Safety of Single Doses of CSL889 in Adult Patients With Sickle Cell Disease

Study Overview
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Brief Summary
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This is a phase 1, first-in-human, multi-center, open-label, single dose cohort study to evaluate the safety and tolerability, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and biomarkers of target engagement of CSL889 following single intravenous (IV) doses in subjects with sickle cell disease (SCD). The study involves sequential dose escalation of cohorts with between-group assessments of key safety and PK variables.

Official Title
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A 2-Part, Phase 1, Multi-Center, Single-Dose, Open Label, Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CSL889 in Adult Patients With Sickle Cell Disease

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Biological: CSL889


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of SCD as documented in the subject's medical record Aged 18 to 60 years, inclusive Stable SCD for at least 30 days before Day 1. Stable SCD is defined as the subject being at his or her medical baseline, with no evidence of worsening of disease over the last 30 days (including VOC, recent major surgery, hospitalization, serious infection, significant bleeding, cerebrovascular accident, seizures, or IV opioids)(Part A) Uncomplicated VOC requiring parenteral opioid treatment and admission to hospital for management. Uncomplicated VOC is defined as sickle cell pain without the following associated clinical features (Part B): Fever (> 38.5 °C) Hypotension (< 90/60 mmHg) Hypoxia (< 90% oxygen saturation on room air, or requiring oxygen therapy to maintain oxygen saturation above 90%) New neurological signs and / or symptoms clinically suggestive of stroke or transient ischemic attack Signs and / or symptoms of Acute Chest Syndrome, accompanied by any new pulmonary infiltrate on chest radiography (chest X-ray to be performed if clinically indicated and according to local clinical guidelines) Subject is either not taking one of the study permitted SCD therapies (hydroxyurea, L-glutamine, L-glutaminecrizanlizumab, and/or voxelotor) or subject has been taking one or more of those for at least 30 days before Day 1 and is on a stable, well tolerated regimen that is planned to continue without change throughout the study Exclusion Criteria: History of primary hemorrhagic stroke History or evidence of inherited bleeding diathesis or significant coagulopathy at risk for bleeding Weight >110 kg (242 lbs) Surgery within 30 days before Day 1 or any preplanned surgeries during the study (minor surgeries may be permitted under local anesthesia before screening, with permission of the medical monitor) Female subjects who are pregnant or breastfeeding Female subject of childbearing potential or fertile male subject either not using or not willing to use an acceptable method of contraception to avoid pregnancy during the study and for 30 days after receipt of CSL889. Treatment with any other drug / biologic that is newly approved for SCD during the conduct of this study within 90 days before Day 1. Exceptions: crizanlizumab [Adakveo®] and voxelotor [Oxbryta®] ] are permitted (where prescribed). Treatment with another investigational product within 30 days or within 5 half-lives of the product (whichever is greater) before Day 1 Vaccination within 30 days before Day 1, or planned vaccination during the study Body-mass index < 16 kg/m2 or weight < 50 kg (110 lbs) History of anaphylactic-type reactions, transfusion related reaction, asthma, or autoimmune disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CSL889 Cohort A1 (Dose 1)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort A2 (Dose 2)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort A3 (Dose 3)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort A4 (Dose 4)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort A5 (Dose 5)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort A6 (Dose 6)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort B1 (low dose)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|
| Experimental: CSL889 Cohort B2 (high dose)<br>CSL889 administered as a single IV infusion | Biological: CSL889<br>* Administered as an IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with treatment-emergent adverse events (TEAEs) by Cohort |  | Up to 32 days after start of CSL889 infusion | 
| Percentage of subjects with TEAEs by severity by Cohort |  | Up to 32 days after start of CSL889 infusion | 
| Percentage of subjects with TEAEs by causality by Cohort |  | Up to 32 days after start of CSL889 infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed serum concentration (Cmax) of CSL889 by Cohort |  | Up to 32 days after CSL889 infusion | 
| Area under CSL889 serum concentration-time curve (AUC) from time 0 to time t (AUC0-t) by Cohort |  | Up to 32 days after CSL889 infusion | 
| Maximum observed serum concentration (Cmax) of CSL889 by Cohort AUC extrapolated to infinity (AUC0-inf) by CSL889 dose level |  | Up to 32 days after CSL889 infusion | 
| Time of Cmax (tmax) of CSL889 by Cohort |  | Up to 32 days after CSL889 infusion | 
| Terminal half-life (t1/2) of CSL889 by Cohort |  | Up to 32 days after CSL889 infusion | 
| Clearance (CL) of CSL889 by Cohort |  | Up to 32 days after CSL889 infusion | 
| Volume of distribution (Vz) of CSL889 by Cohort |  | Up to 32 days after CSL889 infusion | 
| Percentage of subjects with detectable antibodies to CSL889 by Cohort |  | Up to 32 days after CSL889 infusion |