| Eligibility |
Inclusion Criteria:
- 1. Male or female between 18 and 55 years of age, inclusive, at time of informed
consent.
1. Female subjects of childbearing potential must be non-lactating, not pregnant as
confirmed by a negative urine serum pregnancy test at Screening and admission to
CRU, and using, and agree to continue using, an effective method of contraception
for at least 4 weeks or barrier method for 2 weeks prior to first study drug
administration until 30 days after the last dose of study drug.
2. Female subjects of non-childbearing potential must be surgically sterile (e.g.,
hysterectomy, bilateral tubal ligation, oophorectomy) or post-menopausal (no
menses for >1 year with follicle stimulating hormone (FSH) >40 U/L at Screening).
3. Female subjects of childbearing potential must not donate ova during the study
and for at least 30 days after the last dose of study drug.
4. Male subjects who have not had a vasectomy and/or subjects who have had a
vasectomy but have not had 2 post surgery negative tests for sperm must agree to
use an acceptable method of contraception from time of first dose of study drug
until 30 days after the last dose of the study drug, and to not donate sperm
during the study and for at least 30 days after the last dose of study drug.
2. BMI between 28.0 and 45.0 kg/m2, inclusive. 3. Healthy per investigator
judgment as documented by medical history, physical examination, vital sign
assessments, 12-lead ECG, clinical laboratory assessments, and general
observations. Note that Screening, abnormalities or findings outside the normal
ranges for any clinical assessments that are considered clinically significant by
the Investigator (clinical laboratory tests, ECG, vital signs) may be repeated
once at the discretion of the Investigator(s), and results that continue to be
outside the normal ranges must be judged by the investigator to be not clinically
significant and acceptable for study participation.
4. Able to understand the procedures and requirements of the study and provide
written informed consent and authorization for protected health information
disclosure.
5. Willing and able to comply with the requirements of the study protocol.
Exclusion Criteria:
- Subjects presenting with any of the following will not qualify for entry into the
study:
1. Current or past clinically significant history of cardiovascular,
cerebrovascular, pulmonary, gastrointestinal, hematologic, renal, hepatic,
immunologic, metabolic, urologic, neurologic, dermatologic, psychiatric, or other
major disease, as determined by the investigator in consultation with the medical
monitor, which may impact safety. History of cancer (except treated non-melanoma
skin cancer) or history of chemotherapy use within 5 years prior to Screening.
2. Any surgical or medical condition or history that, in the opinion of the
investigator in consultation with the medical monitor, may potentially alter the
absorption, metabolism, or excretion of study treatment, such as, but not limited
to, gastric bypass surgery or significant small bowel resections.
3. Contraindication to study drug or its excipients and/or history of allergic or
anaphylactic reactions or clinically significant allergic reaction.
4. Resting heart rate <45 or >100 bpm, systolic blood pressure <90 or >160 mm Hg, or
diastolic blood pressure <50 or >110 mmHg.
5. On screening ECG and by history:
1. A marked baseline prolongation of QT/QTcF interval (e.g., repeated
demonstration of a QTcF interval >450 msec for males and >470 msec for
females).
2. A history of additional risk factors for Torsades de Pointes (e.g., heart
failure, hypokalemia, family history of Long QT Syndrome) or a family
history (immediate family member or grandparent < 60 years of age) of sudden
cardiac death of unknown origin.
6. Use of any prescription medication or over-the counter medications (including
multivitamins, herbal-containing preparations and products with cannabidiol
[CBD]) within 14 days prior to admission to CRU.
Exceptions:
1. Hormonal contraceptives and hormone replacement therapies (oral, injectable,
transdermal, or implanted) are permitted.
2. Topical medication for skin disorders may be added at the discretion of the
PI in consultation with the Medical Monitor, if it is determined there is no
significant systemic absorption of the medication which may impact other
exclusions of medications noted above.
3. Acetaminophen may be taken during screening and as needed to treat an AE
during the study, but subjects should not receive acetaminophen within 24
hours of admission to the CRU.
4. Ibuprofen (or other nonsterioidal anti-inflammatory drug [NSAID]) is
prohibited within 7 days prior to admission to the CRU.
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7. Consumption of any food or drink/beverage containing grapefruit or grapefruit
juice, apple or orange juice, pomelo juice, star fruit, Seville or Moro (blood)
orange products within 7 days before admission to CRU. Vegetables from the
mustard green family (e.g., kale, broccoli, watercress, collard greens, kohlrabi,
brussels sprouts, mustard), food containing poppy seeds (e.g., muffins, bagels,
and cakes) must not be consumed within 24 hours before admission to CRU.
8. History of significant drug abuse (i.e, cocaine, phencyclidine, opioid
derivatives including heroin, and amphetamine derivatives)within one year prior
to Screening or frequent use of soft drugs (such as marijuana) within 1 month
prior to the Screening visit, or hard drugs (such as cocaine, phencyclidine,
opioid derivatives including heroin, and amphetamine derivatives) within 1 year
prior to screening. Marijuana use (and other tetrahydrocannabinol [THC]
containing products) is prohibited within 7 days prior to Screening and
throughout the study. .
9. History of regular alcohol consumption exceeding 14 drinks/week [1 drink = 5
ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of
hard liquor] within 6 months of Screening.
10. Positive urine drug screen for drugs of abuse or positive phosphatidylethanol
(PEth) blood test result >200 ng/mL based on PEth 16.0/18.1 (POPEth) at Screening
or on admission to the CRU. In instances of an exclusionary PEth value,
consideration for enrollment/study continuation can be provided if the principal
investigator and medical monitor agree the subject's history is not consistent
with alcohol abusePositive urine drug or urine alcohol test at Screening or on
admission to CRU.
11. Current nicotine use or vaping regularly more than 5 cigarettes or the equivalent
per week. Use of nicotine patches for smoking cessation is not permitted within 7
days of dosing.
12. Positive test results of hepatitis B surface antigen (HBsAg), hepatitis C virus
antibody (HCV Ab), or human immunodeficiency virus (HIV1/2) antibody.
13. Diabetes, reflected by a fasting plasma glucose level of =126 mg/dL andor a
reflex hemoglobin A1c (HbA1c) =6.5%.
14. Neutropenia, defined as absolute neutrophil count =1000/µL.
15. Participation in another clinical trial at the time of screening or exposure to
any investigational agent, including topical agents, within 30 days or 5
half-lives prior to admission to CRU, whichever is longer.
16. Donation of plasma within 7 days prior to dosing. Donation or loss of blood
(excluding volume drawn at screening) of 50 mL to 499 mL of blood within 30 days,
or more than 499 mL within 56 days prior to the first dosing.
17. Having a condition that the investigator believes would interfere with his/her
ability to provide written informed consent, comply with study instructions, or
which might confound the interpretation of the study results or put the subject
at undue risk. Subjects with a history of hypo- or hyperthyroidism, peripheral
neuropathy, malignant hyperthermia, cataracts or chronic recurrent rash that is
considered clinically significant by the investigator are excluded.
18. Familial (mother/father/sibling) and/or personal history of retinal detachment
any time in the past.
19. Evidence of the following on screening ophthalmologic examination:
1. Peripheral retinal pathology requiring treatment, retinal tears, or lattice
that require treatment.
2. Diabetic retinopathy with macula exudates or macula edema as shown by
optical coherence tomography and examination.
3. Any active macular disease that affects the vision, including macula pucker
(epiretinal membrane) and macular degeneration.
4. Visually significant cataract as determined by ophthalmologist.
5. Any previous intravitreal injection of anti-VEGF agents for macular
degeneration.
6. History of prior vitrectomy.
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