With fresh $100M, Alzheon lays out strategy for Alzheimer’s approval next year

2024-06-12

交易

临床2期临床3期临床结果上市批准

Despite a pair of drug approvals within the last three years and millions of patients in need, Alzheimer’s disease treatments have struggled with a gamut of safety, efficacy, and accessibility problems. As a third anti-beta amyloid antibody – Eli Lilly’s donanemab – nears FDA clearance, Alzheon is taking a different tack with its lead programme that it thinks will address all three pain points that have plagued drug development in the field.

On Wednesday, the biotech raised a $100-million series E to wrap up the APOLLOE4 Phase III study of valiltramiprosate (ALZ-801) in patients with early Alzheimer’s, and ready it for commercialisation. The round, led by Alerce Medical Technology Partners, brings Alzheon’s total equity financing to $185 million.

The pivotal trial is expected to read out in the third quarter, and the company plans to begin a regulatory submission to the FDA by year-end. If all goes well, CEO Martin Tolar expects the oral small molecule to be available to US patients in 2025.

“We truly are at the dawn of a new era,” he said. “We understand the biology [of Alzhiemer’s] and we have an opportunity to transform the standard of care with our treatment.”

Genetically defined disease

Alzheon was founded over a decade ago to develop a treatment for Alzheimer’s by methodically determining which toxic agent is driving the disease, and which biomarkers are effective at tracking progression and gauging the efficacy of a given treatment.

Notably, Alzheon’s clinical programme is initially enrolling patients who are homozygous for APOE4, a strong genetic risk factor of the disease.

Around two-thirds of patients with Alzheimer’s have one copy of the gene, but in people with two copies, “virtually everybody” will develop the disease, Tolar said. About 15% of Alzheimer’s patients are homozygous for APOE4.

While the high-risk group might seem the most likely to benefit from treatment, both of Biogen and Eisai’s anti-beta amyloid antibodies, Leqembi (lecanemab) and the now-abandoned Aduhelm (aducanumab), as well as Lilly’s donenamab, have not been as effective in APOE4-homozygous patients and in fact had increased side effects in this population.

Plaque precursors

While Alzheon has also landed on beta amyloid as the main cause of Alzheimer’s, the team importantly singled out small, soluble amyloid aggregates – the precursors of the plaques targeted by most antibody therapeutics – as the molecules responsible for disease pathology.

Beta amyloid is a key neurological protein that responds to damage, but as we age, levels of the monomer increase and the brain becomes less efficient at clearing it. As the molecule accumulates, it can misfold and begin aggregating into toxic, soluble oligomers that cause damage to the brain, Tolar explained.

The brain will then sequester these aggregates into insoluble amyloid plaques, which have been the target for much of the drugs in development for Alzheimer’s.

But, Tolar said, plaques are “the wrong target” to achieve cognitive and functional improvement, which the company says it has demonstrated in multiple published studies. Rather, the key is to prevent these plaques from forming in the first place – valiltramiprosate accomplishes by blocking beta amyloid from clumping into oligomers.

Positive safety, efficacy signs

So far, clinical data seem to support Alzheon’s tactic. While Leqembi and donanemab led to patient improvements of 27% and 29%, versus placebo, respectively, on the Clinical Dementia Rating scale, Phase II results for valiltramiprosate demonstrated an 81% functional benefit on the same measurement.

“These patients usually are at the edge of a cliff. They are a little forgetful. But in a year and a half they don't recognise their children, their spouses. And we can keep them stable for two years,” Tolar commented. “These are the data that really gave us confidence [in valiltramiprosate], and in fact helped us raise $100 million at a time where nobody can raise money.”

Additionally, because plaques can occur in blood vessel walls, they could also be the reason why amyloid-related imaging abnormalities (ARIA), which can cause both brain oedema and haemorrhage, are a serious side effect associated with both Leqembi and donanemab.

However, since valiltramiprosate doesn’t act on plaques, it could be a safer option. “We have shown in over 3000 patients, in a three-year follow-up, that we don't have an increase in brain haemorrhages,” Tolar said.

Another potential benefit of valiltramiprosate is simply by virtue of its oral administration, which would make it cheaper and easier for patients to take for years to stave off disease progression, rather than an antibody IV infusion.