Amyloid Remains a Key Target in Next-Generation Alzheimer’s Treatments

Brain and Pills_Taylor Tieden for BioSpace

Pictured: A colorful brain surrounded by pill bottles/Taylor Tieden for BioSpace

With 164 clinical trials assessing 127 drugs in the pipeline, momentum in the Alzheimer’s space is on an upward swing—and while the field has expanded from its initial targets of amyloid beta and tau, experts believe they will remain a pivotal part of the treatment landscape.

Five or 10 years ago, 75% of the drugs in development for Alzheimer’s were anti-amyloid beta (Aβ) or anti-tau drugs, said Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation. “Today that’s completely reversed, as 75% of the drugs in clinical development are non-amyloid, non-tau drugs,” Fillit told BioSpace.

The framework for new approaches coming down the pipeline is to confront the leading risk factor for Alzheimer’s disease: age. The majority of clinical development aims to address age-related issues such as neuroinflammation, epigenetic autophagy, metabolic and mitochondrial disorders, and vascular problems, Fillit noted.

Beta-amyloid has long been a prime suspect in Alzheimer’s disease progression. The protein is chemically sticky and accumulates in plaques that are a hallmark trait of the degenerative disease. While the so-called amyloid hypothesis has been “very exciting” for years, “nobody believes . . . that there’s a single target,” said Lisa Ricciardi, CEO of Cognition Therapeutics, which is focused on neurodegenerative and neuro-ophthalmic diseases.

Fillit concurred, saying that combination therapy is the future and anti-amyloid therapies will remain an important part of treating patients.

Optimizing Administration and Brain Penetration

With Biogen and Eisai’s Leqembi on the market and an FDA advisory committee convening today to discuss Eli Lilly’s donanemab—both amyloid-clearing antibody treatments—companies developing anti-amyloid therapeutics are pivoting toward next-generation development. Two key areas targeted for improvement are administration and blood-brain barrier penetration, Fillit said.

Both Leqembi and donanemab are administered intravenously, every two weeks for the former and every four weeks for the latter. In addition to infusion center visits, patients on these therapies are looking at a series of imaging requirements to ensure brain health as they’re treated. Long-term data is not yet available for these new antibodies, so length of treatment is still unknown.

Aiming to relieve some of the burdens of treatment, both subcutaneous versions and oral therapies targeting beta-amyloid are currently in development.

Aliada Therapeutics’ monthly, subcutaneous antibody, ALIA-1758—in-licensed from J&J’s Janssen and moving toward Phase I ascending dose clinical studies—is uniquely engineered for both delivery and plaque clearing.

Targeting pyroglutamate amyloid beta, which is similar to the epitope targeted by donanemab, ALIA-1758 utilizes the transferrin receptor to drive its cargo to cells and force degradation and elimination of the plaques, explained John Dunlop, chief scientific officer at Aliada. By transporting the cargo in this way, a higher concentration of the antibodies is delivered across the blood-brain barrier to drive therapeutic benefit, he told BioSpace.

While first-generation anti-amyloid therapies show “some” evidence of efficacy, “I think we all agree in the field: there is significant room for improvement,” Dunlop said.

Meanwhile, Cognition is tackling amyloid beta with an oral, brain-penetrant small molecule. Instead of focusing on removing plaques from the brain, Cognition’s candidate, CT1812, prevents the binding of toxic oligomers to synapses in a neuroprotective approach that acts earlier in the amyloid cascade to slow cognitive decline and disease progression, Ricciardi explained. An 18-month Phase II trial is underway with 540 early-to-mild Alzheimer’s patients, and Cognition expects results from an earlier Phase II trial mid-summer, she said.

With the currently approved anti-amyloid antibodies, “a very tiny amount of the drug actually makes it into the brain,” Ricciardi said, so Cognition’s founding scientists prioritized a high degree of blood-brain barrier (BBB) penetration for its lead asset.

Roche is also focused on the BBB dilemma. After a failed attempt at developing an anti-amyloid antibody for Alzheimer’s, the Swiss pharma is now testing an antibody delivered by its Brainshuttle module, which also utilizes the transferrin receptor. Initial data shows trontinemab had “substantially higher CNS exposure due to shuttling” than the first drug, gantenerumab, with dose-dependent amyloid plaque lowering capabilities.

Eisai and Biogen are on board with improving administration, too. The partners initiated a rolling Biologics License Application (BLA) last month for a weekly, subcutaneous version of Leqembi.

Improving Safety

Fillit said about 20% of patients experience an adverse event from the current anti-amyloid antibody treatments, but most are not serious. Only around 2% of patients have a serious adverse event, he noted, so with Alzheimer’s being one of the leading causes of death, the “product profile in terms of risk and benefit is favorable.”

However, certain populations are not eligible for treatments like Leqembi. Patients with two copies of APOE4, a gene variant that carries a high risk of Alzheimer’s, and those on anticoagulants who are at higher risk for brain swelling and bleeds, leading to warnings in the product’s label.  

“When you look at the criteria for patients who can actually take the [antibody] and you use all the exclusion criteria, it comes down to a fraction of the population. That was surprising to me,” Ricciardi said.

In contrast, Cognition’s trials have been open to all comers with mild-to-moderate Alzheimer’s. So far, Ricciardi said the company has yet to see the amyloid-related imaging abnormalities (ARIA)—a form of brain swelling—that have occurred with Leqembi and donenamab. Since CT1812 works preventatively, it isn’t removing plaques, which can lead to tears in the vessels of the brain or swelling, she explained.

Similarly, due to its mechanism, Aliada’s candidate doesn’t engage the microglia and isn’t associated with release of pro-inflammatory cytokines. The company therefore does not anticipate any ARIA incidence as it begins clinical trials, which Dunlop believes should “open up the possibility to really get into a broad population.”

And Roche’s Brainshuttle delivery may allow for lower doses of the antibody due to superior BBB penetration. Experts believe this could lower ARIA risk. In its Brainshuttle AD trial, Roche reported a “low incidence of ARIA despite robust amyloid lowering,” with two asymptomatic or mild cases of ARIA in the higher 1.8 mg/kg cohort.

Combination Treatments

Overall, experts believe amyloid beta will be an important target in a multi-pronged approach to treating the progressive, memory-robbing disease.

In the future, “we’re going to have precision medicine for Alzheimer’s disease with combination therapy,” Fillit predicted.

In Cognition’s START trial, patients are allowed to come in on background Leqembi. Those who have been on the antibody for three to four months can be included in the trial in order to see how the drugs work together.

“As far as I know, that’s the first trial looking at real-time combination therapy,” Ricciardi said. Cognition is hoping to find a “great homeostasis” in the combined effort, with Leqembi clearing out old plaques while CT1812 protects the neurons and clears out oligomers.

Amyloid triggers a pathological cascade of immune activation, brain inflammation and changes to the tau protein, Dunlop said. Aliada is thinking carefully about a complementary tau-targeting asset for its pipeline.

As more targets emerge for Alzheimer’s disease, one thing is clear to Aliada’s leadership team, Dunlop added: “Amyloid is always going to be around.”

Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

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