Melanogenic effect of dersimelagon (MT‐7117), a novel oral melanocortin 1 receptor agonist

Suzuki, Tsuyoshi; Kawano, Yuko; Matsumoto, Atsuhiro; Kondo, Masahiro; Funayama, K.; Tanemura, S.; Miyashiro, Masahiko; Nishi, Arasuke; Yamada, Katsuhiko; Tsuda, Minoru; Sato, Atsushi; Morokuma, Kazunori; Yamamoto, Yasuo

doi:10.1002/ski2.78

Cited by 15 publications

(51 citation statements)

References 26 publications

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“…1 H). MT-7117 showed in vitro agonistic activity for mouse MC1R with EC 50 values of 0.77 ng/mL (= 1.14 nmol/L) [ 27 ]. These results indicate that the level of systemic exposure of MT-7117 reasonably exceeded the EC 50 values of mouse MC1R agonistic activity.…”

Section: Resultsmentioning

confidence: 99%

“…MT-7117 behaves as a full agonist for MC1R and is selective for MC1R among other MCRs. Moreover, MT-7117 was shown to darken the coat color of mice and the skin of monkeys by inducing pigmentation in vivo [ 27 ]. MT-7117 is currently being studied in a phase 3 clinical trial (NCT04402489) as a potential therapeutic option for patients with a history of phototoxic reactions from erythropoietic protoporphyria or X-linked lymphoproliferative syndromes.…”

Section: Introductionmentioning

confidence: 99%

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Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

et al. 2022

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Background Activation of melanocortin 1 receptor (MC1R) is known to exert broad anti-inflammatory and anti-fibrotic effects. The purpose of this study is to investigate the potential of dersimelagon, a novel oral MC1R agonist, as a therapeutic agent for systemic sclerosis (SSc). Methods The effects of dersimelagon phosphoric acid (MT-7117) on skin fibrosis and lung inflammation were evaluated in bleomycin (BLM)-induced SSc murine models that were optimized for prophylactic and therapeutic evaluation. Microarray-based gene expression analysis and serum protein profiling were performed in the BLM-induced SSc models. The effect of MT-7117 on transforming growth factor-β (TGF-β)-induced activation of human dermal fibroblasts was evaluated in vitro. Immunohistochemical analyses of MC1R expression in the skin of SSc patients were performed. Results Prophylactic treatment with MT-7117 (≥ 0.3 mg/kg/day p.o.) significantly inhibited skin fibrosis and lung inflammation, and therapeutic treatment with MT-7117 (≥ 3 mg/kg/day p.o.) significantly suppressed the development of skin fibrosis in the BLM-induced SSc models. Gene array analysis demonstrated that MT-7117 exerts an anti-inflammatory effect via suppression of the activation of inflammatory cells and inflammation-related signals; additionally, vascular dysfunction was extracted as the pathology targeted by MT-7117. Serum protein profiling revealed that multiple SSc-related biomarkers including P-selectin, osteoprotegerin, cystatin C, growth and differentiation factor-15, and S100A9 were suppressed by MT-7117. MT-7117 inhibited the activation of human dermal fibroblasts by suppressing TGF-β-induced ACTA2 (encoding α-smooth muscle actin) mRNA elevation. MC1R was expressed by monocytes/macrophages, neutrophils, blood vessels (endothelial cells), fibroblasts, and epidermis (keratinocytes) in the skin of SSc patients, suggesting that these MC1R-positive cells could be targets for MT-7117. Conclusions MT-7117 demonstrates disease-modifying effects in preclinical models of SSc. Investigations of its mechanism of action and target expression analyses indicate that MT-7117 exerts its positive effect by affecting inflammation, vascular dysfunction, and fibrosis, which are all key pathologies of SSc. The results of the present study suggest that MT-7117 is a potential therapeutic agent for SSc. A phase 2 clinical trial investigating the efficacy and tolerability of MT-7117 in patients with early, progressive diffuse cutaneous SSc is currently in progress.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

et al. 2022

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“… 4 , 6 Multiple lines of evidence indicate that MC1R plays a key role in the production of eumelanin, which is involved in both photoprotection and chemoprotection in response to sunlight exposure. 6 , 7 …”

Section: Introductionmentioning

confidence: 99%

“…In preclinical studies, dersimelagon exhibited high affinity for human MC1R, with half maximal effective concentration (EC 50 ) values in the nanomolar range. 6 In animal models, dersimelagon stimulated melanin production and increased skin pigmentation. 6 …”

Section: Introductionmentioning

confidence: 99%

Absorption, metabolism, and excretion of [¹⁴C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers

Tsuda¹,

Ogawa

Endou³

et al. 2023

Pharmacology Res & Perspec

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Dersimelagon (formerly MT‐7117) is a novel, orally administered nonpeptide small molecule selective agonist for melanocortin 1 receptor currently being investigated for the treatment of erythropoietic protoporphyria, X‐linked protoporphyria, and diffuse cutaneous systemic sclerosis (dcSSc). Findings of studies evaluating the absorption, distribution, metabolism, and excretion (ADME) of dersimelagon following a single dose of [ 14 C]dersimelagon in healthy adult volunteers ( N = 6) who participated in phase 1, single‐center, open‐label, mass balance study (NCT03503266), and in preclinical animal models are presented. Rapid absorption and elimination were observed following oral administration of [ 14 C]dersimelagon in clinical and nonclinical studies, with a mean T max of 30 min in rats and 1.5 h in monkeys, and a median T max of 2 h in humans. In rats, there was a widespread distribution of [ 14 C]dersimelagon‐related material, but little or no radioactivity was detected in the brain or fetal tissues. In humans, elimination of radioactivity in urine was negligible (excretion of radioactivity into the urine: 0.31% of dose), and the primary route of excretion was feces, with more than 90% of the radioactivity recovered through 5 days postdose. Based on these findings, dersimelagon is not retained in the human body. Findings from humans and animals suggest dersimelagon is extensively metabolized to the glucuronide in the liver, which is eliminated in bile, and hydrolyzed to unchanged dersimelagon in the gut. The results to date for this orally administered agent elucidate the ADME of dersimelagon in human and animal species and support its continued development for the treatment of photosensitive porphyrias and dcSSc.

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“…Dersimelagon, a novel synthetic orally administered non-peptide small molecule that acts as a selective agonist for MC1R, is currently being investigated for the prevention of phototoxicity in patients with EPP and XLP and inhibition of the fibrotic process in patients with diffuse cutaneous systemic sclerosis (dcSSc). In preclinical studies, dersimelagon exhibited the highest affinity for human MC1R compared with other melanocortin receptors, with a half maximal effective concentration (EC 50 ) in the nanomolar range [5]. Dersimelagon also has been shown to induce melanogenesis in both in vitro and in vivo studies, with increased melanin production occurring in a concentration-dependent manner in a mouse B16F1 melanoma cell line [5].…”

Section: Introductionmentioning

confidence: 99%

Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist

Ogasawara¹,

Ogawa²,

Ide³

et al. 2023

Eur J Clin Pharmacol

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Purpose To describe outcomes from the first-in-human study of dersimelagon, an investigational oral selective MC1R agonist, under development for the treatment of erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Methods In this double-blind, placebo-controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of dersimelagon in healthy participants were evaluated. Results Dersimelagon was generally well tolerated in healthy participants, with the most common TEAEs being lentigo (52.8%) and skin hyperpigmentation (50.0%) after multiple doses. Systemic exposure to dersimelagon in plasma (based on AUC0-∞ and Cmax) increased in a slightly more than dose-proportional manner over the 1- to 600-mg single-dose range. Following multiple doses, dersimelagon was rapidly absorbed (median Tmax ranging from 4 to 5 h postdose on days 1 and 14). Mean t1/2 ranged from 10.56 to 18.97 h on day 14, and the steady state of plasma concentration was generally reached by 5 days of multiple dosing. There were no observable effects of age or race on the PK profile of dersimelagon or its metabolite dersimelagon glucuronide. No treatment-related effects on melanin density (MD) were observed following single doses of dersimelagon; however, after multiple doses, increases in MD were observed in participants receiving 150 and 300 mg dersimelagon. Conclusion Our study results indicate that dersimelagon is generally well tolerated and demonstrates a generally consistent PK profile across diverse subgroups. Treatment-related increases in MD warrant further investigation in a larger study population and in patients with EPP and XLP. Trial registration A Study to Investigate the Safety, Tolerability and Pharmacokinetics of MT-7117 in Healthy Subjects, NCT02834442, https://clinicaltrials.gov/ct2/show/NCT02834442, registration began July 2016.

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Melanogenic effect of dersimelagon (MT‐7117), a novel oral melanocortin 1 receptor agonist

Cited by 15 publications

References 26 publications

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

Absorption, metabolism, and excretion of [¹⁴C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers

Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist

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Melanogenic effect of dersimelagon (MT‐7117), a novel oral melanocortin 1 receptor agonist

Cited by 15 publications

References 26 publications

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

Dersimelagon, a novel oral melanocortin 1 receptor agonist, demonstrates disease-modifying effects in preclinical models of systemic sclerosis

Absorption, metabolism, and excretion of [14C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers

Results from a first-in-human study of dersimelagon, an investigational oral selective MC1R agonist

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Absorption, metabolism, and excretion of [¹⁴C]dersimelagon, an investigational oral selective melanocortin 1 receptor agonist, in preclinical species and healthy volunteers