A Study of NN2802, an Anti-c-Kit Antibody, in Healthy Participants and in Adults With Chronic Spontaneous Urticaria (CSU)

Inclusion Criteria(Part A):

1. Participants must sign an IRB/IEC approved informed consent form before any study specific procedures are performed.

2. Healthy adult male and female participants between 18 and 65 years of age, inclusive, at the time of screening.

3. Participants must have suitable veins for cannulation or repeated venipuncture.

4. If female, meets one the of following criteria:

   1. Is of childbearing potential and agrees to use a highly effective contraceptive method from at least 28 days prior to the Screening visit through to at least 105 days after study drug administration.

      OR

   2. Is of non-childbearing potential, defined as surgically sterile, or is in a postmenopausal state.

5. If male, meets one the following criteria:

   1. Abstinence from penile vaginal intercourse as their usual and preferred lifestyle.
   2. Unable to procreate, defined by surgically sterile
   3. Agrees to use male condom when having sexual intercourse with a woman of childbearing potential.

6. Body mass index (BMI) between 18.0 and 26.0 kg/m2, inclusive.

7. Normal or clinically acceptable physical examination, clinical laboratory test values, ECG, and vital signs, as determined by the Investigator.

8. Total bilirubin, ALT, AST and creatinine ≤ upper limit of normal (ULN).

9. No known history of active tuberculosis.

10. Participant has a negative tuberculosis test at screening

Inclusion Criteria(Part B):

1. Participants must sign an IRB/IEC approved ICF before any study-specific procedures are performed.

2. Adult male and female participants between 18 and 75 years of age, inclusive, at the time of screening.

3. Weight ≥40 kg.

4. Diagnosis of CSU refractory to H1-antihistamines used alone or in combination with a leukotriene receptor antagonist, at the time of randomization, as defined by all the following:

   1. CSU diagnosis ≥ 6 months, with supporting documentation
   2. Presence of itch and hives for ≥ 6 consecutive weeks at any time prior to enrollment, including inadequate disease control despite treatment with H1-antihistamines, either alone or in combination with leukotriene receptor antagonists, for at least 2 consecutive weeks during this period.
   3. UAS7 (range 0-42) of ≥16 and ISS7 (range 0-21) of ≥8 during the 7 days before treatment.
   4. In-clinic UAS ≥4 on one of the screening visit days, despite use of H1 antihistamines alone or in combination with H2-antihistamines and or leukotriene receptor antagonist) for CSU.

5. Prior anti-immunoglobulin E (IgE) therapy is allowed (e.g., omalizumab), with the last dose administered at least 5 half-lives of the respective drug prior to randomization.

6. If female, meets one the of following criteria:

   1. Is of childbearing potential and agrees to use a highly effective contraceptive method. OR
   2. Is of non-childbearing potential, defined as surgically sterile, or is in a postmenopausal state.

7. If male, meets one the following criteria:

   1. Abstinence from penile vaginal intercourse as their usual and preferred lifestyle.
   2. Unable to procreate, defined by surgically sterile
   3. Agrees to use male condom when having sexual intercourse with a woman of childbearing potential.

Exclusion Criteria(Part A):

1. Female who is lactating.

2. Female who is pregnant according to the pregnancy test at screening or prior to study drug administration or plans to become pregnant during the study or within 105 days following study drug dosing.

3. Donated blood in the 3 months prior to screening, plasma in the 7 days prior to screening, or platelets in the 6 weeks prior to screening.

4. Consume more than 14 units of alcohol per week (if male) or consume more than 11 units of alcohol per week (if female), or history of alcohol or drug/chemical abuse within 12 months prior to study drug dosing, as determined by the Investigator.

5. Positive drugs of abuse (including marijuana) or alcohol screen test.

6. Participants who smoke more than 9 cigarettes, or equivalent in tobacco per day, or inability to abide by the smoking policy of the clinical research unit.

7. Participants who have used the following within 7 days of dosing, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety:

   1. any non-prescribed (i.e., over-the-counter) systemic or topical medication.
   2. any herbal remedy, vitamin, or mineral supplement.

8. Participants who have received:

   1. any prescribed systemic or topical medication within 14 days or 5 half-lives (whichever is longer) prior to dosing, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
   2. any antihistamines within 5 half-lives prior to dosing.
   3. immunosuppressive drugs within 60 days prior to dosing.
   4. COVID-19 vaccination within 30 days prior to dosing.
   5. standard vaccinations within 14 days prior to dosing or other live or live-attenuated vaccine 3 months prior to dosing.
   6. slow-release medicinal formulations considered to still be active within 14 days or 5 half-lives (whichever is longer) prior to dosing, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
   7. for male participants, medications that are known to affect sperm count or motility within 30 days prior to dosing

9. Received any medications, including St. John's Wort, known to chronically alter drug absorption or elimination processes, within 30 days prior to dosing, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.

10. History of anaphylaxis, clinically significant drug allergies or allergic conditions (excluding non-active seasonal allergies), as determined by the Investigator.

11. Is currently participating in another clinical study or has received an investigational medicinal product (IMP) within the following time period prior to dosing: 30 days, 5 half-lives, or twice the duration of the biological effect of the IMP (whichever is longer).

12. Participants who have previously received NN2802.

13. History of malignancy within 5 years prior to dosing, except treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma.

14. History or evidence of any bacterial, viral, parasitic, or system fungal infections within 30 days prior to dosing. Exception: a simple, short duration common cold resolved more than 14 days prior to dosing.

15. Recent infection (within 3 months prior to dosing) requiring inpatient hospitalization or IV antibiotics.

16. Clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to dosing, as determined by the Investigator.

17. History or evidence of any clinically significant disorder (including psychiatric), condition, or disease that, in the opinion of the Investigator, may pose a risk to participant safety or interfere with the study evaluation, procedures, or completion.

18. Infectious Disease Risk

    Participants will be excluded if any of the following apply at screening:

    1. Positive test for HIV (Human immunodeficiency virus) antibodies.
    2. Positive or indeterminate HBsAg, or positive IgM HBcAb, or positive Total HBcAb and positive HBV DNA, or positive HCV Ab and positive HCV RNA.

19. Received or scheduled to receive a live vaccination within 3 months prior to dosing and until 3 months following study drug dosing.

20. Previously enrolled in or withdrawn from this study.

21. Inability or unwillingness to reside at the clinical research unit during the confinement period, or inability to be available for follow-up visits or protocol required procedures.

22. Participants who, in the opinion of the Investigator, should not participate in this study.

Exclusion Criteria(Part B):

1. Clearly defined cause for chronic urticaria, including any of the following:

   1. Symptomatic solar-, cholinergic-, heat-, cold-, aquagenic- or contact induced urticaria, artificial urticaria, symptomatic urticaria or vibratory angioedema
   2. Diseases with symptoms of urticaria and/or angioedema, such as: urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary or acquired angioedema, hematological or any other malignancies

2. History or evidence of any clinically significant disorder (including psychiatric), condition, or disease other than CSU, that, in the opinion of the investigator, may pose a risk to participant safety or interfere with the study evaluation, procedures, or completion.

3. Females who are lactating, or who are pregnant according to the pregnancy test at screening or prior to study drug administration, or plan to become pregnant during the study.

4. Participants who have received:

   1. immunosuppressive drugs (e.g., cyclosporine, tacrolimus) within 60 days prior to dosing.
   2. COVID-19 vaccination within 30 days prior to dosing.
   3. Standard vaccinations within 14 days prior to dosing or other live or live attenuated vaccine 3 months prior to dosing.
   4. Previous use of IgE therapy (e.g., Omalizumab) within 5 half-lives of the respective anti-IgE therapy prior to dosing.

5. Anticipated requirement for the use of any leukotriene receptor antagonist (Montelukast, Zafirlukast) use between Day 1 and EOS (inclusive).

6. Uncontrolled, clinically significant system disease such as diabetes mellitus, cardiovascular disease including moderate-to-severe heart failure (New York Heart Association class III/IV), moderate-to-severe liver disease, or hypertension, as determined by the Investigator.

7. History of anaphylaxis, clinically significant drug or food allergies or any other clinically significant allergic conditions (e.g., excluding mild seasonal allergies), as determined by the Investigator.

8. Is currently participating in another clinical study or has received an investigational medicinal product (IMP) within the following time period prior to dosing: 30 days, five half-lives, or twice the duration of the biological effect of the IMP (whichever is longer).

9. Participants who have previously received NN2802 or any other c-kit targeting agent within the following time period prior to dosing: 30 days, five half-lives, or twice the duration of the biological effect of the IMP (whichever is longer).

10. History of hypersensitivity or allergy to NN2802 or its excipients.

11. History of malignancy within 5 years prior to dosing, except treated and considered cured cutaneous squamous or basal cell carcinoma, in situ cervical cancer, or in situ breast ductal carcinoma.

12. Known or clinically suspected active helminthic parasitic infection, as determined by the Investigator based on medical history and clinical presentation.

13. Active infection or history of infection as follows:

    1. Any active infection for which oral anti-infectives (antibiotics, antivirals, antifungals) were used ≤ 14 days prior to first dose of study drug).
    2. A serious infection requiring hospitalization or IV anti-infectives (antibiotics, antivirals, antifungals) ≤ 30 days prior to first dose of study drug.
    3. Recurrent or chronic infections or other active infections that in the opinion of the investigator might cause this study to be detrimental to the participant.

14. Clinically significant illness, medical/surgical procedure, or trauma within 4 weeks prior to dosing, as determined by the Investigator.

15. Infectious Disease Risk

    Participants will be excluded if any of the following apply at screening:

    1. Positive test for HIV (Human immunodeficiency virus) antibodies.
    2. Positive or indeterminate HBsAg, or positive IgM HBcAb, or positive Total HBcAb and positive HBV DNA, or positive HCV Ab and positive HCV RNA.
    3. Tuberculosis (TB) risk

16. Laboratory abnormalities at screening:

17. Clinically significant electrocardiogram (ECG) findings unless approved by Cardiologist or Study Medical Monitor.

18. Received or scheduled to receive a live vaccination within 3 months prior to dosing and until 3 months following study drug dosing.

19. Previously enrolled in or withdrawn from this study.

20. Active substance abuse (drug or alcohol) within 24 weeks prior to first dose of study drug, as determined by the investigator.

21. Inability or unwillingness to be available for follow-up visits or protocol required procedures.

22. Participants who, in the Investigator's opinion, should not participate in this study.