Novo Nordisk Launches Pivotal Phase IIIa Trial of Oral Semaglutide in Early Alzheimer’s Disease with 3,700-Patient Enrollment

On December 16, Novo Nordisk announced the initiation of a Phase III clinical trial program to evaluate oral semaglutide for the treatment of Alzheimer’s disease. This decision was made following an assessment of preclinical animal model data, real-world evidence, and post hoc analyses from large cardiovascular outcomes trials, as well as discussions with regulatory authorities.

Data from animal model studies suggest that GLP-1 plays a key role in the treatment of Alzheimer’s disease, including improving memory function and reducing the accumulation of phosphorylated tau protein. Semaglutide has also been shown to alleviate neuroinflammation that may potentially impact cognitive and physical functions. Real-world evidence based on the US Truven claims database registered in Denmark and the US FDA FAERS database also indicates a potential association between GLP-1 therapy and a reduced risk of dementia.

Furthermore, Novo Nordisk conducted a post hoc analysis of trial data from three large cardiovascular outcomes studies—LEADER, SUSTAIN 6, and PIONEER 6. Among 15,820 patients with type 2 diabetes, with a median follow-up duration of 3.6 years, 47 cases of dementia (early-stage mild Alzheimer’s disease) were identified: 32 in the placebo group and 15 in the GLP-1 receptor agonist group (liraglutide or semaglutide). Statistically, this represented a significant 53% reduction in the incidence of dementia, thereby providing evidence supporting the use of GLP-1 receptor agonists for the treatment of dementia.

As planned, Novo Nordisk will directly initiate a pivotal Phase IIIa study involving approximately 3,700 patients with early Alzheimer’s disease, commencing patient recruitment in the first half of 2021. The study primarily aims to evaluate the efficacy and safety differences between oral semaglutide (14 mg, once daily) and placebo, with an expected treatment duration of approximately two years.

Mads Krogsgaard Thomsen, Executive Vice President and Chief Scientific Officer at Novo Nordisk, stated, “We are eager to address the high unmet medical needs in serious chronic diseases; therefore, we are pleased to initiate the Phase 3 development program for semaglutide as a treatment for Alzheimer’s disease. Over the past few decades, Alzheimer’s disease has been a widely researched field, yet unfortunately, there have been no significant medical breakthroughs. Given the growing need to meet medical demands and the increasing evidence supporting the potential role of GLP-1 in the treatment of Alzheimer’s disease, we will explore the therapeutic benefits of oral semaglutide for early-stage Alzheimer’s disease.”

Alzheimer’s disease is one of the increasingly prominent public health challenges, causing significant adverse impacts on patients and their families and leading to a growing global socioeconomic burden. Currently, it is estimated that 70 to 100 million people worldwide are affected by early-stage Alzheimer’s disease (mild cognitive impairment and mild dementia).

Oral semaglutide (7 mg and 14 mg) has been approved in the United States, Europe, and Japan as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. It demonstrated excellent safety and tolerability across 10 clinical trials involving 9,543 patients, with the most common adverse events being predominantly transient, mild nausea.

On December 4, Novo Nordisk submitted a marketing application to the FDA for once-weekly subcutaneous injection of 2.4 mg semaglutide, as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) who have at least one weight-related comorbidity.