Study to Assess the Safety, Tolerability, Pharmacokinetics and Immunogenicity of AK006 in Healthy Subjects and Subjects With Chronic Spontaneous Urticaria

Study Overview
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Brief Summary
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This is a Phase 1, double-blind, randomized, placebo-controlled study that will evaluate the safety, pharmacokinetics (PK), immunogenicity (immune response), and explore the clinical activity of single and multiple ascending doses of AK006 when administered intravenously (IV) to healthy participants and participants with chronic spontaneous urticaria (CSU).

Official Title
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A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Sequential, Single- and Multiple-Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Immunogenicity of AK006 in Healthy Subjects and in Subjects With H1 Antihistamine Refractory Chronic Spontaneous Urticaria

Conditions
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Healthy Participants, Chronic Spontaneous Urticaria

Intervention / Treatment
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* Drug: AK006
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: To be included in the study, the participant must: Weigh between 60 and 120 kg (inclusive) and have a body mass index (BMI) between 20 and 32 kg/m2, inclusive Be in good general health with no significant medical history and has no clinically significant abnormalities on physical examination (Part A and B only) Have a diagnosis of chronic spontaneous urticaria (CSU) for at least 6 months (Part C only) Be on a stable dose of a single 2nd or later generation H1-antihistamines for the treatment of CSU, between 1× and 4× the licensed dose and frequency, by Day -14 of the Screening Period and must be willing to remain on the same stable dose throughout the study (Part C only) Have moderate to severe CSU that is refractory to stable doses of a single 2nd or later generation H1-antihistamines between 1× and 4× the licensed dose and frequency at the time of randomization as defined by the following (Part C Only): Presence of hives and itch for at least 6 consecutive weeks prior to the Screening Visit. Weekly urticaria activity score (UAS7) of at least 16 and weekly hive severity score (HSS7) of at least 8 for the 2 consecutive weeks prior to randomization (Day 1) while on the stable dose of an H1-antihistamines as described above (Note: participant must have completed at least 4 daily Urticaria Patient Daily Diary (UPDD) questionnaires during each of these qualifying weeks to remain eligible for study participation). Key Exclusion Criteria: A participant who meets any of the following exclusion criteria will not be eligible for inclusion in the study: Male participants sexually active with a woman of childbearing potential, or female participants of childbearing potential who are not willing to use a highly effective method of contraception from the time of first dose of investigational product (IP) until 120 days after the last dose Female participants who are pregnant, lactating, or planning to become pregnant during the study. Abnormal laboratory values, or findings in physical examination, ECG (QTc >450 ms for males and >470 ms for females), or vital signs considered to be clinically significant by the investigator. Treatment with any prescribed (excluding hormonal contraceptives) or nonprescribed systemic or topical medication (including herbal product, and vitamins) within 21 days prior to the first dose of IP (excluding acetaminophen) (Part A and B only).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Single (Part A) and multiple (Part B) ascending dose study in healthy participants with a multiple dose expansion (Part C) in participants with chronic spontaneous urticaria.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A - Single Ascending Dose (SAD) Cohorts<br>Part A: Healthy adult participants will receive a single intravenous infusion of AK006 or matching placebo. The dose of AK006 will be increased per cohort. There will be up to 5 cohorts evaluated. | Drug: AK006<br>* Intravenous Infusion<br>Drug: Placebo<br>* Intravenous Infusion<br>|
| Experimental: Part B - Multiple Ascending Dose (MAD) Cohorts<br>Part B: Healthy adult participants will receive multiple intravenous infusions of AK006 or matching placebo. The dose of AK006 will be increased per cohort. There will be up to 3 cohorts evaluated. | Drug: AK006<br>* Intravenous Infusion<br>Drug: Placebo<br>* Intravenous Infusion<br>|
| Experimental: Cohort C<br>Part C: Adults with Chronic Spontaneous Urticaria will receive multiple intravenous infusions of AK006 or matching placebo. Up to 2 dose levels may be evaluated. | Drug: AK006<br>* Intravenous Infusion<br>Drug: Placebo<br>* Intravenous Infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events (AEs) | AEs, serious AEs, and treatment emergent AEs (AE that starts after start of investigational product) | Screening to Day 113 (Part A) and Screening to Day 141 (Part B and C) | 
| Incidence of AEs of special interest | Infusion-related reactions, anaphylaxis, and opportunistic infections | Day 1 to Day 113 (Part A) and Day 1 to Day 141 (Part B and C) | 
| AEs leading to discontinuation | AEs | Day 1 to Day 113 (Part A) and Screening to Day 141 (Part B and C) | 
| Incidence of clinically significant abnormal laboratory values, electrocardiograms (ECGs), and vital signs | Incidence of clinically significant abnormal laboratory values, electrocardiograms (ECGs), and vital signs | Day 1 to Day 113 (Part A) and Day 1 to Day 141 (Part B and C) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AK006 serum concentration at end of infusion | AK006 Serum concentration (ng/mL) at end of infusion | Day 1 (Part A) and Day 29 (Part B) | 
| AK006 area under the concentration-time curve (AUC) from time 0 to the time of last quantifiable concentration (AUC[0-last]) | AK006 AUC(0-last) (ng x h/mL) | Day 1 to Day 113 (Part A) and Day 29 to Day 141 (Part B) | 
| AK006 AUC from time 0 extrapolated to infinity (AUC[0-inf]) | AK006 AUC(0-inf) (ng x h/mL) | Day 1 to Day 113 (Part A) | 
| Total systemic clearance of AK006 after intravenous dose (CL) | AK006 CL (L/h/kg) | Day 1 to Day 113 (Part A) and Day 1 to Day 141 (Part B) | 
| Systemic steady-state volume of distribution (Vss) of AK006 | AK006 Vss (mg/L) | Day 1 to Day 113 (Part A) and Day 1 to Day 141 (Part B) | 
| AK006 Terminal elimination phase half-life (t1/2) | AK006 t1/2 (hours) | Day 1 to Day 113 (Part A) and Day 1 to Day 141 (Part B) | 
| Predose AK006 serum concentration (Ctrough, before the next dose) [Part B] | AK006 Ctrough (ng/mL) | Day 29 (pre-dose) | 
| AK006 AUC over the dosing time interval (time 0 to 28 days) (AUC[tau]) (Part B) | AK006 AUC(tau) (ng x h/mL) | Day 1 to Day 28 with each dosing interval | 
| AK006 Anti-drug Antibodies (ADAs) | Presence and the titer of AK006-ADAs | Day 1 to Day Day 113 (Part A) and Day 1 to Day 141 (Part B and C) |