TAK-994 (Ox2R agonist) ✔️

Takeda Pharmaceuticals

Confirmed correct on March 31, 2023 in Ishikawa et al. in J. Pharm Exp. Ther. (2023).

TAK-994 is an oral orexin 2 receptor (OxR2) agonist developed by Takeda Pharmaceuticals (TAK 0.00%↑) for the treatment of narcolepsy. This compound was in phase 2 (NCT04820842) before development was discontinued in 2021 due to liver toxicity.

OxR2 is a G-protein coupled receptor that is expressed in the brain and is involved in sleep regulation. OxR2 knockout mice exhibit narcolepsy-like phenotypes. On the flip side: OxR2 antagonists, like daridorexant, have been developed to treat insomnia. So, people think that an agonist of OxR2 may help for narcolepsy.

This is an unusual post because it concerns a discontinued compound. Nevertheless, OxR2 agonist development—and the narcolepsy therapeutics field at large—are both very much alive. In fact, Takeda is currently pursuing their backup OxR2 agonist, TAK-861, right now. So, perhaps the tale of TAK-994 may be useful to those in this field.

What caught my eye about TAK-994 is that the structure was never disclosed, even after discontinuation. Even the Wiki page for TAK-994 says the chemical structure has yet to be disclosed. So of course, my interest was piqued.

This was one of the very first compounds that I looked into in this detective work. Admittedly, I was stumped for quite a long time. Why? Because there is a lot of data on these OxR2 agonists and Takeda knows how to keep a secret!

But this just pushed me to be more…resourceful :)

I won’t go into excrutiating detail into my meanderings for this compound. But I will try to capture the gist of why this was not that easy.

Let the confusion begin

TAK-994 was the first oral OxR2 agonist to enter the clinic for narcolepsy. It was the successor to TAK-925 (danavorexton), a first-gen, intravenous OxR2 agonist that was the first to show that narcolepsy could be slightly alleviated by agonizing OxR2.

This is important to know because there are several patents on TAK-925 and its family of compounds. TAK-925 methods of use patents continue to be published. Takeda appears to have established itself quite solidly in the OxR2 agonist space. As of today, Takeda has 8 main patent families for OxR2 agonists—each of which have their own subfamilies/updates.

5 of the 8 patent families relate to TAK-925. These include:

• Substituted Piperidine Compound and Use Thereof

• TAK-925 for Use in Treating Narcolepsy

• A Method for Increasing the Concentration of Methyl 3-((Methylsulfonyl)Amino)-2-(((4-Phenylcylcohexyl)oxy)methyl)piperidine-1-carboxylate or a Salt Thereof With an Inhibitor of Cytochrome P450

• An Orexin 2 Receptor Agonist for the Treatment of an Orexin-Mediated Disease or Disorder

• Use of an Orexin 2 Receptor Agonist for Post Operation Recovery

That leaves us with 3 patent families that TAK-994 could be in:

• Heterocyclic Compound and Use Thereof

• Heterocyclic Compound

• Substituted Pyrrolidine Compound and Use Thereof

Both patents describe composition of matter on 2 distinct SAR campaigns, with synthesis and % agonist activity against isolated OxR2 enzyme. For some compounds, some PK properties like intrinsic clearance in mice was included.

But company slides and poster presentations centered on in vivo data in mouse models of narcolpsy.

So we are missing the link between patent and company presentations :(

Some who wander are lost

An example of the type of preclinical data they present on TAK-994. This was found in an SEC filing but these data were also presented at SLEEP 2018 & WORLD SLEEP 2019.

I put this project on the backburner for a couple months to let it simmer in my brain.

To make a super long story short: for the longest time, I had a feeling that TAK-994 could be structurally related to TAK-925 in the form of a prodrug. My bias was that I began looking into TAK-994 fresh after I figured out GS-5245 (read the TL;DR of the remdesivir/GS-441524/GS-5245 story here).

Takeda often discussed TAK-994 with TAK-925 and, to my ears, it sounded like TAK-994 was the oral version of TAK-925. Very thin evidence, in retrospect. But this is really where my mind was at the time. I was definitely influenced by my train of thought for GS-5245 and (a little bit) less experience than now and it certainly showed. And no, the Japanese patents did not make things easier.

It’s a small detail, but at least at the time the dash notation between TAK-994 / TAK-925 offered some support that these 2 might be structurally related. From April 6, 2021 company presentation.

I mention this unfruitful detour because the purpose of Molecular Sherlock is to show how I arrived at my conclusions. Which, sometimes, do not happen just like that. So, these are teaching points for me that hopefully might help you too :)

I made it out of the woods

So how did I finally figure out the strucutre of TAK-994? It turned out that, what began as a giant impediment with my GS-5245 way of thinking, ultimately lead me to the answer I sought.

That is to say, this mystery ends just as the one with GS-5245 did: the EU Clinical Trials Register. My favorite trials registry, which houses trials held in the EU with EudraCT protocols.

Searching for TAK-994 returns 2 entries:

Clicking on any one of the “Trial protocol” countries and scrolling will lead to the CAS number!

Searching for CAS number 2274802-95-6 in PubChem returns…

Firazorexton, the international nonproprietary name! Phew. So TAK-994 = firazorexton. Funny, because firazorexton has a Wiki page too…but the connection had yet to be cemented. Guess some Wiki edits are in order!

Have a compound that you want me look into? Suggest a compound here.