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New disease findings and old clinical trials
FRAMINGHAM, Mass.—Alzheon Inc., a biopharmaceutical company focused on treatments for neurodegenerative and neuropsychiatric disorders, recently published the first report to associate efficacy of an amyloid-targeted drug with the number of APOE4 alleles an individual possesses in The Journal of the Prevention of Alzheimer’s Disease.
The results could lead to a novel precision medicine approach in Alzheimer’s disease (AD) drug development, the authors claimed. Pivotal studies of ALZ-801, an oral prodrug of tramiprosate, to target AD patients who are APOE4 carriers, will be initiated in 2017.
According to Dr. Susan Abushakra, chief medical officer of Alzheon, “There is a lot of evidence supporting the important role of beta amyloid in Alzheimer’s disease (AD). Most genetic mutations that lead to familial AD involve the amyloid precursor protein (APP) gene leading to increased production of beta amyloid. The few genetic mutations that are protective from AD also involve the APP gene and lead to less production of beta amyloid. The APOE4 (apolipoprotein E) allele, the strongest risk factor for AD, plays an important role in beta amyloid metabolism and is associated with more beta amyloid production and deposition.”
Abushakra explained that there is a strong rationale for drugs that target and inhibit amyloid aggregation and neurotoxicity, which are hallmarks of Alzheimer’s disease. She believes that a greater understanding has now emerged about the reasons that the first generation of disease modification trials with amyloid-targeted agents, which were completed before the availability of amyloid imaging, have failed.
“Most first-generation studies enrolled patients based only on a clinical diagnosis of AD, without amyloid imaging,” she said. “We now know that a high percentage of patients in these studies do not actually have amyloid, especially the APOE4 non-carriers. Therefore, amyloid-targeted drugs do not have a chance to show benefit in such studies.”
The fact that amyloid drugs have such a large body of clinical evidence is being “mined” as an asset, according to Abushakra. Instead of “closing the books” on failed studies with amyloid-targeted drugs for Alzheimer’s treatments, researchers are drawing insights from new disease findings and previous clinical trials to guide further-refined studies with still-promising drugs in more targeted populations. Alzheon’s work with analyzing the Phase 3 data for tramiprosate is an example of leveraging past clinical studies to identify and accelerate new treatment opportunities with an oral, amyloid-targeted drug candidate.
Abushakra believes that the key reasons that the first generation of amyloid-targeted agents failed are that they did not include amyloid PET imaging, thus a high percentage of patients did not actually have amyloid pathology and neurotoxicity. She also notes that they included patients with mild and moderate disease (as primary analysis), and consistently the efficacy signals with most agents were seen in the mild but not the moderate subgroups. As she explained, with the first-generation amyloid antibodies, APOE4 carriers, who have a high load of vascular amyloid, had increased risk of a severe side effect in the brain (vasogenic edema/ARIA-E and micro-hemorrhages/ARIA-M) at high doses of these antibodies. This led to use of lower sub-efficacious doses in Phase 2 and Phase 3 that did not clear amyloid. Thus, the risk of ARIA can be a dose-limiting toxicity for some antibodies. She noted that this is not the case with Alzheon’s drug candidate, which is an oral drug, not an injectable antibody, and its active molecule, tramiprosate, did not show increased risk of ARIA in clinical studies.
Alzheimer’s patients who are APOE4 carriers are more responsive to amyloid-targeted medications because they have a higher load of vascular amyloid compared to non-APOE4 carriers, according to Abushakra. “Furthermore, APOE4/4 homozygotes have 95-percent likelihood of having amyloid pathology and of showing potential efficacy with an amyloid-targeted drug,” she said.
Abushakra added, “With amyloid-targeted agents, it is critical that intervention happen at the early to mild stage of the disease, to decrease the toxicity from the beta amyloid and the secondary neuron loss. Intervention at the moderate stage is probably too late to demonstrate meaningful effects on slowing the course of the disease, because a lot of neuronal loss may have already occurred.”
Alzheon has a very strong clinical dataset in APOE4/4 homozygotes, a biologically and clinically relevant population at highest risk for development of AD, highest beta amyloid load and fastest deterioration of cognitive impairment—and a very straightforward approach to accurate diagnosis of AD using APOE4 genotyping (simple blood test), according to Abushakra.
As she explained, “The magnitude of the effect that we have seen, particularly in the mild AD population (MMSE 22-26), suggests the potential for significant delay of disease progression and even cognitive improvement. To date, no clinical trials in AD patients have been conducted in APOE4/4 homozygotes. Alzheon is trailblazing in the design of the planned studies with ALZ-801. The studies with ALZ-801 will utilize a ‘precision medicine’ approach, where the study population will be based on APOE4 genotype. AD patients with APOE4/4 genotype have the highest diagnostic accuracy and have thus shown largest benefit. The studies with ALZ-801 will focus on the mild AD group, since they show the most robust efficacy.”