IHP-102 reduces pain and modulates complement activation in a sickle cell mouse model Free

Background: Sickle cell disease (SCD) is characterized by painful vaso-occlusive events (VOEs) initiated by white blood cell (WBC) adhesion to the endothelium, followed by red blood cell (RBC) adhesion, deoxygenation, sickling and microvascular occlusion. Hemolysis of sickled RBCs then activates the complement system, exacerbating tissue damage and pain. Disease modifying agents like hydroxyurea may reduce the frequency of pain events in responders, but there is an urgent need for interventions that can modify the course of a VOE once it has started. IHP-102, a glycan-based therapeutic, targets multiple VOE mechanisms, including P-selectin and complement, and has shown promise in reducing pulmonary vessel occlusion in humanized SCD mice. Our objective was to evaluate the ability of IHP-102 to reduce established acute hypoxia-induced pain behaviors when administered as a rescue therapy, and to explore its impact on systemic complement activation as a potential biomarker.

Methods: 10-12 male and 11-12 female Townes HbSS (SCD) and 6 HbAA (control) mice (8-12 weeks old) were used per group in this study. Baseline assessments for mechanical allodynia and hyperalgesia (von Frey test with 0.16g and 1.0g filaments) and cold hyperalgesia (cold plate) were obtained. 24-72 hours later, acute VOE-like pain was induced via hypoxia exposure (3 hours at 8% O2, followed by 1 hour of reoxygenation at 21% O2). Following hypoxia exposure (at the beginning of the reoxygenation period), mice received a subcutaneous (SC) injection of IHP-102 (0, 1, 3, 10 mg/kg) and were assessed for pain behaviors at 1-, 4-, 24- hours post-injection. Following a drug washout and recovery period (2 weeks), mice were re-exposed to hypoxia and IHP-102 (10 mg/kg, SC) or control conditions, and peripheral blood and kidneys were collected at 4 hours to assess complement system activation. Data were analyzed by Kruskal-Wallis, Mann-Whitney tests, and linear mixed models using GraphPad Prism 10. P-values less than 0.05 were considered statistically significant.

Results: HbSS mice exhibited robust acute hypoxia-induced pain behaviors, including increased paw withdrawal frequency (PWF) to von Frey filaments (0.16 and 1.0g) and increased cold plate responses, indicating mechanical allodynia and hyperalgesia, and cold hyperalgesia. Rescue administration of IHP-102 (3 and 10 mg/kg) significantly reduced PWF from 0.16g filament at 4- and 24-hours post-hypoxia. While 10 mg/kg IHP-102 reduced PWF to 1.0g von Frey filament at 1, 4, and 24 hours, 3 mg/kg was only effective at 4 hours. In the cold plate test, 3 and 10 mg/kg significantly reduced the number of cold responses in HbSS mice at 1, 4, and 24 hours. IHP-102 treatment had no significant effect on HbAA control mice. Finally, plasma C3a was not different between male and female mice, nor between HbAA and HbSS mice of the same sex. Hypoxia exposure increased plasma C3a concentrations compared to unexposed HbSS mice, and IHP-102 (10 mg/kg) attenuated this hypoxia-induced increase.

Discussion: This study demonstrates that IHP-102 can reduce established hypoxia-induced cold hyperalgesia and mechanical hyperalgesia when administered as a rescue therapy in HbSS mice. The observed reduction in systemic complement anaphylatoxin C3a following IHP-102 administration suggests that its therapeutic effects may, in part, be mediated through complement modulation, providing a valuable systemic biomarker for treatment efficacy. The ability of IHP-102 to reduce pain behaviors after hypoxia onset is crucial, as it mimics a real-world scenario where individuals with SCD are already experiencing a pain crisis following a trigger like hypoxia. Ongoing analyses are investigating the effects of acute hypoxia and IHP-102 on complement deposition in the kidney. With successful completion of further pre-clinical assessments and future clinical trials, IHP-102 has the potential to become a game-changing self-administrable VOE treatment, enabling targeted, non-opioid at-home pain management for SCD patients.