had in their brains, a bit like treating people with a statin without knowing their cholesterol level.

With regard to the bapineuzumab therapy, the magnitude of amyloid clearance seems consistent and real, but at around 20 percent is modest. That is far less than was expected from prior autopsy studies of immunized patients or animal studies which suggested the vaccines might have a much bigger effect. This is a new insight and we might need to lower our expectations. The potential promise with this technology is that we might be able to test how different doses of therapy affect amyloid clearance at an early stage, allowing companies to select the most optimal dose for definitive trials.

Going beyond amyloid, at the end of the day, one can clear all the amyloid in the brain and if the patient does not improve, it still is not a useful therapy. So what's missing is for the field to now show that clearing amyloid eventually leads to a meaningful cognitive and functional benefit for the individual.

Some minor methodologic issues: differences at baseline in cognition and amyloid burden (not unexpected in small studies) between treatment groups add a bit of uncertainty as to interpretation. The method for computing standardized uptake values relative to cerebellum (i.e., the amyloid ratios) varies slightly from one study to another, and one sees different ratios being called normal or abnormal. This makes it hard to compare findings across studies and across tracers. So I think we need head-to-head comparisons and also some standardization of the way one determines a positive from a negative scan.

At HAI and AAN in Toronto, and ICAD in Honolulu, we will see lots of new data on these tracers in terms of cognitive correlates in normals and MCI subjects. I also expect AVID's florbetapir (formerly known as AV-45) will be the first to present validation data from a multicenter autopsy study. Once the validation is complete, this will really jumpstart the use of PET amyloid imaging in secondary and primary prevention trials of both drugs and lifestyle interventions. It will also give us more insight into the role of amyloid in aging and dementia, and allow us to test mechanistic hypotheses.

View all comments by P. Murali Doraiswamy

- Chris Carter
  PolygenicPathways
- Posted: 20 Jul 2011
This is more a question than a comment. Both PIB and β amyloid antibodies bind to the same relatively small peptide, β amyloid. Is there any work testing whether they displace each other?

View all comments by Chris Carter

Make a Comment

To make a comment you must login or register.

Paper

Tools

Comments

Make a Comment

This paper appears in the following:

News

Webinars