Pharmacodynamic characterization of rytvela, a novel allosteric anti-inflammatory therapeutic, to prevent preterm birth and improve fetal and neonatal outcomes

Abstract:

Background

Preterm birth is the leading cause of neonatal morbidity and mortality. Studies have shown that interleukin-1 plays a major role in the pathophysiology of preterm birth participating by inducing the production of pro-inflammatory mediators and uterine activating proteins leading to labor. More importantly, uteroplacental inflammation, associated with preterm birth parturition pathways, is detrimental to fetal tissues and leads to long term sequelae. Our group has developed an allosteric antagonist of the interleukin-1 receptor, rytvela, found to be potent and safe in preventing preterm birth by suppressing inflammation via the inhibition of the MAP-Kinase pathway while preserving the NF-kB pathway (important in immune vigilance). Rytvela has been shown to inhibit inflammatory upregulation and uterine activation while preserving fetal development.

Objectives

The study aimed to further pre-clinical development of rytvela by evaluating its optimal dose and minimal duration of treatment to inhibit the inflammatory cascade, prolong gestation and promote neonatal outcome.

Study design

Pregnant CD-1 mice were injected with LPS (10 ug i.p.) or interleukin-1 (1 ug/kg i.u.) on gestational day 16 to induce preterm labor. Rytvela was injected at different doses (0.1, 0.5, 1, 2, 4 mg/kg/day s.c.) from gestational day 16 to 19. To evaluate the minimal duration of treatment, mice were injected with Rytvela (2 mg/kg/day s.c.) over the course of 24, 36 or 48 hours. Rate of prematurity (gestational day<18.5) and neonate survival and weight were evaluated. Gestational tissues were collected at gestational day 17.5 to quantify cytokines, pro-inflammatory mediators, and uterine activating proteins by RT-qPCR and ELISA. Neonatal lungs and intestines were collected from postnatal day 5 to 7 and analyzed by histology.

Results

Rytvela exhibited a dose-response profile and achieved E_MAX at a dose of 2 mg/kg/day by reducing 70% of LPS-induced preterm births as well as 60% of IL-1β-induced preterm births. Rytvela also attained E_MAX at a dose of 1 mg/kg/day by increasing neonate survival by up to 65% in both models of preterm birth. Rytvela protects fetuses from inflammatory insult as of 24 hours preserving lung and intestinal integrity and prevents preterm birth and fetal mortality by 60% and 50% respectively as of 36 hours of treatment.

Conclusions

The E_MAX of Rytvela was achieved at 2 mg/kg/day with improved birth outcome and prevented inflammatory upregulation upon (only) 36 hours of treatment. Rytvela exhibits desirable properties for the safe prevention of preterm birth and fetal protection.