A PHASE 1, PLACEBO-CONTROLLED STUDY TO DETERMINE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF ESCALATING SUBCUTANEOUS DOSES OF LJPC-401 (SYNTHETIC HUMAN HEPCIDIN) IN HEALTHY ADULTS
Author(s): ,
Dan Yaeger
Affiliations:
La Jolla Pharmaceutical Company,San Diego,United States
,
Antonio Piga
Affiliations:
Università degli Studi di Torino,Turin,Italy
,
Ashutosh Lal
Affiliations:
University of California San Francisco Benioff Children's Hospital,Oakland,United States
,
Antonis Kattamis
Affiliations:
National and Kapodistrian University of Athens ,Athens,Greece
,
Sam Salman
Affiliations:
Linear Clinical Research,Nedlands,Australia
,
Brian Byrnes
Affiliations:
La Jolla Pharmaceutical Company,San Diego,United States
,
George Tidmarsh
Affiliations:
La Jolla Pharmaceutical Company,San Diego,United States
Lakhmir Chawla
Affiliations:
La Jolla Pharmaceutical Company,San Diego,United States
EHA Library. Kattamis A. Jun 15, 2018; 214932; PF470
Prof. Antonis Kattamis
Prof. Antonis Kattamis
Contributions
Abstract

Abstract: PF470

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background
LJPC-401, synthetic human hepcidin, is being developed as a therapeutic treatment for various conditions of iron overload, including transfusion-dependent anemia and hemolytic anemia.

Aims
To determine the safety, tolerability, and pharmacokinetics (PK) and pharmacodynamics (PD) of escalating doses of LJPC-401 in healthy adults.

Methods
This was a phase 1, placebo-controlled, double-blind, randomized, single-center study. Healthy adult subjects (aged 18-65 years) were assigned to 1 of 4 dose cohorts (5, 10, 20, and 30 mg) with 6 subjects per cohort receiving LJPC-401 and 2 receiving volume-matched placebo. A single-dose subcutaneous injection was administered on day 1, and dose cohort escalations occurred only after the final subject at each dose level had been observed for ≥3 days with no evidence of study drug–related toxicity. Safety assessments included treatment-emergent adverse events (TEAEs), physical and laboratory evaluations, and immunogenicity. PK parameters of baseline-corrected serum LJPC-401 were obtained by noncompartmental analysis, with blood samples collected at predose, and at 0.5, 2, 4,8, 24, 48, and 168 hours postdose. PD endpoints included effects on serum iron, ferritin, transferrin, and iron-binding capacity.

Results
Overall, 32 subjects (mean age 29.1 years; 53.1% female; 93.8% white) were enrolled, completed the study, and were included in all analyses. All subjects (100%) in the LJPC-401 dose groups (n=24) and 2 subjects (25%) in the placebo group (n=8) experienced at least 1 TEAE. All TEAEs were mild in severity, and there were no serious AEs, TEAEs leading to early discontinuation, or deaths reported during the study. The most frequently occurring TEAEs were injection site reactions (ISRs; LJPC-401 100% vs placebo 12.5%), catheter site phlebitis (12.5% vs 0%), and headache (8.3% vs 0%). ISRs did not generally require treatment, and all but one resolved before study end. No serum samples were confirmed positive for anti-LJPC-401 antibodies, and there were no trends or changes in physical or laboratory test results with LJPC-401. PK results indicated that LJPC-401 maximum serum concentration (Cmax) and area under the serum concentration-time curve from time 0 to 24 hours postdose (AUC0-24) increased with dose over the tested dose levels; increases were generally linear between 5 and 20 mg. Peak concentrations of LJPC-401 occurred ~2 hours postdose for all doses with a return to baseline hepcidin levels by ~24-48 hours postdose. The mean (standard deviation [SD]) baseline serum iron value was 88.46 (22.70) μg/dL, and all 4 doses of LJPC-401 significantly decreased serum iron levels compared with baseline (P<0.0001 overall); the mean maximum reduction was 33% to 65% at 8 hours postdose. A larger reduction in serum iron was generally associated with an increase in dose up to 20 mg. There was no apparent difference in the maximum reduction of serum iron between the 20- and 30-mg dose levels.

Conclusion
LJPC-401 was well tolerated at doses between 5 and 30 mg in healthy adults and showed decreased serum iron levels that returned to baseline levels within 48 hours. In patients at risk for iron overload (abstract submission by Lal et al) serum iron reductions were sustained up to day 8 in most patients.

Session topic: 30. Iron metabolism, deficiency and overload

Keyword(s): hepcidin, iron overload, Pharmacokinetic, Safety

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