Nurown top line data released

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KevinM

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PALS
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06/2019
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Tallahassee
I know that today’s release of the phase 3 data is an incredible letdown for so many PALS hoping this would be the treatment that might halt or restore function. So many had pinned their hopes on dramatically positive results, which did not occur. It does seem to have a positive effect on early stage patients, and the biomarkers identified are helpful, but it fell far short of everyone’s hopes and dreams.

As Brian Wallach said, it works, but the question is for whom and at what rate of infusions. I think it also demonstrates the power of the placebo effect given the very high rate of response in those patients.

My neurologist had expressed his doubts about dramatic results several months ago after parsing all the previous data, and it appears he was right. What a shame. Kevin
 
Disappointing. I'm trying to wrap my head around the concept of such a strong placebo effect. Is this as simple as the power of positive thinking? Maybe we should all be told we're being given a magic pill?? OR does this point to the inaccuracy of the ALSFRS measurements? I've heard they can be imprecise. This disease is so friggin complicated.

Thanks for the update, Kevin.
 
Very disappointing. My first thought when I saw the results was that perhaps the process of the injection, etc. is having a physiological effect. Maybe having the injection alone stimulates some neuronal regeneration or something. Or it could be issues with the ALSFRS measurements as Eric suggests. It seems odd that the placebo effect would be so big for actual functional changes for a disease like ALS.
 
I would be very curious to learn how many of those who reported such positive results actually received the placebo. It seems like many of the videos and testaments from those who claimed dramatic results were early in the disease or had very slow progression (such as Matt Bellina, Mark Bedwell, Thurman Maynard, etc.)
 
I am sorry I know a lot of people hoped for so much.
I think it will always be true that whatever the treatment we are more likely to see results in early disease. Same as cancer treatment.
this is very painful for people who saw it as their last hope but it does not look like a complete failure
 
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I was confused by a couple of stories I read. Was the goal improvement or slowed progression ?
 
Is there still a potential pathway to the FDA approving NurOwn since it appears there was some benefit to early stage slow progressors? Or is this it?
 
The goal is/was slowed progression, Nona. The articles that say "improvement" are clumsily saying that they are hoping for "improvement" [over placebo] in the number of average ALSFRS points that PALS decline in an average month, essentially. Points are still lost, but not as many.

There is no evidence that any therapy in development will repair pre-existing neuronal damage. The "improvement" that some people report reflects, in part, that if you slow progression, some muscles may have time to take over for others in certain movements, as happens even in breathing, if you rest the muscles with BiPAP.

BTW, the "placebo effect," rmt, seen to the extent that placebo and antidepressants, for example, have equivalent results in some trials, isn't just mind over matter, though that's a phenomenon in trials as well as real life. Besides many not-controlled-for differences between the treatment and control groups, there are imprecise outcome measures (the ALSFRS is a categorical joke), fluctuating symptoms, regression toward the mean, and an uncertain baseline.

It is not unusual for a therapy to miss the primary endpoint in its first registration trial and still end up on the market, benefiting some specific group, though smaller than the universe for which we might hope. I suspect that will be the case for NurOwn, Jaclyn. Then, like any other tech, a body of knowledge will build up, to enable more personalized and effective treatment.

If PALS use BiPAP optimally; mobility devices before falling; keep their weight, hydration and nutritional status robust (with a feeding tube if/as needed); continue to do things they enjoy even in modified form, etc., they can [round, context-dependent numbers] double their lifespan as compared with not doing these things. There is no therapy in development that can equal that claim.

Best,
Laurie
 
(black) market of nurown(like) will rise now. if it is approved by fda, price will be lounched, but it is not. it will have same effect, approved or not. you will get it significantly cheaper, but it will be harder to get it.
it will be available very soon in countries like ukraine, cyprus etc.
invested too much money.
if you think that i am talking stupid things, take a look at the stock market. it doesnt lie.
price of brainstorm (bcli) dropped from app 12 usd to 4 usd in one day - yesterday.
read my lips. you will get it sooner and cheaper.
 
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Call me jaded, but I saw this coming for a couple of years. They were just too guarded with publishing results. When there is something that has any effect will be very upfront with their results. As we used to say down south, Never buy a pig in a poke.
Vincent
 
I was a bit pessimist as well, Vincent, but tried to remain cautiously optimistic. That being said, I do think there are inherent flaws in ALS trial designs and targeted endpoints. As Laurie said, the FRS is a categorical joke, and there is too much heterogeneity among PALS to find therapies that work across the full spectrum.

To me there are some similarities with the monoclonal antibody therapy for COVID. it is recognized to be effective, but only if given early and for those with mild-moderate disease. It is not proven effective if given as a Hail Mary for late stage patients.

I think this may be true for several proposed ALS therapies as well, and NurOwn could be one of those. To me ALS treatments are all about subsets, and it my my opinion that no trial currently underway will be effective across the board. Kevin

P.S. great to hear from you!
 
I really appreciate the measured discussion here, in contrast to some of the social media posts about the Nurown results.

As for the placebo effect, the FRS, as a self-reported and somewhat subjective scale, is vulnerable to respondents' mood swings and wishful thinking. And that is made easier by the fact that sometimes we're sitting on the fence on some scoring -- I know that there are a couple of FRS categories where I am always unsure about whether to score myself a 3 or a 4. But it's not worthless. The ALS TDI Precision Medicine Program study that some of us are a part of is an attempt to use wrist and ankle monitors to more precisely measure muscle strength in people with ALS over time. This study was initiated in part to improve on the FRS. But their report last year on their findings noted that the results from their electronic monitors over time tracked pretty closely with self-reported FRS by the participants over time. So the FRS can be a reasonably reliable measurement. But when it's used as a metric by hopeful participants getting a placebo in a high profile clinical trial, the risk of distorted self-reporting driven by wishful thinking would have to be high.
 
If I may comment here...

I’ve written before I think the ALS break through may come the much larger
Alzheimers research currently under way here and world wide.
I follow Alzheimers and forum/sites closely because of my wife Ann.
The funding for Alzheimers research right now greatly surpasses the funding
for ALS because the number of people affected is greater. It's no longer
considered a rare disease like it was 20 - 30 years ago.

Below is just a small portion of what I have copied to my Word files.

On the surface, amyotrophic lateral sclerosis (ALS) and Alzheimer's disease share two commonalities: Both are progressively debilitating neurodegenerative conditions--meaning symptoms get worse--and, at least for now, neither has an effective treatment, let alone a cure.

On the molecular level, a recently identified connection between these devastating diseases could help advance the search for new therapies, according to Jeetain Mittal, the Sam and Ruth Madrid Endowed Chair in Chemical and Biomolecular Engineering in Lehigh University's P.C. Rossin College of Engineering.

Previous research is only the tip of the iceberg. The next step is to take a look at the actual mutations associated with ALS and Alzheimer's and get to the bottom of how they affect the assembly of TDP-43 to give us a better understanding of what causes their malfunction. Then, we can support researchers developing new therapeutic strategies."

Mittal and Brown University collaborator Nicolas Fawzi are focused on TAR DNA-binding protein 43, or TDP-43. Neuronal deposits of this essential human protein are found in people living with Alzheimer's and related types of dementia, as well as those diagnosed with ALS (also known as Lou Gehrig's disease).

Something to consider. Back to NurOwn.

PS. The reason so much focus is now on Alzheimers sadly is money.
ALS is somewhat considered a relatively short term terminal disease.
Alzheimers is showing to be a long term terminal disease. Fortunately
many (most) ALS’ers do not lose their mental capacities. Alzheimers
is the opposite so care becomes a much different situation.

Also sadly, many Alzheimer patients die of other complications or just
plain old age, Ann’s sister was diagnosed in her 60s… she is now in
her early 80s. She has been a nursing home now going onto 8 years…
she doesn’t recognize any of us. Other than the Alzheimers she is
healthy. The cost of long term care is a costly burden for Medicare.

In home care for Alzheimers is more complicated than in home care
for those with ALS. Not getting into a long description… it’s the
mental capacity thing.
 
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Um, the fact that the FRS tracked with selected muscle strength doesn't validate it as a categorical scale used to evaluate other domains. It's a circular argument. The FRS is being used in part to validate new devices for measuring strength.

In MS, for example, you now have a timed walking test that the FDA has accepted as a primary endpoint, whereas the EDSS that was formerly used suffers from some of the same issues as the FRS. especially since most MS patients suffer periodic exacerbations before/instead of relentless progression. So we can at least ask, "Did walking improve or worsen, and how much?" instead of inappropriately combining several questionable measures.

The FDA is conservative about new primary endpoints. It takes decades to get stuff done, and lots of $ to validate the endpoint, and you have to start early. In ALS, that didn't happen. However, a shift is in progress, as others have mentioned.

Al, when I was in pharma, I did some work combining mechanistic thinking on several neurodegenerative diseases, including ALS, schizophrenia, and Alzheimer's. We're still not sure if TDP-43 is a chicken or an egg, or both, but lots of intriguing stuff.

Best,
Laurie
 
As I said in other threads better biomarkers are sorely needed and those who are able need to help us get there for the future is not for ourselves. Observational studies are key but a number of trials are trying to incorporate these at least as secondary outcomes.

it is worth noting that there are opportunities for family members or friends to participate as normal controls too.
 
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