Epileptic spasms during infancy (infantile spasms, IS) are a rare epilepsy syndrome with dire prognosis. Current treatments, effective in about 55% of cases, include hormonal therapy (adrenocorticotropic hormone [ACTH] = adrenocorticotropin or corticosteroids) or vigabatrin (also in combination with hormones). In addition to their limited efficacy, these treatments may also carry serious adverse effects. Thus, the search for new effective drugs to treat this rare disease is desirable. In this study, we determined the efficacy of ACTON PROLONGATUM® (AP; Ferring Pharmaceuticals) in comparison with Acthar® Gel (Mallinckrodt) and full 39 amino-acid rat ACTH molecule (Genscript) in the rodent model of IS consisting of prenatal priming with betamethasone and repeated postnatal trigger of spasms with N-methyl-d-aspartate. Treatment with these ACTH varieties was given on postnatal days (P)12, P13, and P14 in a prospective test (treatment onset on P12 AFTER induction of spasms). Two independent arms were investigated: subcutaneous (SC) and intramuscular (IM) deliveries that were evaluated separately. In the SC arm, there was a significant suppression of the number of spasms after both Acthar® Gel and AP on P13 and P15 compared with gelatin control. In the IM arm, a significant suppression of the number of spasms was achieved only after AP on both P13 and P15 indicating that after IM delivery, Acthar® Gel was not as effective as AP. In this study, we confirmed the efficacy of two ACTH formulations (gelatin-based Acthar® Gel and carboxymethyl cellulose-based AP) in the model of IS. ACTON PROLONGATUM® may become a valuable therapy for IS. In our animal model, AP was at least as efficient as the standard of care, Acthar® Gel.,Copyright © 2020 Elsevier Inc. All rights reserved.