Merck study failure may signal doom for a broad group of pivotal Alzheimer’s studies focused on the amyloid theory of treatment.

by John Carroll

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The BACE theory in Alzheimer’s R&D is simple. Cut off the flow of amyloid beta to the brain and you can eliminate what is widely believed — though not proven — to be a cause of the disease. Do that, and you could bend the course of this devastating illness in millions of people with mild to moderate forms of the disease.

And Merck $MRK just spent a fortune to demonstrate that it may well be completely wrong.

To be sure, Merck ran a clean study for verubecestat, the leading BACE drug in the clinic, and displayed the data on 1,958 patients for all to see today in the New England Journal of Medicine. Investigators carefully tracked amyloid beta flows in cerebrospinal cords and found that the drug did what it was intended to do, with a dramatic reduction of the toxic protein. 

It had no effect, with patients in the two dosage groups tracking in parallel decline on both cognition and function, the two classic measures for Alzheimer’s. 

The conclusion they reached is that the damage already present in the brains of patients with Alzheimer’s may be too extensive to treat with any BACE drug. And they also concede that the amyloid theory itself may be just flat wrong.

This suggests that once dementia is present, disease progression may be independent of Aβ production or, alternatively, that the amyloid hypothesis of Alzheimer’s disease may not be correct. Because Aβ deposition takes place years before clinical symptoms become apparent, it has been proposed that treatments targeting amyloid should be implemented early in the disease process, before the onset of clinical symptoms.

Soon after this study failed, Merck also threw in the towel on their second pivotal trial, noting it too was a flop. Those data are still being evaluated, but it underscores the belief that all of the BACE studies — including those at Eli Lilly $LLY, partnered with AstraZeneca $AZN, or Biogen $BIIB, allied with Eisai — are headed straight to failure.

Biogen is also rolling the dice on aducanumab, which the company has touted as a leading amyloid beta therapy. But with investigators in the field openly wondering whether the amyloid theory has lured a long lineup into a clinical disaster zone, it’s likely to face growing skepticism that it can develop a safe, effective therapy with just one drug.

This doesn’t by any means eliminate work in the area. True, Pfizer recently pulled out after spending hundreds of millions of dollars on their programs. But startups like Denali believe that new and better technology can give them better odds at success, while Celgene is jumping in with its own new pipeline. Others want to see if combination approaches using tau and amyloid beta together could work. 

Merck’s suggestion about going even earlier in the disease process has also prompted a range of studies in pre-symptomatic patients, while the FDA has signaled its interest in coming up with biomarkers to help speed new studies.

After more than 200 R&D projects ended in disaster, though, Alzheimer’s is looking like an increasingly daunting challenge, with no clear path forward that would inspire confidence among patients with the disease.

Merck study may signal doom for a broad group of pivotal Alzheimer’s studies

Possible reason why ‘magic’ mushrooms evolved

By Rafi Letzter

“Magic” mushrooms seem to have passed their genes for mind-altering substances around among distant species as a survival mechanism: By making fungus-eating insects “trip,” the bugs become less hungry — and less likely to feast on mushrooms.

That’s the upshot of a paper published Feb. 27 in the journal Evolution Letters by a team of biologists at The Ohio State University and the University of Tennessee.

The researchers studied a group of mushrooms that all produce psilocybin — the chemical agent that causes altered states of consciousness in human beings — but aren’t closely related. The scientists found that the clusters of genes that caused the ‘shrooms to fill themselves with psilocybin were very similar to one another, more similar even than clusters of genes found in closely related species of mushrooms.

That’s a sign, the researchers wrote, that the genes weren’t inherited from a common ancestor, but instead were passed directly between distant species in a phenomenon known as “horizontal gene transfer” or HGT.

HGT isn’t really one process, as the biologist Alita Burmeister explained in the journal Evolution, Medicine and Public Health in 2015. Instead, it’s the term for a group of more or less well-understood processes — like viruses picking up genes from one species and dropping them in another — that can cause groups of genes to jump between species.

However, HGT is believed to be pretty uncommon in complex, mushroom-forming fungi, turning up much more often in single-celled organisms.

When a horizontally transferred gene takes hold and spreads after landing in a new species, the paper’s authors wrote, scientists believe that’s a sign that the gene offered a solution to some crisis the organism’s old genetic code couldn’t solve on its own.

The researchers suggested — but didn’t claim to prove — that the crisis in this case was droves of insects feasting on the defenseless mushrooms. Most of the species the scientists studied grew on animal dung and rotting wood — insect-rich environments (and environments full of opportunities to perform HGT). Psilocybin, the scientists wrote, might suppress insects’ appetites or otherwise induce the bugs to stop munching quite so much mush’.

FDA grants fast-track status to promising new drug for treating the cognitive symptoms of schizophrenia

Forum Pharmaceuticals announced that the FDA has granted Fast Track designation to encenicline for the treatment of cognitive impairment in schizophrenia.

Forum recently completed patient enrollment for the COGNITIV SZ phase 3 clinical trial program which includes two randomized, double-blind, placebo-controlled studies. The program is evaluating the safety and efficacy of two oral doses of once-daily treatment with encenicline as a pro-cognitive treatment compared to placebo when added to chronic, stable, atypical antipsychotic therapy in people with schizophrenia.

Primary endpoints of the trials include effect on cognitive function and effect on clinical function. The two global 26-week trials enrolled a total of more than 1,500 patients at approximately 200 clinical sites.

Encenicline is an orally administered, selective, and potent agonist of the alpha 7 receptor found in hippocampal and cortical neurons involved in cognition.

In a phase 2 trial, which was sponsored by Forum and results of which were released in March, 319 schizophrenia patients were randomized to receive either encenicline in one of two doses daily, or a placebo, for 12 weeks.

Patients in both encenicline dose groups showed significant cognitive improvement based on various measures, according to a presentation made at the 15th International Congress on Schizophrenia Research. In a subset of 154 patients, the improvement was greater in the higher-dose group (0.9 mg) than the lower-dose cohort (0.27 mg).

Ecstasy and other drugs temporarily legal in Ireland

Possession of ecstasy and other drugs is currently legal in Ireland, but only for a day, after a court ruling on Tuesday morning.

A written judgment released by the Republic’s court of appeal said part of the Misuse of Drugs Act 1977, which allows certain substances to be controlled, is unconstitutional, meaning all government orders banning substances such as ecstasy and magic mushrooms are void – and it is not an offence to possess them.

Specifically, the court found that the act was being added to via ministerial order and without consulting the Oireachtas (both houses of the Irish parliament) and deemed this unconstitutional.

The appeal court’s ruling came in favor of a man who was prosecuted for possession of methylethcathinone, which was among a number of substances put on the controlled drugs list in 2010.

Stanislav Bederev denied the charge of having the substance for supply in 2012, and then brought a high court challenge in Dublin seeking to stop his trial, claiming that additions to the 1977 act were unconstitutional.

Bederev’s legal team argued it was not lawful to put the substance on the controlled drug list because there are no principles and policies guiding the introduction of such rules – and specifically no consultation with the Irish parliament.

The Irish government now has to force through emergency legislation in its parliament on Tuesday evening in response to the ruling.

The emergency law won’t come into place until the Republic’s second chamber, the Seanad, endorses the legislation. Following that the country’s president, Michael D Higgins, will have to gave his approval.