Antiamyloid Drug Shows Gene-Dose Effect in Alzheimer's

Pauline Anderson

November 17, 2016

The oral antiamyloid drug tramiprosate benefits a subgroup of patients with ε4 alleles of the apolipoprotein E (APOE) gene, without increasing vasogenic brain edema, a side effect linked to other drugs that target amyloid, a new analysis of phase 3 data suggests.

The study showed a gene dose-related benefit of tramiprosate, with the largest effect among APOE ε4 homozygotes (2 alleles), intermediate benefit for APOE ε4 heterozygotes (1 allele), and no benefit in APOE ε4 noncarriers (0 alleles).

It makes sense that people with more amyloid would respond better to an amyloid-targeting drug, according to lead study author Susan Abushakra, MD, chief medical officer of Alzheon, the company developing a prodrug of tramiprosate.

While 95% of homozygous persons have amyloid in the brain, about 80% of heterozygous persons have amyloid and only up to 60% of APOE ε4 noncarriers have amyloid, she said.

"When you do a study putting everyone together, it's like adding apples and oranges; you're treating people who don't have amyloid, so they can't respond to the drug."

In this new analysis, homozygous patients taking the higher-dose drug "had clinically relevant efficacy on cognition and function without having the side effect of vasogenic edema, which would limit the dose you can give them," said Dr Abushakra.

The paper was published online October 24 in the Journal of the Prevention of Alzheimer's Disease.

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.

The NA trial results, which became available in 2007, did not show significant efficacy on the co-primary outcomes of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). The EU trial was subsequently terminated before completion.

In these trials, APOE ε4 status was a prespecified covariate. It was found to be significant for both primary outcomes (P < .05).

Now, researchers have further analyzed the primary, secondary, and safety outcomes of these studies based on the number of APOE ε4 alleles in APOE ε4 homozygous, heterozygous, and noncarrier 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. In this group, a significant drug-placebo difference was observed on the ADAS-cog at the last study visits (visit 65: –3.47 [P = .0066]; visit 78: –2.60 [P = .043]).

There was a positive trend on the CDR-SB at week 65 (–0.79; P = .063) and a numeric benefit at week 78.

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.

In this group taking the low-dose drug, there was numeric benefit on ADAS-cog and nonsignificant effects on CDR-SB at weeks 65 and 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.

The noncarriers had nonsignificant effects on both outcomes at the low dose. Placebo was significantly better than the higher dose of tramiprosate on both outcomes in this group.

"We call it the gene-dose effect because the more alleles patients had, the more amyloid they had, and the better they responded to the drug," said Dr Abushakra.

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.

The 12-item Neuropsychiatric Inventory showed a positive trend at week 52 (P = .015) with a 138% drug benefit, and a numeric benefit at 78 weeks. The Mini-Mental State Examination (MMSE) showed small effects that were not significant at these visits.

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.

"What we saw was that as you remove the moderate patients from the analysis, the response of the milder ones keeps getting better," said Dr Abushakra. "The mildest people, who have an MMSE score of 22 and above, are the ones where we almost see real stabilization of their cognition and marked improvement in their function."

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, she said.

This finding is consistent with other programs in the amyloid field and is something that the researchers plan to study further, said Dr Abushakra.

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. The most common AEs were gastrointestinal (GI) and included nausea, vomiting, and weight loss.

A new formulation (ALZ-801), which conjugates the drug to a naturally occurring amino acid called valine, has improved oral absorption and "helps tramiprosate get through the upper GI tract," said Dr Abushakra.

A phase 1 study showed that this pro drug has more sustained and consistent blood levels. "That's important because it translates into better brain levels, which is what we want," said Dr Abushakra.

Alzheon is advancing ALZ-801 into phase 3 studies in APOE ε4/ε4 patients with AD.

"Our plan is to study a well-defined population genetically — that's the homozygotes," said Dr Abushakra. "This is very much like a precision medicine approach that people have taken in oncology. It focuses on a certain genotype and should help improve the chances of success for this program."

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.

"If you have a drug that has a good safety profile that will help prevent accumulation of amyloid, it would be a good approach to use it in primary prevention," said Dr Abushakra. "It's something we would consider certainly in the future."

Reached for a comment James Hendrix, PhD, director of Global Science Initiatives, Alzheimer's Association, who has a background in drug development, was intrigued by the finding that people homozygous for this mutation seemed to have the greatest drug effect.

"To say that if you have APOE ε4 status, drugs will have a more dramatic impact on your treatment is something I hadn't seen before and it's very interesting."

The results lead to "a lot of questions," said Dr Hendrix. For example, if an effective antiamyloid treatment becomes available, should this type of patient selection be used to determine who should be on it?

Dr Hendrix would have liked to know more about the noncarrier nonresponders in this study. "These people were in the mild to moderate stage of AD so what's really driving their disease? Is it tau? Is it something else? We really don't know a lot about the nonresponders, but for folks in this APOE ε4 category, it appears that amyloid could be what's driving their disease."

Alzheon Inc funded these analyses and manuscript preparation. BELLUS Health (previously Neurochem), the original sponsor, had funded the tramiprosate phase 3 studies. Dr Abushakra is an employee of Alzheon Inc. Dr Hendrix has disclosed no relevant financial relationships.

J Prev Alzheimers Dis. Published online October 24, 2016. Abstract

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