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Clinical trial using bryostatin-1, anybody has any experience
Nurtyk
Posted: Monday, April 15, 2019 1:55 AM
Joined: 4/15/2019
Posts: 3


This one seems very promising. There are peer reviewed results from previous phase 2 study where the drug showed very good results.

https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180759

And now they are trying to duplicate those results on larger ongoing phase 2b study.

https://clinicaltrials.gov/ct2/show/NCT03560245?term=neurotrope&rank=1

I think it's the only active trial for severe patients which may be particularly interesting to many but unfortunately the study is fully enrolled already. But once the results are ready in August/September and if they are positive I assume this treatment will be expedited so that it could become available fairly soon.

Is anybody here familiar with the drug or these trials?


Lane Simonian
Posted: Monday, April 15, 2019 10:21 AM
Joined: 12/12/2011
Posts: 4589


I have been following this drug for awhile now and it continues to confound me.  The latest results suggests that the drug may help those with severe Alzheimer's disease who are not taking Namenda.  Bryostatin is a protein kinase C activator (mostly protein kinase C epsilon but to a certain extent protein kinase C alpha).  Protein kinase C alpha activation is an event that takes place early in Alzheimer's disease which may explain why bryostatin only seems to help those in the later stages of Alzheimer's disease.  Paradoxically, some protein kinase C activation can contribute to both memory and learning whereas too much protein kinase C activation can lead to memory loss.  The drug itself may stimulate the first during the later stages of Alzheimer's disease, while some of the dilutents given along with the drug may help reduce the latter.  
Nurtyk
Posted: Monday, April 15, 2019 10:59 AM
Joined: 4/15/2019
Posts: 3


I don't think there's anything that makes it to work just for the severe patients. That just seems to be a way to proceed quicker towards approval. If I would have to guess I would say the company will run trials for earlier phase patients if they get good results from the current trial.

What seems especially exciting is that the amount of improvement they reported from previous phase 2 was bigger than any other drug has ever reported. And the improvement seemed to increase until the end of the trial. So there's a possibility that patients will keep getting even better once they are dosed longer.

Anyway, I think everyone should check the results and I was interested in hearing if anybody have any first hand experience on this drug or have any friends that have talked about it.

 


Lane Simonian
Posted: Monday, April 15, 2019 1:16 PM
Joined: 12/12/2011
Posts: 4589


The previous phase 2a results were for just nine patients with mild Alzheimer's disease.  Neurotrope presented the results as follows:

An additional secondary objective of the study was the evaluation of efficacy following a single dose of bryostatin. As expected with a single dose of bryostatin, there was no measurable improvement in cognition in this mildly impaired patient population. It is important to note that in previous animal studies improvement of learning and memory was first observed following multiple doses of bryostatin.

https://www.prnewswire.com/news-releases/neurotrope-announces-positive-final-results-from-its-phase-2a-safety-study-for-the-treatment-of-alzheimers-disease-300051581.html

It is possible that multiple doses would have made their condition better but it may also have made their condition worse (even for late Alzheimer's disease lower doses work better than higher doses).   I suppose at some date in the fairly distant future, Neurotrope may come back to this "population."

In any case, when the company began to see improvements in compassionate use patients with late stage Alzheimer's disease that is when they began to test the drug for later stages in the disease.  They saw improvements in moderate to severe Alzheimer's patients not taking Namenda, but there were also some improvements in some individuals taking the placebo.  The common element in the placebo and the drug group was a compound called povidone (polyvinylpyrrolidone) which increases the stability of antioxidants.  In the end, bryostatin may show a statistically significant improvement in cognition for moderate to severe Alzheimer's disease over placebo, but that is what we are waiting to see for certain.


Nurtyk
Posted: Tuesday, April 16, 2019 2:35 AM
Joined: 4/15/2019
Posts: 3


I think they chose the severe cases for two simple reasons.

1. There's no other treatment potent enough to even try to treat this patient group. So there's essentially no options and no competition. And therefore the path to approval is quickest in this group.

2. It takes just a relatively small amount of patients and a short period of time to prove the efficacy in this patient population. So they save time, money and can get the treatment available for patients sooner.

If they can prove the efficacy for severe cases, the company and FDA will certainly expedite the treatment to cover mild cases as soon as possible. And after the first proof of efficacy they will have the resources to do it or most probably bigger pharma company will buy them out and will take care of pipeline expansion.

But all that will happen only if they can get positive results from the current confirmatory trial. And since the results so far have been better than any other treatment has ever generated, it's really very exciting to see what those will be like in the Summer. Positive results could offer immediate hope for all patients and caregivers that are dealing with disease that is too far progressed for anything else to offer any help or hope.


Vik
Posted: Tuesday, April 16, 2019 9:41 AM
Joined: 2/26/2019
Posts: 172


Research and develoment is CRITICAL in finding a cure for any of the dementias or mixed dementia!  The brain is the most complicated organ in our body so the cure will also b complicated. Very important to support research, AND IMPORTANTANT for people with dementia to donate their brain to research on this terrible disease!
Lane Simonian
Posted: Friday, April 19, 2019 9:37 AM
Joined: 12/12/2011
Posts: 4589


Overall, here is a positive report about the effects of bryostatin-1 on late Alzheimer's disease.

https://www.kansas.com/news/business/biz-columns-blogs/carrie-rengers/article229253744.html


Lane Simonian
Posted: Monday, September 9, 2019 2:37 PM
Joined: 12/12/2011
Posts: 4589


Another unfortunate outcome.

https://www.biospace.com/article/neurotrope-s-alzheimer-s-drug-flunks-phase-ii-trial/


HowDoYouDeal
Posted: Thursday, September 12, 2019 3:29 PM
Joined: 2/17/2019
Posts: 220


Lane,

 Any chance you could summarize what you think these results show. I am looking at these numbers and I want answers without reading the descriptions. Why are the placebo numbers so high? What does the number in brackets represent again?



HowDoYouDeal
Posted: Thursday, September 12, 2019 3:38 PM
Joined: 2/17/2019
Posts: 220


Wait a minute, this is saying that the only way a person could get into the study, for this drug that they are predicting will do amazing things is -

Is to stop taking all your Alzheimer's drugs for 30 days beforehand?

And they wonder why it didn't succeed?


HowDoYouDeal
Posted: Thursday, September 12, 2019 3:40 PM
Joined: 2/17/2019
Posts: 220


Patients who had received memantine (Namenda XR, Namenda, Namenda Titration Pak) were excluded unless they had stopped taking the drug for at least 30 days before enrollment. 

  

  Come on!  I thought the industry understood that the progressive nature of AD disease meant it understood that making a trial that didn't include regular Alzheimer medications would cause harm!

Its against the whole physician "do no harm motto" oath thing. Did we not get past this?

  Neurotrope announced that its Phase II trial of Bryostatin-1 in moderate to severe Alzheimer’s disease did not show statistical significance on the primary endpoint, change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score.

In other words, another Alzheimer’s drug bites the dust.

The Phase II trial was designed to evaluate the safety and efficacy of the drug for cognitive deficits in patients with moderate to severe Alzheimer’s. This was defined as a Mini Mental State Exam 2 score of 4 to 15 and patients not currently taking memantine. The patients with randomized one to one to receive either 20 micrograms of Bryostatin-1 or placebo, receiving seven doses for 12 weeks.

 

Patients who had received memantine (Namenda XR, Namenda, Namenda Titration Pak) were excluded unless they had stopped taking the drug for at least 30 days before enrollment.

  

An average increase in SIB totals of 1.3 points was observed in the Bryostatin-1 cohort and 2.1 points for the placebo groups at Week 13. The change was not statistically significant.

“We are disappointed in the topline results from the confirmatory Phase II study,” said Charles S. Ryan, Neurotrope’s chief executive officer. “Having just received the data, we are conducting a full review to determine potential next steps and will provide an update of our plans when appropriate. We sincerely thank the patients, physicians, study coordinators and the entire Neurotrope team for their support of this novel study.”

Company shares plunged almost 80% at the news. It is the second time in slightly over two years the drug did not meet its target.


Lane Simonian
Posted: Thursday, September 12, 2019 8:05 PM
Joined: 12/12/2011
Posts: 4589


The story behind this company is rather lengthy and a bit odd.  Neurotrope began testing for mild Alzheimer's disease but the results were uneven at best.  

An additional secondary objective of the study was the evaluation of efficacy following a single dose of bryostatin [safety and tolerability were the first objective]. As expected with a single dose of bryostatin, there was no measurable improvement in cognition in this mildly impaired patient population. It is important to note that in previous animal studies improvement of learning and memory was first observed following multiple doses of bryostatin.  

Then the company tested the drug in compassionate use cases for late Alzheimer's disease and several people appeared to improve.

Neurotrope followed this up with a new phase two trial for moderate to severe Alzheimer's disease, but the results were not statistically significant.  In looking at the data it appeared that participants not taking Namenda did substantially better on the drug than those taking Namenda.  Also, in most cases, they improved several points more than those on placebo (although some on the placebo also improved).  The company then ran a "confirmatory" trial with a larger group who had not taken Namenda for at least the previous 30 days and then to the shock of everyone who thought the drug could not fail: the placebo group improved more on average than the drug group.

Both the drug group and the placebo group received three dilutents (povidone, polyethylene glycol, and polysorbate 80).  Povidone increased the stability of antioxidants and polyethylene glycol and polysorbate 80 are direct antioxidants.  That is likely why many in the placebo group showed an improvement.

Bryostatin-1 is a protein kinase C activator and protein kinase C can improve memory and learning via NMDA receptors, so the idea was that if you don't block Namenda receptors with Namenda people will improve with bryostatin-1.  But Namenda receptor activation also can lead to the death of neurons; that is why Namenda is prescribed in the first place to inhibit this process.    Moreover, the routes by which Namenda receptor activation contributes to memory and learning are mainly blocked in Alzheimer's disease, so trying to activate protein kinase C to improve memory and learning does not make much sense.  If anything, in the larger trial taking byrosatin-1 seemed to dampen the improvement that was seen in the placebo group taking antioxdants.

In the larger picture, I think this is the key to treating Alzheimer's disease.

Oxidative stress and free radical generation in the brain along with excitotoxicity leads to neuronal cell death. It is inferred from several studies that excitotoxicity, free radical generation, and altered synaptic function encouraged by oxidative stress are associated with AD pathology. NMDARs maintain neuronal excitability, Ca2+ influx, and memory formation through mechanisms of synaptic plasticity. Recently, we have reported the mechanism of the synapse redox stress associated with NMDARs altered expression. We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470891/


HowDoYouDeal
Posted: Wednesday, October 16, 2019 11:29 AM
Joined: 2/17/2019
Posts: 220


So, are any companies chomping at the bit to develop just the Antioxidants themselves, since they seemed to work?

If not, can people get access to these dilutents on their own, or would they need to be injected?

Both the drug group and the placebo group received three dilutents (povidone, polyethylene glycol, and polysorbate 80).  Povidone increased the stability of antioxidants and polyethylene glycol and polysorbate 80 are direct antioxidants.  That is likely why many in the placebo group showed an improvement.


Lane Simonian
Posted: Wednesday, October 16, 2019 2:49 PM
Joined: 12/12/2011
Posts: 4589


One of the best questions ever asked on these boards and the sad answer is no: companies are not chomping at the bit to develop antioxidants, even though they seemed to work in the placebo group in the Neurotrope clinical trial. 

There are a number of reasons for this.  One may be that natural antioxidants almost always seem to work better than synthetic antioxidants.  Most of the antioxidant trials for Alzheimer's disease occur outside the United States; there is not a financial incentive for them to occur within the United States.

Second in terms of the outcome of Neurotrope is that most of the backers of the compnay reject the idea that the dilutents explained the difference between the placebo and the drug group.  Before the results were released, the backers of Neurotrope argued that improvement in some inidividuals taking the placebo was just a matter of the placebo effect.  They further believed that the dilutents were just inert ingredients.  When the placebo group on average did better than the drug group then they dropped the placebo effect argument and threw up their hands and said we just don't know why the placebo group responded better.  The irony is that the scientist who developed Neurotrope's bryostatin-1 knew the drug needed antioxidants to be effective.

https://www.ncbi.nlm.nih.gov/pubmed/18313045

As it turned out the antioxidants were more effective than the drug plus antioxidants.

I don't know this for sure, but the antioxidant dilutents might only work well when injected (the same is also true for certain antibioitics).  They just don't stand out (from the bit that I have read) as great antioxidants, at least not when taken orally.

The larger issue is that the clinical trial results using antioxidants have produced many different results.  Unfortunately, the largest trial involved Vitamin C (which can become a prooxidant under certain conditions), Vitamin E (differet forms of which can have different impacts), and alpha lipoic acid (the form used in the trial was not likely well-absorbed).  Some proclaimed after this trial that antioxidants cannot be used to treat Alzheimer's disease.

The type of antioxidant used in important, and the best ones have either stablized or partially reversed certain aspects of Alzheimer's disease in a variety of clinical trials.