This trial, for the first time, demonstrated the efficacy and safety of the HDM SLIT-tablet in pediatric patients with moderate-to-severe HDM AR (JapicCTI-152953).

The effects of a novel prolyl endopeptidase (PEP) inhibitor, (S)‐2‐[[(S)‐2‐(hydroxyacetyl)‐1‐pyrrolidinyl]carbonyl]‐N‐(phenylmethyl)‐1‐pyrrolidinecarboxamide (JTP‐4819), on the PEP activity in the brain and on the contents of substance P (SP)‐ and arginine‐vasopressin (AVP)‐like immunoreactivity (LI) in the cerebral cortex and hippocampus of young and aged rats were investigated using enzyme immunoassay. JTP‐4819 exhibited a concentration‐dependent in vitro inhibitory action on PEP activity in the brains of both young and aged rats, with IC50 values of ∼0.7 and 0.8 nM, respectively. A single dose of JTP‐4819 (3 mg/kg, p.o.) increased the SPLI content in the cerebral cortex but not the hippocampus of aged rats (23–24 months old). In addition, repeated administration of JTP‐4819 (1 mg/kg, p.o., for 21 days) increased the SPLI content in the cerebral cortex and restored the SPLI content in the hippocampus, which had decreased with aging. In contrast, single (1 mg/kg, p.o.) and repeated (1 mg/kg, p.o., for 21 days) administration of JTP‐4819 only tended to increase the AVPLI content of the hippocampus and cerebral cortex in aged rats, respectively. These results indicate that JTP‐4819 increases the cerebral and hippocampal SPLI content in aged rats by inhibiting the action of PEP.

The trial confirmed the efficacy and safety profile of the SQ HDM SLIT tablet in Japanese adult and adolescent patients with moderate-to-severe HDM-induced AR. These data support the robust efficacy and safety profile of previously reported European data.

The effect of a novel prolyl endopeptidase (PEP) inhibitor, (S)-2-[[(S)-2-(hydroxyacetyl)-1-pyrrolidinyl] carbonyl]-N-(phenylmethyl)-1-pyrrolidine-carboxamide (JTP-4819), on neuropeptide metabolism was investigated in the rat brain. JTP-4819 exhibited a strong in vitro inhibitory effect on cortical and hippocampal PEP activity, with the IC50 values being approximately 0.58 +/- 0.02 and 0.61 +/- 0.06 nM, respectively. JTP-4819 also inhibited the in vitro degradation of substance P (SP), arginine-vasopressin (AVP), and thyrotropin-releasing hormone (TRH) by rat brain supernatants, with the IC50 values being respectively 3.4, 2.1, and 1.4 nM in the cerebral cortex and 3.3, 2.8, and 1.9 nM in the hippocampus. Oral administration of JTP-4819 at doses of 1 and 3 mg/kg increased SP-like immunoreactivity (LI) and AVP-LI in the cerebral cortex. JTP-4819 also increased hippocampal SP-LI and AVP-LI at doses of 1 and 3 mg/kg, as well as hippocampal TRH-LI at a dose of 3 mg/kg. These findings suggest that JTP-4819 inhibited the degradation of SP, AVP, and TRH in the rat brain secondary to the inhibition of PEP, and thus increased cortical and hippocampal SP-LI and AVP-LI as well as hippocampal TRH-LI.

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