Clinical safety of oral administration of hbi-002 carbon monoxide drug product in healthy subjects and individuals with sickle cell disease

Abstract

Abstract HBI-002 is a liquid drug product containing carbon monoxide (CO) intended for oral administration with target peak CO-hemoglobin (COHb) levels not exceeding 10%. On the basis of studies in murine Townes and NYDD Sickle Cell Disease (SCD) vascular stasis models of Vaso-Occlusive Crises (VOC), where vascular stasis reduction with improved hematological markers together with markedly increased HO1 and Nrf2 and decreased NfF-kB activation versus vehicle control indicated potential clinical benefit ( Belcher JD, et al. PLoS One. 2018 Oct 11;13(10):e0205194), a Phase 1 clinical study was successfully conducted, and a Phase 2 clinical study in subjects with SCD with HBI-002 is ongoing. These studies are being conducted according to GCP, under the supervision of DSMBs. The Phase 1 was an open label clinical study (NCT03926819) in 20 healthy adult subjects with orally escalating dose HBI- 002. The study included 16 males and 4 females ages 25 to 54 years, weighing between 64 and 100 kg; the study subjects were 40% Black, 40% White, 15% Asian, and 5% Multiple. In the single ascending dose (SAD) phase, COHb increased in a dose-dependent manner. In the multiple dose (MD) phase of the study, with 7 days of daily dosing, the average peak COHb saturation for the final selected dose in the MD phase (2.7 mg/kg) was 8.2%, with a maximum COHb saturation in a single subject (4.4 mg/kg) of 15.6% and the feasibility of dosing to targeted COHb levels up to 10% was demonstrated. The COHb levels fell post-dosing returning to baseline by 24 hours post-dose, without accumulation. HBI-002 administration was not associated with any SAE, and the AEs that occurred were Grade 1 and of short duration. Subjects were monitored for 30 days post-dosing for adverse events (AE). Peripheral venous COHb levels were assessed after each dose. Clinical, chemistry, hematology as well as urinalysis observations were conducted pre- and post- dose. No clinically significant abnormal laboratory findings were reported. Possibly or probably related safety issues considered possibly or likely related to the HBI-002 were all Grade 1 single events: increased blood lactate, drowsiness, fatigue, chills, dizziness, nausea, light-headedness and bloating. The Phase 2a study (NCT06144749); (NHLBI R44HL131065) is an open label study being conducted in 12 adults with Sickle Cell Disease, with data from the first 6 subjects presented. The 6 subjects ranged in age from 22 to 50 years (avg 33 years), 4 male and 2 female Black subjects. Weight ranged 46.5 kg to 91.2 kg (avg 65kg). 4 of the 6 subjects were receiving hydroxyurea. All had previous evidence of sickle-related organ damage (5 acute chest syndrome; 2 stroke; one priapism; 2 splenic sequestration). All 6 subjects had an optional PICC line placed to facilitate blood drawing. Subjects were initially dosed at 1.6 mg/kg for at least 3 days targeting COHb levels between 4% and 7% (low dose phase), and then, once safety was shown after 3 days with the lower dose, increased to 2.7 mg/kg targeting COHb levels between 7% and 10% (high dose phase). PK samples were drawn on the first low dose and first high dose days. Dosing was daily for 14 days, with follow up extended through a further 30 days. Dosing was decreased or increased to ensure the COHb level target range was achieved. Baseline predose COHb levels ranged between 2.1% and 3.5% (study criteria of ≤3.5%) and with the lower dose rose to levels ranging between 4.5% and 7.3% and with the higher dose between 6.0% and 11.5%. No SAEs were reported. The following adverse events (possibly and probably related) were reported in one subject each: VOC pain; nausea; back pain; constipation, and three subjects reported headache. Lab abnormalities were one subject with raised von Willebrand (vWF) complex (Factor VIII and vWF activity and antigen). PICC-line associated AEs were consistent with the literature (Maserejian, et al. Blood 2015, 126 (23):2057;Ali, et al. Cureus. 2024 Aug 11;16(8):e66628): one PICC line became infected with consequent grade 2 nosocomial infection, corrected by PICC line withdrawal and antibiotic cover. A second subject's PICC line became occluded with an axillary vein thrombosis (grade 2). Overall, all 6 subjects tolerated the HBI-002 dosing with only minor HBI-002-related adverse events, but with PICC line-associated AEs in 2 of the 6 subjects.