Tag Archives: Immune checkpoint blockade

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

&&&&&

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 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)