If not BAN2401, what about Atuzaginstat? (Say that 3 times fast.)

Back in February 2019, we wrote about the bacterium p. gingivalis, reporting the growing evidence that it may play a role in Alzheimer's disease.  We discussed this further in the second edition of Beating the Dementia Monster.  The microbe causes gum disease, and some believe it may be the sole cause of Alzheimer's disease.  Whether it's the sole cause or not, interest in the role of p. gingivalis has been growing, and one drug is showing particular promise as a treatment.  That drug is COR388 or Atuzaginstat.  A stage 2/3 clinical trial just passed an important milestone that's worth talking about.

The drug was developed by the biopharmaceutical company Cortexyme.  The trial involves about 640 test subjects and is intended to run for a year.  In December, the trial reached the 6-month point, and an independent committee reviewed the results so far in what's called a futility study.  This was intended to determine if there is enough evidence of the drug's efficacy and safety to justify continuing the trial.  You may recall that some trials of aducanumab were terminated by a futility study, when they failed to meet some interim goals.  

So the big news is that the independent Data Monitoring Committee reviewed the 6-month data for 300 of the test subjects and found sufficient evidence of safety and efficacy to recommend continuing the trial to the end.  That's good news, because this system is intended to protect people from unnecessary exposure to experimental drugs that may be dangerous and/or ineffective.  Presumably, the committee found good evidence that the drug is both safe and effective.

Cortexyme expects to complete the trial, process the data, and present the final results by December 2021.

P. gingivalis is known to generate an enzyme called gingipain which causes inflammation.  This occurs first in gum disease, but p. gingivalis and gingipain can almost always be found in the brains of people deceased with Alzheimer's disease.  Atuzaginstat targets the generation of gingipain.

In the past month or so we have reviewed the status of an array of promising treatments for Alzheimer's disease.  Alzheimer's disease is very complex, and these treatments target different mechanisms influencing how the disease develops.  Many believe that we will eventually be treating Alzheimer's disease simultaneously with several different drugs.  Perhaps Atuzaginstat will be one of them.  

All stop on atuzaginstat?

Back in January 2021 we wrote a couple of times about the proposed drug therapy atuzaginstat ... or COR388.  We also discussed it in the appendix of the second edition of Beating the Dementia Monster.  We thought it was a promising approach to treating Alzheimer's disease by going after the bacteria p. gingivalis.  We explained that there is correlation between gum disease caused by p. gingivalis and Alzheimer's disease.  We were hopeful that treating the bacteria would treat AD.  But the FDA just ordered full stop on the phase 2/3 trial.  The sponsoring company, Cortexyme, reported halting the research in this press release.  And then their stock price fell 34%.

Why the stop?  The FDA ordered it after a review of the trial data identified hepatic adverse events.  So it's about safety.  It's not clear to me if the data also showed or failed to show any improved memory or cognition.

But all is not lost.  Cortexyme has another drug, COR588, that is already in clinical trials in Australia.  It is a more advanced drug that pursues the same hypothesis as COR388 -- attacking p. gingivalis will improve memory and cognition.  It seems to be safer and more effective.

You should already know that I am somewhat skeptical of the amyloid hypothesis and its implications -- that removing beta amyloid from the brain is the right way to treat Alzheimer's disease.  This is the guiding principle behind most of the pharmaceutical therapies under development.  I'm hopeful that going after p. gingivalis instead will be more rewarding.

The case for porphyromonas gingivalis as the cause of Alzheimer's disease gets stronger ... a lot stronger

In Beating the Dementia Monster we wrote about a connection between gum disease and Alzheimer's disease.  We noted that some believe gum disease is the cause of Alzheimer's disease, and defeating gum disease should defeat Alzheimer's disease.  This is hard to believe, considering all of the dynamics around how the disease develops and progresses.  But there's some new research findings that at least reinforce our understanding of some kind of strong connection between the bacterium p. gingivalis and the disease.  In fact, there is growing evidence that beta amyloid, considered a culprit in development of Alzheimer's disease is, in fact, part of the body's mechanism for keeping p. gingivalis from damaging brain cells.

In January 2021, we wrote about a new treatment candidate, atuzaginstat, that we hoped would be an effective antibiotic treatment against p. gingivalis.   We wrote that it had begun a phase 2/3 trial and had then passed an important milestone.  We looked forward to final results in December 2021.

While December isn't here yet, good news continues to come from the ongoing trial, sponsored by the pharmaceutical company, Cortexyme.  The news is that, among the 230 Alzheimer's patients selected as current phase test subjects, 100% showed evidence of p. gingivalis infection in their cerebrospinal fluid (CSF).  I don't know what other surveys have been done to associate antibodies and other biomarkers for p. gingivalis in CSF, but this certainly shows that the association is really, really common.  

Does that mean that killing off all of the p. gingivalis will reverse Alzheimer's disease?  That remains to be seen.  However, other research finds that the greater the p. gingivalis infection, the faster the cognitive decline.  This suggests that controlling the infection may control the rate of decline.

In late August, the pharmaceutical industry held it's annual Biomarkers for Alzheimer’s Disease Summit (online).  During the summit, Leslie Holsinger, Executive Vice President, Research and Development at Cortexyme, Inc. presented the status of the trial and discussed the significance of what's been learned so far.  Her presentation slides are here.  To me, the most interesting information was the graph on page 7 relating the speed of cognitive decline to the severity of gum infection. 

Also fascinating is the graphic on page 8 showing Cortexyme's understanding of disease progression from initial gum infection, to infiltration of the brain by the bacterium, the secretion of gingipains by the p. gingivalis, the mischief the gingipains cause, fragmentation of tau proteins (as we discussed in Beating the Dementia Monster), the involvement of ApoE proteins (from the famous "Alzheimer's gene"), and finally the body's response via beta amyloid production and inflammation.

Page 19 had some interesting test results for a female Alzheimer's disease patient from the now-complete phase 1 study.  It was a test I am familiar with in which the test subject must explain what they see in a picture.  After 28 days of treatment, the improvement is obvious.  Of course, that's just one person, but who knows what more we'll learn from the current trial?

So ... moral of the story?  Floss your teeth!