MK-0616 (PCSK9 inhibitor) ✔️
Merck & Co.
Confirmed correct on March 29, 2023 at ACS Spring 2023 First Time Disclosures.
MK-0616 is an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor developed by Merck & Co. ( MRK 0.00%↑ ) for the treatment of hypercholesterolemia. It was recently evaluated in a phase 2 trial (NCT05261126) and a pivotal phase 3 trial is planned for the second half of 2023.
Phew! What a structure that was to draw!
Oral PCSK9 inhibitors like MK-0616 are very hyped because they expand the therapeutic targets available to lower low density lipoprotein cholesterol (LDL-C)—management of which is dominated by statins. So far, PCSK9 has been targeted by injectable mAbs (alirocumab and evolocumab) and siRNA (inclisiran). An oral PCSK9 inhibitor would thus be a huge logistical advance. A good summary of the potential benefits with oral PCSK9 inhibitors can be found on the Drug Hunter website.
PCSK9 is a negative, post-translational regulator of the LDL receptor. The LDL receptor binds LDL, which binds and transports cholesterol to tissue. Excessive buildup of LDL-C in the arteries over time leads to atherosclerotic cardiovascular disease (ASCVD). So, removal of LDL-C by PCSK9 inhibition, for instance, can help prevent ASCVD.
Beating around the bush
In 2021, Merck published a series of macrocyclic peptide inhibitors of PCSK9 in J Med Chem. This paper highlighted their optimization of bicyclic peptide inhibitors to tricyclic peptide inhibitors for improved PK and potency. They highlight one tricyclic peptide example, 44, to demonstrate their efforts.
But example 44 is NOT MK-0616. Let me show you how I know.
Bean countin’
Let’s hop on over to the the EPO, my favorite patent database. This is where I went first. First, I searched “merck, pcsk9”. No dice. So then I tried “merck, hypercholesterolemia”. After scrolling down a bit, I found something interesting.
WO/2023 023245 A1: Compounds for treating conditions related to PCSK9 activity. And the front cover has a structure! What luck!
Immediately, I checked to make sure that this example compound is not the same as example 44 from Tucker et al. paper. It’s not.
This patent, at first glance, this appeared to be one related to composition of matter. The title seemed to suggest this. I thought the structure shown would just be a representative example of the compound libraries found within.
But this was not the case!
Turns out, this is actually a formulation/dosing patent that focuses specifically on various salt forms (A-) of Compound 1. The patent also includes data from what appears to be an unregistered phase 1 PK study in healthy volunteers.
Why do I think this was an unregistered trial? If we search “merck, pcsk9” in trials.gov, we encounter 3 trials—2 of which are phase 1 trials: one with simvastatin (a statin) and another with MK-0616, which is ongoing.
Because the patent was published on February 23, 2023 and provides data from the phase 1 healthy volunteer study, we know that this cannot be the phase 1 study in patients with moderate renal impairment, which is currently recruiting (item 3, NCT05070390). As further proof, the study details listed in the patent and in the renal impairment trial do not line up. For instance, the patent study (healthy volunteers) was performed in a total of 60 males. In contrast, the renal impairment study aims to recruit 18 participants of any sex.
So, the study of MK-0616 in patients with moderate renal impairment and the healthy volunteer study described in the patent are not the same.
They can run but they can’t hide!
As I mentioned, this patent includes actual PK/PD data from the unregistered phase 1 trial in healthy volunteers.
We can see that they tested 6 dose levels in a total of 7 cohorts (there were 2 100 mg dose groups: 1 with labrasol, 1 with sodium caprate). The oral bioavailability is ~2%.
The patent also describes a multiple ascending dose phase 1 study in males and females, in which Compound 1 was administered QD for 14 days. A graph shows the relationship between treatment with Compound 1 and LDL-C levels over time.
Interesting! So how can we use this info to pinpoint whether Compound 1 is MK-0616?
Turns out, Merck presented phase 1 PK/PD data with MK-0616 a couple years ago at the 2021 AHA meeting. And, well, look what we have here…
Don’t blink now.
Same graphs! I’ve highlighted the distinctive features of each graph that indicated to me that these are the same data. But if you go line by line, you can see that it all matches up.
So there we have it! Comound 1 in the ‘245 patent = MK-0616!
That’s all I got for ACS Spring 2023 first disclosures! The other 2 presentations are on an ADC and a PROTAC, so I won’t be going over those here (not small molecules & yes I know this PCSK9i was pushing it at ~1550 g/mol!).
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