KT-474 (IRAK4 degrader) ✔️
Kymera Therapeutics
Confirmed correct on August 16, 2023 at ACS Fall National Meeting.
I’m back with another ACS compound to be disclosed in just a couple weeks! KT-474 is an IRAK4 degrader being developed for atopic dermatitis or hidradenitis suppurativa (NCT04772885). It was the compound that I was actually looking for last week…but I figured out KT-413 first:
P.S. I’ll be in SF for ACS Fall 2023 & I’d love to meet some Molecular Sherlock readers! DM if you wanna grab a coffee! Also (shameless plug)…feel free to stop by my poster (#3600) on Wed, August 16 from 7-9 pm. I’ll be talking about some of the work I did at MD Anderson on phosphonate prodrug inhibitors of enolase 2 for ENO1-deleted cancers :)
Without further ado…
KT-474 is an IRAK4-specific degrader being developed by Kymera Therapeutics ( KYMR 0.00%↑) for the treatment of atopic dermatitis or hidradenitis suppurativa. It was recently evaluated in phase 1 (NCT04772885), with phase 2 trials planned for 4Q2023.
As I mentioned in my previous post, I actually was looking for this compound but figured out KT-413, a heterobifunctional IRAKIMiD degrader, first! So consider this a Part 2 of the previous post because my meanderings began there.
Where we left off
After realizing that the Kymera patents I was looking at corresponded to KT-413 (an IV drug), rather than KT-474 (PO drug), I decided to go back to square 1: Espacenet.
Sorted by priority and scrolled further than I had previously with KT-413.
This part was a bit tricky because so many of their IRAK4 patents had the same name !!! I’ve lost count of how many Kymera patents titled “IRAK4 degraders and uses therof” I saw. Almost threw me off! Nevertheless, I managed to find something actually useful: a solid forms patent (‘899).
At first, I thought this was going to be a solid forms patent for KT-413, because I hadn’t yet encountered one. But as a scrolled through, I realized I was dealing with a different structure!
Compound 1. Promising lead! How many other IRAK4 degraders could Kymera have taken up to late-stage development?
This ‘899 patent didn’t have any biological data in it, so its helpfulness had run its course. I looked to the ISR at the very end for some pointers.
There was only 1 other Kymera patent referenced (WO2020113233), so I went there. The TL;DR of this part of my search is: out of the 1837 pages (!!) I did find the same structure as Compound 1 in the ‘899 patent, labeled I-483.
Always good to get the X-check. This patent had hundreds of degraders with some in vitro and in vivo characterization. But very little in the way of helpful in vivo data for I-483, unfortunately. So back to Espacenet I went to see if I could find any other helpful leads.
IRAK4 degraders and synthesis thereof
No sooner than when I had begun did I find a PROCESS PATENT: IRAK4 degraders and synthesis thereof (‘556)…
…which contained the same Compound 1 as the ‘899 crystalline forms patent!
This ‘556 process patent is also where I first learned that Compound 1/I-1/I-483 whatever is an ORAL compound.
VERY IMPORTANT DETAIL. Because KT-474 is an ORAL degrader.
So, it looked like I was on the right track to finding my way out of this tunnel.
For 1 compound, Kymera sure files a lot of patents. And they only leave little morsels for clues in each one. So beyond learning that Compound 1 was an oral compound, this ‘556 patent did not have much else that could help me.
So back to Espacenet I went.
IRAK4 degraders and uses thereof (pt. 1)
After I thought I was wandering around in circles with these patent names, I finally landed on IRAK4 degraders and uses thereof (‘269).
This ‘269 patent describes the toxicokinetics (TK) the same Compound A as the ‘899 cyrstalline forms patent. It also describes the toxicokinetics two isomers of Compound A (called Compound B and Compound C).
In addition to the TK properties of these compounds, the patent also states the intended indications: atopic dermatitis and hidradenitis suppurativa.
Good! Same as what the ph1 for KT-474.
So, even though they list 3 compounds (Compound A = a mix of isomers, Compound B and C are individual isomers), I can determine that the likely clinical candidate is Compound A. Not just because there is also a solid forms patent (‘899) on Compound A. But also because it is clear from this patent that they are performing bioequivalence PK studies of each isomer.
These data were almost certainly part of their IND package for the FDA and are meant to show that the plasma PK of each isomer (B and C) are essentially the same. So, by administering Compound A (mix of B and C), there shouldn’t be too much deviance in PK (e.g. if Compound A = 70% B, 30% C the PK would be similar to if Compound A = 30% B, 70% C).
Additionally, their 4-week NOAEL study in dogs was performed with Compound A.
IRAK4 degraders and uses thereof (pt. 2): same title, different data
Compelling evidence so far. I’m pretty confident that Compound A = KT-474 at this point. But of course, I want some data that ties everything together.
So back to Espacenet I went—where I found another patent (‘268) with the same title but different number!
Like the ‘269 patent, this one also described the same Compound A + its isomers (Compound B, Compound C), but focused on Compound A.
It also reinforces the point that Compound A is an ORAL compound—similar to what’s described in the ‘556 process patent. It also specifies that Compound A is administered as 25 mg dose strength tablets. Same as what’s indicated in the starting dose for the ph1 trial.
This ‘268 patent also includes the RESULTS of their ph1 as examples. So here’s where it all comes together.
Beginning with the TITLE of the trial…
…which is the same as the one used for the KT-474 ph1. Just replace “Compound A” for “KT-474”.
Throughout this search, I was—in parallel—browsing through Kymera’s published scientific presentations. Conveniently, they had a whole slide deck on the KT-474 ph1 data that they presented at the 5th Annual Targeted Protein Degradation meeting!
So when I encountered this slide…
…I knew I had seen something similar in the ‘268 patent!
Exact same mean & median IRAK4 changes at each dose level! With the same N per cohort and p-values! Check.
Later in the ph1 slide deck, they also present these cytokine data:
Look at the SAD7 data for R848 (left graph) and LPS (right graph). These are the EXACT SAME % changes described in Table 5 of the ‘268 patent for each cytokine!
Finally, some PK data: the ph1 slide deck describes SAD and MAD plasma PK.
And lucky for us all, the ‘268 patent has these VERY SAME DATA !
SAD study data:
MAD study data:
JUST WOW.
So there you have it! Ahead of ACS Fall 2023: Compound A = KT-474!
Have a compound that you want me look into? Suggest a compound here. If you have a specific project that you’d like me to consult for (yes, I do that), email me at molecular.sherlock@gmail.com !