Trial testing cholesterol-lowering med as potential Alzheimer’s intervention
First participant dosed in US study still enrolling people with very early disease
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NewAmsterdam Pharma has dosed the first participant in a large mid-stage clinical trial assessing the safety and effectiveness of its cholesterol-lowering treatment candidate obicetrapib as a potential aid for people with preclinical Alzheimer’s disease.
The biopharmaceutical company is developing the oral med for individuals at risk of cardiovascular disease who have high levels of low-density lipoprotein, or LDL, the so-called bad cholesterol. Obicetrapib is designed for individuals for whom existing therapies are not well tolerated or effective enough.
In this new U.S. trial, New Amsterdam is aiming to evaluate whether the therapy could also potentially benefit adults with “biomarker evidence suggestive of preclinical Alzheimer’s disease who do not have noticeable memory or functional symptoms,” according to a company press release. The developer says it’s testing obicetrapib as a possible intervention treatment.
“The commencement of this trial is an important step in our effort to understand whether obicetrapib may affect biological changes associated with [Alzheimer’s] before noticeable symptoms develop,” said Michael Davidson, MD, NewAmsterdam’s CEO. Davidson noted that the development of Alzheimer’s “typically begins years before clinical symptom onset, creating an opportunity for intervention.”
The Phase 2b SPINOZA study (NCT07794670) is enrolling an estimated 400 people ages 55 to 85 at a single site in Nashville, Tennessee. Eligible participants will have no evident symptoms but biomarker evidence consistent with early Alzheimer’s.
Alzheimer’s is the most common form of dementia, a group of conditions characterized by a decline in memory, thinking, and other cognitive abilities that can affect everyday activities. The disease is marked by the buildup of toxic clumps of two proteins, beta-amyloid and tau, which can damage nerve cells. These changes can begin years before symptoms become apparent.
It’s thought that lipid metabolism — how the body and brain process cholesterol and other fats — may also be involved in Alzheimer’s. Certain variants in the APOE gene, particularly APOE4, increase the risk of developing the disease. This gene provides instructions to produce a protein involved in transporting cholesterol and other fats.
Obicetrapib aims to lower levels of LDL cholesterol
Obicetrapib is a low-dose cholesteryl ester transfer protein (CETP) inhibitor designed to alter cholesterol metabolism. CETP helps move cholesterol between different types of lipoproteins in the bloodstream. By blocking CETP, obicetrapib lowers the levels of LDL cholesterol.
An earlier Phase 2a trial (NCT05161715) sponsored by New Amsterdam explored its effects on brain lipid metabolism in 13 people with early Alzheimer’s carrying at least one copy of the ApoE4 variant. In that open-label study — meaning both researchers and participants know the medication being given — participants received 10 mg of obicetrapib daily for 24 weeks, or about six months.
The results showed reductions in levels of 24- and 27-hydroxycholesterol in the cerebrospinal fluid, the liquid that surrounds the brain and spinal cord. This suggested improved cholesterol metabolism in the brain.
Participants also experienced an 8% increase in blood beta-amyloid 42/40 ratio, suggesting less beta-amyloid clumping in the brain. Lower levels of the beta-amyloid 42/40 ratio have been associated with an increased risk of Alzheimer’s.
‘Growing body of evidence’ links Alzheimer’s and metabolism
More recent evidence came from a prespecified analysis of Alzheimer’s biomarkers from a late-stage trial dubbed BROADWAY (NCT05142722). That Phase 3 study, which involved more than 2,500 participants, was originally designed to evaluate obicetrapib for cardiovascular disease rather than Alzheimer’s. The analysis covered 1,535 participants, of whom 367 were APOE4 carriers.
After one year, people treated with obicetrapib had significantly lower increases in blood p-tau217, an early biomarker of Alzheimer’s, compared with those given a placebo. The difference was also significant among APOE4 carriers. Favorable trends were seen in additional biomarkers, including blood levels of p-tau181 and beta-amyloid 42/40 ratio.
“The findings from our BROADWAY Alzheimer’s disease biomarker analysis, together with the growing body of evidence linking lipid metabolism to Alzheimer’s disease pathology, provide a strong scientific rationale for further evaluating the effect of obicetrapib on biomarkers associated with disease progression and neurodegeneration,” Davidson said.
Additionally, the findings helped shape SPINOZA’s design. The study is enrolling participants with biomarker evidence consistent with early Alzheimer’s who carry two copies of the APOE4 variant, two copies of the APOE3 variant, or one copy of each variant.
The trial’s participants will be randomly assigned to receive either 10 mg of obicetrapib or a placebo once daily for one year, with treatment groups balanced according to APOE genotype, according to New Amsterdam.
The study’s main goal is to measure changes in blood levels of p-tau217. Secondary outcomes include changes in other Alzheimer’s biomarkers, such as the beta-amyloid 42/40 ratio, as well as changes in cognitive performance using the Preclinical Alzheimer’s Cognitive Composite 5 (PACC5).
Judith Rein
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