Tag Archives: Alzheimer’s disease

Overblown Stock Market Reaction to Simufilam results

The stock market reaction to Simufilam’s 1 year open label results is extremely overblown.  Here is a link to the results — https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-announces-positive-top-line-clinical-results

First: no other therapy has shown improvement in Alzheimer patients.  The best they can claim is a slower rate of decline.

Second: In 30+ years of clinical neurologic practice, I never saw anyone with Alzheimer’s get better after a year. One or two remained stable for a year, but everyone else got worse. Cassava’s results are impressive (with nearly half improving at one year)  and unique. There is little reason to doubt them, given the way the data has been handled.

Third: even though not a controlled study, a placebo effect is extremely unlikely given my clinical experience with Cognex (Tacrine) when it came out — for details please see — https://luysii.wordpress.com/2023/01/25/why-cassavas-simufilam-results-are-not-a-placebo-effect/

Fourth: the realities of clinical practice.  Assuming that Simufilam is released with data similar to the 1 year results, as a physician I would be remiss if I didn’t offer a drug with nearly a 50% chance of improvement at one year, given the current miserable therapeutic landscape.  Back in the day no patient refused trying Cognex.  Then there is the likelihood of being sued for NOT giving Simufilam, as people were sued for not giving tissue plasminogen activator for stroke, a therapy with minimal evidence for it when it came out — for details please see — https://luysii.wordpress.com/2015/09/02/reproducibility-and-its-discontents/

Fifth: the fact that not everyone responds to Simufilam is irrelevant to eventual FDA approval.  Given all the illnesses we are heir to, even the best drug for any particular illness among the many does not work for everyone with it.  For more on these thoughts please see – https://luysii.wordpress.com/2023/01/26/the-fact-that-not-everyone-responds-to-simufilam-is-irrelevant-to-its-eventual-fda-approval/

Why Cassava’s Simufilam results are not a placebo effect

Any open label study without controls is subject to the reasonable criticism that any benefits seen are due to the placebo effect.  Neurologic and Psychiatric disease trials can have large (33%) placebo effects (e.g. migraine, depression).

This is very unlikely to be the case with the 1 year results of the open label trial of Simufilam in 200 patients with Alzheimer’s disease.  “47% of patients improved on ADAS-Cog over 1 year, and this group improved by 4.7 points”

It is based on my clinical experience with a drug for Alzheimer’s disease released 30 years ago — Tacrine (Cognex).  Initially it was touted as helping Alzheimer’s disease (e.g. improving thinking and memory) although later it was held to slow the decline.   The local medical school advertised it aggressively (primarily as a marketing device).

So I put my Alzheimer patients on Cognex.  I wanted them to get better. They wanted to get better, and their families and caregivers certainly did.  Just about all of them thought it might have helped on followup visits in the first month.  I couldn’t see much difference.  By the second month, they weren’t sure, and later in the first year they didn’t think it helped, and most weren’t using the drug after 1 year.

Not only that, but I was in a call group with 4 other neurologists, and they saw exactly the same thing.  I was practicing in an area with a catchment area of over a million people, and every local neurologist I talked to had the same experience. People thought that “Cognex helped” for a month or two and then they didn’t

This a classic example of a placebo effect.  Moreover it occurred in a therapeutic trial for Alzheimer’s disease.  Crucially, the placebo effect was quite transient and  absent at 1 year.

This is why the Simufilam results mentioned above are not a placebo effect.

Those not interested in neuropharmacology can stop at this point.  There were excellent clinical and theoretical reasons for the use of Tacrine.

Clinically it was apparent that drugs that blocked the effects of the neurotransmitter acetyl choline on one type of its receptors (muscarinic) profoundly impaired memory. Scopolamine is one such drug.  One of the earliest and most invariable symptoms of Alzheimer’s disease is deficient memory.

That’s the clinical part.  Here’s the theory.  So logically, increasing acetyl choline should help memory.  How to do this?  Well there are enzymes that break acetyl choline down (the acetyl cholinesterases).  So by inhibiting cholinesterases, acetyl choline levels in the brain should increase, and memory should be improved.

Impeccable logic and theory.  Unfortunately, like many such it didn’t work.

4 diseases explained at one blow said the protein chemist — part 1

A brilliant paper [ Science vol. 377 eabn5582 pp. 1 –> 20 ’22 ] explains how changing a single amino acid (proline) to another  can cause 4 different diseases, depending on the particular protein it is found in (and which proline of many is changed).

There is so much in this paper that it will take several posts to go over it all.  The chemistry in the paper is particularly fine.  So it’s back to Biochemistry 101 and the alpha helix and the beta sheet.

Have a look at this

https://cbm.msoe.edu/teachingResources/proteinStructure/secondary.html

If you can tell me how to get a picture like this into a WordPress post please make a comment.

The important point is that hydrogen bonds between the amide hydrogen of one amino acid and the carbonyl group of another hold the alpha helix and the beta pleated sheet together.

Enter proline : p//en.wikipedia.org/wiki/Proline.  Proline when not embedded in a protein has a hydrogen on the nitrogen atom in the ring.  When proline is joined to another amino acid by a peptide bond in a protein, the hydrogen on the nitrogen is no longer present.  So the hydrogen bond helping to hold the two structures (alpha helix and beta sheet) is no longer present at proline, and alpha helices and beta sheets containing proline are not has stable.  Prolines after the fourth amino acid of the alpha helix (e. g. after the first turn of the helix) produce a kink.  The proline can’t adopt the alpha helical configuration of the backbone and it can’t hydrogen bond.

But it’s even worse than that (and this observation may even be original).  Instead of a hydrogen bonding to the free electrons of the oxygen in the carbonyl group you have the two electrons on the nitrogen jammed up against them.  This costs energy and further destabilizes both structures.

Being a 5 membered ring which contains the alpha carbon of the amino acid, proline in proteins isn’t as flexible as other amino acids.

This is why proline is considered to be a helix breaker, and is used all the time in alpha helices spanning cellular membranes to cause kinks, giving them more flexibility.

There is much more to come — liquid liquid phase separation, prion like domains, low complexity sequences, frontotemporal dementia with ALS, TDP43, amyloid, Charcot Marie Tooth disease and Alzheimer’s disease.

So, for the present stare at the link to the diagram above.

I’ve hit the big time at last

I find this hard to believe, but the interview I did with Joe Springer on Friday 4 February  now has its own cliff notes —  It was a lot of fun while I was doing it, but the stress came before and afterwards.  People did seem to like it, judging by the comments they made while I was talking.

Why most criticisms of Cassava Sciences are irrelevant, and two which are not

Most criticisms of Cassava Sciences are irrelevant (see later), but there are two which could doom the company.  Here they are.

Both criticisms involve the results of the 1 year open label trial of Simufilam. You will recall that patients improved on average.  The study was criticized for cherry picking patients and data.  However a closer reading of the results found that 5/50 patients improved their ADAS-Cog Score by 50% after a year on the drug — for details please see https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

These results are spectacular and absolutely nothing like this has been seen in untreated (or even treated) Alzheimer patients.

So what are the criticisms? Forget cherry picking of the data, as Cassava didn’t do it, and even if they did these results are so spectacular that cherry picking is irrelevant.

Doom criticism #1 — the data are false and made up by Cassava.  In Montana this was a practice in the gold mining days, when a few nuggets were sprinkled in an otherwise worthless mine to delude the unwary.  This was called salting the mine.

This is unlikely as the data were reported from sites producing the data, not Cassava.  Further Lindsay Burns told me that the 5 spectacular results came from 5 different sites administering the drug.  I was worried that one site was screwing up and measuring ADAS-Cog incorrectly.

Doom criticism #2 — People are paid to enter these studies.  How much isn’t clear.  Could the 5 have faked the dementia and then gotten better on subsequent testing?  Cassava tests to make sure  subjects are actually taking the drug.   This is a possibility but remote.

Now for the irrelevant criticisms.

#1 The mechanism of action of simufilam makes no sense.  It certainly is quite radical — for details see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/.

Why is it radical?  The nicotinic cholinergic receptor is an ion channel.  Binding of another protein to it is not postulated to open the channel, but to alter its binding to another protein (filaminA) inside the cell. This is a totally new mechanism for drug action on ion channels — binding to the channel so its binding to something inside the cell changes.  Simufilam is held to change the conformation of filamin A.

Well that’s pretty damning.  Why can it be ignored?

Because the mechanism of the aBeta peptide being the cause of Alzheimer’s has a huge amount of beautiful chemistry behind it — for details see — https://luysii.wordpress.com/2021/10/21/amyloid-structure-at-last-3-the-alzheimer-mutations/

Here’s a quote  from the post — skip this if you don’t have the necessary biochemical background, but to anyone with knowledge of protein chemistry it is beautiful and essentially confirms the amyloid hypothesis of Alzheimer’s disease

“In 2007 there were 7 mutations associated with familial Alzheimer’s disease (10 years later there were 11). Here are 5 of them.

Glutamic Acid at 22 to Glycine (Arctic)

Glutamic Acid at 22 to Glutamine (Dutch)

Glutamic Acid at 22 to Lysine (Italian)

Aspartic Acid at 23 to Asparagine (Iowa)

Alanine at 21 to Glycine (Flemish)

All of them lower the energy of the amyloid fiber.

Here’s why

Glutamic Acid at 22 to Glycine (Arctic) — glycine is the smallest amino acid (side chain hydrogen) so this relieves crowding.  It also removes a negatively charged amino acid next to the aspartic acid.  Both lower the energy

Glutamic Acid at 22 to Glutamine (Dutch) — really no change in crowding, but it removes a negative charge next to the negatively charged Aspartic acid

Glutamic Acid at 22 to Lysine (Italian)– no change in crowding, but the lysine is positively charged at physiologic pH, so we have a positive charge next to the negatively charged Aspartic acid, lowering the energy

Aspartic Acid at 23 to Asparagine (Iowa) –really no change in crowding, but it removes a negative charge next to the negatively charged Glutamic acid next door

Alanine at 21 to Glycine (Flemish) — no change in charge, but a reduction in crowding as alanine has a methyl group and glycine a hydrogen.

As a chemist, I find this immensely satisfying.  The structure explains why the mutations in the 42 amino acid aBeta peptide are where they are, and the chemistry explains why the mutations are what they are. ”

Evidence just doesn’t get any better than this.

So we have  beautiful convincing evidence that amyloid from the aBeta protein causes Alzheimer’s disease.  EXCEPT  that— innumerable trials of getting rid of the amyloid in the Alzheimer brain have not helped and often made things worse.

So criticizing Cassava’s theory of why Simufilam appears to do what it does is like a med school classmate (he went to the University of Chicago) who was always saying — “That’s how it works in practice, but how does it work in theory?”

#2 There are problems with the electrophoresis data of years ago, and with the biomarkers of Alzheimer’s disease. Possibly true, but people don’t visit doctors because of abnormal biomarkers.  Such criticisms are irrelevant to the therapeutic results Cassava has reported.

So it’s time to proceed with the studies currently entering patients.  It is important to note that the FDA has approved the study and the way it will be done, Cassava will stand or fall on the placebo controlled study.  They won’t be asked to do a new one.

Amyloid Structure At Last ! 4 Polymorphs

Henry J. Heinz claimed to have 57 varieties of pickles in 1896, but Cell [ vol. 184 pp. 4857 – 4873 ’21  ] Page 4862 claims that 24 amyloid polymorphs of alpha-synuclein have been found and structurally characterized.

What does this actually mean in English? The previous 3 articles in this series have discussed the structure of amyloid — the most relevant being https://luysii.wordpress.com/2021/10/11/amyloid-structure-at-last/

Basically, in amyloid some of the protein backbone flattens out so it lies in a single plane, and thousands of the planes stack on top of each other producing the amyloid fiber.  In the case of alpha-synuclein some 56 of the 144 amino acids comprising the protein flatten out.   Just as throwing a chain with 56 links on the floor will give different conformations of the chain,  the conformation of alpha-synuclein is different in each of the polymorphs.

So what?

Well, different polymorphs of another protein, the tau protein which forms the neurofibrillary tangle in Alzheimer’s give rise to at least 25 clinically distinct neurological diseases called tauopathies (3 more are chronic traumatic encephalopathy, corticobasal degeneration, and Pick’s disease).  In each of the these four diseases, a different conformation of tau is seen.

Then Nature [ vol. 598,  pp. 359 – 363 ’21] blows the field wide open, finding 19 different conformations of tau in clinically distinct diseases. Each clinical disease appears to be associated with a distinct polymorphism.  This is also true for the polymorphisms of alpha-synuclein, with distinct conformations being seen in each of Parkinsonism, multiple system atrophy and Lewy body dementia.

In none of the above diseases is there a mutation (change in amino acid sequence) in the protein

Back to alpha-synuclein.  How did they get the 24 different conformations?  They incubated the protein under different conditions (e.g. different salt concentrations, different alpha-synuclein concentrations, different salts).

Why is this incredibly good news? 

Because it moves us past amyloid itself, to the conditions which cause amyloid to form.  Certainly, removing amyloid or attacking it hasn’t resulted in any clinical benefit for the Alzheimer patient despite billions being spent by Big Pharma to do so.

We will start to study the ‘root causes’ of amyloid formation.   The amino acid sequence of each protein is identical despite the different conformations of the chain in the amyloid. Clearly the causes must be different for each of the different polymorphs of the protein.  This just has to be true.

Some cynic said that people who talk about the root causes of crime never get their hands dirty.  Hopefully neuroscience is about to take off its gloves.

This is why alternative approaches to Alzheimer’s disease, such as Cassava Biosciences manipulation of filamin A, might bear fruit.   For details please see — https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

Just got this back from one of the authors of the Nature paper

“Yes, studying the conditions that lead to all these different structures
is certainly high on our to-do list now.”

 

Cassava Sciences — the clinical reality underneath the stock gyrations.

The stock of Cassava Sciences (symbol SAVA) has undergone some wild gyrations this year.  On 14 September it traded at 41.70, today just two weeks later it is trading in the upper 60s.

The important thing to keep in mind, is that 1 year out on treatment with SAVA’s drug Simufilam 50 patients with mild Alzheimer disease were (as a group) slightly improved.  This is absolutely unprecedented.  The best that previous therapy could accomplish was a slightly slower rate of decline — see arshttps://science.sciencemag.org/content/sci/373/6555/624.full.pdf — for a recent review of other therapy attempts.  So Cassava’s results are unprecedented.   While Alzheimer (and other dementia) patients fluctuate from day to day (like the tides from minute to minute) at the end of a year they are all worse.

These results have not been attacked, unlike their data on the effect of Simufilam on biomarkers which has been criticized by a person of standing — Elizabeth Bik — https://scienceintegritydigest.com/2021/08/27/cassava-sciences-of-stocks-and-blots/#more-2692.

But that’s irrelevant and guilt by association at best.  As a clinical neurologist, no one was ever brought to see me because of their biomarkers.

They have released part of their 1 year results — https://www.cassavasciences.com/news-releases/news-release-details/cassava-sciences-announces-top-line-results-12-month-interim.  There is a lot more that I’d like to know, but a press release is not a detailed scientific paper.

What follows is a lot of commentary and speculation about the 1 year data which we haven’t seen yet.

The results concern the first 50 patients to complete one year on the drug.  The dropout rate is stated to be under 10%.  Presumably this includes death, in a cohort (presently at around 200) with a significant mortality.  It would be interesting to know how many patients on entry made it to one year.

As a clinical neurologist I was particularly impressed with part of their data at 9 months.  Here’s a link — keep it handy — https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389.

They measured cognitive changes by something called ADAS-Cog — a full description can be found in the following post — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

ADAS-Cog score counts errors, so a perfect score would be 0, and a terrible score would be 70.  The range of deficit on entry was 16 – 26 (but possibly on something else called the MMSE) — this is what the 1 year results used.  The 9 month results used ADAS-Cog.  Perhaps they are actually the same thing — I don’t know.

On the link — https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389 — look at the diagram titled “Individual Patient Changes in ADAS-Cog (N = 50).

There were 5 patients out of 50 at 9 months with improvements of 11 – 14, which would mean that they were pretty close to normal if their entry score was 16 and 50% improved if their score was 26.  From here out I’m just calling them ‘the 5’.

The 9 month report doesn’t discuss this, and only a clinician would know, but this is the way neurologic patients respond to treatment.  Some do extremely well while others have no effect.  Why?  It’s probably because not really understanding causation, we classify patients clinically (it’s all docs have after all).

I ran a Muscular Dystrophy Clinic for 15 years back in the day.  The Muscular Dystrophy Association was founded by parents of weak kids.  They didn’t know that some weakness was due to the muscle itself (what we’re now calling muscular dystrophy), some was due to disease affected the nerves from the spinal cord to the muscle (what we call a neuropathy now) and others were due to disease of the cells in the spinal cord giving rise to the nerves to the muscle (motor neuron disease).  That all came later.

It is quite presumptuous to say that Alzheimer’s disease is just one thing.  Perhaps the 5 patients doing so very well had it from a different (as yet unknown) cause than the other 45.  Even so such a treatment would be worth having.

So here are a few questions for the folks at Cassava about their data

l. Some 16 different sites were involved in the open label study.  Were all of ‘the 5’  from the same site (doubtful — but if true, perhaps they tested ADAS-Cog differently, casting doubt on these results).

2. What were the ADAS-Cog scores initially on ‘the 5’.

3. What happened to ‘the 5’ in the past 3 months (did they maintain improvement, slide back, or improve further?)

4. We must have lots more people passing the 3, 6, 9 month markers.  Have their results paralleled that of the first 50 reaching the mileposts?   It would be very useful to know if there are now more than 5 with improvements over 10 in ADAS-Cog at 9 months.

The slightly slowing of improvement at 1 year relative to 9 months is typical of neurologic disease.  When L-DOPA was first available in the USA in 1970, some patients because so normal that you couldn’t tell they had Parkinson’s disease, and for a few years, neurologists (myself included) thought we were actually curing the disease.  Of course we weren’t and the underlying pathology of Parkinsonism (death of neurons using dopamine) continued unabated.  The L-DOPA just helped the surviving neurons function more efficiently.  Something similar may be going on with Simufilam and Alzheimer’s.

Now for some blue sky about Simufilam. Just as the gray hair on the head of an 80 year old looks the same under the microscope as one from a prematurely gray 30 year old, the brain changes of Alzheimer’s disease (the senile plaque)  are the same regardless of the age of onset.  Assuming that the senile plaque is in someway related to dementia (despite the lack of effect of therapies trying to remove it) and given that we all accumulate a few as we age, could Simufilam improve cognition in the elderly?   Would it then be intellectual viagra and the blockbuster drug of all blockbuster drugs.

 

Cassava Sciences 9 month data is probably better than they realize

My own analysis of the Cassava Sciences 9 month data shows that it is probably even better than they realize.

Here is a link to what they released — keep it handy https://www.cassavasciences.com/static-files/13794384-53b3-452c-ae6c-7a09828ad389.

I was unable to listen to Lindsay Burn’s presentation at the Alzheimer Association International Conference in July as I wasn’t signed up.  I have been unable to find either a video or a transcript, so perhaps Lindsay did realize what I’m about to say.

Apparently today 25 August there was another bear attack on the company and its data.  I’ve not read it or even seen what the stock did.  In what follows I am assuming that everything they’ve said about their data is true and that their data is what they say it is.

So the other day I had a look at what Cassava released at the time of Lindsay’s talk.

First some background on their study.  It is a report on the first 50 patients who had received Simulfilam for 9 months.  It is very important to understand how they were measuring cognition.  It is something called ADAS-Cog11

Here it is and how it is scored and my source — https://www.verywellhealth.com/alzheimers-disease-assessment-scale-98625

The original version of the ADAS-Cog consists of 11 items, including:1

1. Word Recall Task: You are given three chances to recall as many words as possible from a list of 10 words that you were shown. This tests short-term memory.

2. Naming Objects and Fingers: Several real objects are shown to you, such as a flower, pencil and a comb, and you are asked to name them. You then have to state the name of each of the fingers on the hand, such as pinky, thumb, etc. This is similar to the Boston Naming Test in that it tests for naming ability, although the BNT uses pictures instead of real objects, to prompt a reply.

3. Following Commands: You are asked to follow a series of simple but sometimes multi-step directions, such as, “Make a fist” and “Place the pencil on top of the card.”

4. Constructional Praxis: This task involves showing you four different shapes, progressively more difficult such as overlapping rectangles, and then you will be asked to draw each one. Visuospatial abilities become impaired as dementia progresses and this task can help measure these skills.

5. Ideational Praxis: In this section, the test administrator asks you to pretend you have written a letter to yourself, fold it, place it in the envelope, seal the envelope, address it and demonstrate where to place the stamp. (While this task is still appropriate now, this could become less relevant as people write and send fewer letters through the mail.)

6. Orientation: Your orientation is measured by asking you what your first and last name are, the day of the week, date, month, year, season, time of day, and location. This will determine whether you are oriented x 1, 2, 3 or 4.

7. Word Recognition Task: In this section, you are asked to read and try to remember a list of twelve words. You are then presented with those words along with several other words and asked if each word is one that you saw earlier or not. This task is similar to the first task, with the exception that it measures your ability to recognize information, instead of recall it.

8. Remembering Test Directions: Your ability to remember directions without reminders or with a limited amount of reminders is assessed.

9. Spoken Language: The ability to use language to make yourself understood is evaluated throughout the duration of the test.

10. Comprehension: Your ability to understand the meaning of words and language over the course of the test is assessed by the test administrator.

11. Word-Finding Difficulty: Throughout the test, the test administrator assesses your word-finding ability throughout spontaneous conversation.

What the ADAS-Cog Assesses

The ADAS-Cog helps evaluate cognition and differentiates between normal cognitive functioning and impaired cognitive functioning. It is especially useful for determining the extent of cognitive decline and can help evaluate which stage of Alzheimer’s disease a person is in, based on his answers and score. The ADAS-Cog is often used in clinical trials because it can determine incremental improvements or declines in cognitive functioning.2

Scoring

The test administrator adds up points for the errors in each task of the ADAS-Cog for a total score ranging from 0 to 70. The greater the dysfunction, the greater the score. A score of 70 represents the most severe impairment and 0 represents the least impairment.

The average score of the 50 individuals entering was 17 with a standard deviation of 8, meaning that about 2/3 of the group entering had scores of 9 to 25 and that 96% had scores of 1 to 32 (but I doubt that anyone would have entered the study with a score of 1 — so I’m assuming that the lowest score on entry was 9 and the highest was 25).  Cassava Sciences has this data but I don’t know what it is.

Now follow the link to Individual Patient Changes in ADAS-Cog (N = 50) and you will see 50 dots, some red, some yellow, some green.

Look at the 5 individuals who fall between -10 and – 15 and think about what this means.  -10 means that an individual made 10 fewer errors at 9 months than on entry into the study.  Again, I have no idea what the scores of the 5 were on entry.

So assume the worst and that the 5 all had scores of 25 on entry.  The group still showed a 50% improvement from baseline as they look like they either made 12, 13, or 14 fewer errors.  If you assume that the 5 had the average impairment of 17 on entry, they were nearly normal after 9 months of treatment.  That doesn’t happen in Alzheimer’s and is a tremendous result.   Lindsay may have pointed this out in her talk, but I don’t know although I’ve tried to find out.

Is there another neurologic disease with responses like this.  Yes there is, and I’ve seen it.

I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them.

12 to 14 fewer errors is a big deal, an average decrease of 3 errors, not so much, but still unprecedented in Alzheimer’s disease.   Whether this is clinically meaningful is hard to tell.  However, 12 month data on the 50 will be available in the fourth quarter of ’21, and if the group as a whole continues to improve over baseline it will be a very big deal as it will tell us a lot about Alzheimer’s.

Cassava Sciences has all sorts of data we’ve not seen (not that they are hiding it).  Each of the 50 has 4 data points (entry, 3, 6 and 9 months) and it would be interesting to see the actual scores rather than the changes between them in all 50.  Were the 5 patients with the 12 – 14 fewer errors more impaired (high ADAS-Cog11 score in entry) or less.

Was the marked improvement in the 5 slow and steady or sudden?   Ditto for the ones who deteriorated or who got much worse or who slightly improved.

Even if such dramatic improvement is confined to 10% of those receiving therapy it is worth a shot to give it to all.  Immune checkpoint blockade has dramatically helped some patients with cancer  (far from all), yet it is tried in many.

Disclaimer:  My wife and I have known Lindsay since she was a teenager and we were friendly with her parents.  However, everything in this post is on the basis of public information available to anyone (and of course my decades of experience as a clinical neurologist)

 

What Cassava Sciences should do now

Apparently someone important didn’t like the way Cassava Sciences analyzed their data and their stock tanked again today..  Unfortunately all of this seems to be behind a paywall, and the someone important isn’t named.  I’d love a link if any reader knows of one — just put it in as a  comment below.

I’m not important, but I thought Cassava’s results were quite impressive.  They had enough cases and enough time for the results to be statistically significant

For one thing,  Cassava dealt with severely impaired people (see below) who would be expected to show greater neuronal dropout, senile plaques and neurofibrillary tangles, than recently diagnosed patients.   Neuronal loss is not reversible in man, despite hoards of papers showing the opposite in animals.

Since everything turns on ADAS-CoG, here is a link to a complete description along with some discussion — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/

On a slide from Cassava’s presentation yesterday the ADAS-CoG average of the 50 patients on entry 9 months ago was 16.6.  With a perfect score of 70, it’s clear that these people were significantly impaired (please look at the test items to see how simple the tasks in ADAS-CoG actually are).    So an improvement of 3 points at 9 months  is significant, particularly since a drop of 5 points is expected each year — yes I’ve seen plenty of Alzheimer patients with ADAS-CoG scores of zero or close to it.

So an increase of 3 points in this group is about a16% improvement.

Here’s what Cassava should do now.  Their data should be re-examined as follows.  Split the ADAS-CoG scores into 3 groups: highest middle and lowest. Quartiles are usually used, but I don’t think 50 patients is enough to do this.  Then examine the median improvement in each of the three.  I’d use median rather than average as with small numbers in each group, a single outlier can seriously distort things — think of the survival of Stephen Hawking in a group of 12 ALS patients.

If the patients with the highest ADAS-CoG scores have the highest median improvement, there is no reason mildly impaired individuals should have a less than 16% improvement in their scores.  This means that a person with ADAS-CoG of 60 should achieve a perfect score of 70,  e.g. return to normal.

This would be incredibly useful for early Alzheimer’s disease.

There is a precedent for this.  Again it’s Parkinson’s disease.

As I mentioned in an earlier post, I was one of the first neurologists in the USA to use L-DOPA for Parkinsonism.  All patients improved, and I actually saw one or two wheelchair bound Parkinsonians walk again (without going to Lourdes).  They were far from normal, but ever so much better.

However,  treated mildly impaired Parkinsonians became indistinguishable from normal, to the extent that I wondered if I’d misdiagnosed them. These results were typical.   For a time, in the early 70s neurologists thought that we’d actually cured the disease.  It was a very heady time.  We were masters of the neurologic universe — schizophrenia was too much dopamine, Parkinsonism not enough. Bring on the next neurotransmitter, bring on the next disease.

We hadn’t cured anything of course, and the underlying loss of dopamine neurons in the substantia nigra continued.  Reality intruded for me with one such extremely normal appearing individual I’d diagnosed with Parkinsonism a few years earlier. He needed surgery, meaning that he couldn’t take anything by mouth for a while.  L-DOPA could only be given orally, and he looked quite Parkinsonian in a day or two.

If reanalysis of the existing data shows what I hope, Cassava Sciences should start another study in Alzheimer patients with ADAS-CoG scores of over 50.  If I’m right the results should be spectacular (and lead to immediate approval of the drug).

A little blue sky.  Sumafilam will then come to be known as intellectual Viagra, as all sorts of oldsters (such as yrs trly) will try to get it Alzheimer’s or no Alzheimer’s.

If you decided to buy Cassava Sciences yesterday everything went perfectly (except the price)

Yesterday I laid out the pros and cons of buying Cassava Sciences that day.  The post is reproduced below the ***

Everything I hoped for came true.  The 50 patients on Sumafilam were followed for 9 months and their ADAS-CoG score improved by 3 points.  This is unprecedented for any Alzheimer’s drug.  Historical controls show that Alzheimer patients lost 5 points a year on ADAS-CoG.  So this is a potential net gain with therapy vs. no therapyof  6 – 7 ADAS-CoG points.  Recall that a perfect ADAS-CoG score is 70.  I’ve been unable to find what the average score of 50 patients was on entry.  The paper isn’t published, but is public record results having been presented at conferences (such as today).  Recall that historical controls must be used as the study was open label (e.g. no concurrent controls).

Addendum 30 July:  Since everything turns on ADAS-CoG, here is a link to a complete description along with some discussion — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/

On a slide from Cassava’s presentation yesterday the ADAS-CoG average of the 50 patients on entry 9 months ago was 16.6.  With a perfect score of 70, it’s clear that these people were significantly impaired (please look at the test items to see how simple the tasks in ADAS-CoG actually are).    So an improvement of 3 points at 9 months is significant, particularly since a drop of 5 points is expected each year — yes I’ve seen plenty of Alzheimer patients with ADAS-CoG scores of zero or close to it. 

However using historical controls is a no no particularly in neurology and cardiology.

Why?

From an old post “MDs gradually woke up to the fallacy of using historical rather than concurrent controls particularly in studies of therapies to prevent heart attack and stroke, as the rates of both dropped significantly in the past 50 years, and survival from individual heart attacks and strokes also improved.

 

However, I think using ADAS-CoG is OK in Alzheimer’s as we’re  talking about a disorder with no useful therapy.

 

I’m pleased that I saw the possibility of continued improvement in cognition in yesterday’s post.

 

So all my hopes for the drug came true, yet the stock tanked, closing at 103 down 32 points (down 24%) !

 

Why?  Well, in the past few months, all companies with drugs for Alzheimer’s disease have been fluctuating in price together, and one of them (to remain nameless to protect the innocent) had the temerity to release a 25 day study today on their drug based on 14 patients.  The stock was down 60%.

 

So Cassava got tarred with this brush.

 

Another likely reason is that the rise in Cassava was fueled by very small investors.  If you watched the transactions on a day SAVA was soaring, the purchases were rarely over 200.  So many of them were likely buying because others were.  So they sold when others were.  Lemmings anyone?

 

Nonetheless, SAVA’s data is much better than Biogen’s awful (and expensive) Aduhelm, so that Sumafilam is almost certain to be approved (1) if the data continue to be good (2) if a controlled trial controlled underway produces the same result.

 

So I think, in the long run, that the stock has a bright future, but as John Keynes said “In the long run we are all dead”

 

*** Yesterday’s post

 

Should you buy Cassava Sciences today?

Tomorrow Cassava Sciences will announce the interim results of an open label trial of its Alzheimer drug Sumafilam in 50 patients receiving the drug for 9 months. Should you buy the stock today?

The stock (symbol SAVA) has had a huge run this year starting at 7 and closing yesterday 27 July ’21 at 127.50.

I’ve been interested in the stock for several reasons

l. As a neurologist, I’ve watched patients, family members and friends deteriorate and die, being totally unable to help them.

2. I’ve known one of the principals in the company since she was a teenager in Montana — Lindsay Burns https://luysii.wordpress.com/2021/02/02/montana-girl-does-good-real-good/

3. Sumafilam is thought to work by a completely different mechanism of action than previous approaches (all of which have failed to produce a useful drug)– https://luysii.wordpress.com/2021/03/25/the-science-behind-cassava-sciences-sava/

In fact some of these therapies have actually made Alzheimer’s worse [ Nature Reviews Drug Discovery vol. 18 p. 327 ’19 ]

Tomorrow’s results should move the stock significantly.  If there is no improvement in cognition the stock will plummet.  If there is improvement the stock should soar, at least double again.  Why? Because we have no useful therapy.  Forget Biogen’s drug Aduhelm — the FDA advisory committee resigned in protest after the drug was approved, as the evidence for help was minimal at best.

Of course I’m rooting for the drug as a clinician and as a friend of Lindsay.

There is some evidence that the results tomorrow will show that the drug helps

A prior analysis after six months showed patients taking Cassava’s medication had a 10% improvement on cognition and 29% improvement on an inventory of dementia-related behavior, like delusions and anxiety.

 

The author of the article didn’t realize just how unprecedented these results are.  The numbers of patients (50) and the time (6 months) are long enough to make statistical fluke unlikely.

 

It is even possible that the patients will continue to improve — from the 6 month results, in which case the stock will go bananas.

 

Here’s why.
This isn’t in the books, but there is a precedent for continued improvement on Sumafilam based on my clinical experience with Parkinson’s disease.

 

I was one of the first docs able to prescribe L-DOPA for Parkinsonism in 9/70.  L-DOPA was released in the USA that month, after unconsciounable delay by the FDA.  I’d just left the Air Force and was starting to finish up my neurology residency at the University of Colorado.  The chief (James Austin) called me in and tasked me with setting up the brand new L-DOPA clinic.

 

 
We didn’t know what the drug would do, so we proceeded very cautiously.  Giving a little, watching, waiting, giving a little more, watching, waiting.  Wash rinse repeat.  The results were dramatic, as (like current therapy for Alzheimer’s disease), previous therapy was lousy. 

 

What became apparent to me, was that patients continued to improve ON THE SAME DOSE.   One of the mistakes GPs would make in subsequent years was increasing the dose quickly, since improvement was continuing (on the theory that if a little is good more would be better).  This pushed patients into toxicity (reversible fortunately). 

 

Something similar happens with all the antidepressants we have (except the ketamine derivatives).  You almost never see improvement in the first week or two. 

 

Do I know what tomorrow’s results will be?  Do I have inside information?  No.  Both my wife’s parents had decades long careers at the Securities and Exchange Commission (SEC), and I well know how they regard trading on inside information.

 

So these thoughts are just educated guesses.  If you are trying to decide whether or not to buy the stock, I hope they will be helpful to you.  Full disclosure: I do have a small position in the stock and am anxiously awaiting tomorrow’s results.