Novo Nordisk’s quiet entry into the year of Alzheimer’s

An upcoming study could show whether diabetes drugs like Novo’s Victoza might have an effect on slowing cognitive decline.

With Biogen’s aducanumab filing setting the stage for a US FDA showdown 2020 is set to be the year of Alzheimer’s disease. And the Danish diabetes specialist Novo Nordisk could soon have a chance to join the party.

This is courtesy of an investigator-sponsored study testing the hypothesis that neurodegeneration is linked to low insulin and insulin resistance, and thus that a GLP-1 analogue diabetes drug like Novo’s Victoza could improve cognitive function. However outlandish this sounds, Novo shares hit an all-time high last week, and at least one source put this down to Alzheimer’s.

On Wednesday the Danish newspaper Børsen floated the idea that Victoza’s promise in Alzheimer’s lay behind the spike, citing analysts at Berenberg who suggested that positive data could unleash hidden potential. A note from Bernstein the following day asked, “Is Alzheimer’s type 3 diabetes?”, and posited a role for GLP-1 drugs.

Insulin signalling

What does the theory claim? Simply put, diabetes has been associated with dementia, and impaired insulin signalling has been suggested as the common mechanistic link.

A correlation between blood glucose levels and rate of cognitive decline can be seen even without clinical diabetes, some have suggested, but type 2 diabetes almost doubles the risk of developing Alzheimer’s and is associated with accelerated cognitive decline in people with mild cognitive impairment.

Others have suggested that insulin plays a role beyond glucose metabolism, and could be involved in memory and learning. One paper describes the function of insulin receptors in the brain, and says defects in these receptors have been identified in neurons from Alzheimer’s brains.

Of course, correlation does not equal causation, and a sceptical pharma sector has remained on the sidelines. Indeed, it is striking that the number of clinical trials testing the hypothesis can be counted on the fingers of one hand, and none has a corporate pharma company sponsor.

Studies of diabetes drugs in dementia
Drug Trial design Status Sponsor Results
Victoza (GLP-1 analogue) 6mth treatment looking for reduction of intracerebral amyloid deposition in the CNS of Alzheimer's patients Completed 2013 (n=34) University of Aarhus Published 2016
Measures cognitive function in type 2 diabetics Completed 2019 (n=30) Third Military Medical University No data published
Elad, double-blind, placebo-controlled, in Alzheimer's Fully recruited (n=204) Imperial College London Due Q1 2020
Bydureon (GLP-1 analogue) Open-label, measures progression of cognitive dysfunction in subjects with mild cognitive impariment vs placebo Recruiting (n=40) Universitaria di Parma Were due Jul 2019
Jardiance (SGLT2 inhibitor) Hypothesises that elevating ketone bodies can delay onset and progression of cognitive impairment in diabetics >55 Recruiting (n=100) National Institute on Aging Due Dec 2022

This could change if the Elad trial of Victoza, being run by Imperial College London, generates promising data this quarter.

With an enrolment target of 204 subjects with mild Alzheimer's dementia the study is by far the biggest to date to look at a diabetes drug in cognitive impairment; not only that, it has a double-blind, placebo-controlled design, and a relatively long, 12-month treatment period.

As primary endpoint it measures rate of glucose metabolism in the brain, but those seeking stronger signs of promise will look to secondary measures investigating various scales measuring cognition, including Adas, CDR-sum of boxes and ADCS-ADL.

Beyond the in vitro and preclinical data there is little hard evidence to suggest a positive outcome. The only clinical trial of this type of approach to generate data was conducted by the University of Aarhus, and showed that six months’ treatment with Victoza was associated with an increase in glucose metabolism versus placebo – though the effect was not statistically significant.

Two other academic studies have been completed recently – one of Victoza and another of Astrazeneca’s Bydureon – but no data have been published. And beyond Elad only one other trial is ongoing: a US study in over-55 non-diabetics is testing whether Boehringer Ingelheim/Lilly’s Jardiance elevates levels of ketone bodies and has an effect on brain metabolism as measured by magnetic resonance.

The clinical evidence backing aducanumab is scant, and yet the drug is increasingly seen as a likely approval in Alzheimer’s this year. Expect Novo analysts to seize on any hint of Victoza efficacy in Elad.

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