By Richard Robinson January 23, 2020

Investigators review the scientific evidence for targeting amyloid oligomers and outline the case for a new drug in development for Alzheimer's disease, ALZ-801, an orally administered prodrug of tramiprosate.

What is the right target for drugs for Alzheimer's disease (AD) and what is the right population to test them in? For one biopharmaceutical company, the answers are amyloid-beta (Abeta) oligomers and APOE4 homozygotes, and they plan to test a drug that inhibits oligomerization in this genetic subgroup of AD patients in the coming year.

But while the target is increasingly recognized as an important one in AD pathogenesis, not every expert believes that the rationale for restricting such a trial to the small number of AD patients who carry two copies of e4 is compelling.

The case for oligomeric forms of Abeta as central to AD is persuasive, according to Marwan Sabbagh, MD, FAAN, co-author of a November 4, 2019 perspective in the journal Alzheimer's & Dementia that reviews the scientific evidence for targeting amyloid oligomers and outlines the case for the new drug. Dr. Sabbagh is the Camille and Larry Ruvo Chair for Brain Health and director of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas, NV. His co-authors are neurologists Martin Tolar, MD, PhD, and Susan Abushakra, MD, both of Alzheon, the company that is developing the drug, called ALZ-801, a prodrug of tramiprosate.

Monomeric forms Abeta don't tend to cause damage or activate microglia, and plaques are essentially graveyards, said Dr. Sabbagh. Oligomers, on the other hand, cause damage particularly to synapses, and microglial activation often starts when you get to the oligomeric phase, so we as a field think that oligomeric species tend to be more toxic than other species of Abeta.

The distinction between amyloid species is important, he added, because different treatmentsespecially the monoclonal antibodiestarget different forms of amyloid. Crenezumab and solanezumab bind most strongly to monomers, while bapineuzumab targets both soluble forms and plaques. The newest group of monoclonals, including aducanumab and BAN 2401, target both oligomers and plaques, but with different selectivity.

The concept of targeting oligomers was recently given a boost by the whipsaw change in fate for aducanumab. After announcing disappointing results and withdrawing the drug from further development early in 2019, Biogen this fall announced they had reanalyzed their data to suggest it did in fact lead to slowing of cognitive decline in patients with early AD, and that they would be submitting it to the US Food and Drug Administration for approval of the drug.

The data suggest that monoclonals that include oligomers within their targets have had better effects than the previous generation of monoclonals, both in terms of clearance of amyloid, and downstream cognitive effects, Dr. Sabbagh said, including reduction in tau and clinical stabilization, so targeting oligomeric species seems to be holding up scientifically.

All of that has led Alzheon to move ahead with a phase 3 trial of ALZ-801, an orally administered prodrug of tramiprosate. In preclinical studies, ALZ-801 inhibited the formation of oligomers without affecting fibrils or plaques. Those studies have shown that multiple molecules of tramiprosate reversibly bind and envelop the Abeta monomer, stabilizing it and preventing it from aggregating into an oligomeric form.

Previous clinical trials of ALZ-801 have shown good long-term safety, but phase 3 trials of tramiprosate did not demonstrate efficacy in the whole group of patients with mild to moderate AD. However, a prespecified analysis published in 2017 in The Journal of Prevention of Alzheimer's Disease did show that those patients carrying two copies of the APOE4 allele experienced a statistically significant slowing of decline in the Alzheimer's Disease Assessment Scale-Cognitive Subscale compared with placebo.

This time, the trial will not enroll across the AD spectrum, but instead will be limited to patients with early AD who are e4/e4 homozygotes. In this group, the production of amyloid is elevated and the clearance is reduced, said Dr. Sabbagh, and the clinical course is both more uniform and more rapid than in the general AD population. Researchers are hoping that this will allow an efficacy signal to emerge clearly and quickly. The 78-week phase 3 trial is expected to start this year.

The rationale for specifically targeting oligomers is sound, William Klein, PhD, professor of neurology at Northwestern University in Chicago told Neurology Today. Dr. Klein, who studies Abeta oligomerization, said, This is an intensely studied field, and most of the results point to disruption of signaling by oligomers in particular.

That appears to trigger phosphorylation of tau, a major step in AD pathogenesis, he noted. Much about Alzheimer's disease is controversial, but there have been [more than] 4,000 papers on Abeta oligomers, and the preponderance of evidence favors these as being important players.

There is an additional reason for targeting Abeta oligomers, Dr. Klein noted. The transition from monomeric Abeta to higher molecular weight forms is not a linear set of reactions, but rather a spiderweb of pathways, and so depleting fibrils, for instance, as some therapies have attempted, does not necessarily deplete oligomers. It's not a simple equilibrium, he said.

Depletion of monomers is also a challenge, because it is really hard to get rid of enough monomer to really make a difference in the quantity of oligomers, he said. A lot of the products haven't been developed to uniquely focus on oligomers, which is why they have requirements for very high doses, and lead to side effects.

Restricting the trial to e4 homozygotes is more problematic, said Paul Aisen, MD, professor of neurology and director of the Alzheimer's Therapeutic Research Institute at the University of Southern California Keck School of Medicine.

APOE genotype is the most important risk factor for sporadic AD, and determination of APOE genotype has played an important role in our trials for many years, Dr. Aisen said, but mainly as a covariate in assessing outcomes, not as an inclusion criterion for enrollment. Treating only those with two copies of the e4 allele is certainly a valid approach, but it raises important regulatory issues.

If the study is successful, he asked, where does that leave the one third of AD individuals that don't carry an e4 allele? Will approval be restricted to e4 carriers? Do you have an obligation to test in the e4-negative group?

In addition, Dr. Aisen said it is not clear why this drug should have a special effect on e4 homozygotes versus other patients who also produce amyloid. The drug doesn't target the biology of e4 in particular, he pointed out, and so it is not clear that the drug effect should be restricted to one genotype versus another. I would expect an anti-aggregation agent to work across genotypes. My own view is that unless you are testing a drug that is specifically related to APOE, it may be more appropriate to target your therapeutics for everybody with AD.

Dr. Sabbagh receives stock options as an advisor to ALzheon on the design of their phase 3 clinical trial. Dr. Klein has stockin Acumen Pharmaceuticals, which he co-founded in the 1990s. Acumen has a humanized antibody that is very specific for A-beta oligomers and is being readied for clinical trials in 2020; his lab received research funding from AbbVie and RxGen for oligomer-related studies. Dr. Aisen had no disclosures.

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Is Targeting Oligomers in APOE4 Homozygotes the Path... : Neurology Today - LWW Journals