Pharmacology Orexin-2 agonist causes "visual disturbances"

[S.J.B.]

From FiercePharma:

Jazz Pharmaceuticals is pressing pause on a phase 1 sleep disorder med due to adverse events despite one executive saying that it “achieved proof of concept.”

The comments were relayed by Chief Medical Officer Kelvin Tan at a conference hosted by Evercore ISI on Tuesday and poured cold water on the near-term prospects of the asset recently licensed from Sumitomo Pharma. Tan said that the drug, JZP441, demonstrated proof-of-concept in healthy volunteers as measured by the Maintenance of Wakefulness Test (MWT).

However, reports of “visual disturbances” and cardiovascular effects have forced the company to pause the trial while they investigate further.

Psychedelic and stimulant effects, maybe? I wonder if that's due to on-target agonism or an off-target effect.

Takeda was investigation an orexin agonist as well, but they dropped it last year for liver toxicity. Nothing mentioned about viaual disturbances in that case.

 

[someguyontheinternet]

Based on cardiovascular disturbances I'm guessing there are some off target effects

 

[AlsoTapered]

DSP-0187 (JZP441)

So Jazz BOUGHT the design and subcontracted Sumitomo to conduct the trials. This is not unusual as, if their is are serious adverse effects, each can release press statements passing the blame which is one of the dirty secrets of the drug development cycle.

｜NIPH Clinical Trials Search

の詳細情報です。進捗状況,試験名,対象疾患名,実施都道府県,お問い合わせ先などの情報を提供しています。

rctportal.niph.go.jp

It would appear to be this compound:

1 hosted at ImgBB

Image 1 hosted in ImgBB

ibb.co

A quick 3DQSAR using over known OX2 ligands gives an insight into the pharmacophore but it's obvious that HTS has resulted in many examples containing moieties containing significant ring-strain. I can think back all the way to the man-made Trovan disaster. In the case of Trovan (trovafloacin) their was a small but measurable percentage of people who metabolized the drug in an unexpected manner. In the case of Trovan the result was serious, sometimes fatal liver damage.

Thirty years later and it's still not an issue that has been adequately addressed. But to fail in Phase I trials may indicate a severe problem.

Interesting that it was Daiichi-Sankyo who originally developed the candidate... and sold it. One wonders if it's problems were identified in animal models and yet they were able to sell it on. That is also within the great tradition of drug development.

 

[ecstacylover]

Oh wow that's interesting!

It's known using ex vivo electrophysiology that orexin-B (endogenous peptide ligand for OX2R) increases spontaneous EPSCs in layer V pyramidal cells, as does serotonin (and presumably psychedelics). In the case of orexin-B, evidence suggests this is due to activation of presynaptic OX2R on midline and intralaminar thalamic neurons which terminate in layer V cortex.

Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous...

link.springer.com

 

[AlsoTapered]

It reminds me of gaboxadol. Someone noted that muscimol induced sleep at low doses and so a HTS program threw up a candidate and it made it's way all the way to phase 1 human trials... where, to the surprise of nobody, it proved to be hallucinogenic even at therapeutic doses.

It's a classic case. Effective hypnotics that are not subject to misuse are potential blockbusters so management are keen to try every lead.