Calico/ Abbvie is still working on ISRIB and clinical trials are in process. If anyone is trying ISRIB, please report on results. I wouldn’t trust suppliers from China (without good HPLC purity analysis done by an independent lab in the US).
“We can… take an old mouse and train it to do something, but it has a hard time learning. If you give it ISRIB, it learns like a teenager. So we can rejuvenate the learning behavior.”
German biochemist Peter Walter and his Argentine colleague Carmela Sidrauski announced a momentous discovery just over a decade ago. They had found a molecule that was simple yet capable of tremendously enhancing the memory and learning capacity of their mice at the University of California, San Francisco. The experimental drug, called ISRIB, can be easily taken orally. The molecule has since achieved revolutionary results in animals: it has reversed age-related mental decline, restored memory loss due to head trauma, and improved memory in mice with Down syndrome.
The ISRIB molecule modulates the so-called integrated stress response, associated with this cell quality control mechanism. Walter, who is also a sculptor in his spare time, has made a statue with the real structure of this experimental drug. “It is made of bronze and weighs a quarter of a ton. I have it in my basement. The molecule is small and, if you are a chemist, it is pretty,” he explains. In 2015, Walter and Sidrauski licensed the ISRIB patent to Calico, a company linked to the founders of Google. The scientist answered questions from EL PAÍS in Bilbao, just hours before collecting the Frontiers of Knowledge Award.
Question. What are the potential therapeutic applications of ISRIB? You have talked about Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis…
Answer. We have tested it in various laboratory mouse models with neurodegeneration, cognitive defects, learning problems… And we see effects in a huge number of them. In my lab, we can basically cure head trauma in mice. After suffering brain damage, like football players, they cannot memorize anything, but ISRIB restores their memory completely. We can also take an old mouse and train it to do something, but it has a hard time learning. If you give it ISRIB, it learns like a teenager. So we can rejuvenate the learning behavior.
An interesting summary of the clinical trials from the AlzForum link you provided:
FINDINGS
In September 2021, Calico and AbbVie began a Phase 1 study of the safety and pharmacokinetics of ABBV-CLS-7262 in 30 people with ALS, conducted at two sites in Canada. The design calls for a four-week comparison of three oral doses with placebo, followed by up to three years of open-label treatment. The placebo-controlled portion finished in January 2023. Trial completion is set for December 2025.
In March 2023, the company began an open-label exploratory Phase 1b/2 study in adults and children with vanishing white-matter disease. This genetic degenerative condition is caused by reduced EIF2b activity due to mutations affecting its subunit proteins. Three age-defined cohorts will receive treatment for 96 weeks, against primary outcomes of adverse events and plasma drug concentration. Completion is slated for October 2026.
Also in March 2023, a Phase 2/3 trial began testing ABBV-CLS-7262 in ALS. This study is part of the Healey ALS platform trial, a multicenter clinical collaboration testing different interventions in parallel against a common placebo group. The study will compare two different doses in 300 patients, enrolled 3:1 to active treatment or placebo. The primary outcome is disease progression on the ALS-Functional Rating Scale-Revised, and mortality. Secondary outcomes include muscle strength, respiratory function, and serum neurofilament light chain levels. Enrollment was completed in April 2024 (press release). The trial is planned to finish in September 2024.
In 2023 and 2024, the company completed three additional Phase 1 studies in healthy adults. One explored the effects of ABBV-CLS-7262 on the pharmacokinetics of rosuvastatin and digoxin in 12 participants. Another assessed food effects. From March to June 2024, the company tested the effects of ABBV-CLS-7262 on heart electrical activity. This study evaluated possible effects on the electrocardiogram QTc interval in 72 healthy adults. An ongoing Phase 1 study is assessing safety, pharmacokinetics, elimination, and major drug metabolites after a single dose of radioactive [14C] ABBV-CLS-7262 in healthy men.
It looks like Denali Therapeutics has a drug targeted at the same pathway, and its getting close to being approved by the FDA (from this pipeline / phase image).
It seems to be doing very well in clinical studies (from the Alzforum page above):
FINDINGS
In February 2020, Denali began a Phase 1 trial testing single and multiple ascending oral doses of DNL343 in 88 healthy adults. The primary outcomes are safety and plasma pharmacokinetics measured up to 20 days. Secondary outcomes include DNL343 uptake into the CSF, renal clearance, and pharmacodynamic measures of integrated stress response protein and mRNA levels in blood by ELISA and quantitative PCR. The study was expected to end in October 2020, but was delayed to August 2021 after enrollment was paused due to COVID-19 (press release). Denali presented results at a conference in October 2021 (press release). DNL343 was claimed to be safe and well-tolerated up to 14 days of dosing, and to have entered the CNS with pharmacokinetics suited to once-daily dosing. The company reported changes in blood biomarkers of the ISR, confirming target engagement.
In December 2020, a second Phase 1 trial began to investigate effects of formulation and food on DNL343’s safety and pharmacokinetics in 31 healthy men and women. It was completed in June 2021.
In August 2021, a Phase 1b trial began recruiting 30 people with ALS to compare multiple doses of DNL343 against placebo on measures of safety and pharmacokinetics. The 28-day study is to be followed by an 18-month, open-label extension. The trial will run through December 2023.
On December 5, 2022, Denali announced interim results of the 1b trial (press release). Once-daily oral dosing for 28 days was “generally well tolerated” by 20 participants who had completed the double-blind portion of the study. The ratio of CSF to blood drug concentrations ranged from 1.02-1.23. Treatment inhibited ISR pathway biomarkers ATF4 and CHAC1 in blood.
Also on December 5, Denali and the Massachusetts General Hospital announced that DNL343 would advance to a Phase 2/3 study in the Healey ALS Platform Trial, an ongoing, multicenter clinical trial evaluating potential new treatments for ALS (press release). The study began in May 2023 to randomize 240 patients to daily drug or placebo for 24 weeks. The primary outcome is disease progression on the ALS-Functional Rating Scale-Revised, and mortality. Secondary outcomes include muscle strength, respiratory function, and serum neurofilament light chain levels. In May 2024, enrollment finished (press release). The trial will run through July 2025.
In early 2024, the company completed a Phase 1 trial assessing the absorption, metabolism, and secretion of [14C]-DNL343 in healthy men.
Calico/AbbVie are also evaluating an EIF2b activator in ALS (see ABBV-CLS-7262).
I belong to a group that does group buys of research chemicals to treat chronic illness. JC is our primary supplier. We have tested their products many times and they are always good.
Yes - I’ve been looking for that same dosing information and have not found any. If anyone has , or can, find good references for the human dosing being tested, please post.
Interesting… I guess thats a start, but I would really like to have a known and reliable source for this key information (e.g. someone in Abbvie or Calico, or contractors doing the clinical studies) other than some random / anonymous poster on an internet discussion forum. I run into Calico people here in the SF Bay Area at longevity meetups, etc. occasionally, I’ll try to validate this.
I also know we have some Calico people here in our forums, so if they can send me a DM with any information confirming this dosing I’d appreciate it.
Of course the other weak link in this is the Chinese supplier. Has anyone here run any of their compounds through an analytical chemistry lab here to validate the compound is what they say it is, and the purity?
Whoever is organizing this “group buy” on the US side of things, should really incorporate the cost of the US analytical chemistry analysis so people can have confidence in what they are getting. Generally we have not seen great results from Chinese compound suppliers…
Every month or two we see “shocking” reports of nutritional supplements (from random small companies, likely with suppliers from China for the raw materials) that don’t turn out to be what they say they are supposed to be: Truly shocking Astaxanthin brand testing results
Hi Cohen - I’m not aware of how to use this information. I just installed WhatsApp and it wants a phone# or name. When I enter either of these pieces of information, WhatsApp doesn’t find anything. Can you help me?
JC is JennyChem. I think it would be a good idea to validate any chemical coming out of China, to be sure it is what they say it is, and to validate the purity.
