Synonyms: Ozempic, Rybelsus
Therapy Type: Other
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3), Parkinson's Disease (Phase 2)
Company: Novo Nordisk A/S
Approved for: Type 2 Diabetes
Semaglutide is a synthetic, long-acting analog of glucagon-like peptide-1, used to treat diabetes. OzempicTM is a once-per-week injection formulation, while RybelsusTM is is a daily pill. RybelsusTM was approved by the U.S. FDA in September 2019 as the first GLP-1 analog that does not need to be injected. It is also approved for use in Japan and the European Union.
GLP-1 is a hormone produced in the gut that activates receptors in the gut, liver, and pancreas to stimulate insulin release, and restore insulin sensitivity (for review, see Knudsen and Lau, 2019). GLP-1 crosses the blood-brain barrier and may improve insulin signaling in the brain (Hölscher, 2018; Salameh et al., 2020). GLP‐1 also promotes hippocampal synaptic plasticity, cognition, and cell survival (During et al., 2003). In some people with Alzheimer’s disease, there is evidence for insulin resistance in the brain, providing a rationale for testing semaglutide as a potential therapeutic for AD. Other GLP-1 analogs, for example exendin-4 and liraglutide, are currently in clinical trials for Parkinson’s or Alzheimer’s diseases.
There are few published preclinical studies for semaglutide in Alzheimer’s. A cell-based study implicated the drug in enhanced autophagy and reduced apoptosis (Chang et al., 2020). The drug is reported to be active in rodent models of Parkinson’s (Zhang et al., 2019; Zhang et al., 2018) and stroke (Yang et al., 2019).
In September 2018, researchers at the University of Oslo registered a Phase 2 trial of semaglutide for Parkinson’s disease. The study aims to enroll 120 newly diagnosed PD patients who will receive 1 mg drug or placebo by weekly injection for two years, followed by an additional two years of open-label administration. As of February 2020, the trial had not begun recruiting.
A Phase 2a trial of semaglutide tablets in 60 people with mild Alzheimer's disease has received funding from the Alzheimer's Association's Part the Cloud program, but is not registered yet.
On December 16, 2020, Novo Nordisk announced it would begin development of semaglutide in people with early Alzheimer’s disease (see press release). Beginning in the first half of 2021, the Phase 3a program will enroll 3,700 people for a planned two-year course of a once-daily 14 mg semaglutide pill or placebo. The company said the decision was based on evaluation of GLP-1 data from preclinical models, real-world studies involving patient registry and insurance claims databases, and post hoc analysis of data from three large cardiovascular outcome trials of semaglutide and liraglutide. That analysis reportedly found a 53 percent reduction in the risk of developing dementia in people with Type 2 diabetes who took either GLP-1 agonist compared to placebo.
In March 2021, the company registered two Phase 3 trials, each enrolling 1,840 people with mild cognitive impairment or mild dementia due to Alzheimer’s disease, confirmed by amyloid PET or CSF Aβ42. The sole primary outcome is change in CDR-SB. Secondary outcomes include other standard cognitive and functional scales, as well as cardiovascular events and stroke. The trials include a one-year extension, and will start in May 2021.
For details on semaglutide trials, see clinicaltrials.gov.
Last Updated: 20 Apr 2021
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