Memorandum

Interest in Novo Nordisk’s foray into Alzheimer’s disease grows – January 22, 2020

Investigator-led phase 2b ELAD trial expected to readout in February 2020; Resurgence of Alzheimer’s as “type 3 diabetes” concept

Multiple pieces of reporting in the media have highlighted Novo Nordisk’s investigation of GLP-1 Victoza (liraglutide) in Alzheimer’s disease, including recent articles from BioSpace (“Is Alzheimer's Type 3 Diabetes? Novo Nordisk is Willing to Find Out”), Vantage (“Novo Nordisk’s quiet entry into the year of Alzheimer’s”), and Danish newspaper Børsen.

We picked up on similar themes at JPM 2020, where CSO Dr. Mads Thomsen detailed the ongoing, investigator-led phase 2b ELAD trial (n=204) of Victoza in Alzheimer’s at the Imperial College London, which is set to readout in February 2020 (next month!). See our initial coverage of this trial at the time of initiation here. In terms of trial design, participants were randomized to either a 1.8 mg daily injection of Victoza (liraglutide) or placebo over 12 months. The study’s primary outcome is change in cerebral glucose metabolic rate, but more importantly, secondary outcomes will assess changes in cognition using established Alzheimer’s scoring systems. If results are positive, Novo Nordisk plans to meet with FDA/EMA to determine if there is a “fast and effective path” into pivotal studies for a potential indication in Alzheimer’s-related dementia. Promisingly, a study update announced that “people receiving liraglutide reported a perceived change in their symptoms after they stopped taking the drug,” so all trial participants will be offered the opportunity to join a 12-month open-label extension trial following ELAD completion.

Novo Nordisk appears confident in the potential of GLP-1 in this disease area, as CSO Dr. Thomsen shared at JPM 2020 that post-hoc analysis of the clinical programs for liraglutide and semaglutide have shown a statistically significant reduction in dementia diagnoses with GLP-1 treatment (roughly a 50% lower rate, albeit in a small sample size of ~75 total events). Elsewhere on the recent conference circuit, we also picked up on commentary from Novo Nordisk’s Global CMO Dr. Steven Gough at Targeting Metabesity 2019, where he highlighted the work Novo Nordisk is doing with GLP-1 in Alzheimer’s. Dr. Gough specifically mentioned that preclinical data show reductions in tau tangles (a marker of neurodegenerative disease) with liraglutide/semaglutide treatment.

  • Though interest in GLP-1s to treat Alzheimer’s has increased in recent months, the idea is certainly not a new one. A previous 2016 study of liraglutide on degenerative changes conducted by the University of Aarhaus found an increase in glucose metabolism vs. placebo, though findings were not statistically significant. Even in popular culture, renowned journalist Mark Bittman published an article in NYT entitled “Is Alzheimer’s Type 3 Diabetes?” back in September 2012. diaTribe has also extensively covered the connection between type 2 diabetes and Alzheimer’s – see here for their 2015 article on the topic.

  • Elsewhere in the overlapping landscape of Alzheimer’s and diabetes, vTv is currently investigating its oral small molecule azeliragon in a phase 2/3 trial of patients with both mild Alzheimer’s and type 2 diabetes. The study seeks to confirm post-hoc findings from the phase 3 STEADFAST trial (October 2018), which demonstrated a statistically significant (p=0.01) improvement on the Alzheimer's Disease Assessment Scale-Cog (ADAS-COG) in people with diabetes treated with azeliragon (n=33) compared to the placebo group (n=22) after 12 months. Patients treated with azeliragon demonstrated improved cognition and function, reduced brain atrophy, and decreases in inflammatory biomarkers.

  • “In epidemiological studies, diabetes has been shown again and again to approximately double a person’s risk of developing dementia, and related comorbidities like obesity and heart disease exacerbate this even further,” noted Abigail Dove (Karolinska Institutet, Stockholm, Sweden), a former associate at Close Concerns, now a researcher focused on the interplay between cardiometabolic disease and dementia. “What gives me optimism about the possibility of GLP-1’s for brain disorders is that they address this entire cluster of dementia-associated cardiometabolic risk factors: diabetes, obesity, and heart disease.” The idea of glucose dysregulation as a major player in dementia pathology has certainly caught the attention of the dementia field, particularly as it looks for new therapeutic targets in the aftermath of so many recent high-profile negative trials for Alzheimer’s/dementia therapies. 

 

--by Rhea Teng, Martin Kurian, and Kelly Close