Phase 1, First in Human (FIH), Open-Label, Single-Arm, Ascending Dose Study to Assess the Safety, Tolerability and Preliminary Immunogenicity of ITI-9001 in Japanese Patients With Japanese Red Cedar (JRC) Pollinosis

Phase I, open-label, single-arm, ascending dose study to evaluate the safety, tolerability, and preliminary immunogenicity of ITI-9001. The study will be conducted in 2 parts -Part A and Part B.

Part A is a 'dose escalation' phase where two different doses will be given (a low dose and a high dose), where the total duration of study participation for each patient will be approximately 6 months.

Part B is an 'expansion' phase using the highest tolerated dose from Part A, where a total duration of study participation for each patient will be approximately 12 months if they receive all 3 planned doses and complete all 4 subsequent visits. Part B contains ITI-9001 and a placebo.

• ITI-9001 (Drug): ITI-9001 is a self-amplifying RNA (saRNA) immunotherapy formulated with lipid nanoparticles for intramuscular injection. The saRNA encodes a CryJ2-LAMP-1 fusion protein, targeting Japanese Red Cedar (JRC) pollen allergy. ITI-9001 is designed to enhance antigen presentation and stimulate robust immune responses, aiming to reduce allergic symptoms in JCP-sensitive patients.
• Placebo (Other): Saline placebo injection

Primary outcomes

• Frequency and severity of dose-limiting toxicities (DLTs) [From enrollment to Day 382]: DLTs will be summarized by frequency and severity from first study drug administration through End of Study (see timeframe below)

Other outcomes

• Measurements of blood antibody titers from immune biomarkers, and skin prick tests [From screening through Day 382]: Immune biomarkers of pharmacodynamic activity, including blood antibody titer assessments from screening through end of study (see timeframe below)

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

1. Signed and dated informed consent form (ICF)
2. Female of non-childbearing potential or male aged 18-65 years (inclusive). Women are not considered to be of childbearing potential if they have had a hysterectomy or tubal ligation, or are postmenopausal (≥12 months without menstruation, or FSH in postmenopausal range for women <55 years)
3. Confirmed JCP sensitivity by positive skin prick test (wheal diameter ≥3 mm)
4. Confirmed JCP sensitivity by ImmunoCAP (serum JCP-specific IgE ≥ class 2)
5. ≥2 year history of seasonal rhinoconjunctivitis symptoms requiring medication upon JCP exposure
6. Contraception requirements: <br> a. Women of non-childbearing potential: negative serum pregnancy test ≤3 days before first dose <br> b. Men: surgically sterile, or agree to abstinence or use 2 highly effective methods of contraception during study and for 3 months after last dose if partner is of childbearing potential (male condom + oral hormonal contraceptives, intrauterine device, or intrauterine hormone-releasing system)
7. No significant ischemic heart disease or myocardial infarction within 6 months before first study drug administration; adequate cardiac function at screening (QTcF ≤470 msec for females or ≤450 msec for males; average of triplicate ECGs). Participants with ventricular arrhythmia assessed case-by-case
8. Willing and able to participate and comply with all study procedures

Exclusion Criteria:

1. Women of childbearing potential (do not meet inclusion criterion #2)
2. Respiratory function: <br> a. Fever ≥38°C (100.4°F) on day of study drug administration <br> b. FEV1 <80% as predicted on spirometry <br> c. Current smoker/tobacco user <br> d. History of asthma requiring daily medication (except exercise-induced or mild intermittent asthma)
3. Contraindications: <br> a. Known allergy to ITI-9001 components <br> b. Contraindication to intramuscular injections or blood draws <br> c. History of intolerance or severe allergic reaction to previous immunotherapy <br> d. History of anaphylaxis requiring medical intervention (including severe reactions to mRNA vaccines)
4. Prior/concurrent treatments: <br> a. Participation in another therapeutic clinical trial within 30 days before screening <br> b. Prior or current immunotherapy for JCP <br> c. Specific or nonspecific immunotherapy within 1 year prior to screening <br> d. Biologics (e.g., anti-IgE, anti-IL-5, anti-TNFα) <br> e. mRNA vaccine within 28 days before first study drug administration <br> f. Live vaccine within 28 days or inactivated/toxoid vaccine within 7 days before first study drug administration <br> g. Chronic (more than 30 days) systemic corticosteroids (inhaled, oral, IM, IV, potent topical) <br> h. Inability/unwillingness to discontinue beta-blockers up to 48 hours before first study drug administration and during the study <br> i. Inability/unwillingness to comply with washout periods for antihistamines and other allergy medications (per Table 3)
5. Medical history/comorbidities: <br> a. Clinically significant abnormalities on physical exam, labs, or medical history that jeopardize safety or validity of results (except HEENT findings consistent with allergic rhinitis) <br> b. Malignant tumor diagnosed or treated within 5 years prior to first study drug administration (except adequately treated non-melanoma skin cancer or carcinoma in situ) <br> c. Congenital or acquired immune deficiency or suppression (e.g., malignancy, infection, chemotherapy, radiation, corticosteroids) <br> d. History of organ transplant, hematologic malignancy, or autoimmune disease <br> e. History of stroke, transient ischemic attack, unstable angina, myocardial infarction within 3 months prior to first study drug administration <br> f. Symptomatic congestive heart failure (NYHA Class III-IV), unstable angina, significant arrhythmia, or LVEF <45% <br> g. History of myocarditis or pericarditis <br> h. Risk factors for torsades de pointes or use of medications known to prolong QT/QTc (except low-risk premedications) <br> i. Clinically significant gastrointestinal, renal, hepatic, neurologic, or hematologic disease <br> j. HIV/AIDS, hepatitis B, or hepatitis C infection <br> k. Recurrent sinusitis, urticaria, or angioedema within past 12 months prior to first study drug administration <br> l. Symptomatic overlap with JRC pollinosis requiring regular medications <br> m. Alcohol or drug abuse within 1 year before screening or current dependence