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.
Chemiotics II 
Comments
Luysii, You obviously have deep understanding of neurochemistry and a passion for Alzheimer’s. Have you ever looked at the science behind Cognition Therapeutics’s CT1812? It seeks to mimic the effect of the Icelandic A673T mutation by preventing ABeta from binding and actually seems to cause it to be diplaced with the binding sites having a stronger affinity for the drug. I refer you to Izzo in Alzheimer’s and Dementia 2021;17:1365-1382 and other references in this https://ir.cogrx.com/static-files/c342afad-21ed-4a35-b91a-41f1e6a5b10e presentation. I would love to hear your thoughts.
Richard — sorry for the delay in responding — apologies ! ! I’ll have a look and get to you. In the meantime have a look at the response to Dr. Lipman below.
Luysii,
Thank you beforehand for looking at CT1812. Though the NIH is not supposed to “talk” to the FDA, you’d think the $169M in grants Cognition has received to date would be of some benefit if it comes down to a “compassionate” approval. I find Dr. Lipman’s comments encouraging and if I recall correctly, none of the early cytokine cancer drugs had significant results. “Do no harm” is the rule, after that, all bets are off. Fortunately CT1812 seems to be safe as mother’s milk and on the encouraging side, there was a significant drug response with an increase in Abeta in the CNF in an under-powered phase I trial. If only we could be sure a marker based result would be acceptable as an indication of efficacy (as a proxy for a cognitive benefit)…CGTX has a market cap of $37.5M (really) and cash available of $153M…so there is a disconnect somewhere.
I follow the Simufilam saga with interest.
Luysii, As a retired psychia
Luysii, As a retired psychiatrist, I have to think the Cassava CMS study may quickly be less blinded by the emergence of behavioral symptoms that may require additional medical treatment in the group not receiving simufilam. I would suspect that would become evident in the first few months off the medication and could facilitate the accelerated approval by the FDA. The reports for the open label studies were very impressive for the reduction of behavioral symptoms as the simufilam took effect.
In addition, you should be aware that a recent study by a Japanese group demonstrated that filamin-A is implicated in tau aggregation in another tauopathy progressive supranuclear palsy. The authors actually cited several of the articles from the Cassava scientists in the bibliography. You can view that at: https://www.science.org/doi/10.1126/sciadv.abm5029.
To be clear on my connection to this controversial topic, I have been a sometimes Cassava Sciences investor. I have also been following an intense public discussion occurring on the Yahoo Finance website on the webpage for the Cassava stock (sava) in the “conversations” section. The article above has been mentioned at least 3 times there by members of the public. Oddly, within 24 hrs the entries from the public citing this article have been removed from the visible discussion and can’t be found. It appears there is someone who does not want this article publicized.
Ken — sorry for the delay in responding. Interesting point about clinically obvious effects of discontinuance. The time line for the effects to appear isn’t clear. It’s only a few days for L-DOPA, sometimes quite a bit longer for someone discontinuing anticonvulsants. You’d be more likely to know how long it is for antipsychotics.
Your other point about possible mechanism of action of simufilam is true, but such arguments can be ignored. Here is probably more detail than anyone wants about the beautiful evidence that aBeta causes Alzheimer’s. Although the mechanism leads to an obvious therapy, none of them have worked.
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.
Luysii, Sorry for my delayed response, I have been traveling for family occasions, Provo, Utah for the remarriage of my eldest granddaughter and NYC for the birth of my youngest granddaughter. That and keeping my property here in Northern California fire safe has been quite time consuming.
In response to your question, antipsychotic discontinuation usually leads to the return of hallucinations and delusions and other behavioral symptoms within about 30 days depending on the illness involved and the half life and mechanism of action of the medication. In Alzheimer’s, the behavioral issues are often impulsivity and agitation as well as hallucinations and delusions. Simufilam has not been reported to have activity on dopamine or serotonin receptors, it would seem that the interruption in the disease process by the drug itself leads to a downstream reduction in behavioral symptoms. It has a 4.5 hour elimination half-life, one would think behavioral symptoms would be quick to resume in the CMS study but biological systems are not always that predictable as you point out above By now, the CMS clinicians most likely have a ball park figure for the time for return of behavioral symptoms.
As you know, antipsychotic meds are contraindicated in dementia patients due to the increased number of fatalities in this patient group when on these medications. Pimavanserin which is approved for psychotic symptoms in Parkinson’s disease is now being considered by the FDA for approval for psychotic symptoms associated with non-parkinsonian dementias. The researchers are having difficulty demonstrating significant efficacy once again stressing the importance for the simufilam work. The FDA decision on pimavanserin approval is expected on 8/4/2022
With respect to your discussion of gene mutations, I find the information on how the substitute amino acids effect the amyloid structure fascinating. I won’t venture a guess why amyloid removal isn’t working but reducing amyloid aggregation is!
Ken: One interesting point about the L-DOPA and congener side effect of hallucinations. My Parkinsonian patients who had them, always knew that they were hallucinations and didn’t like them. I don’t think this was in the books when I was in practice. Perhaps it is now. As I recall, schizophrenics (usually?/often?rarely?) think their hallucinations are real.
Another point, not in the books, is that for a L-DOPA and congener naive patient, improvement continues on the same dose for several weeks. I know this because I ran one of the first L-DOPA clinics in 9/20 when it was released. We didn’t know what the drug would do, and started with low doses, increasing them very slowly, and watched our patients like hawks. The parallel with delayed improvement (if such actually exists) on the antidepressants we had back then (tricyclics mostly) was uncanny.
Luysii. Yes, that’s correct, some schizophrenic patients have limited insight in to the content of their hallucinations or sometimes in to the fact they are hallucinating at all. Antipsychotics in very low doses to prevent worsening of the Parkinson’s disease can sometimes help L-DOPA induced hallucinations as you know. Pimavanserin is a serotonin based drug and less likely to worsen Parkinson’s while still treating the L-DOPA induced hallucinations.
With respect to treatment delay, it occurs in the newer antidepressants as well as the tricyclics. Most medications seem to take time to work in treating chronic diseases but depressed folks tend to be understandably more impatient and the delay may be longer. Simufilam does not appear to be an exception in that it appears to take a few weeks for an effect and then more weeks to reach the full effect.
Well therapeutic delay doesn’t appear to occur with ketamine, which is one of the things that makes it so striking. The antidepressant effects of ketamine remain long after it has been destroyed by metabolism, so the effects can’t entirely be due to its NMDAR antagonism, or its ability to potentiate AMPAR function. It’s as though the ketamine flips a switch which remains on.
A good paper and editorial on how ketamine may work is [ Neuron vol. 110 pp. 2283 – 2298, 2201 – 2203 ’22 ]. It focuses on the ion channel carrying the M current (KCNQ2)
Thanks for referring me those articles, they’re fascinating. To be clear, we still do not refer to ketamine as an antidepressant though we use it to treat depression resistant to standard antidepressants. As you know, some of the results are miraculous. Typically, the ketamine is given intravenously or intranasally with the newer L-ketamine. The patients come in to the clinic every 3-4 weeks for the treatments which are supervised by a nurse. The information you sent me does seem to be getting to at least part of the ketamine mechanism of action which is through the voltage gated potassium channels. Interestingly, these channels have been associated with resilience in multiple species. The anticonvulsant retigabine(Ezogabine) which works on the same potassium channels is also being studied for antidepressant effects. Would be great if this work leads to the launching of a safe group of depression alleviating molecules which are safe, non-abusable, and with a rapid onset of a therapeutic effect.