NewAmsterdam’s low-density lipoprotein (LDL) cholesterol-lowering therapy, obicetrapib, has shown promise in diminishing a key biomarker of Alzheimer’s disease – potentially signifying the drug’s role in the preventative setting.
This is evidenced by the results of a post hoc responder analysis within a sub-study of the Phase III BROADWAY trial (NCT05142722). In the trial, the drug triggered a significant reduction in the levels of p-tau217 – a biomarker linked to Alzheimer’s – in patients with at least one copy of the APOE4 gene, which is associated with a heightened risk of the neurodegenerative disease.
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The data was presented at the Alzheimer’s Association International Conference (AAIC), taking place in London from 12 to 15 July.
After treatment, patients with one and two copies of APOE4 given obicetrapib experienced a 7.7% and 2.6% median drop in p-tau217 levels compared with a 16.1% and 7.9% increase in the placebo arm – equating to a difference of 23.8% and 10.4% between levels of the biomarker between the treatment and placebo groups, respectively.
While obicetrapib’s impact was most pronounced in patients with two copies of this gene, with just over three times more patients given the drug experiencing a p-tau217 reduction of 5% or more versus placebo, those with one APOE4 copy also accrued benefit, as there were 2.1 times more responders in this patient group. The drug had no impact on patients with two copies of the APOE3 – a factor which NewAmsterdam says strengthens the view that obicetrapib compensates for APOE4-linked lipid transport dysfunction rather than providing a non-specific benefit.
The BROADWAY trial evaluated obicetrapib’s adjunctive impact alongside lipid-lowering therapy in patients with atherosclerotic cardiovascular disease (ASCVD) and heterozygous familial hypercholesterolemia (HeFH).
Of all the BROADWAY patients, nearly half exceeded the 0.42 pg/mL p-tau217 threshold, which indicates a high likelihood of Alzheimer’s-linked amyloid-beta plaque buildup in the brain, despite receiving regular cardiovascular care and having no neurological evaluation.
This finding, NewAmsterdam says, highlights the “critical gap between cardiovascular and dementia care”. In conversation with Clinical Trials Arena, the company’s CEO, Michael Davidson, noted that obicetrapib’s potential to prevent both vascular strokes and Alzheimer’s dementia could make the drug a “game changer in overall dementia prevention”.
Following this positive outcome, NewAmsterdam plans to initiate the double-blind, placebo-controlled SPINOZA trial, Davidson confirmed, which will look at the impact of obicetrapib in high-risk patients based on their APOE genotype and biomarker status.
Incorporating learnings from BROADWAY, SPINOZA will also incorporate an open-label extension (OLE) to the study, in which all patients will receive obicetrapib.
Looking behind the curtain on the LDL-lowering approach
While disease-modifying therapies (DMTs) are now on the market for Alzheimer’s disease, there are a lack of targeted interventions that could hold preventative potential in the disease.
In this context, NewAmsterdam hopes that obicetrapib, which acts by lowering levels of ‘bad’ cholesterol, known as LDL-C, while increasing levels of ‘good’ cholesterol, or HDL-C, could offer as a potential preventative therapy.
“We don’t know exactly why Alzheimer’s disease occurs, but we do know that the main genes associated with the disease all impact lipid metabolism; think APOE4, ABCA1, ABCA7 and TREM2,” Davidson said. Because of this, it’s possible that a lipid-altering therapy could benefit patients at risk of Alzheimer’s, he added.
According to Davidson, LDL-C lowering drugs like obicetrapib are likely to show the most benefit early on in the disease before neurodegeneration-associated cognitive decline begins to occur, as this approach could hold the potential to prevent the disease in the first place.
While many currently operate under the pretence that Alzheimer’s cannot be prevented, Davidson hopes this will change with preventative studies, which hold the potential to highlight APOE4 testing as beneficial and actionable with emerging treatment options.
