Tag Archives: Simufilam

Finally, an article in the press that’s not a hit piece on Cassava

Cassava Biosciences has had the worst press imaginable with hit pieces in the Wall Street Journal, Science magazine, the New Yorker and the New York Times.  Finally Nature News has a balanced article showing how the shorts have been attacking the company and its drug — https://www.nature.com/articles/d41586-023-00050-z.

I’d written about this before and that post can be found after the ***

The Nature article discusses concerns by Elizabeth McNally editor of the Journal of Clinical Investigation, that journals are being manipulated by short sellers claiming that an article is fraudulent.

“Typically, when a whistle-blower contacts a journal about concerns over manipulated images or otherwise questionable data, the allegations are taken on good faith, McNally told Nature. The idea that whistle-blowers could be doing this for their own financial gain “was very eye-opening to me”, she says.”

One particular criticism of Cassava found in the Nature article is rather amusing. “Amid the allegations about Cassava’s data, researchers have expressed concern over how Simufilam works. Aside from the preliminary studies by Cassava and its collaborators, the strategy of stablilizing filamin-A to tackle Alzheimer’s hasn’t been on anyone’s radar, says George Perry, an Alzheimer’s researcher at the University of Texas at San Antonio. “The fact that it hasn’t been widely studied means that it hasn’t been confirmed.”

The fact that filamin-A hasn’t been on anyone’s radar is actually in its favor, since aBeta, the great white whale of Alzheimer’s research has been impaled with multiple expensive harpoons, with minimal benefit to patients.

The Nature article notes that some of the FDA petitioners wanted the Simulfilam studies stopped, something any drug company with a competing product for Alzheimer’s might wish, but should never ask for.

****

The copy of this post was changed to respond to the valid criticisms of Dr. Elizabeth Bik.

 

Cassava shorts should be worried

Yesterday, 1 November ’22, a blockbuster  article was published in the Journal of Clinical Investigation (JCI) written by its editor Elizabeth McNally — https://www.jci.org/articles/view/166176.

It is just over a year ago since the first of the articles attacking Cassava Sciences appeared.  The first was in the New Yorker which profiled Jordan Thomas as the second coming of Christ for exposing supposed fraudulent data published by Cassava principals —

Radden Keefe P. The Bounty Hunter. The New Yorker. Updated January 17, 2022. Accessed October 11, 2022. https://www.newyorker.com/magazine/2022/01/24/jordan-thomas-army-of-whistle-blowers.

There were similar articles in Science — 2022;377(6604):358–363

and the New York Times https://www.nytimes.com/2022/04/18/health/alzheimers-cassava-simufilam.html.

They relied on the same assertions given to the FDA asking that the clinical trials be stopped because of ‘danger’ to the patients.

It’s worth reading McNally’s article completely.  It isn’t very long.

A few highlights (“the Journal” refers to the JCI)

“Throughout 2022, the Journal has been repeatedly contacted to comment on the 2012 JCI paper. Although we cannot be certain, there now appear to be new “short and distorters.” A recent round of emails was sent simultaneously to multiple journals and editors, identifying 25 articles with potential problems and providing recommendations on how the journals should respond. Importantly, these accusatory emails do not identify any financial conflicts of interest on the part of the whistleblowers. The emails insist that an investigation begin within 24 hours and request that the journals update them on investigative progress. As an editor, I am expressing concern because this represents a new means of manipulating the scientific publishing industry.”

So journal editors are like docs. They talk to each other to find out what’s really going on.  It is likely that McNally called up other journal editors to find out if her experience was common.

Here is why those sending the eMails should not sleep well of a night.

“Last, if the Journal uncovers allegations made for the purposes of stock manipulation, with evidence of misinformation, the JCI may elect to express its concern to the US Securities and Exchange Commission or the Department of Justice.”

It’s about time.

Whether the ‘whistle-blowers’ are guilty of anything will be determined by the suits (from investors losing money on Cassava, or perhaps Cassava itself) which are almost sure to follow.

As some of you know, I think Cassava’s data is even better than they realize. Be warned the following link is long, detailed and will require your concentration  — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/

Why the results of the open label trial of Simufilam will be misinterpreted

Cassava Sciences said they will release the results of the 200 person open label trial this year.  I think the results are likely to be misunderstood.

First: a disclaimer.  I have no inside information about the results of the trial.  I have known Lindsay Burns since she was in high school, as my wife and I were friendly with her parents when I practiced neurology in Montana.  Lindsay comes from smart .people, father Horatio went through Harvard in under 4 years getting a degree in physics.

Lindsay and I have been contact for over 10 years, mostly concerning the science behind Alzheimer’s disease and Simufilam,.  We do schmooze a bit about Montana and our time there and the vituperation she and Cassava Sciences have been exposed to.

Lindsay and I are well aware about the use of inside information, particularly since both of my wife’s parents had lifelong careers at the SEC, beginning in the depression.

Let’s assume that the results in the open label trial on 200 patients for 1 year are similar to those released in August of 2021 on the first 50 patients in the study to have been on Simulfilam for 9 months.

10% of the patients likely had at least a 50% improvement in their ADAS-Cog-11 score, and over 50% had some improvement.  Some, of course got worse, so the overall improvement of the group  at 9 months as a whole was slight but real.

Let’s say the results on the whole 200 are similar, with 20 or so patients showing similar 50% improvement, but the group overall showing only slight improvement.

These results, even though open label and unblinded, would be unprecedented.  People with Alzheimer’s have good and bad days, but NONE are better after a year.  Throw in all the studies with monoclonal antibodies against aBeta, and you won’t see results like this.  The best they have to offer is a slightly slower (25 – 50%) rate of decline.  This is also true for the demented patients I saw in over 30 years of clinical practice.  So even though the study is open label, we have a ton of controls outside the study.

Even if Simufilam significantly helps 10% of those receiving it, these are results worth having and should lead to early adoption of Simufilam

6 months down the road the Cognition Maintenance Study (which is blinded and placebo controlled) should give a more definitive answer, leading to early adoption.

Here is a link to a more lengthy analysis of the first 50 cases to go 9 months

Cassava Sciences 9 month data is probably better than they realize

Here is a link to a description of the Cognition Maintenance study

Cassava’s Cognition Maintenance Study may prove Simufilam works

FDA Amylyx approval 7 September implies Simufilam will be FDA approved this year

On 7 September an FDA advisory board reversed itself and recommended approval for a drug for ALS — https://www.wsj.com/articles/amylyxs-als-drug-backed-by-fda-advisers-11662590651?mod=newsviewer_click.  The head of the FDA Office of Neuroscience (Billy Dunn) gave a verbal endorsement, making it likely that Amylyx’s drug would be approved.

What does this have to do with the approval of Simufilam this year? Amylyx did a post-hoc, retrospective “responder analysis” that showed patients who did respond to drug (vs placebo) had “an usually strong response”, i.e., a bunch of non-responders in the general population masked the beneficial effects of the drug. This, after the same committee in March turned the drug down due to lack of efficacy in the studied cohort as a whole.

You may recall that I thought Cassava’s results with Simufilam were better than they realized after they released the data on the first 50 patients in the open trail reaching the 9 month endpoint. The full post published 25 August 2021 can be found below the &&&&&. 5/50 had a greater than 50% improvement in their ADAS-Cog11 score (by more than 10 points).  Data like this in Alzheimer’s has never been seen before in any study, or in my clinical experience.  So the data can not be explained by Cherry-picking.  The only other explanations are (1) Fraud (2) incompetent ADAS-Cog11 measurement (3) people without Alzheimer’s entering the study for the money, all of which I think are remote.  Also, the average decline at one year in ADAS-Cog in Alzheimer patients is 5 points.

So Cassava has data similar to Amylyx’s on the first 50 of the 200 in the open label study.  The last of the 200 will complete their full year on the drug by the end of 2022, at which point data will be released.  If the results on the 200 patients are similar to those on the first 50 (say 20/200 having significant (greater than 50% change for the better in ADAS-Cog) improvement, Cassava will have a (strong in my opinion) argument for Simufilam approval.

Clinicians know that patients always respond variably to any sort of therapy. We now know why.  Given that the human genome contains 3,200,000,000 positions.  Full genome sequencing of well over 100,000 people has shown that any two people will differ at one position in a thousand — that’s 3,200,000 differences  — source   https://www.ncbi.nlm.nih.gov/books/NBK20363/

 

Gentlemen start your engines

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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)

 

Why Cassava’s 1 year results should allow compassionate use of Simufilam

Cassava reported results on 100 Alzheimer patients in an open label (e.g. no controls) trial of Simufilam for 1 year — https://finance.yahoo.com/news/cassava-sciences-reports-second-quarter-131500494.html.  The average results were unimpressive (to the uninitiated) with only a minimal average overall improvement of an ADAS-Cog11 score of 1.5 points.  This is probably why the stock (SAVA) dropped a point yesterday after the news.  Since everything turns on ADAS-Cog11 here is a link to a complete description — https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929311/.  The test takes about 45 minutes placing it out of reach of a busy practicing clinical neurologist.

Why is even the 1.5 point improvement impressive to the initiated (me)?  Over 32 years in clinical neurology, I’d estimate that I saw at least 1 demented patient each week.  Now probably only 300 or so of the 1,664 were followed for a year.  Guess what?  None of them remained stable for a year, and all got worse.  Absolutely none of them  ever got better after a year.  So at least some stabilization of the disease is possible for a year.  The statistics say that Alzheimer patients lose 5 points a year on ADAS-Cog.

But that’s pretty small beer.  Who wants to keep a demented patient around but stable.  Here is the remarkable part of the Cassava results at a year.

63% of the 100 Patients Showed an Improvement in ADAS-Cog11 Scores, and This Group of Patients Improved an Average of 5.6 Points (S.D. ± 3.8). The statistics say that Alzheimer patients lose 5 points a year on ADAS-Cog.

This is unprecedented and is a strong argument for quick approval of Simufilam (or at least compassionate use).

The cynic will say that I’m just looking at the happy part of the Bell curve.  There must have been people who declined to average the improvement in the 63% down to a measly 1.5 points on the ADAS-Cog.

This is where clinical experience comes in.  No drug helps everyone with a given disease.  “Only 20% of cancer patients respond long term to a type of immune checkpoint blockade (of PD-1)” Science vol. 363p. 1377 ’19.  Nonetheless immune checkpoint blockade of several types was approved by the FDA, simply because there was nothing better available.

So if nearly 2/3 of Alzheimer patients will improve at one year on Simufilam, why not  let the FDA offer it to them now under compassionate use.

 

 

Cassava’s Cognition Maintenance Study may prove Simufilam works

The FDA will approve less than perfect therapies if there is nothing useful for a serious condition.  Consider the following from Proc. Natl. Acad. Sci. vol. 119 e2120512119 ’22

“KRAS is the most frequently mutated oncogene in human cancer, with mutations detected across many lineages, particularly in the pancreas, colon, and lungs. Among the most commonly activating KRAS mutations at codons 12, 13, and 61, G12C occurs in ∼13% of lung and 3% of colorectal carcinomas and at lower frequencies in other tumors.

“In locally advanced or metastatic non–small-cell lung cancer (NSCLC) patients with KRASG12C mutations who have received at least one prior systemic therapy”  treatment with sotorasib resulted in the following “objective response  in 37.1% of the patients, with a median duration of response was 11.1 months.”   This is hardly a cure, but nonetheless “This promising anticancer activity has resulted in accelerated approval from the US Food & Drug Administration”

Which brings me to the current CMS study from Cassava Sciences.  I’ll let them speak for themselves. https://finance.yahoo.com/news/cassava-sciences-reports-first-quarter-130000375.html

Cognition Maintenance Study (CMS) – on-going
In May 2021, we initiated a Cognition Maintenance Study (CMS). This is a double-blind, randomized, placebo-controlled study of simufilam in patients with mild-to-moderate Alzheimer’s disease. Study participants are randomized (1:1) to simufilam or placebo for six months. To enroll in the CMS, patients must have previously completed 12 months or more of open-label treatment with simufilam. The CMS is designed to evaluate simufilam’s effects on cognition and health outcomes in Alzheimer’s patients who continue with drug treatment versus patients who discontinue drug treatment. The target enrollment for the CMS is approximately 100 subjects. Over 75 subjects have been enrolled in the CMS and 35 have completed the study.”

Even though the open label study was not randomized, this one will be.

Only someone who has actually taken care of  patients would know the following.  People who are getting no benefit from a drug will soon stop taking it.  This was particularly true for my experience with Cognex for Alzheimer’s disease.

Which is exactly why the fact that 75 patients who’ve been on Simufilam have decided to continue on in the CMS study.  Presumably they feel they are getting some benefit.

There are two possible hookers to this

l. The patients are being paid to enter CMS

2. The original cohort was 200, not all of whom have finished the 1 year.  So we don’t know how many could have been in CMS but chose not to.

As I discussed in an earlier post, the most impressive thing (to me at least) was that at 9 months 5/50 had significant improvement in their cognition — here’s a link — https://luysii.wordpress.com/2021/08/25/cassava-sciences-9-month-data-is-probably-better-than-they-realize/.

The CMS study should give us an idea of how they fared at 1 year and  at 18 months.

If:

l. gains in cognition were maintained on Simufilam

2. gains in cognition were lost off Simufilam

FDA approval should follow quickly.

Results on the 75 will be available this year.   Also available this year will be 1 year results on all 200 entering the open label study.

There are two other double blind studies in progress which will provide  more definitive answers, but they are far from full and will take much longer to complete.  So stay tuned.

Star of stage screen and radio

No new posts for a while, as I’m going to be interviewed for my thoughts on Cassava Biociences’ drug Simufilam for Alzheimer’s disease.  It will be Friday 4 February 2022 at noon Eastern Standard Time on the following.

You will see what I look (and talk) like.  Wish me luck

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.

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.

 

What controls should Cassava Sciences use for their open label trial?

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.

An open label trial is just that, no placebo, no controls.  Such trials are done in the exploratory phase of drug development to look for side effects and (hopefully) therapeutic effects.

Cassava Sciences has been attacked because their open label study of Simufilam had no controls.  Duh !

Here is a suggestion for the concurrent controls for the Cassava study:  the Biogen study leading to approval of aducanumab (Aduhelm).  It’s a little hard to find out exactly when it was done, but it certainly was within the past 10 years. Here is a link to an article on Alzheimer therapy from Science — https://science.sciencemag.org/content/sci/373/6555/624.full.pdf

Cassava’s work is nowhere to be found.  The article contains the following

“Although the marked decrease in amyloid deposits can be viewed as biological evidence of disease modification, this was accompanied by a decidedly mixed outcome on cognitive testing, with one aducanumab trial (EMERGE, NCT02484547) meeting its prespecified primary and secondary endpoints at the highest dose, whereas the other (ENGAGE, NCT02477800) did not achieve them.”

So use Biogen’s data on aducanumab as the placebo control (which I and the FDA advisory committee think it is).  There is a reason the entire committee resigned after the FDA approved the drug.

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)