Gotterdammerung

In a move that would make Machiavelli proud, the corporate leadership of Cassava Sciences has booted out the people (Lindsay Burns PhD and Remi Barbier) who developed Simufilam, the only drug which makes the company worth anything.

Only after a Nobel is awarded (if Simufilam does what early returns imply) to Lindsay for helping legions of patients with Alzheimer’s and their families will we find out what really went on.

Hopefully Lindsay and Remi have enough company stock to profit from their work.

We will have an answer later this year when the P3 study is reported. In the past people have tried to stop it and failed. The study will end 30 September when the last patient has completed dosage. Well over 75% have completed the study as of 17 July.

In case you have been on another planet, the P3 study has 800 patients with early Alzheimer’s taking Simufilam and is placebo controlled and double blind. The FDA has reviewed the study structure and will accept it without asking for changes in it.

My reasons for believing Simufilam will work relies on early data released 3 years ago, where 10% of the patients receiving Simufilam for 9 months showed a 50% improvement.

I was an active clinical neurologist from 1968 to 2000 and I can tell you that while Alzheimer and all demented patients fluctuate from day to day, none of them show 50% improvement over baseline 9 months later.

The monoclonal antibodies for Alzheimer’s were approved because they slowed the rate of decline, not because they made anyone better. Also it is quite clear that Simufilam does not cause one of the complications of the monoclonal — brain hemorrhage.

I suggest you pour over the following post in detail. Here is the link

Cassava Sciences 9 month data is probably better than they realize

And here is the post:

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)