Evaluation of NWRD08 for HPV-16 and/or HPV-18 Related Cervical HSIL

A Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Study to Evaluate the Efficacy and Safety of NWRD08 in Patients With HPV16/18-Positive Cervical High-Grade Squamous Intraepithelial Lesion (HSIL)

This is a randomized, double-blind, placebo controlled Phase 2 study to determine the efficacy and safety of NWRD08 administered by intramuscular (IM) injection followed by electroporation (EP) in adult women with histologically confirmed cervical high grade squamous intraepithelial lesion (HSIL) (cervical intraepithelial neoplasia grade 2 [CIN2] or grade 3 [CIN3]) associated with human papillomavirus (HPV) 16 and/or HPV18.

This is a Phase II, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy and safety of NWRD08 in patients with HPV16 and/or HPV18 positive cervical high-grade squamous intraepithelial lesion (HSIL). Eligible subjects will be randomized in a 2:2:1:1 ratio to four arms: 2 mg NWRD08, 4 mg NWRD08, and their respective matching placebo arms.

Participants will receive intramuscular injections of either NWRD08 or matching placebo at the corresponding dose at Week0, 4, 8, and 16 (a total of 4 doses).

Efficacy evaluations at Week 36 will include colposcopy, histopathological biopsy, cervical cytology, and HPV testing.

Inclusion Criteria:

Subjects had to meet all of the following inclusion criteria:

1. Aged 18 to 60 years, female.

2. Confirmed by the central laboratory, histopathology results demonstrated cervical HSIL with concurrent HPV16 and/or HPV18 positivity.

3. Colposcopy results during screening must meet the following criteria:

1. The colposcopy must be satisfactory, allowing clear visualization of the entire acetowhite area or the extent of suspected cervical intraepithelial neoplasia (CIN) lesions, including the upper border of the lesion.
2. If the upper border of the lesion is unclear, endocervical curettage (ECC) results must be negative.
3. The cervical lesion area must be less than 75% of the surface of the ectocervix.

4. Fully understand the study and voluntarily sign the informed consent form, able to communicate well with the investigator and complete all treatments, examinations, and visits as required by the study protocol. The informed consent form must be signed before performing any study-specific procedures.

5. At screening, the investigator judges the electrocardiogram (ECG) as normal or without clinically significant findings.

6. Normal function of major organs within 1 week before the first dose: Blood routine: Hemoglobin (Hb) ≥100 g/L; platelet count (PLT) ≥75×10⁹/L; white blood cell count (WBC) ≥3.0×10⁹/L; absolute neutrophil count (ANC) ≥1.5×10⁹/L.

Liver: Total bilirubin (TB) ≤1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤1.5 × ULN; plasma albumin ≥30 g/L.

Kidney: Serum creatinine (Scr) ≤1.5 × ULN, or creatinine clearance rate ≥60 mL/min (calculated by Cockcroft-Gault formula) (if serum creatinine >1.5 × ULN).

7. Women of childbearing potential must be willing to consistently and correctly use a contraceptive method with a failure rate of less than 1% per year from the time of signing the informed consent form until the end of the study. Acceptable methods include:

1. Hormonal contraceptives: Combined or progestin-only methods, including oral contraceptives, injections, implants, vaginal rings, or transdermal patches. Subjects with a history of hypercoagulable states (e.g., deep vein thrombosis, pulmonary embolism) must not use hormonal contraceptives.
2. Abstinence from penile-vaginal intercourse.
3. Intrauterine device (IUD) or intrauterine system (IUS).
4. Female subject's male partner sterilized for at least 6 months prior to study entry, and this male is the subject's sole sexual partner.
5. Condom use, with emergency contraception required in case of accidents such as slippage or breakage.
6. Postmenopausal patients (defined as at least 12 consecutive months of amenorrhea without alternative medical causes, with serum follicle-stimulating hormone levels within the laboratory reference range for postmenopausal women) or those sterilized for more than 12 months prior to screening may be considered not requiring contraception.

Exclusion Criteria:

Patients with any of the following were excluded from the study:

1. Any histopathologically confirmed cervical adenocarcinoma/adenocarcinoma in situ (AIS), high-grade vulvar, vaginal, or anal intraepithelial lesions or invasive cancer.

2. Female participants who are pregnant, breastfeeding, or planning to become pregnant during the study.

3. Administration of any live vaccine within 4 weeks prior to the first dose and/or any non-live vaccine within 2 weeks prior to the first dose.

4. Use of blood or blood-related products (including immunoglobulins) within 3 months prior to the first dose or planned use during the study.

5. Prior receipt of therapeutic HPV vaccines (excluding prophylactic HPV vaccines) before screening.

6. Treatment for cervical HSIL within 4 weeks prior to the first dose.

7. Presence of metal implants or implantable medical devices within the electroporation area.

8. Participation in another clinical trial within 30 days prior to screening or being in the follow-up period of another clinical trial.

9. Continuous (for more than 1 week) systemic treatment with corticosteroids (at a dose equivalent to >10 mg/day prednisone or equivalent doses of other corticosteroids) or other immunosuppressive drugs within 30 days prior to screening, with the following exceptions.

   1. Inhaled, ophthalmic, or topical use of corticosteroids at doses ≤10 mg/day prednisone or equivalent is permitted.
   2. Physiological corticosteroid replacement therapy at doses ≤10 mg/day prednisone or equivalent is permitted.

10. History of immunodeficiency or autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, etc.) or current active autoimmune diseases requiring systemic treatment (e.g., use of disease-modifying drugs, corticosteroids, or immunosuppressive drugs).

11. Current or anticipated use of disease-modifying antirheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic disease-modifying drugs (e.g., infliximab, adalimumab, etanercept) during the study.

12. Continuous (for more than 1 week) use of immunosuppressants such as cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, and antilymphocyte globulin, as well as other inhibitors affecting immune function (e.g., IL-6 inhibitors, TNF inhibitors, IL-17/23 inhibitors, JAK inhibitors) within 30 days prior to screening.

13. History of solid organ or bone marrow transplantation.

14. Active infections requiring systemic treatment (including active tuberculosis, active Treponema pallidum infection, and bacterial, fungal, or viral infections requiring systemic therapy).

15. Positive test results for any of the following: hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), Treponema pallidum antibody (TP-Ab), or human immunodeficiency virus antibody (anti-HIV).

16. Participants with active herpes zoster virus infection.

17. Participants with severe dysfunction of other organs or cardiopulmonary diseases.

18. Epilepsy requiring medication (e.g., steroids or antiepileptic drugs).

19. History or current diagnosis of malignancy.

20. History of severe allergies, allergic diseases, or allergic constitution, meeting any of these criteria.

21. Evidence or history of clinically significant cardiac disease, including but not limited to:

1) Congestive heart failure (NYHA Class >2). 2) Unstable angina. 3) Myocardial infarction within the past 3 months. 4) Any supraventricular or ventricular arrhythmia requiring treatment or intervention.

5) QTc interval ≥470 ms. 6) Poorly controlled hypertension (defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg while on antihypertensive medication).

22. Known psychiatric or substance abuse disorders that may interfere with the subject's ability to comply with study requirements.

23. History or current evidence of any condition, treatment, laboratory abnormality, or other circumstance that may increase the risk associated with study participation or study intervention administration, or may interfere with the interpretation of study results, and which, in the investigator's judgment, makes the subject unsuitable for enrollment in this study.