Monepantel (Zolvix) is a deworming agent (anthelmintic) widely used in veterinary medicine (in sheep and cattle). First approved in New Zealand in 2009 then in Europe. Not approved in the US.
It is now tested in amyotrophic lateral sclerosis (ALS). Interesting points (source):
“This study has shown oral Monepantel to be safe and well tolerated by people with MND.”
It is a “potent, inhibitor of the mTOR pathway”
“Monepantel sulfane was found in the cerebrospinal fluid indicating that both the agent and its active metabolite have the ability to cross the blood brain barrier, according to PharmAust.”
Interim results from an open-label extension study found that the “benefits of repurposed monepantel for ALS sustained for up to 2 years” and “patients treated with monepantel had 80% lower risk of death” (source)
Dose used: “Based on the previous pre-clinical efficacy data and clinical safety data, a dose of 10 mg/kg QD is estimated to produce the most robust mTOR inhibition while still being well tolerated. The 10 mg/kg QD dose was the maximum dose evaluated in the Phase 1 Study.” (NCT06177431)
Zolvix costs £590 ($800) for 2.5 L at 25 mg/mL. For a 70-kg adult, the above dose costs $270 per month.
Great for ALS folks, but otherwise… interesting. Lots of molecules are interesting. Sirolimus probably doesn’t cross the BBB, though I’m still not 100% sure that’s accurate. There are indications that everolimus does and it’s useful in brain cancer. But apart from treating morbidity, what impact is there for mTOR inhibitors in the brain? Especially for those who don’t at present have any diagnosed ND? What does Monepantel do for people apart from these conditions or subpopulations.
It might be a great candidate for the worm challenge, and maybe ITP down the road. Somebody should try to get the ball rolling.
For PD, I’d have to think. I don’t make assumptions with PD, I’ve been burned too many times.
I’ll let some of my more adventurous colleagues on the forum have a go with this first! But the evidence we have suggests likely safety … I just like more human experience before going on a long term treatment - and I suspect one would do it cyclically, not every day?
Sirolimus does not cross the BBB in any meaningful way. Everolimus might be tiny bit better. They might still be beneficial for the brain but the effect is indirect.
Worms: they’re already testing all mTOR inhibitors so it will be tested normally.
ITP: why? mTOR inhibition in the brain won’t extend lifespan of mice.
Could monepantel be useful to restore mitophagy in the brain and clear “bad proteins” in ALS, AD, PD, etc.? In people with MCI? What about in healthy people intermittently?
I think that would be sensible. We would need to know the half life and how it compares in inhibition to Rapamycin as well as what other effects (side or otherwise) it may have. However, I would think that intermittent inhibition would be best.
It would potentially be good in synergy with other interventions, but not mTOR inhibitors as that might get too confusing.
o3 gives this: (rapamycin’s IC50 is in the nanomolar territory)
Short answer
A rigorously determined, enzyme-level IC₅₀ for Monepantel against purified mTOR has not been reported in the scientific literature.
What is available are cell-based data showing that micromolar concentrations of the drug suppress mTOR signalling (loss of phospho-mTOR Ser²⁴⁴⁸, reduced p-Raptor, p-p70S6K, etc.) and arrest cell growth:
Read-out
Typical concentration range
Source
Loss of phospho-mTOR (Ser2448) in ovarian-cancer cells
If you need a working estimate of the concentration that functionally blocks the mTOR pathway in cells, the published evidence points to the low-double-digit micromolar range (~10 µM, give or take 5 µM).
Because no biochemical IC₅₀ exists, any comparison with classic mTOR inhibitors (e.g., rapamycin, everolimus) must be made cautiously; Monepantel may inhibit mTOR indirectly or via upstream regulators.
If you require a precise value (for modelling or medicinal-chemistry work), a dedicated kinase assay (e.g., radiometric or TR-FRET with recombinant mTORC1/2) would be needed.
Oh, I don’t know about that. I can easily hypothesize how brain rejuvenation might impact lifespan, just based on hormone regulation impacting the whole body. But first we’d need a clear idea of what mTOR inhibition does in the brain - we have outcome studies for the heart, but what about the brain (aprt from ND conditions).
Biochemical vs. cellular values
An enzyme-level IC₅₀ is rarely quoted because rapamycin needs FKBP12; the ternary FKBP12-rapamycin complex binds the FRB domain of mTOR rather than the catalytic cleft. The HEK-293 pulse assay above is the closest practical surrogate and consistently yields ≈ 1 × 10⁻¹⁰ M.
mTORC1 only
Acute rapamycin blocks mTORC1; mTORC2 is largely refractory unless exposure is prolonged. If your experiment tracks 4E-BP1 rather than S6 K you may need 10- to 100-fold higher drug.
Cell-type variability
Differences in phosphatidic-acid levels, FKBP12 abundance, and FRB mutations shift the apparent IC₅₀ into the low- or mid-nanomolar range in some tumour lines. Always run a pathway read-out (e.g. p-S6 K) in your own system to confirm.
Practical takeaway
For most in-vitro or cell-culture work, start with 1 nM rapamycin when the goal is to silence mTORC1, then titer down (0.1 nM) or up (10–100 nM) based on your read-out and cell sensitivity.
When Mannick talks about TOR101, and its almost 100% inhibition of mTORC1, while completely sparing mTORC2, I always wonder why prolonged use of TOR101 doesn’t also inhibit mTORC2 just as rapamycin does. Clearly there is something more going on, than just the length of time mTORC1 is inhibited, otherwise, if time of inhibition was the only factor, then both should eventually inhibit mTORC2.
I think Monepantel is interesting within the context of ALS/MND PD etc. However, it also seems relatively weak compared to rapamycin. With Rapamycin you can safely get a one off dose perhaps equivalent to 100g of monepantel which would be a non starter (I assume).
That is assuming similar bioavailability which I have not tried to find anything out about.
I wonder if the greater BBB crossing potential of montepantel compensates for it being a weaker inhibitor, because the more potent inhibitor everolimus crosses in tiny amounts, which might result in similar strength effects despite the weaker montepantel.
And if monte is such a weak mtor inhibitor overall, then it’s useless in rest of the body and only useful in the brain on account of its ability to cross the BBB.
That may be true. I am intending to enter the ALS longitude prize if the agreement is OK. This gets announced either on Tuesday or Wednesday this week (it is not that clear).
If they OK this I will be looking at mTOR options. Personally, however, I am sticking with high dose rapamycin as I understand its effects and limitations.
Right. Unless I understand what it’s doing in the brain, I’m not jumping on monte just yet. Of course, if you have some form of ND, then you have to look hard at this. Let’s wait on the ALS results and maybe we can get some insight as to mechanism.
I think the mechanism in terms of mTOR inhibition encouraging PINK1/Parkin style mitophagy is clear. That reverses the effect of the damage caused by ROS on the mtDNA, but does not do it fast enough to prevent the total damage growing. If they added a few other things (particularly melatonin) they could make some real progress.