STC-15 (METTL3 inhibitor) ✔️
STORM Therapeutics
Confirmed correct on August 16, 2023 at ACS Fall National Meeting.
STC-15 (formerly STM3480) is a first-in-class oral inhibitor of METTL3 developed by STORM Therapeutics that is currently in phase 1 trials for the treatment of advanced cancers (NCT05584111).
METTL3 stands for N6-adenosine-methyltransferase 70 kDa subunit. Not sure how acronym for that works out…presumably the methyltransferase part.
This is the first compound I’m covering from a private company!
Some brief bio background
METTL3 is one enzyme that is part of a methyltransferase complex that methylates internal adenosine residues on mRNA, forming N6 methyladenosine (m6A). So, METTL3 is involved in post-transcriptional regulation. This enzyme has been implicated in the initiation of acute myeloid leukemia (AML).
STORM Therapeutics previously published a paper in describing the preclinical activity of a METTL3 inhibitor (STM2457) in Nature in 2021 in collaboration with a group at Cambridge. This is a DIFFERENT compound than STC-15, as I will show. Decoy compound!
Though much of STORM’s published work has focused on the therapeutic use of METTL3 inhibitors in AML, their phase 1 is also enrolling patients with advanced solid cancers.
But they can’t hide
Let’s jump straight to Espacenet and see what we find.
Type in “storm therapeutics” (yes, with the quotes!) and search by descending priority.
Today is my lucky day because a process patent for a METTL3 inhibitor immediately shows up. So I start there.
When I first saw this cover page, I was a little worried that I might have my work cut out for me because they mention INHIBITORS (plural). And as I scrolled past synthetic intermediates in this patent, I thought “Ahhhh nooo,” because again, I thought I was going to have to go on a deep sea fishing expedition.
Lucky for me, this was not the case. Because the succession of synthetic intermediates stopped…
…and I realized this patent was actually just describing 1 final compound.
Aside from it saying that the Formula I structure is a “preferred embodiment,” how did I know that the Formula I structure, rather than the Formula VIII structure was likely to be the final compound?
Zero percent chance they’re leaving an aldehyde just floating there on their final compound.
The process patent also describes the reductive amination step to get from Formula VIII to Formula I.
As I’ve mentioned in many previous posts, process chemistry patents are extremely useful because they tend to indicate that the compound in the patent is in late stage development.
The point of narrowing down to ONE compound in this particular process patent is to: 1.) get a handle on the general shape of the pharmacophore and 2.) have a reference compound for me to compare data to as I continue in my search.
Now that my front-running structure is Formula I, I jump down to the ISR page(s) at the end of the patent.
Okay, looks like we have some additional patents that we can look through. Of these listed ones, I am particularly interested in WO2021/111124 because a specific example (example 2, pages 211-212) is cited. So I go there.
A composition of matter patent. Jumping to pages 211-212 yields the same compound described in Formula I of the process patent. Good confirmation that the Formula I compound is indeed the final compound.
Okay let’s not lose sight of the bigger picture here. We now know, with high confidence, that the Formula I structure is a METTL3 inhibitor. This compound is likely far along in the development pipeline—especially considering that STORM Therapeutics does not have any other late-stage published patents on METTL3 inhibitors so far.
STORM’s pipeline also suggests that this their “main” METTL3 inhibitor (aka, no backup compound indicated).
So, what we are missing right now is the link between the name “STC-15” and the Formula I structure. Basically, the question is: how can we show that the Formula I structure = STC-15?
Did someone say venetoclax?
More digging needed.
Before returning to the patent space, I browsed some of the company publications on STC-15. The most recent poster described the synergistic activity of STC-15 with venetoclax, an FDA-approved BCL2 inhibitor for leukemia/lymphoma.
Very interesting. Why? Because oncology companies will sometimes patent combination therapy data. So, I kept this in mind as I returned to the patent space.
And as it turned out, I did indeed find a patent on combo therapies with METTL3 inhibitors, including with BCL2 inhibitors!
The 3 METTL3 inhibitors they describe are: 1.) STM3006, 2.) STM3480, 3.) STM3675. This is when I realized that the compound in Formula I from the process patent (‘124) was formerly called STM3480 because they have the same structure.
This was encouraging because it means that the Formula I compound was ALSO in a combo therapy patent—another late stage development patent. Good, good.
As I browsed through this combo patent, I began to realize that while STORM mentions the above 3 METTL3 inhibitors, in reality, the majority of their in vitro and in vivo data were on just ONE of these 3 inhibitors. That’s right, it was STM3480—aka Formula I compound from the process chemistry patent.
So it seems that the other 2 METTL3 inhibitors (STM006 & STM3675) were largely left wayside. A few examples did include these compounds. But the vast majority of data in the combo therapy patent centered on STM3480 + drug 2.
Again, this was good support that the Formula I compound from the process chemistry patent (aka, STM3480) may indeed be THE METTL3 inhibitor, STC-15. Especially since I knew that STORM had presented a poster at AACR in 2023 on combination therapy with STC-15 + venetoclax.
Squinting hard & connecting the dots
All this suggested that I was indeed on the right path. But we needed MORE to seal the deal.
So back to the company website I went to search for clues beyond the patents—perhaps in their presentations (because they are not a publicly traded company, so no SEC filings for me).
Conveniently though, there was a WHOLE TAB dedicated to STC-15!
So I clicked.
A nice section dedicated to the mechanistic rationale behind STC-15 and RNA methyltransferase in cancer.
At the very bottom of this section, I found something with POTENTIAL.
Tumor volume data for combination therapy with STC-15 & anti-PD1! Where had I seen data on the combination of METTL3 inhibitor + anti-PD1? 🤔
That’s right friends: the COMBO THERAPY PATENT (‘216)!
Now, just needed to figure out what model the graph from the company site was generated in. So, I browsed through the rest of the company presentation PDFs to try my luck once more.
And indeed, I was lucky—for I found what I was searching for: a poster STORM presented at SITC 2022.
Look carefully and you will see that the company site graph was pulled from this poster.
So what have we learned here? The graph on STC-15 on the company site was generated in the A20 syngeneic lymphoma model.
Very important detail!
In fact, this was the linchpin for me. Because when I looked back at the data in the combo therapy patent (‘216), I found just what I was looking for:
Tumor volume data with STM3480 and an anti-PD1 in the A20 model.
At first glance, these two graphs may look dissimilar. The SITC poster A20 data was over 68 days while the patent A20 data was over 40 days. The y-axes on teh SITC poster and the patent are also dissimilar: max of 2000 mm3 vs. 1800 mm3.
But look very closely. And you will see what I am looking at.
For the first 40 of the study, the patent data (i.e. shape of graphs) largely match what is shown in the SITC poster. With some obvious caveats, like exclusion of the day 26 day for the vehicle.
But the important part is that the combo data with STC-15 + anti-PD1 (red trace) are the same. Right down to the error bars at day 26, 27, and 28.
For STC-15 treatment alone (navy trace), the different x-axes are not doing us any favors here for showing the similarity in data.
But what DOES indicate that these are the same data is the final data point at day 33, which shows mean tumor volume of ~1250 mm3 in both graphs. Importantly, the ERROR BARS for this last data point: a lower bound of ~950 mm3 and an upper bound of ~1600 mm3.
And finally in the anti-PD1 group (purple trace), there is the distinct peak shape in both graphs at day 24.
Finally, the dates also line up.
The combo therapy patent (‘216) was filed by STORM on June 1, 2022 (1 year from provisional patent application).
SITC 2022 took place from November 8-12, 2022.
But the DEADLINE for REGULAR ABSTRACTS (STORM’s abstract was regular, not a late-breaker) was July 28, 2022.
This means that STORM waited until the latest possible time to file their combo patent (1 year from provisional filing date) while also being able to submit their regular abstract by the July 28, 2022 SITC deadline.
Since the actual conference took place from November 8-12, 2022, STORM was able to continue the A20 mouse experiment with STC-15 + anti-PD1 for anther 28 days, which is what their graph from their SITC 2022 poster shows.
The dates line up!
All of this leads me to conclude that…
Formula I compound in the process chemistry patent = STM3480 = STC-15!
And there you have it! The first of the fall ACS 2023 compounds :)
Have a compound that you want me look into? Suggest a compound here.
Word is that Storm Tx just disclosed this as the correct structure at Gordon Conference yesterday. Nice work, Sherlock!