VX-548 (NaV 1.8 inhibitor) ✔️
VX-548 (NaV 1.8 inhibitor) ✔️
Vertex Pharmaceuticals
Note: Originally figured this one out on January 30, 2023. Structure was confirmed to be correct on February 1, 2023.
VX-548 is an oral NaV 1.8 inhibitor developed by Vertex Pharmaceuticals (VRTX 0.00%↑). It is currently in phase 3 trials as a non-opioid treatment for acute pain (NCT05661734, NCT05558410, NCT05553366). NaV 1.8 is a voltage-gated sodium ion channel involved in nociception.
This compound came across my radar thanks to Matt Hall (@cispt2 on Twitter). A compound in phase 3 trials with no publicly disclosed structure? My interest is piqued!
To orient myself on what time frame we are working with here, I made a mental note that the first trial on the Trials Registry began on July 19, 2021.
The answer is always buried in the patents
Next, onto the patent landscape. Interestingly, a total of 7 patents describing the same series of Nav1.8 inhibitors all have the same publication and priority dates.
A key thing to note is that the priority dates for this set of patents is on June 4, 2021. This is about 1 month before the first registered trial with VX-548. A step in the right direction.
Of the patents in this series, the two that caught my eye are the solid dosage forms & dosing regimens (WO 2022/256708 A1) and the process chemistry (WO 2022/256660 A1) patents. Both of these patents describe the same molecule. The fact that these 2 patents exist indicates that this particular molecule is far along in development, and is likely under clinical evaluation.
This is a good tip in the right direction and suggests this compound may be VX-548. But we need more evidence—a link between this structure and some (pre)clinical data. Luckily, the solid dosage forms (‘708) patent has just what we need to figure this out.
Connecting the dots, part 1
From our initial scan of the ongoing trials, we see that VX-548 is currently being investigated in painful diabetic peripheral neuropathy (DPN; NCT05660538).
I specifically point this trial out because later in the solid dosage forms patent, we see a prophetic human clinical trial design for painful DPN.
Notice how both the phase 2 DPN trial and the prophetic trial design both test the investigational agent (“Compound 1” or VX-548, respectively) against pregabalin and a placebo.
In addition, some simple math for the number of subjects planned shows that the total number of planned subjects is 50 + 25 + 25 + 50 = 150. If we assume some level of consistency in group distribution, then the number of subjects assigned to placebo is likely 25. This gives a total of 175 participants, which is the same as what’s anticipated in the phase 2 DPN trial.
Not convinced? Me neither. At least this info alone wouldn’t sway me. So we need more evidence—something more definitive. Luckily, the solid dosage forms patent is a treasure trove and we have just what we need to seal the deal.
Connecting the dots, part 2
Example 4 in the solid dosage forms patent describes real data (not prophetic!) for a trial of “Compound 1” in subjects with pain following bunionectomy.
Details matter and can be very big giveaways. In looking at the bunionectomy data, I am immediately drawn to a few things: 1.) HB/APAP arm, 2.) the fact that there are 5 treatment arms, 3.) specific number of subjects per treatment arm. There are definitely many more fine details that one can pick up on here, but my thought process is this: with any luck, I’ll find some data that at least matches these 3 criteria.
After a bit more digging around, I came across this March 31, 2022 press release!
In it, they very helpfully provided a table of the bunionectomy efficacy results (SPID48 scores). Lo and behold, these data are a perfect match to the Example 4 data in the solid dosage forms patent, right down to the sig figs!
And there we have it! We can see that “Compound 1” in the solid dosage forms & process chemistry patents = VX-548.
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Suzetrigine（VX-548） is an orally active and specific NaV1.8 inhibitor. Suzetrigine has analgesic activity and can be used to study acute pain and neurotransmission.
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