KIN-3248 (pan-FGFR inhibitor) ✔️
Kinnate Biopharma
Confirmed correct on August 16, 2023 at ACS Fall National Meeting.
KIN-3248 is an irreversible, pan-fibroblast growth factor (FGFR) inhibitor by Kinnate Biopharma (KNTE 0.00%↑) that is currently in phase 1 to treat patients with advanced tumors harboring FGFR2/3 mutations (NCT05242822).
Dysregulation of FGFRs is important in cancer because of their role in mediating downstream pathways involved in cell proliferation, survival, and angiogenesis in cancer.
There are currently 3 FDA-approved FGFR inhibitors: pemigatinib (FGFR2i), erdafitinib (FGFR2/3i), and futibatinib (FGFR2 fusion or rearrangements, with pan-FGFR activity). KIN-3248 is a pan-FGFR inhibitor that is designed to overcome acquired resistance mutations that arise in FGFR2/3 when treated with isoform-specific inhbitors.
…On a silver platter
I’ll serve this one striaght up because I’m pretty sure Kinnate made a KEY OVERSIGHT when writing up their patent.
As we all know, these companies love to call their lead compound “Compound 1” when they get to the methods of use, combination therapy, and solid forms patent stages. Kinnate is no different.
Except they made a big mistake in their methods of use patent (WO 2023/107979).
Throughout the patent, they refer to their FGFR inhibitor as “Compound 1”.
EXCEPT in Example 2, TABLE 4.
As you can see, their description refers to “Compound 1” but Table 4 actually says “KIN-3248”.
Looks to me like they forgot to conceal the name in the table! Big mistake. How do I know this wasn’t intentional? Well, this is the only place in the patent where they refer to the KIN-3248 codename; the rest of the patent uses “Compound 1.” Also, why would they deliberately make it so easy?
So, big mistake on their part. When you look at what the Compound 1 structure is in their patent, it shows this…
…With the conjugated double bond being the standout reason it is an irreversible inhibitor.
More proof
This error was not the first thing I encountered when I began my search. And in addition to this obvious giveaway, there are other supporting lines of evidence that this is indeed the correct compound.
If you wanna know what else I found before encountering Kinnate’s fatal flaw, read on.
In the methods of use patent (‘979), they also show the IC50 of Compound 1 against both WT and mutant FGFR family members in Example 1, Table 2.
If you look at Figure 19 in their April 2023 SEC 10K, you will find this table comparing the IC50 values of KIN-3248 vs. other FDA-approved FGFR inhibitors:
If you look carefully, you can see that the IC50 values for KIN-3248 in the 10K filing and Compound 1 in the patent are the same for each respective kinase.
So, more proof that Compound 1 in the ‘979 methods of use patent = KIN-3248.
Solid support
In addition to their ‘979 patent, Kinnate also has a solid forms patent (WO 2023/107980) that was published on the same day as their ‘979 methods of use patent (June 15, 2023).
A short patent. But the most important feature is that the Compound 1 described is the exact same Compound 1 described in the ‘979 methods of use patent.
Cool. All later stage patents (methods of use, combo, solid forms, etc.) stem from composition of matter patent(s) containing the (huge) SAR effort. I wanted to trace this Compound 1 back to the original SAR COM patent.
There are 3 COM patents from Kinnate that describe FGFR inhibitors.
At first, I thought I might find Compound 1 in the newest patent (‘870) since it was published on the same day (June 15, 2023) as both the methods of use (‘979) and solid forms (‘980) patents.
‘870 is a short patent with just 72 examples. I searched with no success of pinpointing Compound 1. While there some structures came very close, none of the structures contained a di-fluorinated aromatic ring.
This led me to the 2021 ‘969 patent, since the core structure of other 2021 patent (‘971) was dissimilar from Compound 1.
Before long, I found what I was looking for…Example 78!
Nothing else useful in this patent on the detective work front. So, curiosity satisfied, I moved on.
Back to the ‘979 methods of use patent.
2 pictures paint 2,000 words
As you can tell, their ‘979 methods of use patent was quite a useful resource.
Towards the end of this patent, they describe the activity of Compound 1 in various FGFR-mutant tumor xenografts in mice. One such example was in an RT-112 FGFR3-driven bladder cancer model.
If you look at Figure 22 in their April 2023 SEC 10K, you will find this…!
And if you squint, you will see…!!!
They are the same! Again, shows that KIN-3248 = Compound 1.
And finally, when we get to the clinical trial plan in the ‘979 methods of use, we can see that the plan for Compound 1 matches the exact same plan described for KIN-3248 in Kinnate’s 2023 World Congress on GI Cancer poster. Right down to the dosing and p-values (3 sig figs !!!)
So there you have it…KIN-3248 = Compound 1. What a case….!
P.S. If you want a summary of all the details for their phase 1 trial design, you’ll find it all in this patent. Yes, they’ve presented on some of these details in their poster, but this patent aggregates it nicely.
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