Drug design, development and therapy · 2026
Pharmacological and Safety Evaluation of the Small Molecule MP-004 Following Topical Ocular Administration for the Treatment of Inherited Retinal Dystrophies.
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Lara-López Araceli, Rodríguez-Hidalgo María, Sarasola-Gastesi Miren, González-Imaz Klaudia, Zayas-Arrabal Julián, Sagartzazu-Aizpurua Maialen, Miranda Jose Ignacio, Espinosa Ana, López de Munain Adolfo, Aizpurua Jesús María, Gil-Bea Francisco Javier, Vallejo-Illarramendi Ainara, Ruiz-Ederra Javier
Аннотация
PURPOSE: MP-004 is a novel small molecule under development as a non-invasive therapeutic for inherited retinal dystrophies (IRDs), including retinitis pigmentosa. MP-004 halts photoreceptor degeneration by modulating calcium dysregulation and oxidative stress, two critical pathways involved in IRDs. Here, we evaluated its ocular concentration and safety profile following topical administration in three animal species (mouse, rabbit, and pig).
RESULTS: Formulation of MP-004 with 0.3% hyaluronic acid substantially enhanced retinal concentrations in mice compared to non-formulated compound (6.67 vs 1.27 µg/g at 4 h). MP-004 reached the retina in all species evaluated, with minimal systemic exposure. In mice, serum concentrations were below 5 ng/mL, while in rabbits, the compound was undetectable in blood and peripheral tissues 12 h post-dose. Interestingly, in rabbits the maximum serum concentration was 43.6 ng/mL with a half-life of 20 minutes, whereas the maximum retinal concentration was 387 ng/g and the half-life of 6.34 h. Seven-day repeated-dose toxicity studies in mice and rabbits showed no systemic or ocular toxicity. In rabbits, only transient ocular redness was observed following administration, with no evidence of corneal damage or systemic adverse effects. Hematological and biochemical parameters remained within normal limits in both species. Importantly, retinal and optic nerve concentrations remained detectable in rabbits 7 days after the final dose, while the compound had been systemically eliminated, supporting prolonged retention in target tissues.
CONCLUSION: These findings demonstrate that MP-004 is well tolerated and achieves effective retinal concentrations via topical delivery, overcoming a major barrier in retinal drug development. The favorable pharmacokinetic and safety profile across species, including anatomically relevant models, supports the advancement of MP-004 toward regulatory preclinical studies and subsequently, its clinical translation as a non-invasive therapy for IRDs.
RESULTS: Formulation of MP-004 with 0.3% hyaluronic acid substantially enhanced retinal concentrations in mice compared to non-formulated compound (6.67 vs 1.27 µg/g at 4 h). MP-004 reached the retina in all species evaluated, with minimal systemic exposure. In mice, serum concentrations were below 5 ng/mL, while in rabbits, the compound was undetectable in blood and peripheral tissues 12 h post-dose. Interestingly, in rabbits the maximum serum concentration was 43.6 ng/mL with a half-life of 20 minutes, whereas the maximum retinal concentration was 387 ng/g and the half-life of 6.34 h. Seven-day repeated-dose toxicity studies in mice and rabbits showed no systemic or ocular toxicity. In rabbits, only transient ocular redness was observed following administration, with no evidence of corneal damage or systemic adverse effects. Hematological and biochemical parameters remained within normal limits in both species. Importantly, retinal and optic nerve concentrations remained detectable in rabbits 7 days after the final dose, while the compound had been systemically eliminated, supporting prolonged retention in target tissues.
CONCLUSION: These findings demonstrate that MP-004 is well tolerated and achieves effective retinal concentrations via topical delivery, overcoming a major barrier in retinal drug development. The favorable pharmacokinetic and safety profile across species, including anatomically relevant models, supports the advancement of MP-004 toward regulatory preclinical studies and subsequently, its clinical translation as a non-invasive therapy for IRDs.