A Phase III Trial Based on the Peripheral Amyloid Sink Concept Succeeds in Slowing Alzheimer's Disease

Results announced by the sponsors of a recently concluded phase III trial in Alzheimer's patients do not represent a cure, but the treatment did more than halve the progression of the condition. The approach involved removing amyloid-β from the blood rather than from the brain. Levels of amyloid-β are dynamic, and there is an equilibrium between the amount found in the brain and the amount found elsewhere. Past studies have shown that reducing amyloid in the blood can reduce its presence in the brain, the result of a new equilibrium.

This seems like an important confirmation of the amyloid hypothesis of Alzheimer's disease, at a time at which it is coming under increasing attack. The long history of failed attempts to show clinical benefits from clearing amyloid-β have led to a diversity of competing theory and initiatives, and an increased focus on tau aggregration rather than amyloid aggregation as the major cause of pathology in the later stages of the condition. I'd also take this as indirect support for the impaired drainage view of Alzheimer's, in which the paths by which cerebrospinal fluid exits the brain atrophy with age, and thus rates of removal for a range of forms of metabolic waste are reduced.

Alzheimer Management by Albumin Replacement (AMBAR) is an international, multicenter, randomized, blinded, and placebo controlled, parallel group clinical trial that enrolled mild and moderate Alzheimer patients from 41 treatment centers in Europe and the United States. The study was designed to evaluate the efficacy and safety of short-term plasma exchange followed by long-term plasmapheresis with infusion of Human Albumin combined with intravenous immunoglobulin in patients with mild and moderate Alzheimer's disease.

AMBAR is based on the hypothesis that most of the amyloid-beta protein - one of the proteins accumulated in the brains of Alzheimer's patients - is bound to albumin and circulates in plasma. Extracting this plasma may flush amyloid-beta peptide from the brain into the plasma, thus limiting the disease's impact on the patient's cognitive functions. Additionally, Albumin may represent a multi-modal approach to the management of the disease due to it's binding capacity, antioxidant, immune modulatory, and anti-inflammatory properties.

The AMBAR study included 496 mild and moderate Alzheimer patients, randomized in three treatment groups and one control (placebo) group. The participants were 55-85 years old and the efficacy of treatment was measured by changes in cognition and in daily living activities scores. An independent contract research organization (CRO), oversaw the trial's clinical monitoring phase and managed the data collection and analysis stages. The trial employed a randomized and double-blind design, meaning that neither patients nor evaluators knew whether subjects were receiving the treatment or the placebo.

The analysis of AMBAR data in moderate patients has shown positive, highly relevant results in a cohort of patients suffering from moderate Alzheimer's disease. In the three-combination arms the differences to placebo showed between 50 and 75% less decline for the Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog) in the treated patients and between 42 and 70% less decline for the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. In the arm with all patients treated with plasma exchange the difference to placebo achieved a 66% less decline for the ADAS-Cog scale in the treated patients and a 52% less decline for the ADCS-ADL scale.

Link: https://www.grifols.com/en/view-news/-/new/grifols-ambar-results-demonstrate-a-significant-reduction-in-the-progression-of-moderate-alzheimers-disease


How does this affect the prospects for Leucadia? It offers an alternative that is apparently effective for Alzheimer's and is further along in the approval process.

Posted by: Morpheus at October 30th, 2018 9:05 AM

Leucadia's approach should be considerably cheaper. Plasmapheresis is costly. But it is really comparing apples to oranges. If they both have benefit, you'd want to do both. That goes for anything that might drain excess amyloid from the brain. Further, the approach here only targets amyloid, but Leucadia should be addressing all metabolic waste in the area of the brain drained through the cribriform plate.

Posted by: Reason at October 30th, 2018 9:19 AM

Probably it could bring the same benefits as the statins. Not a real fix but reduces the damage....

Posted by: cuberat at October 30th, 2018 2:04 PM

Anyway, looks very promising ! The first real success in slowing progression!

Posted by: Ariel at October 30th, 2018 5:16 PM

More directly than being good news for Leucadia's view, this is good news for the other ways to get rid of amyloid beta, such as the other conventional immunotherapies in clinical trials (there are 3-4 that have shown actual efficacy at removing Aβ) and also next-generation techniques such as the catalytic antibodies being pursued by Covalent Bioscience. (See: covalentbioscience.com/index.php/alzyme/ and fightaging.org/archives/2017/12/covalent-bioscience-is-one-of-the-current-crop-of-sens-rejuvenation-biotechnology-startup-companies/ Disclaimer: I am an investor in Covalent.)

This is also good news for early diagnostics for Aβ load as early ways to detect AD risk. There is a bunch of interesting work in this area on minimally invasive ways to detect Aβ easier than PET or spinal tap, including those based on detection through the eye (lots of research at a handful of labs around the world; eg doi.org/10.1172/jci.insight.93621 and doi:10.1167/iovs.15-17406 and doi.org/10.3389%2Ffnins.2016.00536 plus at least 2 startups: NeuroVision and Optina) and also approaches that detect ratios of Aβ isotopes in blood: doi.org/10.1016/j.jalz.2017.06.2266

Posted by: Karl Pfleger at October 30th, 2018 10:46 PM

Exactly cuberat - just taking statins would have this effect!

Posted by: Mark at October 31st, 2018 4:24 AM

I don't think the statin analogy necessarily holds, though, since statins cause major side effects for a portion of the patient population. The only major downsides to this treatment seem to be cost and time.

There might even be a benefit to patients in terms of providing an opportunity to socialize. Sadly, kidney dialysis companies were using this feature of dialysis treatment to discourage patients from pursuing kidney transplants ('you'll miss your friends'), even though health outcomes are much better for transplant recipients.

@Karl Pfleger
Interesting news about Aβ detection.

Posted by: CD at October 31st, 2018 11:42 AM

This is really encouraging, as as Ariel mentions, it's the first successful attempt at slowing progression. While the treatment may be costly, it's worth noting that untreated Alzheimer's itself has very large costs.

Posted by: Vasco at November 11th, 2018 9:59 AM
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