NewAmsterdam Pharma Reports Positive Topline Data of Alzheimer Agent Obicetrapib from Phase 3 BROADWAY Trial

Philip Scheltens, MD, PhD

(Credit: AstronauTx)

Newly announced positive topline data from a prespecified Alzheimer disease (AD) biomarker analysis of the phase 3 BROADWAY clinical trial (NCT05142722) showed that treatment with obicetrapib (NewAmsterdam Pharma), an investigational oral low-dose CETP inhibitor, significantly reduced absolute changes in p-tau217, a notable AD biomarker. The company noted that it plans to present the full results from the AD substudy analysis at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada.¹

BROADWAY aimed to assess plasma AD biomarkers in patients (n = 2530) with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) whose low-density lipoprotein cholesterol (LDL-C) was not adequately controlled. The 52-week study also included a prespecified substudy (n = 1727), comprising a subpopulation of APOE3/4 or 4/4 carriers (n = 367).

Overall, the company reported statistically significant lower absolute changes in p-tau217, the primary outcome measure, compared with placebo in both the full intention-to-treat population (P <.002) and in APOE4 carriers (P = .0215) over a 12-month treatment period. Additional outcome measures from the study included neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), p-tau181, and Aβ42/40 ratio absolute and percent change over that time period.

“These findings have significant implications for AD prevention, especially for the over 25% of the population that carries one or two APOE4 risk alleles and who currently lack FDA-approved prevention options,” Philip Scheltens, MD, PhD, professor emeritus at Amsterdam University Medical Center, said in a statement.¹ “The ability to reduce pathological biomarker progression suggests a potential to alter disease trajectory in this population, thereby delaying or preventing the onset of symptoms. The established safety profile of obicetrapib, demonstrated across multiple large clinical trials, combined with its oral administration, may greatly facilitate clinical implementation.”

The phase 3 BROADWAY trial, an international randomized, double-blind, placebo-controlled study, investigated the efficacy and safety of 10 mg obicetrapib compared with placebo as an adjunct to maximally tolerated lipid-lowering therapies. Conducted at sites in North America, Europe, Asia and Australia, enrolled patients (n = 2530; mean baseline LDL-C, 100 mg/dL; women, 34%; median age, 65 years) were randomized 2:1 to receive 10 mg obicetrapib or placebo once daily for 52 weeks.

The primary end point, least square (LS) mean percent change from baseline in LDL-C among those treated with obicetrapib 10 mg compared with placebo, demonstrated a reduction of 33% with imputation after 84 days of treatment. The company noted that secondary end points also included percent changes from baseline of obicetrapib 10 mg compared with placebo in ApoB, Lp(a), ApoA1, HDL-C, non-HDL-C, total cholesterol, and triglycerides at day 84, and on LDL-C levels at days 180 and 365. Additional exploratory outcome measures in the trial included time from randomization until the first confirmed occurrence of major adverse cardiovascular events in the obicetrapib arm compared with placebo.

READ MORE: Plasma GFAP May Enrich Patient Selection, Reduce PET Scans Required for Alzheimer Trials

“These findings strongly support a potential preventive strategy for Alzheimer's disease,” Michael Davidson, MD, chief executive officer at NewAmsterdam Pharma, said in a statement.¹ “In this study obicetrapib, a potent CETP inhibitor, improved the progression of key plasma biomarkers of AD pathology over a 12-month period in patients with ASCVD. These data further differentiate obicetrapib and underscore the critical role CETP inhibition may have in mitigating the risk of AD progression, alongside the significant cardiovascular benefits obicetrapib has shown in our pivotal Phase 3 trials.”

The company noted that the AD substudy results from BROADWAY build on data from its phase 2a trial where researchers aimed to evaluate the pharmacodynamics, pharmacokinetics, safety and tolerability of obicetrapib in early AD patients carrying at least 1 copy of APOE4. In the trial, patients (n = 13) were given 10 mg obicetrapib and were followed for 24 weeks. All told, treatment with the agent led to reported reductions in the levels of 24- and 27-hydroxycholestrol in both plasma and cerebrospinal fluid. Overall, the agent was observed to be well-tolerated, with no serious adverse events reported nor were any AEs considered to be related to the study drug.

“These results are the culmination of over two decades of dedicated scientific research. Approximately two thirds of patients with Alzheimer’s disease carry the ApoE4 risk isoform that is associated with a much greater risk of developing AD, and the data shared today support our belief that CETP inhibition and specifically raising small functional HDL particles offers a novel and targeted approach to reducing that risk,” John Kastelein, MD, PhD, FESC, chief scientific officer at NewAmsterdam, said in a statement.¹ “When viewed alongside the totality of evidence generated to date, including improvements in LDL-C, small LDL particles, Lipoprotein (a), and key biomarkers associated with diabetes and renal function, these novel data on the prevention of AD-associated pathology further strengthen obicetrapib’s profile as a uniquely differentiated therapy with the potential to address multiple interrelated drivers of chronic cardiometabolic disease and neurodegeneration.”

REFERENCES
1. NewAmsterdam Pharma Announces Positive Topline Alzheimer’s Disease Data from BROADWAY Clinical Trial. News Release. NewAmsterdam Pharma. Published June 9, 2025. Accessed June 10, 2025. https://ir.newamsterdampharma.com/news-releases/news-release-details/newamsterdam-pharma-announces-positive-topline-alzheimers