Antiamyloid Drug Shows Gene-Dose Effect in Alzheimer’s, Source: Medscape, 17.11.2016

Research shows that the APOE ε4 isoform reduces clearance of amyloid β (Aβ) peptides and promotes their aggregation. Patients with the APOE ε4 genotype have a 4- to 12-fold higher risk of developing Alzheimer’s disease (AD) and the mean age at onset of AD is decreased by about 10 to 15 years in these carriers. They also progress more rapidly from early AD to dementia.

Tramiprosate is a chemically modified form of the amino acid taurine that is naturally found in some foods. In animal models, tramiprosate reduces oligomeric and fibrillar (plaque) amyloid. In a phase 2 study in patients with AD, the drug was found to cross the blood-brain barrier and to reduce cerebrospinal fluid Aβ-42 levels with maximum reductions at the highest tested dose of 150 mg twice daily.

Two Trials

Two similar randomized, double-blind phase 3 trials tested this drug over 78 weeks in patients with mild to moderate AD. Both had three groups: tramiprosate at 100 mg twice daily, the drug at 150 mg twice daily, and placebo.

The North American (NA) study enrolled 1052 patients and the European (EU) study enrolled 973. About 15% of study subjects were patients with the APOE ε4/ε4 genotype.

Researchers have analyzed the primary, secondary, and safety outcomes of these studies based on the number of APOE ε4 alleles in APOE ε4 homozygous, heterozygous, and no carrier patients.

The analysis showed that the APOE ε4/ε4 homozygous group in the NA study who took the high dose of tramiprosate had the most consistent benefit on the co-primary outcomes.

The cognitive effect of the 150-mg twice-daily dose in APOE ε4/ε4 AD patients corresponds to a 40% benefit over placebo at week 78. This, said the authors, is clinically meaningful because it exceeds the 25% benefit over placebo that is considered clinically meaningful in AD trials.

The effects of the high dose in the homozygous group on global function translate into a 25% benefit on CDR-SB at week 78.

Intermediate Benefit

The APOE ε4 heterozygous group showed nonsignificant drug effects on ADAS-cog at both doses but significant benefit on CDR-SB at the low dose (0.73; P = .0078 at week 78) and a positive trend at the high dose.

This is called the gene-dose effect because the more alleles patients had, the more amyloid they had, and the better they responded to the drug.

A possible explanation for the gene-dose effect is that tramiprosate may have a direct effect on the APOE ε4 protein, a mechanism that is being further investigated, said the authors.

As for secondary outcomes, there was a consistent numeric benefit on the Disability Assessment for Dementia (DAD) at weeks 26, 52, and 78. At this last week, the effect was about equal to a 25% drug benefit.

In the EU study reanalysis, results suggested a benefit over placebo at the higher dose at week 52 but not at earlier time points. The authors pointed out that the EU efficacy data are limited by the early termination of the study.

On the basis of a sensitivity analysis, tramiprosate efficacy appeared to be greater and more sustained in patients with mild AD.

Tramiprosate inhibits aggregation of amyloid monomers into soluble oligomeric species that cause synaptic toxicity. So it makes sense that mild patients who have more synapses with more integrity are more likely to benefit from a protective effect of such a drug.

Evaluations of brain MRI in a subset of 426 patients did not reveal any events of vasogenic brain edema on either dose of tramiprosate. Vasogenic edema, which can be serious, has been observed as a side effect in clinical studies of some injectable antiamyloid antibodies.

The adverse events (AEs) were similar in nature between the two studies and among the three APOE ε4subgroups.

Looking to the future, this drug could possibly be used early on in patients at genetically high risk for AD, in whom subtle cognitive changes often begin as early as the 50s, with some developing frank dementia in their 60s.


Animal Study Hints at Gene Therapy’s Possible Promise for Alzheimer’s 

(Source Imperial College London, news release, 10.10.2016.)

A new research in mice suggests that Gene therapy might one day offer a way to prevent and treat Alzheimer’s disease. Scientists at Imperial College London used a modified virus to deliver a gene called PGC1-alpha into the brain cells of mice. Previous research suggests this gene may prevent the formation of a protein called amyloid-beta peptide.

Amyloid-beta peptide is the main component of amyloid plaques, the sticky clumps of protein in the brains of Alzheimer’s disease patients. These plaques are thought to cause brain cell death. These very early findings could lead to a way of preventing Alzheimer’s or stopping it in the early stages, according to study senior author Magdalena Sastre.

Alzheimer’s is the most common type of dementia. It causes memory loss, confusion, and changes in mood and personality. There is no cure. “There are many hurdles to overcome, and at the moment the only way to deliver the gene is via an injection directly into the brain,” Sastre said in a college news release.

It’s also important to note that therapies that look promising in mice often don’t work in humans. “However, this proof-of-concept study shows this approach warrants further investigation,” she added. Sastre is a senior lecturer in the department of medicine.

David Reynolds, chief scientific officer for Alzheimer’s Research UK, said studies like this one are important because current treatments do not stop progression of Alzheimer’s damage. “This research sets a foundation for exploring gene therapy as a treatment strategy for Alzheimer’s disease, but further studies are needed to establish whether gene therapy would be safe, effective and practical to use in people with the disease,” Reynolds said in the news release.