A Study to Assess the Efficacy and Safety of AK002 in Subjects With Antihistamine-Resistant Chronic Urticaria

This open-label study is to assess the effects of AK002, given as monthly intravenous infusions at up to 3 mg/kg. A total of 47 patients will be enrolled across 2-4 sites. All patients enrolled in the study will receive 6 monthly infusions of AK002 and will then be followed for another 8 weeks. Some patients will have the option to receive an additional 12 months of extended dosing.

• AK002 (Drug): AK002 is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal antibody directed against Siglec-8, a member of the CD33-related family of sialic acid-binding, immunoglobulin-like lectins (Siglecs).

Primary outcomes

• Change in Urticaria Control Test (UCT) Score From Baseline to Week 22 in the Main Study Phase [Baseline to Week 22 (Main Study Phase)]: The UCT score consists of 4 items, and each UCT item has 5 answer options (scored with 0-4 points), where low points indicate high disease activity and low disease control of chronic urticaria. The UCT score, ranging from 0 to 16, is calculated by adding all 4 individual item scores. A UCT score of 16 points indicates complete disease control and a change of the UCT score of 3 or more points was regarded as clinically relevant (minimal clinically important difference \[MCID\]).

Other outcomes

• Safety and Tolerability of up to 12 Additional Doses of AK002 in Subjects With CU in the Extended Dosing Phase [Through study completion, up to 52 weeks (Extension Dosing Phase)]: Adverse events were assessed during the Extended Dosing Phase of the study, and only the 5 subjects who entered the Extended Dosing Phase were included.

Sex: All, ages: 18 Years to 85 Years

Inclusion Criteria:

1. Adults (≥ 18 and ≤ 85 years old)
2. Body weight <125 Kg
3. Informed consent signed and dated
4. Able to read, understand, and willing to sign the informed consent form and comply with study procedures
5. Diagnosis of CU for at least three months, refractory to antihistamine treatment in single or 4-fold dosage
6. Willing, committed, and able to return for all clinic visits and complete all study-related procedures, including willingness to have IV infusion of study drug administered by a qualified person
7. Females of childbearing potential must have a negative pregnancy test at Baseline. Female subjects must be willing to use highly effective contraception (Pearl- 4 Index < 1). A woman will be considered not of childbearing potential if she is post-menopausal for greater than two years (FSH >40mL) or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy)
8. No participation in other clinical trials 4 weeks before participation in this study
9. Uncontrolled CU (UCT <12) at the time of enrollment

Exclusion Criteria:

1. Acute urticaria
2. Concurrent/ongoing treatment with immunosuppressives (e.g., cyclosporine, methotrexate, dapsone, or others) within 4 weeks or 5 half-lives prior to Baseline, whichever is longer
3. Significant medical condition rendering the patient immunocompromised or not suitable for a clinical trial
4. Significant concomitant illness that would adversely affect the subject's participation or evaluation in this study
5. History of malignancies within five years prior to screening other than a successfully treated non-metastatic cutaneous, basal, or squamous cell carcinoma and/or in situ cancer
6. Presence of clinically significant laboratory abnormalities
7. Lactating women or pregnant women
8. Substance abuse (drug or alcohol) or any other factor (e.g., serious psychiatric condition) within the last 5 years that could limit the subject's ability to comply with study procedures
9. Subjects who are detained officially or legally to an official institute or those that have been committed to an institution by virtue of an order issued either by the judicial or the administrative authorities will be excluded from the study
10. Use of omalizumab within the last 3 months
11. Receipt of intravenous IgG therapy 30 days prior to Baseline
12. Plasmapheresis 30 days prior to Baseline
13. Use (daily or every other day) of Doxepin 14 days prior to Baseline
14. Receipt of inactive vaccination or live attenuated vaccine 30 days prior to Baseline
15. Use of H2 antihistamines 7 days before Baseline
16. Intake of leukotriene antagonists within 7 days prior to enrollment
17. Intake of systemic corticosteroids (e.g., oral or depot) within 14 days prior to enrollment
18. Positive screening for ova and parasite test at Baseline
19. Treatment of helminthic parasite within 6 months of screening
20. Positive HIV serology at screening
21. Positive Hepatitis serology at baseline, except for vaccinated patients or patients with past but resolved hepatitis at screening
22. Donation or loss of >500ml of blood within 56 days prior to administration of study drug or donation of plasma within 7 days prior to administration of drug
23. Known hypersensitivity to any ingredients of AK002 or drugs related to AK002 (e.g., monoclonal antibodies, polyclonal gamma globulin)

Participant flow

Outcome results

• Change in Urticaria Control Test (UCT) Score From Baseline to Week 22 in the Main Study Phase (Primary), Mean, Score on a scale: CholU 6.5 +/- 6.15; UF-Cohort 3.4 +/- 4.09; CSU-XN 11.1 +/- 4.07; CSU-XF 4.8 +/- 6.97
• Safety and Tolerability of up to 12 Additional Doses of AK002 in Subjects With CU in the Extended Dosing Phase (Other pre specified), Count of participants, Participants: AK002 5

Adverse events

Time frame: Adverse events were reported from the first dose of AK002 until the end of Follow-up (Week 28 in the Main Study Phase, Week 52 in the Extended Dosing Phase).

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2019-02-04)
• Statistical Analysis Plan (PDF, 2019-02-13)

• Henrik Rasmussen, MD, PhD, Study director, Allakos Inc.