Safety and Tolerability Study of Xisomab 3G3 in Healthy Adult Subjects

A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Xisomab 3G3 in Healthy Adult Subjects

The purpose of this study is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of xisomab 3G3 in healthy adult subjects.

Inclusion Criteria:

1. Healthy adult male and/or female (non-childbearing potential only), 18 to 48 years of age, inclusive, at screening.

2. Continuous non-smoker who has not used nicotine containing products for at least 3 months prior to dosing and throughout the study.

3. Body mass index (BMI) ≥ 19 and ≤ 29.0 (kg/m2) and weight between 50 and 125 kg (inclusive) at screening.

4. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs or ECGs, as deemed by the PI or designee.

5. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine must be between the lower limit of normal (LLN; or up to 15% below LLN as not indicative of hepatic or renal disease in healthy subjects) and the upper limit of normal, inclusive, at screening and check-in.

6. aPTT, PT/INR, and platelets, must be within the limits of normal, inclusive, at screening and check-in.

7. Bleeding time must be between 2 to 8 minutes, inclusive, at check-in.

8. For a female of non childbearing potential: must have undergone one of the following sterilization procedures at least 6 months prior to dosing:

   • hysteroscopic sterilization;
   • bilateral tubal ligation or bilateral salpingectomy;
   • hysterectomy;
   • bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and follicle stimulating hormone (FSH) serum levels consistent with postmenopausal status as per PI or designee judgment.

9. A non vasectomized male subject whose sexual partner is sterile or was advised to use one of the following during the course of the study (or prior to study as specified) and for 90 days following dosing:

   • Abstain from sexual intercourse;
   • An intrauterine device with spermicide;
   • A physical barrier method (e.g., male or female condom, contraceptive sponge, diaphragm, cervical cap) with spermicide;
   • An intravaginal system (e.g., NuvaRing®) for at least 3 months prior to dosing;
   • An oral, implantable, transdermal, or injectable hormonal contraceptive for at least 3 months prior to dosing.

   No restrictions are required for a vasectomized male provided his vasectomy has been performed 4 months or more prior to dosing. A male who has been vasectomized less than 4 months prior to dosing must follow the same restrictions as a non vasectomized male.

10. If male, must agree to not donate sperm from dosing until 90 days after dosing.

11. Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol.

Exclusion Criteria:

1. Subject is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.

2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.

3. History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.

4. History or presence of drug abuse within the last 2 years prior to dosing.

5. History of alcoholism within the last 2 years prior to dosing or a current history of imbibing 3 or more units of alcohol per day (1 unit is equivalent to 150 mL of wine or 360 mL of beer or 45 mL of 45% alcohol).

6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug, any ingredients of the study drug, or related compounds.

7. History of a clinically significant allergy of any kind including a history of allergic or hypersensitivity reactions to any drugs.

8. History or presence of:

   • Bleeding disorder(s) and/or at risk of bleeding, including relevant familial history;
   • Clinically significant anemia, in the opinion of the PI or designee;
   • Thromboembolic disease;
   • Bleeding in the gastrointestinal tract or central nervous system.

9. Allergy to rodents.

10. Had a minor surgery or major physical injury less than 4 weeks or major surgery less than 12 weeks prior to screening.

11. Was hospitalized within 2 months of dosing, unless deemed acceptable by the PI or designee.

12. Female subjects of childbearing potential.

13. Female subjects who are pregnant or lactating.

14. Positive urine drug or alcohol results at screening or check in.

15. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV).

16. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.

17. Seated heart rate is lower than 40 bpm or higher than 100 bpm at screening.

18. QTcF interval is >450 msec (males) or >460 msec (females) or has ECG findings deemed abnormal with clinical significance by the PI or designee at screening.

19. Hemoglobin value of less than 11.5 g/dL for females and 13.0 g/dL for males, at screening or check-in.

20. Unable to refrain from or anticipates the use of:

    • Any prescription medications, non-prescription medications, herbal remedies, or vitamin supplements beginning approximately 14 days prior to dosing and throughout the study. Acetaminophen (up to 2 g per 24 hour period) may be permitted during the study and will be documented.
    • Any anticoagulants (i.e., warfarin, Low Molecular Weight Heparin), coagulants, anti-platelet (e.g., clopidogrel), nonsteroidal anti-inflammatory drugs and/or acetylsalicylic acid beginning approximately 28 days prior to dosing and throughout the study. Appropriate sources will be consulted by the PI or designee to confirm lack of pharmacokinetic/pharmacodynamic interaction with study drug.
    • Any investigational drugs or biologics beginning approximately 30 days prior to dosing and throughout the study.
    • Any biologics developed from chinese hamster ovary cell cultures in their life time.

21. Has been on a diet incompatible with the on study diet, in the opinion of the PI or designee, within the 28 days prior to dosing and throughout the study.

22. Donation of blood or significant blood loss within 56 days prior to dosing.

23. Plasma donation within 7 days prior to dosing.

24. Strenuous exercise/physical activity which could cause muscle aches or injury, including contact sports at any time from 72 hours before dosing until completion of the study.

25. Participation in another clinical study within 30 days prior to dosing. The 30 day window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study.

26. Presence of any scars, or tattoos which may obscure the injection site, as deemed by PI or designee.

27. Any condition or circumstance, in the opinion of the PI or designee, which may make the subject unlikely to complete the study or comply with study procedures and requirements, or may pose a risk to the subject's safety.