AGX-201
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| Other names | AGX201; Histamine dihydrochloride; 2-(4-Imidazolyl)ethylamine dihydrochloride |
| Routes of administration | Subcutaneous injection[1][2] |
| Drug class | Histamine receptor modulator; Histamine H1 receptor antagonist; Histamine H3 receptor agonist; Antimigraine agent |
| Pharmacokinetic data | |
| Elimination half-life | 14–61 minutes[3] |
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| Chemical and physical data | |
| Formula | C5H11Cl2N3 |
| Molar mass | 184.06 g·mol−1 |
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AGX-201, also known as histamine dihydrochloride, is a histamine receptor modulator which is under development for the treatment of migraine.[1][4][5][2][6] It is or was also under development for a variety of other indications.[1] The drug is given by subcutaneous injection.[1][2]
It is the dihydrochloride salt of histamine.[2] However, whereas histamine is said to efficiently induce migraine in people with migraine most likely via histamine H1 and H3 receptors, AGX-201 is said to act as an antagonist of the H1 receptor and as an agonist of the H3 receptor.[5] This in turn is said to produce antimigraine effects by reducing the release of pro-inflammatory mediators in trigeminal nerve endings and hence via anti-inflammatory effects.[5][2] The drug is also specifically said to modulate histamine receptors on mast cells to make them more resilient to degranulation as part of its antimigraine activity.[6] The exact mechanism of action of AGX-201 in terms of its antimigraine effects is unknown however.[3] The elimination half-life of histamine dihydrochloride by subcutaneous injection in humans is 14 to 61 minutes.[3]
AGX-201 is under development by AgoneX Biopharmaceuticals.[2][6] As of August 2024, it is in phase 2 clinical trials for this indication.[1][6][5] The drug is or was also under development for the treatment of amyotrophic lateral sclerosis (ALS), attention deficit hyperactivity disorder (ADHD), autistic disorder, epilepsy, multiple sclerosis, neurodegenerative disorders, Parkinson's disease, and schizophrenia, but no recent development has been reported for these indications.[1]
See also
[edit]References
[edit]- 1 2 3 4 5 6 "AGX 201". AdisInsight. 28 August 2024. Retrieved 2026-05-30.
- 1 2 3 4 5 6 Devadoss T, Pingili RB (2024). "Drugs Under Clinical Trials for the Treatment of Migraine". Management of Migraine Pain. Singapore: Springer Nature Singapore. pp. 229–249. doi:10.1007/978-981-97-4529-6_12. ISBN 978-981-97-4528-9.
AgoneX biopharmaceutical registered the clinical study of AGX-201 for migraine prophylaxis (NCT02021474; 2022-10). The objective is to evaluate the efficacy and safety of subcutaneous AGX-201 to prevent migraine. The AGX-201 is chemically 2-(4-imidazolyl)ethylamine dihydrochloride, refer to Fig. 12.7 for the chemical structure. AGX-201 is a dihydrochloride salt of histamine. In the previous study (Millán-Guerrero et al. 2003), metabolite of histamine selectively interacted with histamine type 3 receptor, thereby decreasing neurological inflammation.
- 1 2 3 Yuan H, Silberstein SD (January 2018). "Histamine and Migraine". Headache. 58 (1): 184–193. doi:10.1111/head.13164. PMID 28862769.
Where does histamine work in migraine? Histamine does not penetrate the BBB. [...] Presumably, lower dose histamine and Nα-methylhistamine bind preferentially to H3R, activating negative feedback on histamine release from MCs in proximity to C-fibers. Such a feedback mechanism may also explain why fast histamine infusion (higher concentration) triggers migraine while slow infusion (lower concentration) alleviates migraine in an early study.79 Thus H3R agonism is a possible underlying mechanism for migraine management. Examining the available pharmacokinetic data to date, it was found that 1 mg histamine dihydrochloride (0.6 mg histamine) subcutaneous injection had a CMAX of 4.6-8.2 ng/mL, TMAX 8-23 minutes, and half-life of 14-61 minutes with large individual variation.78,89,90 Thus, subcutaneous absorption is quick, the half-life is relatively short, but no bioavailability assessment is available.78 Estimated from the reported injection-CMAX ratio above, both histamine and Nα-methylhistamine plasma levels from 1-10 ng injections are likely to be very low (estimated 0.008-0.14 ng/mL), which is below the limit of quantitation of 0.5 ng/mL for a typical histamine kit. As the estimated plasma level is much lower than H3R affinity of 1 ng/mL, the exact site and mode of action of histamine underlying migraine prophylaxis are uncertain. Perhaps the injected histamine's higher regional concentration activates local nerves or cells, triggering a certain response cascade. Perhaps low dose subcutaneous histamine may be sufficient to stimulate very sensitive H3Rs on sensitive individuals. Perhaps under the context of an inflamed environment, small extra doses of histamine suppress inflammation.33 Perhaps exogenous histamine restores histamine insufficiency.91 Or perhaps similar in the management of acute myeloid leukemia, exogenous histamine exerts its effect through inhibition of reactive-oxygen species or activation of T cells and NK cells.92 However, such an effect was thought to be mediated by H2R at a higher histamine level. So far, there are insufficient data to answer these questions.
- ↑ "Delving into the Latest Updates on AGX-201 with Synapse". Synapse. 24 February 2026. Retrieved 30 May 2026.
- 1 2 3 4 Pellesi L, Do TP, Hougaard A (April 2024). "Pharmacological management of migraine: current strategies and future directions". Expert Opinion on Pharmacotherapy. 25 (6): 673–683. doi:10.1080/14656566.2024.2349791. PMID 38720629.
Histamine is an efficient inducer of migraine in individuals with migraine by a mechanism that most likely involves H1 and H3 receptor subtypes [74]. AGX-201 is a histamine receptor modulator that acts as an antagonist at H1 receptors and an agonist at H3 receptors. This dual mechanism of action offer a unique approach to mitigate migraine symptoms by reducing the release of proinflammatory neuropeptides from trigeminal nerve endings. Subcutaneous AGX-201 is currently tested in a phase II trial (NCT02021474) enrolling subjects with migraine requiring prophylactic treatment.
- 1 2 3 4 Chaudhari K, Syed BA (April 2024). "The pipeline and market for migraine drugs". Nature Reviews. Drug Discovery. 23 (4): 246–247. doi:10.1038/d41573-023-00182-x. PMID 37978262.
AgoneX Biopharmaceuticals is developing AGX-201, which modulates histamine receptors on mast cells, allowing them to be more resilient to degranulation and ultimately mitigating migraine headaches. [...] Table 1 | Selected therapies that are marketed or in development for migraine [...] Drug (brand name): AGX-201. Company: AgoneX Biopharmaceuticals. Mode of action: Histamine receptor modulator. Status (FDA/EMA): Phase II.