It would be helpful if we could find out the dosing range they are using. They will target the highest value applications first, and other applications could take many years.
It would be reasonable I think, since its now passed Phase 1 safety trials, for biohackers to get their hands on the compound and start testing it for other indications using their dosing information.
. You’re exactly right, if there’s a way to find out the dosage, then it’s probably worth trying. I did a search on reddit and it seems as though some people have tried it, although the results seem mixed. I assume it was also without any idea of an efficacious dose. Is there any way to find out what the ALS treatment protocol is?
I just used my phone to scan the codes in the above flyer to get the web page addresses. If someone could go through the process and attend the webinars they could probably get the dosing information (mg of ISRIB/ Regimen F- ABBV-CLS-7262)
They have weekly webinars on the study - perhaps someone could participate and ask about dosing they are using in the trial
Clinical Trial information here - interesting that they are trying Trehalose as well as ISRIB (and other drugs). They seem to be keeping the dosing information private … unlike all the other drugs.
Participants are randomized to receive either active SLS-005 Trehalose or matching placebo. Drug: SLS-005 Trehalose
Drug: SLS-005 Trehalose
Administration: Infusion
Dose: 0.75 g/kg weekly
Participants are randomized to receive either active ABBV-CLS-7262 or matching placebo.
Drug: ABBV-CLS-7262
Drug: ABBV-CLS-7162
Administration: Oral
Dose: Dose 1 or Dose 2
More information from this page on the drug:
Regimen F: ABBV-CLS-7262, by Calico and AbbVie- Now Recruiting
ABBV-CLS-7262 is an investigational drug developed by Calico Life Sciences LLC in collaboration with AbbVie Inc. ABBV-CLS-7262 aims to restore function in cells affected by ALS by normalizing protein synthesis and preventing further sequestration and aggregation of TDP-43, thereby protecting neurons, and possibly slowing ALS progression.
The integrated stress response (ISR) is a fundamental transient process that regulates cell function during various stressful conditions. Tissue studies suggest that the ISR is chronically induced in people with ALS. It is proposed that TDP-43 aggregates, a hallmark feature in the motor neurons of people with ALS, could be formed by a chronically induced ISR. ABBV-CLS-7262 activates the protein complex eIF2B, which is a key regulator of the ISR. Binding of ABBV-CLS-7262 desensitizes eIF2B to stress and decreases the ISR. Reduction of the ISR restores normal protein synthesis, reduces TDP-43 sequestration in stress granules, and may decrease TDP-43 aggregation.
A prior first-in-human study of ABBV-CLS-7262 showed that this drug was well-tolerated by participants, demonstrated target engagement by increasing eIF2B enzymatic activity, and suppressed the ISR in blood cells. ABBV-CLS-7262 crossed the blood brain barrier at concentrations predicted to be efficacious in ALS. ABBV-CLS-7262 is currently being investigated in a Phase 1b study in people with ALS (NCT04948645), and will be studied further as part of the HEALEY ALS Platform Trial.
Watch this video for more information on the mechanism of action behind ABBV-CLS-7262.
Download General Platform Trial Brochure
Download Regimen F Brochure
Download Lumbar Puncture Brochure
A new paper on ISRIB (this one is out of China):
Upon cold exposure, aged people with lower metabolic rate cannot rapidly increase the higher levels of heat production, and are seriously threatened by the hypothermia, extensive cold stress responses and risk of mortality. Here, we show that brown fat thermogenic activity is obviously deficient in aged mice, associating with reduction of UCP1 expression and inhibition of its mRNA translation. As we considered, aging aggravates brown fat oxidative stress and activates the integrated stress response (ISR), inducing the phosphorylation of eIF2α to block the global mRNA translation. Therefore, small-molecule ISR inhibitor (ISRIB) treatment attenuates the higher level of eIF2α phosphorylation, restores the repression of Ucp1 mRNA translation and improves UCP1-mediated thermogenic function to defend cold stress in aged mice. Furthermore, ISRIB treatment increases the relative lower metabolic rates, and alleviates glucose intolerance and insulin resistance in aged mice. Thus, we have uncovered a promising drug that reverses the aged-related the deficiency of UCP1-mediated thermogenesis to combat cold stress and associated metabolic diseases.
The ITP is currently testing 2BAct, which has oral bioavailability and reaches the brain, and like ISRIB is an eIF2B activator, although it potentially has concerning effects on the heart.
The molecule was well-tolerated in the animal studies described here, and did not elicit any relevant effects in a rat cardiovascular (CV) safety study; however, significant anomalies were observed in a dog CV model. This CV safety liability makes this particular molecule unsuitable for human dosing. [ref]
Essentially what both 2BAct and ISRIB do is tone down the integrated stress response (ISR). The ISR responds to various cellular stressors to promote cell survival, but its excessive or prolonged activation promotes cell death.
For evidence that the ISR is over activated in aging, see Does aging affect the ISR?.
What’s interesting is that various anti-aging strategies (rapamycin, acarbose, calorie restriction, methionine restriction) appear at first glance to increase ISR activation, due to their increasing ATF4 protein levels. However, these anti-aging strategies even more so increase CHOP protein levels, and as CHOP may function to fine-tune the ISR (see Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR), these strategies may actually be preventing excessive ISR activation. The trend towards larger Δ[CHOP]/Δ[ATF4] for the strategies providing the largest lifespan increase further supports fine-tuning/preventing over-activation of the ISR as a potential longevity strategy.
If anyone tries it, please let us know results. Do some double-n-back game testing, or memory testing games, to see how you do before and after dosing.
500 mg of Trans-Isrib – Powder for $60 for “laboratory research” from Science.bio -:Buy Trans-Isrib - Powder, 500mg. MCE offers 5 mg of trans-ISRIB for $60 and more for larger doses -.https://www.medchemexpress.com/isrib.html I don’t know if there is a difference between trans and non-trans ISRIB (not speaking of gender, here!) of if there is a way to purchase ISRIB from these vendors as they don’t sell to ‘patients’. I would have to qualify myself as a ‘researcher’. Aren’t we all at this stage?
Realistic human dosage of ISRIB??. ABBV-CLS-7262 is given once a day, orally, in the Healey trail.but I don’t see how to correlate that to ISRIB. Anyone have data on dosage? .One test on mice administered 0.1 mg/mL at a dose of 2.5 mg/kg by injection (https://www.pnas.org/doi/10.1073/pnas.2209427119) That doesn’t quite get there for human oral consumption.
ISRIB is exciting if it translates well to humans. I don’t see much data in that area after the slew of tests on mice and several articles in 2022.
Keep in mind that ABBV-CLS-7262 that is used in human trials is a mix of the phosphate salt of ISRIB ( also known as Fosigotifator) and tromethamine (Tris - Wikipedia) in equimolar (1:1) proportion : without the tromethamine ISRIB is poorly absorbed. The dosage used in studies appear to be 120-240mg per day.
The active molecule of ABBV-CLS-7262 / Fosigotifator has quite a few differences to ISRIB. Clearly a derivative, but not just a salt or prodrug. “Umbrella labs” advertises it quite cheaply, but their COA is not available and I in no way vouch for the identity, purity, or even existence of the product.
If anyone knows why ISRIB needed to be modified (oral bioavailability?) or what the equivalent dosing is between the various available compounds in this class, I would be very interested.
someone advised me to dilute into mg/mL to get more precise dosing way easier.
Though maybe snorting is an option given how little powder you really need
The preclinical research suggests that ISRIB crosses the blood-brain barrier and has a half-life of around eight hours. The compound’s manufacturer, Calico (a subsidiary of Alphabet focused on longevity), continues to investigate ISRIB’s potential in neurodegenerative and cognitive decline contexts, but there is no public data that I could find on human dose.
what’s dif between ISRIB and ISRIB-A15?
Potency would be my guess. Possibly better BBB transit. The SAR was worked out in
https://chemistry-europe.onlinelibrary.wiley.com/doi/abs/10.1002/cmdc.201500483
, which I can’t access easily. Note Fosigotifator has a similar modification.
Edit: The article was provided below. Yes, the potency (IC_{50}) is improved by a factor of ~7.
I think it bears mentioning that ISRIB is not water-soluble and can not be snorted (not water soluble) or taken sublingually (too large). I found this good post on dissolving ISRIB (it needs DMSO): https://www.reddit.com/r/Isrib/comments/r8y2rc/solubility/
There is a max that can be mixed with DMSO which is usually said to be around 4 to 9 mg per mL. The second poster down probably is right in saying that it doesn’t mix very easily. I have seen ISRIB clump myself in DMSO. It needs some more vigorous mixing is all that needs to be kept in mind with that. Anecdotally, I have had a very good response to ISRIB, when I did not have much of a reaction to other nootropics I’ve taken.
Please share more details. Form of ISRIB you are using, dosing level and timing and duration, any way to measure cognitive results (test scores on double-N-back during dosing, etc.)…?
I’m currently using trans-ISRIB dissolved in DMSO. I did not use dual-N-back before starting it, and there is some suggestion that it has benefits in a single dose, so I might hold off on doing that for right now. It might have had a subtle effect, but I didn’t feel anything immediately after dosing it.
Snorting doesn’t work for water insoluble??
You might be right that it is absorbed to a certain extent, but most of what I found on the absorption of water-insoluble drugs is negative. Here is one example:
https://www.sciencedirect.com/science/article/abs/pii/S0939641123000504
