Note: Originally figured this one out February 12, 2023 and posted it to Twitter the following day.
Another day, another Gilead compound!
GS-9716 is an oral myeloid cell leukemia-1 (MCL-1) inhibitor developed by Gilead Sciences (GILD 0.00%↑). It is currently being investigated in a phase 1 trial (NCT05006794) for the treatment of advanced solid cancers as either a monotherapy or in combination with docetaxel, gemcitabine, or sacituzumab govitecan (Trodelvy). MCL-1 is involved in apoptosis.
Two step authentication
I mentioned on Twitter that I was very surprised by how easy this one was to figure out (~5 minutes). What luck!
I began with my good friend Google. This yields two links that pique my interest:
Poster abstract from the 2022 AACR National meeting (June 15, 2022)
Company presentation from their Oncology Deep Dive (April 14, 2022)
Of course, no structures or a remote clue on what this compound could possibly look like. But the single update slide on GS-9716 caught my attention.
In vivo data! Here we have data on GS-9716 in 2 xenograft models: HCC1187 and MDA-MB-468. Both are triple negative breast cancer (TNBC) models. On the left, we have tumor volumes for GS-9716 as a monotherapy in HCC1187. On the right, we have tumor volumes for GS-9716 in combination with a “control ADC” or Trodelvy.
In my last post on IK-930, I mentioned my love for in vivo data. From a detective standpoint, in vivo data offer several clues. These include the dose, boundaries of the axes, and general shape of the graphs. Here, I made mental notes on these details.
As a post-script, this slide also tells us that these data were presented at AACR 2022. This is good to know. If I can’t get the poster associated with the AACR abstract, at least I have these graphs to work with.
In an attempt to get a vague idea of what the chemical space for MCL-1 inhibitors might look like, I turned to my favorite patent database, the European Patent Office (EPO), and simply searched “gilead, mcl-1'“. Doing so returns 3 relevant patents.
There is 1 composition of matter patent (“MCL-1 INHIBITORS", list item 3) and 2 combination patents (list items 1 & 2).
In my last post, I also mentioned that I combo patents always catch my eye because they suggest that the compound of interest is pretty far along in (pre)clinical development. So I jump there first.
Remember how the company slide showed GS-9716 in combination with Trodelvy and another antibody drug conjugate (ADC)? I also remembered this and jumped to list item 2: “COMBINATION MCL-1 INHIBITORS WITH ANTI-BODY DRUG CONJUGATES” (WO 2022/261310).
Instantly, I recognized the general shape of the graph that I’d seen in the company slides. Then I saw that they had used sacituzumab govitecan (Trodelvy) and a “control ADC” here as well. Eureka! We have something! Time for the side-by-side comparison.
We can see that we are looking at the same graphs. Both graphs show a study performed in MDA-MB-468 xenografts. What gave it away was the shape of the vehicle data (black circles) and the Trodelvy alone data (blue on left, black hexagons on right)—both of which have very distinct shapes. Having oriented myself on those 2 treatment arms, the remaining arms fall into place.
Control ADC = H679-SN-38
GS-9716 = Compound A
Trodelvy = sacituzumab govitecan
In the company slides (left), they only show the 30 mg/kg GS-9716 combinations and have removed the 15 mg/kg GS-9716 dose level.
Combing through the ADC combo patent (‘310), I find the structure associated with “Compound A.”
Check yourself
Done deal right? Nah. As crystal clear as it appears, I still got to make the effort to check. The combo ADC patent (above, ‘310) states that “compound A is described in Example 154 of…WO 2019/222112,” which is the composition of matter patent.
Before jumping to the COM patent (‘112), I scanned the chemo combo patent (WO 2022/261301). Savoring the journey before finishing this story! Similar to the ADC combo patent (‘310), the chemo combo patent also shows the same “Compound A” structure. Good.
This patent, too, names the 2019 COM patent (‘112). So now I looked there for final verification.
And there you have it. Third time’s the charm! Doesn’t get more straightforward than this. Example 154 = Compound A = GS-9716.
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