Eisai, Alzheon Drill Down on Promising Results in High-Risk Alzheimer’s Subset

 

At the AD/PD annual meeting, Eisai presented real-world data suggesting Leqembi’s long-term safety and efficacy in people homozygous for APOE4, who were identified in trials as being at higher risk of brain bleeds while on the treatment. Alzheon, meanwhile, added further detail to trial results of its candidate in patients with the same genetic profile.

Carrying two copies of the gene variant APOE ɛ4 has long been linked to an increased risk of developing Alzheimer’s disease. Cruelly, the same genetic profile was associated with brain bleed events known as ARIA-H and ARIA-E in trials of Biogen and Eisai’s Leqembi, and some regulators, including the European Medicines Agency, have carved out APOE ɛ4 homozygotes as ineligible for the groundbreaking anti-amyloid therapy.

Armed with real-world data, Eisai made a case earlier this month at the AD/PD annual meeting in Copenhagen that most of these treatment-associated bleeds in people with two copies of APOE4 (defined as homozygous) were not as common as in earlier trial data, and that the risk dropped off after six months of treatment. Moreover, most people did not experience disease progression over the course of the study.

Meanwhile, Alzheon, which rolled out topline results at the same meeting last year showing that its candidate, valiltramiprosate, missed its primary endpoint in a Phase 3 trial that enrolled people homozygous for APOE4, was back this year with more details on that study as well as a new data from a Phase 2 trial. Alzheon presented biomarker and brain imaging data to bolster positive results on a cognitive assessment for patients who enrolled in the study with mild cognitive impairment (MCI) rather than later in the course of the disease.

“The conference had a significant focus on biomarkers, and there [have] been such tremendous advances that these biomarkers are really allowing us to understand the underlying biology of the patients that we’re trying to treat with therapies,” Aaron Burstein, head of search and evaluation at the Alzheimer’s Drug Discovery Foundation, told BioSpace. Eisai’s data was “very encouraging” and “provides additional support for the potential use of these agents in the APOE4 carrier status as was approved by FDA,” he said.

As for Alzheon’s results, Burstein said the biomarker data “provided support that the hypothesized clinical benefits they were seeing were associated with measures consistent with actually having effects on the underlying biological processes.”

Genes and Brain Bleeds

Approved by the FDA in July 2023, Leqembi carries a black-box warning noting that APOE4 homozygotes have a higher risk of amyloid-related imaging abnormalities (ARIA) when treated with this class of medication and recommending that providers genetically test patients before prescribing it.

“Consider the benefit for the treatment of Alzheimer’s disease and risk of ARIA when deciding to treat with LEQEMBI.,” the warning states.

An analysis of the Phase 3 trial results found that people homozygous for APOE4 had a 45% chance of developing ARIA-E when taking Leqembi, compared with 13% for noncarriers and 19% for patients heterozygous for the variant. This is thought to be because APOE4 is associated with a greater buildup of amyloid proteins near the blood vessel walls, and when that buildup is removed, “sometimes there’s this leakage that occurs,” explained Lynn Kramer, Eisai’s chief clinical officer.

In the real-world analysis, which included the records of 207 patients at sites across the U.S., the increased risk was less stark than in the trial: 21.2% of APOE4 homozygotes developed ARIA, versus 13.7% of noncarriers. All but one of the cases in each group were asymptomatic.

On the benefits side of the equation, 76% of people with two copies of APOE4 were at the same or an improved disease stage at the final follow-up compared to when they began treatment. On average, patients were followed for 491 days.

Kramer noted that relative to the pivotal trial, homozygous patients in the real-world analysis were, on average, enrolled at a later disease stage. “Our thinking is they should be treated earlier like everybody else if you want to get maximum benefit,” he told BioSpace. “But I think this type of information makes physicians maybe more comfortable in understanding the risks so that they start treating the patients a little sooner.”

In addition, he said, the company intends to continue collecting real-world data in hopes of eventually getting labels changed in countries that don’t include APOE4-homozygous patients in their drug authorizations.

In an extension of Leqembi’s Phase 3 trial, Eisai has seen the difference in disease stage between treated people and matched external controls widen over time, Kramer added. And “after the first six months or so, these ARIA events just occur at the same frequency as they would in the [external control] group. . . . So the risk is really at the beginning. . . . That’s why the benefit improvement is important.”

Toward a Precision Approach

The fact that Alzheon focused on APOE4 carriers in its own trials is no accident. Under its original sponsor, NeuroChem, tramiprosate did not have statistically significant effects in patients with Alzheimer’s in a clinical trial and was put on ice. But posthoc analysis indicated the modified amino acid had benefited participants homozygous for APOE4, said John Hey, chief scientific officer at Alzheon. The startup licensed the drug from NeuroChem and is developing a prodrug version, valiltramiprosate, specifically in that population.

Apart from the drug’s biological effects, an additional reason for focusing on APOE4 homozygotes first, Hey said, is their higher unmet need due to restrictions and warnings around Leqembi’s use.

Among the new results presented at AD/PD, Burstein singled out those showing a sustained reduction in levels of p-tau-217, a biomarker associated with amyloid pathology, as particularly interesting. Patients with MCI in the Phase 2 study have shown a drop in levels of the biomarker compared with baseline that has lasted through four years of follow-up, according to Hey’s presentation. That reduction correlated with clinical measures.

Speaking with BioSpace, Hey highlighted the safety results of the Phase 3 study, which found no difference in ARIA-E rates for the drug versus placebo. For ARIA-H, rates were actually lower in the treatment group. Valiltramiprosate acts to block the formation of toxic aggregates in the brain, and “if you prevent that neurotoxic wave in the neurodegeneration and the sequelae of events that lead to the inflammatory milieu that leads to ARIA . . . you get a benefit on neurovascular outcomes,” Hey suggested.

The next steps for Alzheon, he said, will be to conduct confirmatory studies in APOE4 homozygous and heterozygous patients with MCI. Ultimately, he sees the drug being used for patients when they first begin to show symptoms—or even before—in order to glean maximum benefit from treatment.

“I think as we see the advent of the fluid biomarkers, those will be used increasingly for diagnostic and for precision treatment to give some tools for the physician on how to treat these subjects,” Hey said.

https://www.biospace.com/drug-development/eisai-alzheon-drill-down-on-promising-results-in-high-risk-alzheimers-subset