Recombinant Anti-human IL-17A/F Humanized Monoclonal Antibody Injection in the Treatment of Moderate-to-Severe Active AS

A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Clinical Study of Recombinant Anti-human IL-17A/F Humanized Monoclonal Antibody Injection in the Treatment of Moderate-to-Severe Active Ankylosing Spondylitis (AS)

This is a multicenter, randomized, double-blind, placebo-controlled, and parallel grouping study.

Study procedures: The screening period does not exceed 4 weeks, including 16 weeks for initial treatment, 28 weeks for maintenance treatment and 8 weeks for safety follow-up.

This is a multicenter, randomized, double-blind, placebo-controlled, and parallel grouping study.

Study procedures: The screening period does not exceed 4 weeks, including 16 weeks for initial treatment, 28 weeks for maintenance treatment and 8 weeks for safety follow-up.

Eligible patients are randomized at a ratio of 1:1 (stratification factors include: TNFi-incomplete response vs. TNFi-naive; weight ≥ 70 kg vs. weight < 70 kg) to the following 2 groups (Group 1 and Group 2).

During the initial treatment period, patients in Group 1 shall be treated with XKH004(160 mg, Q4W) by subcutaneous injection while those in Group 2 shall receive a placebo.

During the maintenance treatment period, starting at Week 16 (W16), patients in Group 1 shall maintain the original treatment (continue 160 mg, Q4W) and patients in Group 2 shall switch from placebo to XKH004 (160 mg, Q4W).

Patients who have received TNFi therapy in the initial treatment period will account for approximately 20% of the total sample size to make this population representative.

All patients will undergo the efficacy/safety/immunogenicity assessment procedures specified in the protocol at visit points such as W1, W2, W4 and every 4 weeks thereafter until W44 and W52.

Inclusion Criteria:

1. Male or female age ≥ 18;
2. Ability to understand and communicate with the Investigator, ability to comply with study requirements, and ability to sign the ICF prior to any study assessments;
3. Patients with active AS, who are eligible for the revised New York Criteria (1984) based on radiological evidence (i.e., x-ray) of readings by the study site and have a persistent symptom of chronic back pain for ≥3 months at the age of <45 years for the first onset of symptoms;
4. Patients who meet the criteria for moderate to severe activity defined as follows at screening and baseline visits: 1) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4; 2) Spinal pain ≥ 4 as measured by Question 2 of BASDAI; 3) Total back pain ≥ 4 as measured by Question 1 of Back Pain Intensity Assessment (NRS score);
5. Must have at least one of the following: Inadequate response, or intolerance, or contraindications to NSAIDs. Incomplete response to NSAIDs treatment, defined as no response after ≥ 4 weeks of continuous use of one NSAIDs of approved doses, or noresponse after use of more than 2 NSAIDs of approved doses for a cumulative duration of ≥ 4 weeks (≥ 2 weeks of use of either NSAIDs);
6. Patients who take NSAIDs or analgesics (including opioids with mild potency) or glucocorticoids orally shall maintain a stable dose for at least 2 weeks before randomization (oral dose of glucocorticoids shall be ≤ 10 mg/d of prednisone or equivalent);
7. Patients who have started taking methotrexate [≤ 25 mg/week] or sulfasalazine [≤ 3 g/day] or hydroxychloroquine [≤ 400 mg/day] at least 12 weeks before randomization, and whose dose and route of administration have been stable for at least 4 weeks before randomization can continue this drug (folic acid supplementation is recommended for patients taking MTX); if it is not in stable use, a washout period of at least 4 weeks is required;
8. TNFi-experienced patients must have had incomplete response to at least 12 weeks of treatment with the approved dose, or be intolerant to treatment;
9. Patients who agree to take effective contraception during the study and within 6 months after the last dose.

Exclusion Criteria:

1. Pregnant or lactating women, or women who plan to become pregnant during the study or within 6 months after the last dose;

2. Have participated in a clinical study of XKH004 and received at least 1 dose (including placebo);

3. Allergy to the ingredients or excipients of XKH004，allergy to biologics or allergic constitution;

4. Have participated in another drug clinical study within 3 months or at least 5 half-lives (whichever is longer) before screening, or participated in any medical device clinical study within 1 month before screening;

5. Complete rigidity of the spine or complete fusion of the bilateral sacroiliac joints;

6. Symptoms of fibromyalgia or osteoarthritis that may interfere with the efficacy evaluation as considered by the Investigator;

7. Acute uveitis anterior within 6 weeks before randomization;

8. Patients who have received more than 1 TNFi, or more than 2 non-TNF-α targeted biological immunomodulators, or any biological immunomodulators targeting IL-17 or IL-17R;

9. Patients who are taking or have taken prohibited drugs listed in Table 2, with the mandatory washout period not reached relative to randomization (baseline visit) (5 half-lives of washout for unlisted biologics/drugs);

10. Have received live vaccines (including attenuated vaccines) 2 months before randomization or are planned to receive live vaccines (including attenuated vaccines) during the study. Subjects who had received COVID-19 vaccine within 1 week prior to randomization;

11. Subjects with tuberculosis (TB) infection, or at high risk for acquired TB infection, or with present nontuberculous mycobacteria (NTMB) infection or previous NTMB infection;

    • Patients with latent tuberculosis (LTB) [IGRA positive and diagnosed as LTB by a TB specialist] who did not develop hepatotoxicity (alanine aminotransferase [ALT]/aspartate aminotransferase [AST] maintained ≤3 × ULN) before the first dose of the investigational drug after at least 4 weeks of appropriate anti-TB treatment may be rescreened once. Positive IGRA at the second screening is not an exclusion criterion.

      • Patients with a prior history of active TB involving any organ system were excluded, except in cases where they were deemed as fully recovered by local treatment guidelines after adequate treatment.

12. Patients with the following active infections or a history of infections:

1) Active infection (except for common cold) within 14 days before randomization; 2) Severe infection requiring hospitalization or intravenous infusion of anti-infective drugs within 2 months before randomization; 3) Previous opportunistic infections and recurrent or chronic infectious diseases. Opportunistic infections are infections caused by uncommon pathogens (e.g., Pneumocystis carinii, Cryptococcus and Candida) or unusually severe infections caused by common pathogens (e.g., Cytomegalovirus and Herpes Zoster Virus); 13. Acute or chronic viral hepatitis B or C, or HIV infection;

• Subjects with evidence or positive results for hepatitis B or C were excluded from the study. A positive hepatitis B (HBV) test is defined as a positive hepatitis B surface antigen (HBsAg+); or a positive anti-hepatitis B core antibody (HBcAb+) and an HBV-DNA test >ULN.

  **A positive hepatitis C (HCV) test is defined as a positive hepatitis C antibody (HCV-Ab) and a positive HCV-RNA by quantitative determination.

  14. Subjects with a history of lymphoproliferative diseases such as lymphoma or current signs and symptoms suggestive of lymphoproliferative diseases; 15. Subjects with any active malignant tumors or history of malignancy within 5 years before the screening visit, except for treated and considered cured skin squamous or basal cell carcinoma or cervical cancer in situ; 16. Inflammatory diseases other than AS (including but not limited to Rh arthritis, sarcoidosis (nodule disease), systemic lupus erythematosus or arthritis reactive). Patients diagnosed with Crohn's disease or colitis ulcerative or other IBD may also be included in this study if they have no active symptoms at screening or baseline; 17. Myocardial infarction or stroke within 6 months before screening; 18. Major surgery (including joint surgery) within 3 months before randomization, or surgery planned within 6 months after entering the study; 19. Patients with any uncontrolled, unstable or clinically significant progressive systemic diseases (i.e. cardiovascular, neurological, renal, hepatic, metabolic, gastrointestinal, hematological, immune, etc.) as judged by the Investigator during the study; 20. Subjects with the following laboratory abnormalities at screening, including: 1) ALT, AST or ALP ≥3.0 x ULN; or total bilirubin (TBIL) > ULN (TBIL ≥ 1.5 x ULN if known to have Gilbert's syndrome); 2) White blood cell (WBC) count <3000/μL; 3) Absolute neutrophil count <1500/μL; 4) Absolute lymphocyte count < 500/μL; 5) Hemoglobin (HGB) < 8.5 g/dL or 85 g/L; 6) Blood creatinine > 2 mg/dL (176.8 μmol/L); 7) Any other laboratory abnormalities that may preclude the patient from completing the study or interfere with the interpretation of the study results as judged by the Investigator;

• If the result of a single laboratory test at screening is suspected to be an error value, or a boundary value, or the value does not allow for the determination of a subject's eligibility for inclusion in the study, the test may be repeated once (only once) during screening to confirm the diagnosis. If the retest result still exceeds the threshold, the patient fails screening.

  21. Moderate to severe depressive disorder, i.e. Patient Health Questionnaire-9 (PHQ-9) score ≥ 15. The dosing of antidepressant drugs shall remain stable within 8 weeks before randomization; 22. History of attempted suicide, or suicidal ideation within 1 month prior to the screening visit, i.e., affirmative response ('Yes') to Question 4 or 5 of the C-SSRS (Columbia-Suicide Severity Rating Scale); 23. Patients with other physical or mental conditions that are not suitable for the study as judged by the Investigator.