CNP520 or Placebo

[Boomer46]

Hello,
I am new to ApoE4.info. I am an e4/e4 and am in Generation One Study for CNP520 or Placebo. I had all of the cognitive testing, blood testing, ekg, MRI, and PET scan and at 72 I am a healthy female who has no cognitive impairment at this time. I also take vitamins and supplements and am on a statin drug and 2 blood pressure medicines. I have never been in the hospital except for having two babies and have no other risks. My question is whether anyone else is taking this experimental drug or placebo, and if so, do you know the possible side effects. They did take pictures of my skin and said some people get rashes and itching.

What can any of you tell me about this drug made by Novartis.

Boomer46

[CarrieS]

Hi Boomer46 and Welcome to the Community!
I don't have the expertise to answer your questions so I will leave that to the more knowledgeable but I DID want to welcome you in the mean time. Since you are new to the Forums, please let me point you to the very helpful Wiki addition How To Get The Most Out Of The ApoE4.info Website. While in the Wiki you will find a deeper dive into various topics that may interest you too. Another great resource is our Primer written by physician member Stavia.

You can use the spyglass icon located to the left of your name and search for Generation One Study to find other threads on that topic too.

Regards,
Carrie

[Gillyp]

Welcome to the ApoE4.info community Boomer46. I too don't have any knowledge of the Generation One Study for CNP520 but I'm sure others in our community will be able to comment. It takes courage to get all of this testing done but with the information you now have you will be able to make lifestyle changes that can only help you moving forward. Carrie5 already pointed you in the direction of our Primer which is a excellent resource. You'll find there's so much useful information on the site. We are all here to support each other and to learn. Anything that you can share about your experience going through this study will, I'm sure, be very helpful to the rest of the community. Keep us posted and welcome once again.

[NF52]

Hello,
I am new to ApoE4.info. I am an e4/e4 and am in Generation One Study for CNP520 or Placebo...What can any of you tell me about this drug made by Novartis. Boomer46

A warm welcome, Boomer 46!

I am a 66 year old 4/4 "Baby Boomer". Next week will mark one year since I started a daily dose of CNP520 (or placebo). I know of several other people who have been on it anywhere from 6 months to 18 months on this site, with ages from the early 60's to early 70's. You can check out these forum topics to get some sense of the discussions around the Generations trials: CAD106 and CNP520 and
Generation Study 2

I have had no noticeable side effects. Earlier BACE-1 drugs (not CNP520) resulted in some loss of skin pigmentation in mice; therefore, the study doctors wanted to be sure that wasn't happening in people. However, at my most recent check, in June, I was told that no one has had pigment loss. Dr. Tariot, one of the primary trial doctors nationally, has reported that minor itching is the most serious side effect they've had reported.
(Full disclosure: I've never met Dr. Tariot, but briefly knew his wife, who was a pediatric psychiatrist who consulted with my school district. He was written up in our local newspaper 30 years ago for his determination to spend his career researching Alzheimer's and working directly with patients in a large community hospital setting. He said that seeing his own father-in-law with moderate dementia, he knew that if the disease could be prevented, or the progression delayed it would help families enormously. At a time when many people viewed Alzheimer's as hopeless, he was convinced that a prevention treatment could be found. Little did I think that 30 years later I'd be part of one of his clinical trials trying to prevent AD in myself!]

I spent a fair amount of time looking for information on CNP520 and BACE-1 inhibitors in general before I started and was reassured by the 20-years of science that has gone into studying the amyloid precursor protein (APP) that is at the heart of this anti-amyloid therapy trial. (As an aside, Dr. Bredesen, author of The End of Alzheimer's, apparently studied APP in the 1990's himself.) CNP520 has gone through several years of smaller Phase 1 and 2 clinical trials with about 300 people with no results that forced the trials to be abandoned. I saw results that compared SAEs (serious adverse events) in the placebo and drug populations. Similar percentages of each group reported things like constipation, headache, colds, etc. I think there was one case of a person on the drug having colon cancer, which was judged to be unrelated.

Here's some of the science behind CNP-520; hope it's not overload!
The concept behind BACE-1 drugs is to block the formation of amyloid plaques ("beta amyloid") before they cause damage to the brain. The drug does this by "inhibiting" an incorrect "cut" (or cleavage) in the amyloid precursor protein (APP). I think of it like the old carpenter's axiom: "Measure twice; cut once." Here's an image from Sciencedaily that shows how a rare Icelandic mutation was discovered that prevented "cleaving" at the wrong spot, and the people with this mutation survive into their 90's without AD. (Apologies for not being able to size down the image.)



Below is a 2016 summary of results from the earlier, Phase 1 and 2 clinical trials of CNP520 to determine safety and effectiveness of the goal of reducing amyloid.

Across completed human studies, with a total of > 300 exposed subjects, no dose-limiting safety findings were observed up to 300 mg for 2 weeks, and 85 mg for 3 months. Pharmacometric modelling predicts a daily dose of 50 mg to reach 80% CSF Aβ lowering and a dose of 15 mg to achieve 60% CSF Aβ lowering, in 90% of the subjects. ... Concentrations achieved in humans with 50mg are substantially lower than the concentrations achieved from the no-observed-adverse-effect-level in non-clinical studies in dog and rat, indicating adequate safety margins...Conclusions: Results from completed studies and pharmacometric modelling indicate that both CNP520 doses of 50 mg and 15 mg are expected to significantly reduce Aβ levels in the CSF, with an acceptable safety and tolerability profile for long-term clinical studies to delay the onset of symptoms of AD in APOE4 carriers

.

Here's another article that describes how the study's researchers, and a doctor who is running one of the study sites at the University of Rochester (NY), view CNP520. I know it could be viewed as biased, but it does convey what they believe. RATIONALE FOR CNP520 DOSE SELECTION FOR THE PIVOTAL CLINICAL PROGRAM IN PRECLINICAL AD

The study partners are enthusiastic about CNP520, which performed well in its safety and tolerability studies. In an interview, Dr. Tariot called the CNP520 “likely a best-in-class molecule." “The only adverse events we saw in the entire safety program were a few cases of itchy skin,” said Dr. Tariot, director of the Banner Alzheimer Institute in Phoenix. “One of the reasons we chose Novartis as a study partner is that this drug of theirs looked remarkably clean – so clean that when we were deciding what doses to look at, the decision related only to what degree of BACE inhibition we wanted, not safety.”
The drug seemed very well-tolerated at every dose tested (1 mg, 10 mg, 25 mg, and 75 mg). Generation 1 employs a 50-mg oral dose per day. Generation 2 will investigate both 50 mg and 15 mg. Site investigators are solidly behind the choice, said Anton Porsteinsson, MD, a Generation investigator at the University of Rochester (N.Y.) Medical Center, despite the unveiling at CTAD of worrisome adverse events seen in Merck’s failed EPOCH trial. “I am even more convinced now that BACE inhibitors are drugs that need to be used early and that are probably highly indicated for this population,” he said in an interview.

Finally, here's a link to a November 2017 article by a science writer not connected to the Generations program. He explains some of the background of BACE inhibitors, which were discovered as a rare mutation in healthy Icelanders who lived to their 90's with no dementia. Ace of BACE? Mechanism may block AD before symptoms He also notes some of the concern some scientists have had about completely inhibiting BACE-1 (which CNP-520 doesn't do) and the need to monitor for side effects.
http://www.bioworld.com/content/ace-bac ... d-symptoms

Please feel free to share more of your decision to embark upon the Generations Trial if you'd like, and to post any other questions. (I promise to be more concise next time!!). If you haven't seen it, the PRIMER, by Dr. Stavia, who is also 4/4 is a great resource for how to live each day and what to tackle to improve your health. That is also true of the WIKI. And to help you quote people so they are notified of your replies, or to learn tips for searching for topics, or using Private Messages, check out our How-to Guide, complete with screen shots and step-by-step directions.

You are part of a special group of people, Boomer46. Feel free to reach out whenever you need some support on the journey. This forum is a safe place for all of us! Hugs from the soggy state of Virginia.

[Boomer46]

Thank you all so much for your warm welcome and all of the valuable information that you have provided. I very much look forward to being a part of this group. I will check out the Primer and Wiki for more info. You have shown such compassion toward me - a stranger at this time. I so appreciate it.

[Boomer46]

Thank you so much for all of the information you have shared. I am in the Generation one study and taking the 50 mg tablet of CNP520 or Placebo. Does anyone know if you only get side effects if you have the real pill of CNP520? Since starting the pill 3 weeks ago, I have a slow digestive system and skin itching. My son is a physician and he couldn't tell me whether I might get the side effects from the placebo. He said both pills would be the same except one would contain the medicine and the other would not. Does anyone out there know the answer. Whoever sent me all of that research - thank you so much for taking the time to explain everything.

Regards,

Boomer46

[NF52]

Thank you so much for all of the information you have shared. I am in the Generation one study and taking the 50 mg tablet of CNP520 or Placebo. Does anyone know if you only get side effects if you have the real pill of CNP520? Since starting the pill 3 weeks ago, I have a slow digestive system and skin itching. Regards, Boomer46

Hello again, Boomer 46!
I'm the one who sent that REALLY long post with info. Glad it was helpful; brevity isn't one of my strengths

Itching is one of the side effects noted by some people taking CNP520 in earlier, smaller studies, but it's neither necessary nor sufficient to conclude that you're on the drug and not the placebo. First, it's not "necessary" because apparently only a small percentage of people taking the drug got usually mild itching, so people without itching could be the majority of those taking CNP520. Second, it's not "sufficient" to conclude you're on the drug because itching is such a common symptom, especially in people who might have dry or sensitive skin. (I just walk by weeds and I seem to get poison ivy; stand outside for 10 minutes and might have a dozen mosquito bites; can't wear wool and am allergic to grass, leaves, cat dander and rabbits!)

I do know of at least one woman in the study who said she had constipation in the beginning, and her doctor advised the usual over-the-counter remedies. As far as I know, that went away in a short time period. If I remember correctly, one of the CNP 520 side effect studies I saw reported that about 14% of both placebo and drug groups reported constipation as a side effect. So, could be a side effect, or it could be nothing.

Although I've had no striking side effects (itchy skin to me is "what else is new?") I like to think that I have a 68% chance of being on CNP520, while knowing that some people have to be taking the placebo for the study to be valid. So if that's me, I am taking one very expensive placebo and hope that others are getting a benefit from the drug.

Please feel free to send a Private Message if you have other questions I can help with that you don't want aired in public! (And no, I won't tell you what the 6 month test questions are )

[Boomer46]

As you may know this study ended early because of data collection. The people at Rush were very quiet about what it concluded. Later, I got a letter that I took the placebo so this question doesn't affect me anymore. Thanks for all of the answers. It was interesting to be in a study, and because I have a letter that I took the placebo I am eligible for other studies but have not found one that looks promising to me.

[NF52]

As you may know this study ended early because of data collection. The people at Rush were very quiet about what it concluded. Later, I got a letter that I took the placebo so this question doesn't affect me anymore. Thanks for all of the answers. It was interesting to be in a study, and because I have a letter that I took the placebo I am eligible for other studies but have not found one that looks promising to me.

Thanks for posting again, Boomer46!

I was sorry to see the Generations I (and II) trials of CNP520 (umibecestat) and CAD106 halted in July 2020. As someone who enjoyed the process of going in every 3 months and seeming to do well on the test, while taking a daily pill faithfully, I hoped I was doing something for science and my brain. As others have noted, when clinical trials end suddenly, the trial participants can't get an "early warning" due to the need to prevent insider trading on the drug's stock, but as a result of this trial and others that ended early, participants have successfully advocated for changes in how studies plan for the possibility of an early end. Studies now are careful to explain under what circumstances they will end early, and how people will be notified, usually by phone/text or email based on preference, with a follow-up call ASAP to explain next steps and the offer of further support if needed.

Like you, I found out that I was on the placebo, but not until about May 2021, which apparently was well after some sites shared this information. Prompt reporting as soon as possible of assignment to the study drug or placebo is also a recommendation for further studies.

Scientists did share information about the reasons for the stop and what has been learned about BACE inhibitors in 202o at the Alzheimer's Association International Conference. I was able to hear that presentation, and a summary of is in the AlzForum newsletter from August 2020 here:

Umibecestat-Driven Cognitive Decline Is Reversible

Here are some key points, with some explanation added by me in brackets:

Cognition Restored. While taking umibecestat, [about 1/3 of participants] performed [slightly]worse on cognitive tests than did those on placebo, as seen in their last assessment on drug (top). Four months after they stopped, differences between the groups had all but disappeared (bottom). [Note: the differences were so slight that sites were not aware of the change in some participants being significant until data across all sites was analyzed by an independent evaluator, as part of the study design.]
...
Graf noted that the difference between the drug and placebo groups was not wholly due to worsening on drug, but also to a greater proportion of people in the placebo group than on drug improving on the tests. Practice effects often lead to better cognitive scores as trials in asymptomatic or very mildly symptomatic participants progress. [Note: Study design teams have been focusing on using tests that are less prone to "practice effects" and spacing out key testing to 6 or 12 months intervals with shorter, different assessment sometimes used in between the multi-hour testing..

Graf concluded that there was no long-term impact on disease progression...Pooled data from both trials indicated more loss of hippocampal and whole-brain volume in treatment groups by week 26, irrespective of dose.... The effect sizes were about the same at week 52, suggesting the volume loss was not progressive, said Reiman. Neither did it correlate with worsening total RBANS scores or with immediate or delayed recall.

Among 256 volunteers who had a follow-up MRI within two months of washout, their volume loss appeared at least partially restored. ...The difference in hippocampal volumes between drug and placebo groups was no longer significant.
...Others wondered how to interpret the loss of brain volume. Reiman believes it may reflect changes in the amount of brain fluid due to clearance of Aβ, an explanation proffered for other anti-Aβ therapies (Jul 2004 conference news; Dec 2017 news). In support of this, volunteers who were found to have elevated brain amyloid based on PET or CSF analysis had more brain shrinkage. “In general we are encouraged that we’ve seen only mild cognitive worsening, brain-volume changes that are not related to cognitive changes, and that all changes appear to reverse, or at least in case of MRI, begin to reverse,” said Reiman.
Note: what seems most interesting is the some scientists think the lesson learned is to NOT try to rid the brain of all amyloid, or all amyloid precursor protein, and that is why some current trials (donanemab) are looking to end dosing as early at 26 weeks if PET scans show that the amyloid has decreased below a target level.]
...
Colin Masters, University of Melbourne, Australia, would dial the dosing down even further. Based on the rate of Aβ accumulation over a 20-year period, he believes 10 percent inhibition would be sufficient. He thinks the cognitive/psychiatric adverse events in Generation are due to umibecestat inhibiting the normal function of APP, which is needed for synaptic activity, learning, and memory. “The best strategy going forward, in my view, will be to use an antibody to lower the Aβ load to normal (might take a year or two) and then use a low-maintenance dose of a BACE inhibitor to keep it down,” he wrote to Alzforum.

If a BACE inhibitor is deployed in a future prevention trial, including a primary prevention trial in persons at genetic risk who do not yet have appreciable amyloid plaque deposition, then it will be important to consider ways to conduct the trial with adequate statistical power despite the modest worsening and very early preclinical stage, for example assessing persons with biomarker endpoints and/or with cognitive endpoints after temporary discontinuation of study drug,” Reiman wrote to Alzforum. “It will also be important to consider appropriate risk mitigation strategies.”—Tom Fagan

As for current trials, Rush Medical Center is Chicago seems to be a great site, with patient-centered focus. Trials of several drugs currently in process (BAN2401 and donanemab) and others coming down the pipeline in the next year may be of interest to you. Feel free to send me a Private Message (PM) if you'd like more specifics.

Hope life at age 75 or 76 (if I'm doing the math right) is great. I have just entered that decade myself--much to my amazement since each decade seems to move faster and faster--and both of us still defying predictions of that AD diagnosis at age 68!

[floramaria]

Scientists did share information about the reasons for the stop and what has been learned about BACE inhibitors in 202o at the Alzheimer's Association International Conference. I was able to hear that presentation, and a summary of is in the AlzForum newsletter from August 2020
Note: what seems most interesting is the some scientists think the lesson learned is to NOT try to rid the brain of all amyloid, or all amyloid precursor protein, and that is why some current trials (donanemab) are looking to end dosing as early at 26 weeks if PET scans show that the amyloid has decreased below a target level.]
...
Colin Masters, University of Melbourne, Australia, would dial the dosing down even further. b]Based on the rate of Aβ accumulation over a 20-year period, he believes 10 percent inhibition would be sufficient. He thinks the cognitive/psychiatric adverse events in Generation are due to umibecestat inhibiting the normal function of APP, which is needed for synaptic activity, learning, and memory. “The best strategy going forward, in my view, will be to use an antibody to lower the Aβ load to normal (might take a year or two) and then use a low-maintenance dose of a BACE inhibitor to keep it down,”[/b] he wrote to Alzforum.

Hi NF52, Thank you for posting all of this information about the trial. Very interesting! I am curious about the results of the clinical trials for Alzheimer’s drugs but don’t go to the journals to find them so I appreciate your selecting important sections to share here. Fascinating to read about what they learned in the course of the trial and why it was ended.