Analyzing Wild Optimism and Questionable Studies for Alzheimer’s Drug Development

Analyzing Wild Optimism and Questionable Studies for Alzheimer’s Drug Development

April 28, 2017
By Mark Terry, Breaking News Staff

In December 2015, various leaders in industry, government, science and advocacy representing countries in Europe, North America and Asia, met in Lausanne, Switzerland to create an action plan to find treatments and diagnostic tests for Alzheimer’s disease. The goal? Have this accomplished by 2025.

George Vrandenburg, convener of The Global CEO Initiative on Alzheimer’s disease, said at the time, “Currently, a lack of advanced biomedical tools in the regulatory process, lengthy, fragmented national approval pathways and confusion about the value of Alzheimer’s drugs could all pose substantial challenges to patient access. The goal of the forum was to find innovative processes that surmount these obstacles.”

Let’s come right and say it: 2025 feels wildly optimistic.

In 2016, Jeffrey Cummings and colleagues wrote in Alzheimer’s Research & Therapy, “Under the current conditions, only drugs currently in late Phase I or later could be ready by 2025, and only if the studies progress optimally. If pipeline attrition rates remain high, it is likely that only a few compounds could possibly reach this milestone. There is a great need to reduce the time and risk of AD drug development to reach the 2025 goal.”

A Little Personal

When you make a living primarily writing about the biopharma industry and/or healthcare, you’re probably going to take some topics more personally than others. In my case, my mother died from Alzheimer’s disease, my mother-in-law died of a related dementia, Pick’s disease, and my father-in-law had dementia, possibly Alzheimer’s, when he passed away. My father, on the other hand, was lucid to the end when he died of a rare type of cancer. My wife refers to Alzheimer’s as being like dying twice. First when you lose your memories, and second when your body gives out.

As a result, my wife and I tend to pay attention to research and news about Alzheimer’s disease, whether it’s stories of positive and/or negative clinical trials, or the recent news stories about a possible link between dementia and stroke with diet sodas (a questionable study).

A Little Science

One of the problems with developing drugs for Alzheimer’s disease is that we don’t understand the disease very well. The predominant theory is the “amyloid hypothesis.” Scientists have basically observed that a protein called amyloid-beta builds up in large quantities in AD patients’ brains. These proteins clump into a plaque, which blocks cell-to-cell communication. So, most drugmakers are focused on clearing amyloid-beta.

Another type of protein associated with AD are tau proteins, which occur later in the disease and cause tangles of protein fibers. They seem to damage the transport system in the brain that moves nutrients through the cells. There’s less work being done here because this generally occurs later in the disease.

In 2016, Harvard and Mass General Hospital researchers Rudy Tanzi and Robert Moir published a study in Science Translational Medicine indicating that amyloid-beta was actually linked to an immune reaction to bacteria or other pathogens in the brain.

Another approach, as being investigated by Axovant Sciences and others, focuses on acetylcholine. Acetylcholine is believed to be important for memory, and drugs that boost acetylcholine seem to have some positive effects on AD patients for a while. The four approved drugs for mild to moderate AD—Razadyne (galantamine), Exelon (rivastigmine), Aricept (donepezil) and Cognex (tacrine)—all work by boosting acetylecholine. None of them are really considered great drugs.

A fifth drug, Namenda (memantine) is used to treat moderate to severe AD, and seems to delay progression of some of the symptoms. Researchers aren’t completely sure how the drug works, but they believe it regulates glutamate, which, when produced in the brain in excessive levels, may lead to brain cell death.

There has also been some recent publications suggesting that Alzheimer’s disease is almost like a type of diabetes, a sort of Type 3 diabetes, if you will. Diabetes is a known risk factor for AD, although scientists really don’t understand the link between excess glucose and AD. A recent paper published in Scientific Reports by Omar Kassaar and colleagues proposed a link between AD and high glucose levels as they relate to problems with the immune system.

There are undoubtedly other theories and approaches, but those predominate.

Big Failures

At least one statistic shows that the failure rate for AD drugs is 99.6 percent. Even with loose statistics, that’s quite a bit worse than the often cited 1-in-10 drugs make it to market statistic. The fact is that in excess of 125 drug candidates for AD have failed in late-stage clinical trials.

In November 2016, Eli Lilly threw in the towel on its AD drug, solanezumab. The antibody targeted amyloid-beta. In its Phase III trial, the drug didn’t show significant improvement versus placebo, and didn’t show a statistical slowing in cognitive decline.

In fact, one of the things that is getting analysts and as well as scientists concerned is there have been several drugs that decrease amyloid-beta levels, but there has been no clinical improvement in the disease itself. This has everyone questioning the validity of the amyloid-beta theory.

In September 2016, Danish pharmaceutical company Lundbeck ’s drug, idalopirdine, which was a 5-HT6 antagonist to improve acetylcholine levels, failed a Phase III trial.

And on February 15, 2017, Merck pulled the plug on its Phase II/III trial of verubecestat for AD, after an external data monitoring committee determined there was “virtually no chance of finding a positive clinical effect.”

Verubecestat is a BACE inhibitor. These drugs, in theory, prevent the building up of amyloid-beta.

Those are just the recent high-profile failures.

Who to Watch

There is still hope.

Investors and analysts are watching a couple companies. First up is Axovant Sciences. Axovant’s intepirdine is currently in a Phase III MINSET trial and is expected to report topline results in late September. The trial is enrolling 1,315 patients who are on a stable background therapy of donepezil (Aricept) and they will receive either intepirdine or a placebo.

Investors seem to like Axovant, primarily, from what I can tell, based on the charisma of its founder, Vivek Ramaswamy, a 31-year-old former hedge fund manager. He has no track record of bringing drugs to market, but he’s very good at convincing people to invest in his companies. Intepirdine was acquired from GlaxoSmithKline for $5 million, where it had failed four consecutive mid-stage clinical trials for AD. Personally, I’m not optimistic, although the trial is riding on a combination with the top-selling Alzheimer’s drug, Aricept.

Another company in this space everyone’s watching is Biogen . If I were an investor, I would buy Biogen stock, but since I would largely be doing so on an emotional basis, don’t take that as a recommendation. What I like about Biogen is that they swing for the fences, they think big. That also means, if you take the baseball analogy to its logical conclusion, they strike out a lot.

In December 2016, Biogen released early data from its Phase Ib trial of aducanumab, which is an antibody for amyloid-beta. The bottom line is that the study showed a drop in beta-amyloid in the brains of more than 100 patients receiving the drug. There were also signs of cognitive decline slowing down.

There are a couple issues here. One, it’s an early trial, and as I have written numerous times, late-stage trials are where Alzheimer’s drugs go to die. Lilly’s solanezumab was a similar compound and it flunked in Phase III. Aducanumab is believed to be more potent than solanezumab, but it’s also reported that Biogen’s study is focused on very early-stage AD patients. Either way, results on its Phase III trials are several years off.

There are plenty of other companies working in the field, including Pfizer , AC Immune , Genentech , Allergan , Neurotrope (NTRP) and Accera.

Accera just hit a rough patch. On Feb. 28, 2017, it indicated that its drug, AC-1204 for AD that was in Phase III, did not demonstrate a statistically significant improvement. AC-1204 focuses on the issue of deficient glucose metabolism in AD.

Neurotrope announced on Feb. 28 that it had concluded dosing and patient monitoring of its Phase II trial of bryostatin-1 in AD. Bryostatin-1 is a completely different approach, designed to restore synaptogenesis by activating PKC epsilon. Essentially, it’s designed to reverse Alzheimer’s progression. Unless delayed, results were expected in April. As of this writing, I see no announcements, although they’re probably in the works.

I very much look forward to the day I can report on a cure for Alzheimer’s. I really, really do.

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