Chronic Spontaneous Urticaria
Conditions
Keywords
Chronic Spontaneous Urticaria, Chronic Urticaria, Urticaria, Chronic Idiopathic Urticaria, Chronic Autoimmune Urticaria, Idiopathic Chronic Urticaria, Autoimmune Urticaria
Brief summary
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous lirentelimab (AK002) in adult subjects with H-1 antihistamine refractory chronic spontaneous urticaria. Subjects who complete the randomized, double-blind, placebo-controlled treatment period may have the option to enroll in an open-label extension period and receive up to 6 doses of subcutaneous lirentelimab.
Interventions
Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal antibody directed against Siglec-8
OTHERPlacebo
Placebo
Sponsors
Allakos Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Subject is able to understand the information on the study, has the capacity to consent, and has provided written informed consent. 2. Male and female subjects ≥18 years of age at the time of screening. 3. CSU diagnosis for ≥6 months. 4. Diagnosis of moderate-severe CSU refractory to H1-antihistamine (H1-AH) at a minimum of the licensed dose at the licensed frequency at the time of randomization as defined by the following: presence of hives and itch for ≥6 consecutive weeks prior to Screening Visit 1; UAS7 score (range 0-42) ≥16 and HSS7 score (range 0-21) ≥8 during the 7 days prior to randomization. 5. Subjects that are omalizumab-naïve or omalizumab-exposed. 6. Subjects must be on stable dose of H1-AH, between 1x and 4x of the licensed dose and at the licensed frequency, for treatment of CSU for at least 1 week prior to screening and willing to remain on a stable dose throughout the study. 7. Able and compliant with completing a daily symptom eDiary for the duration of the study and adherent to the study visit schedules. Key
Exclusion criteria
1. History of hypersensitivity to the study drugs or their excipients or to drugs of similar chemical classes (i.e., murine, chimeric or human antibodies). 2. Current use of biologics for any indication. 3. Demonstrated lack of primary response to treatment with a biologic therapy (e.g., omalizumab) for the treatment of CSU. 4. Use of any of the following treatments within 4 weeks prior to the baseline visit or any condition that in the opinion of the Investigator is likely to require such treatment(s) during the first 4 weeks of study treatment: (i) immunosuppressive or immunomodulatory drugs, including but not limited to systemic calcineurin inhibitors (e.g., cyclosporin, tacrolimus), mTOR inhibitors (e.g., sirolimus, everolimus), anti-metabolites (e.g., azathioprine, methotrexate, 6-mercaptopurine, leflunomide, mycophenolate mofetil), alkylating agents (e.g., cyclophosphamide), TNF inhibitors (e.g., infliximab, adalimumab), and eosinophil-depleting drugs (e.g., benralizumab, pramipexole); (ii) routine (daily or every other day during 5 or more consecutive days) doses of systemic hydroxychloroquine; (iii) intravenous immunoglobulin (IVIG); (iv) plasmapheresis. 5. Use of oral Janus kinase (JAK) inhibitors within 8 weeks of the baseline visit. 6. Use of any of the following treatments within 3 weeks prior to the baseline visit: (i) H2 antihistamines (H2-AH); (ii) routine (daily or every other day during 5 or more consecutive days) doses of systemic corticosteroids; (iii) regular (daily or every other day) doxepin (oral); (iv) leukotriene receptor antagonists (LTRA) (e.g., montelukast, zafirlukast). 7. H1-AH use at greater than approved doses or greater than local CSU guideline recommended doses after Screening Visit 1. 8. Previous treatment with biologics: (i) any cell-depleting agents including but not limited to rituximab within 6 months prior to the baseline visit or until lymphocyte count returns to normal, whichever is longer; (ii) other biologics, including investigational biologics (e.g., dupilumab, omalizumab, benralizumab, etc) within 5 half-lives if known or 8 weeks prior to the baseline visit, whichever is longer. 9. Planned or anticipated use of any prohibited medication. 10. Subjects having causes other than CSU for their urticaria including symptomatic dermographism, cholinergic urticaria, or any inducible urticaria. 11. Subjects with known or suspected urticarial vasculitis. 12. Subjects with known or suspected hereditary angioedema. 13. Any other skin disease associated with chronic itch, including atopic dermatitis, that in the Investigator's opinion might influence study outcome and subject's interpretation of symptoms caused by CSU. 14. A helminth parasitic infection diagnosed within 6 months prior to the date that informed consent is obtained and has not been treated with or has failed to respond to standard-of-care therapy. 15. Participation in a concurrent interventional study with the last intervention occurring within 30 days prior to study drug administration (or 90 days or 5 half-lives, whichever is longer, for biologic products). 16. Vaccination with live attenuated vaccines within 30 days prior to initiation of treatment in the study, during the treatment period, or vaccination expected within 5 half-lives (4 months) of study drug administration. This exclusion criterion does not apply to all types and formulations of vaccines (including live attenuated vaccines) currently authorized/approved by FDA or other regulatory authority for the prevention of COVID-19, which may be administered before, during, or after the study. The vaccine should not be administered within 3 days before and within 3 days after the administration of lirentelimab so that any side effects caused by either of the 2 medications can more easily be determined.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Weekly Urticaria Assessment Score (UAS7) From Baseline at Week 12 | Baseline to Week 12 | The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Score (ISS). The daily HSS is recorded on a scale of 0 (none) to 3 (\>50 hives) and the daily ISS is recorded on a scale of 0 (none) to 3 (severe). Therefore, the possible range of the weekly UAS7 score is 0-42, with 42 being the most severe. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Hives Severity Score (HSS7) From Baseline at Week 12 | Baseline to Week 12 | The severity of hives will be recorded by all subjects once daily on a scale of 0 (none) to 3 (\> 50 hives). A weekly HSS score (HSS7) is derived by adding the average daily scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0 - 21. |
| Absolute Change in Itch Severity Score (ISS7) From Baseline at Week 12 | Baseline to Week 12 | The severity of itching will be recorded by all subjects once daily on a scale of 0 (none) to 3 (severe). A weekly ISS score (ISS7) is derived by adding the average daily scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0 - 21. |
| Proportion of Subjects Achieving Weekly Urticaria Assessment Score (UAS7)=0 at Week 12 | At Week 12 | The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Score (ISS). The possible range of the UAS7 is 0-42. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Through study completion, up to 34 weeks (open-label extension period) | Adverse events were assessed throughout the open-label extension period. |
Countries
Germany, Poland, United States
Participant flow
Recruitment details
127 subjects who were enrolled in the main study received up to 6 doses of AK002 or placebo. 117 subjects from the main study continued into the open-label extension (OLE) period and received up to 6 doses of AK002.
Participants by arm
| Arm | Count |
|---|---|
| AK002 SC 300 mg (Main Study) Subjects in this arm received up to 6 doses of 300 mg of lirentelimab (AK002) administered subcutaneously every 2 weeks in the main study.
AK002: Lirentelimab (AK002) is a humanized non-fucosylated immunoglobulin G1 (IgG1) monoclonal antibody directed against Siglec-8 | 66 |
| Placebo (Main Study) Subjects in this arm received up to 6 doses of placebo administered subcutaneously every 2 weeks in the main study.
Placebo: Placebo | 61 |
| Total | 127 |
Baseline characteristics
| Characteristic | AK002 SC 300 mg (Main Study) | Placebo (Main Study) | Total |
|---|---|---|---|
| Age, Continuous | 41 years | 43 years | 41 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 10 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 51 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 13 Participants | 24 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 54 Participants | 43 Participants | 97 Participants |
| Region of Enrollment Germany | 7 Participants | 5 Participants | 12 Participants |
| Region of Enrollment Poland | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 57 Participants | 55 Participants | 112 Participants |
| Sex: Female, Male Female | 50 Participants | 57 Participants | 107 Participants |
| Sex: Female, Male Male | 16 Participants | 4 Participants | 20 Participants |
| Weekly Hive Severity Score (HSS7) | 14.9 Score on a scale STANDARD_DEVIATION 4.2 | 15.8 Score on a scale STANDARD_DEVIATION 4 | 15.3 Score on a scale STANDARD_DEVIATION 4.2 |
| Weekly Itch Severity Score (ISS7) | 16.1 Score on a scale STANDARD_DEVIATION 4.4 | 16.1 Score on a scale STANDARD_DEVIATION 4.3 | 16.1 Score on a scale STANDARD_DEVIATION 4.4 |
| Weekly Urticaria Assessment Score (UAS7) | 31.0 Score on a scale STANDARD_DEVIATION 7.4 | 31.9 Score on a scale STANDARD_DEVIATION 7.8 | 31.4 Score on a scale STANDARD_DEVIATION 7.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 66 | 0 / 61 | 0 / 60 | 0 / 57 |
| other Total, other adverse events | 26 / 66 | 18 / 61 | 22 / 60 | 19 / 57 |
| serious Total, serious adverse events | 1 / 66 | 1 / 61 | 2 / 60 | 2 / 57 |
Outcome results
Primary
Absolute Change in Weekly Urticaria Assessment Score (UAS7) From Baseline at Week 12
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Score (ISS). The daily HSS is recorded on a scale of 0 (none) to 3 (\>50 hives) and the daily ISS is recorded on a scale of 0 (none) to 3 (severe). Therefore, the possible range of the weekly UAS7 score is 0-42, with 42 being the most severe.
Time frame: Baseline to Week 12
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AK002 SC 300 mg (Main Study) | Absolute Change in Weekly Urticaria Assessment Score (UAS7) From Baseline at Week 12 | -7.9 score on a scale | Standard Error 1.9 |
| Placebo (Main Study) | Absolute Change in Weekly Urticaria Assessment Score (UAS7) From Baseline at Week 12 | -8.4 score on a scale | Standard Error 2 |
p-value: 0.817495% CI: [-3.6, 4.5]ANCOVA
Secondary
Absolute Change in Hives Severity Score (HSS7) From Baseline at Week 12
The severity of hives will be recorded by all subjects once daily on a scale of 0 (none) to 3 (\> 50 hives). A weekly HSS score (HSS7) is derived by adding the average daily scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0 - 21.
Time frame: Baseline to Week 12
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AK002 SC 300 mg (Main Study) | Absolute Change in Hives Severity Score (HSS7) From Baseline at Week 12 | -4.0 score on a scale | Standard Error 0.8 |
| Placebo (Main Study) | Absolute Change in Hives Severity Score (HSS7) From Baseline at Week 12 | -4.6 score on a scale | Standard Error 0.9 |
p-value: 0.585795% CI: [-1.6, 2.8]Mixed Models Analysis
Secondary
Absolute Change in Itch Severity Score (ISS7) From Baseline at Week 12
The severity of itching will be recorded by all subjects once daily on a scale of 0 (none) to 3 (severe). A weekly ISS score (ISS7) is derived by adding the average daily scores of the 7 days preceding the visit. Therefore, the possible range of the weekly score is 0 - 21.
Time frame: Baseline to Week 12
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AK002 SC 300 mg (Main Study) | Absolute Change in Itch Severity Score (ISS7) From Baseline at Week 12 | -4.4 score on a scale | Standard Error 0.8 |
| Placebo (Main Study) | Absolute Change in Itch Severity Score (ISS7) From Baseline at Week 12 | -4.3 score on a scale | Standard Error 0.9 |
p-value: 0.963395% CI: [-2.2, 2.1]Mixed Models Analysis
Secondary
Proportion of Subjects Achieving Weekly Urticaria Assessment Score (UAS7)=0 at Week 12
The UAS7 is the sum for 7 days of the daily Hives Severity Score (HSS) and the daily Itch Severity Score (ISS). The possible range of the UAS7 is 0-42.
Time frame: At Week 12
Population: Modified Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AK002 SC 300 mg (Main Study) | Proportion of Subjects Achieving Weekly Urticaria Assessment Score (UAS7)=0 at Week 12 | 6.3 percentage of participants |
| Placebo (Main Study) | Proportion of Subjects Achieving Weekly Urticaria Assessment Score (UAS7)=0 at Week 12 | 0 percentage of participants |
p-value: 0.120195% CI: [-11.4, 23.78]Fisher Exact
Other Pre-specified
Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period
Adverse events were assessed throughout the open-label extension period.
Time frame: Through study completion, up to 34 weeks (open-label extension period)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AK002 SC 300 mg (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 treatment-related adverse events | 6 Participants |
| AK002 SC 300 mg (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 serious adverse events | 2 Participants |
| AK002 SC 300 mg (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with an adverse event leading to study drug discontinuation | 4 Participants |
| AK002 SC 300 mg (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 treatment-related serious adverse events | 0 Participants |
| AK002 SC 300 mg (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 adverse events | 31 Participants |
| Placebo (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 treatment-related serious adverse events | 0 Participants |
| Placebo (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 adverse events | 26 Participants |
| Placebo (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 treatment-related adverse events | 12 Participants |
| Placebo (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with an adverse event leading to study drug discontinuation | 1 Participants |
| Placebo (Main Study) | Safety and Tolerability of up to 6 Doses of Open-label AK002 in Subjects With Chronic Spontaneous Urticaria in the Open-label Extension Period | Subjects with ≥1 serious adverse events | 2 Participants |