This Diabetes Drug Could Halt Alzheimer's Disease.Novo Nordisk's Victoza, ultra-long acting insulin Tresiba had been "encouraging"

5. 2, 2016

 

There is a well-established link between diabetes and Alzheimer's disease.

 

A type-2 diabetes medication from Novo Nordisk prevented the decline of brain glucose metabolism in a small Phase 2a Alzheimer's treatment study.

Other encouraging results are being tested in a larger, more extensive Phase 2b trial to determine if Alzheimer's progression can be halted at an early stage.

A recently published clinical study provides hope that an approved, safe, widely-used diabetes drug can be re-purposed for halting, or at least slowing, the progression Alzheimer's disease.

The treatment of Alzheimer's in this manner comes as a bit of a surprise. It seems to have been more widely discussed in the European press, but not so much in the U.S., leading many to miss the news, and it has potential implications for pharmaceutical and biotech companies working on both diabetes and Alzheimer's treatments.

Alzheimer's disease is a terribly destructive disorder that affects over 5 million Americans and 40 million people worldwide. Nearly everyone knows someone who has been afflicted with this disease. I'll always remember how it affected my grandmother many years ago, and how it essentially rendered her incapable of doing anything on her own, eventually leading to her passing.

There is no cure for Alzheimer's and current medications may only briefly delay its inevitable outcome. Many companies are working on new drugs to treat it but Alzheimer's is extremely difficult to address. No new medicines have been approved for its treatment in over a decade.

The use of diabetes drugs to treat Alzheimer's is motivated by studies that showed people with type-2 diabetes have double the odds of developing Alzheimer's than those without diabetes. Low levels or resistance of insulin are therefore associated with Alzheimer's disease. It is believed that the resulting glucose intolerance increases oxidative stress and causes metabolism issues in the brain. Hence, Alzheimer's disease and also the possibility that diabetes medications could be useful for its treatment.

Last week, encouraging results from a Phase 2a clinical study using a diabetes treatment for Alzheimer's were published in the journal Frontiers in Aging Neuroscience. The study tested a commonly prescribed type-2 diabetes medication, Novo Nordisk's (NYSE:NVO) Victoza, a once-daily GLP-1 injectable, against Alzheimer's disease.

GLP-1 agonist analogues were developed for treating type-2 diabetes but have been shown to be useful in treating other closely related indications such as obesity and potentially NASH. GLP-1 medications have been developed by a few pharmaceutical companies, including Novo's Victoza, with active molecule liraglutide, and their forthcoming second-generation GLP-1 analogue, semaglutide; Byetta (exenatide) jointly from Bristol-Myers Squibb (NYSE:BMY) and AstraZeneca (NYSE:AZN), Eli Lilly's (NYSE:LLY) Trulicity (dulaglutide), and GlaxoSmithKline's (NYSE:GSK) Eperzan/Tanzeum (albiglutide). All of these are potential players if GLP-1s prove beneficial for treating Alzheimer's.

The National Institute on Aging is also currently running a GLP-1 Alzheimer's treatment trial but instead using exenatide. That trial is supposed to be completed by the end of 2016.

Pre-Clinical Evidence

Pre-clinical work leading to the Phase 2a included multiple mouse studies.

One study, published in 2012, investigated the origins of defective brain insulin signaling as a contributor to the cognitive deficits in patients with Alzheimer's disease. They established molecular links between the dysregulated insulin signaling in Alzheimer's and diabetes.

Another study, from 2013, showed more specific mechanisms of action. For those with a deeper understanding of Alzheimer's pathophysiology, an excerpt from the abstract describing the results follows.

"Liraglutide decreased the hyperphosphorylation levels of tau and neurofilament proteins, increased protein O-glycosylation, increased tau bound to microtubules, and also significantly improved the learning and memory ability of the mice. These results suggest that the effects of liraglutide on decreasing the hyperphosphorylation of tau and neurofilament proteins by enhancing O-glycosylation of neuronal cytoskeleton protein, improving the ... signaling pathway, and reducing neural degeneration may be related to its protective effects on Alzheimer's disease-like learning and memory impairment..."

In simpler terms, studies have shown the following key results, as quoted from the lead investigator of the 2012 study:

"After two months of treatment with liraglutide the Alzheimer's mouse model animals performed as well as normal mice and were much better in memory tests than Alzheimer's mice not treated with liraglutide. They also had a large reduction in plaques and inflammation in the brain. Excitingly, the liraglutide-treated mice also had an increase in the number of new nerve cells."

"In older mice, where memory impairments were already significant before treatment was started, liraglutide improved the performance of the Alzheimer's disease-model mice in memory tests after two months. Interestingly, liraglutide also improved spatial learning in older normal mice."

"The number of amyloid plaques and inflammation were significantly reduced in the Alzheimer's mouse model, while the numbers of new neurons and the number of synapses were increased. In normal mice, spatial learning was also improved and there was reduced inflammation in the brain, however numbers of new neurons and synapses were unchanged."

Recent Phase 2a Study

The most recently published 38-subject, 26-week placebo-controlled clinical study examined the effects of liraglutide treatment on amyloid beta accumulation, glucose metabolism, and cognitive skills.

This study's conclusion (emphasis is mine):

We conclude that the GLP-1 analogue treatment prevented the decline of CMRglc [cerebral metabolic rate of glucose consumption] that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the amyloid beta load or cognition measures, for which the study was underpowered.

The observation of the prevention of a decline in cerebral glucose metabolism is an important finding that gives hope for this medication in Alzheimer's treatment.

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While there were no significant changes in the amyloid plaque accumulation and total cognitive scores, the study wasn't sufficiently powered to measure these. A larger and longer duration Phase 2b study will address these factors.

On the other hand, one portion of the cognitive test, the orientation test, had a significant outcome. The placebo group saw a significant impairment in the orientation test while the liraglutide group results did not change. This result is indicative of a protective action from liraglutide.

The lead investigator from the mouse study, now on the Phase 2b human-subject team, said of the Phase 2a study:

Fortunately, the first data we have from human brain tissue and the first clinical trial, it really shows that, yes, the drug gets into the brain and is protective - and seems to work in a similar way it does in animals. That's hugely encouraging.

Current Phase 2b Study

The currently recruiting study is called "Evaluating Liraglutide in Alzheimer's Disease (ELAD)" and is being led by the Imperial College of London. The study is being funded by Novo Nordisk and the Alzheimer's Society.

This is a 206 subject, 12-month double-blind placebo-controlled study involving patients with mild Alzheimer's dementia, meaning Mini Mental State Evaluation score of at least 22 (out of a maximum of 30) and a Clinical Dementia Rating global score of 0.5 or 1.

The primary endpoint is the change in cerebral glucose metabolic rate. Secondary endpoints are the change in scores for the Alzheimer's Disease Assessment Scale-Executive Functioning test, MRI changes, microglial activation, and cerebrospinal fluid biomarkers; and the incidence and severity of treatment emergent adverse events.

Results are expected by the end of 2018.

Conclusion

This is still an early stage of development and there are many unknowns and associated risks. However, the top scientists involved are seeing enough potential to instill hope that liraglutide and other GLP-1 treatments will be useful for treating at least some aspect of Alzheimer's.

Novo Nordisk's Chief Science Officer said, regarding their treatments,

Of the areas outside of diabetes and obesity, I do believe that Alzheimer's is the most promising, as I see it at the moment.

This comment is very encouraging to me, as Novo's scientific leadership is top-notch in the pharmaceutical industry.

If Phase 2b is successful, I expect Novo to pursue a new Phase 2 study with semaglutide, similar to what they did with NASH, likely including their oral version developed in partnership with Emisphere Technologies (OTCQB:EMIS). Novo will share oral GLP-1 sales with EMIS through milestone and royalty payments. This new study would better define dosing and treatment regimens, and would be followed by a large, multi-year Phase 3 study.

For investors, the Alzheimer's market is expected to be greater than $10B by 2021, with GLP-1 treatments likely having multi-billion-dollar annual sales. In terms of the competitive GLP-1 landscape, Novo would have the marketing and sales advantage with an oral pill version over competitors' injectable offerings, assuming their oral semaglutide holds up through future trials.

 

 

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Denmark's Novo Nordisk says US launch 'encouraging'

AFP/The Local · 30 Apr 2016, 17:15

 

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The world's largest maker of diabetes treatments, Novo Nordisk, said on Friday that the US launch of ultra-long acting insulin Tresiba had been "encouraging" as it repo