Key takeaways:
- Obicetrapib is a CETP inhibitor for adults with atherosclerotic heart problems.
- P-tau217 is an early indicator of neurodegeneration.
- Results have been better amongst sufferers with the APOE4 gene.
Day by day doses of obicetrapib over 52 weeks led to vital reductions in plasma p-tau217 and different Alzheimer’s illness biomarkers, in line with information offered on the Alzheimer’s Affiliation Worldwide Convention.
Reductions have been better amongst sufferers who carried the APOE4 gene, Philip Scheltens, MD, PhD, professor emeritus at Amsterdam College Medical Middle, stated in the course of the presentation.
Information derived from the press launch.
“After we take a look at epidemiological proof, it reveals a relationship between CETP exercise and cognitive perform,” Scheltens advised Healio.
Philip Scheltens
Earlier research have discovered related genetic polymorphisms that scale back CETP exercise with maintained cognitive efficiency, in addition to much less threat for Alzheimer’s illness amongst people with longevity, particularly those that carry APOE4, he continued.
One potential cohort examine discovered slower reminiscence decline and 72% much less threat for dementia amongst people with considerably low CETP exercise, Scheltens added.
“Moreover, latest Mendelian randomization analyses demonstrated that genetically decrease CETP focus is related to larger whole mind quantity and decreased threat of Lewy physique and Parkinson’s dementia, with pronounced safety in APOE4 carriers,” he stated.
Obicetrapib is an oral, low-dose CETP inhibitor designed for adults with atherosclerotic heart problems (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) whose lipid-lowering remedy has not adequately managed their LDL ldl cholesterol (LDL-C).
The Broadway examine included 2,530 sufferers (median age, 65 years; 34% feminine) with ASCVD or HeFH who took 10 mg of obicetrapib or placebo with or with out meals as soon as a day for 52 weeks. At baseline, imply LDL-C ranges have been roughly 100 mg/dL within the remedy group, with practically 70% reporting high-intensity statin use.
At 84 days, the imply p.c change from baseline in LDL-C was 33%, with imputation within the remedy group in contrast with the placebo group.
The evaluation of biomarkers for Alzheimer’s illness comprised 1,515 sufferers. The remedy group demonstrated statistically vital decrease absolute modifications in plasma p-tau217 than the placebo group (P = .0019).
The researchers known as p-tau217 one of many first biomarkers to point neurodegeneration, growing as much as 20 years earlier than cognitive impairment onset. It is also considerably extra correct in assessing Alzheimer’s illness than analyses that use plasma or MRI, they added, with efficiency that doesn’t differ considerably from key measurements based mostly on cerebrospinal fluid or PET.
Traits additionally have been favorable in neurofilament gentle chain (NFL) and glial fibrillary acidic protein (GFAP), which the researchers stated predict neurodegeneration with elevated blood ranges related to Alzheimer’s illness and pathology, and in A-beta 42/40 ratios.
The evaluation additionally included 367 sufferers who carried APOE4, which the researchers known as a threat issue for each cardiovascular and Alzheimer’s illness as a result of these sufferers usually exhibit larger ranges of LDL-C, Lp(A) and lowered ldl cholesterol transport and clearance.
Sufferers who used obicetrapib on this group additionally had considerably decrease absolute modifications in plasma p-tau217 (P = .0215).
Imply p.c modifications in biomarkers between sufferers who carried two ApoE-IV proteins and the placebo group included –20.48% (P = .01) for p-tau217; –17.31% (P = .02) for NFL; –15.24% (P = .006) for GFAP; –13.67% (P = .06) for p-tau181; –7.96 (P = .013) for A-beta 42/40 ratios; and –22.65% (P = .032) for p-tau217/a-beta 42/40 ratios.
P.c modifications in p-tau217 development in contrast with the placebo group included –2.99% (P = .019) for the total evaluation set (n = 1,515), –5.74% (P = .022) for the ApoE-IV carriers (n = 367), –5.4% (P = .06) for ApoE4 carriers aged 60 years and older (n = 283), –8.39% (P = .039) for ApoE4 carriers aged 70 years and older (n = 139), and –20.48% (P = .01) for twin ApoE4 carriers (n = 29).
The researchers additional categorized remedy as effectively tolerated and added that its security outcomes and the placebo group’s security outcomes have been comparable.
In an open-label and single-arm trial, 13 sufferers with early Alzheimer’s illness and a minimum of one copy of ApoE4 who acquired 10 mg of obicetrapib skilled reductions in 24-hydroxycholestrol and 27-hydroxycholestrol of their plasma and cerebrospinal fluid at 24 weeks. These sufferers additionally tolerated remedy effectively with no severe antagonistic occasions or antagonistic occasions associated to remedy, the researchers stated.
“This, to my data, is the primary occasion of an oral CETP inhibitor demonstrating measurable results on each tau and amyloid-related biomarkers in asymptomatic people at genetic threat for Alzheimer’s illness,” Scheltens stated.
“Given the rising recognition of p-tau217 as a validated biomarker that begins to rise years earlier than scientific signs, the flexibility to sluggish or scale back its development may symbolize a significant step towards upstream intervention methods,” he stated.
A number of late-stage trials together with the continued PREVAIL cardiovascular outcomes examine, with greater than 9,500 sufferers with atherosclerotic heart problems, at the moment are analyzing obicetrapib, Scheltens stated.
“Whereas the biomarker findings are promising, additional regulatory discussions can be wanted to pursue growth in Alzheimer’s illness,” he stated.
Additionally, Scheltens known as these findings an necessary first step and stated that he’s inspired by the organic sign that was noticed, though dedication prevention trials might want to validate them earlier than these scientific implications are absolutely understood.
Reference:
- Davidson M, et al. Results of obicetrapib, a potent oral CETP inhibitor, on Alzheimer’s illness biomarkers in 1727 sufferers with heart problems. Introduced at: Alzheimer’s Affiliation Worldwide Convention; July 27-31, 2025; Toronto.
For extra info:
Philip Scheltens, MD, PhD, may be reached at neurology@healio.com.
