Retrospective registration

Study to evaluate Cizutamig in patients with immunoglobulin A nephropathy

An Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Preliminary Clinical Activity of Cizutamig in Patients with Immunoglobulin A Nephropathy

Jicheng Lv 

Jicheng Lv 

No. 8, Xishiku Street, Xicheng District, Beijing

Peking University First Hospital,No.8 Xi Shi Ku Da Jie, Beijing, P R China

Peking University First Hospital

Peking University First Hospital

Yes

Peking University First Hospital Ethics Committee

Ke Wang

Peking University First Hospital,No.8 Xi Shi Ku Da Jie, Beijing, P R China

Peking University First Hospital

Peking University First Hospital,No.8 Xi Shi Ku Da Jie, Beijing, P R China

Candid Therapeutics

Immunoglobulin A nephropath,IgAN

Interventional study

N/A

Single arm 

Primary objective: To evaluate the safety and tolerability of cizutamig in patients with IgA nephropathy. Secondary objective: To characterize the PK of cizutamig in patients with IgA nephropathy. Exploratory: To investigate the preliminary clinical activity of cizutamig over time in patients with IgA nephropathy, To assess disease-related biomarkers in patients with IgA nephropathy, To evaluate the PD effects of cizutamig in patients with IgA nephropathy, To assess the immunogenicity of cizutamig in patients with IgA Nephropathy, To assess patient-reported outcomes in patients with IgA nephropathy, To evaluate the relationships between cizutamig PK/exposure, PD biomarkers, safety, and clinical activity, To investigate the effect of cizutamig on affected tissues (kidney biopsy) in patients with IgA nephropathy.

1. 18 to 75 years of age at the time of signing the informed consent form (ICF); 2. Biopsy-confirmed IgAN as specified in the protocol; 24-hour urine protein excretion >=1.0 g/day or 24-hour urine protein to creatinine ratio (uPCR) >=0.75 g/g; 3. Angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker inhibitor (ARBi) started >=12 weeks before Screening unless documented intolerance. Patients must be on maximum or maximally tolerated dose (per investigator discretion) >=4 weeks prior to Screening. 4. A patient who is undergoing treatment with a SGLT2 inhibitor, endothelin A receptor antagonist (ETA), and/or hydroxychloroquine must be on a stable dose for >=12 weeks prior to Screening and agree not to start or modify the dose of any of these medications while on study; 5. At least 3 months before screening, patients have a poor response (defined as lack of clinical efficacy or intolerance) to one or more of the following treatments as judged by the investigator: ACEi/ARBi, SGLT2i, ETAs, glucocorticoids or immunosuppressive therapy (such as mycophenolate sodium, cyclophosphamide, etc.), or new marketed drugs such as tetaceptep and budesonide enteric-coated capsules; 6. eGFR determined by Chronic Kidney Disease Epidemiology Collaboration equation >30 mL/min/1.73m^2;

1.Inadequate clinical laboratory parameters at Screening: a. Peripheral B cells <=15 cells/mL b. IgG < 600 mg/dL c. Hematology i. Absolute neutrophil count <=1.0 × 10^9/L (<=1.0 × 10^3/uL or <=1.0 GI/L) ii. Platelet count <= 75 × 10^9/L (<= 75 × 10^3/μL or <= 75 GI/L) iii. Hemoglobin level <=90 g/L iv. Lymphocyte count < 500 cells/μL (< 0.50 × 10^3/μL or < 0.50 GI/L) d. Chemistry i. ALT and AST levels >=2.0 × ULN ii. Total bilirubin level and alkaline phosphatase > 2 × ULN (or total bilirubin >2.5 × ULN for patients with Gilbert’s syndrome); 2.Patients will be excluded if they are known to have any of the following: a. Any known human immunodeficiency virus (HIV) infection or positive HIV 1 or 2 at Screening b. Positive hepatitis B surface antigen. Patients with positive hepatitis B core antibody must be tested for hepatitis B virus (HBV)-DNA to determine their status; if HBV-DNA is positive, patients should be excluded; if HBV-DNA is negative, the patient may participate in the study. c. Patients with positive hepatitis C virus (HCV) antibody must be tested for HCV ribonucleic acid (RNA); if HCV RNA is also positive, patients should be excluded; if HCV RNA is negative, the patient may participate in the study d. Active tuberculosis (TB) or lack of documentation of completion of treatment for active TB. If the TB test (QuantiFERON? Gold Test or T-SPOT) is positive, patients may have a chest X-ray to rule out latent or active TB if required by local guidelines/standard of care. If the test result is positive and a chest X-ray is negative for active TB, the patient will be allowed to enroll with documentation of completed treatment for active TB or latent TB. ? If the test result is indeterminant, the site should repeat the test. ? A positive test result or 2 successive indeterminant results should be considered as a positive result. ? An indeterminant test result followed by a negative test result should be considered as a negative test result. Patients with latent TB ? With documented completion of anti-TB therapy prior to study participation may enroll in the study. ? Without documented treatment, patients will be considered a screen failure.e. Active infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, or respiratory syncytial virus defined by positive screening test. The patient may be enrolled if either asymptomatic, or afebrile off antipyretics and improving symptoms, for at least 1 week prior to first dose of cizutamig. f. Patient has symptoms and/or signs of confirmed or suspected infection, or fever of 38°C or above, or receiving antimicrobials 1 week prior to first dose of cizutamig. g. Has had any of the following types of infection any time between 3 months prior to Screening and first dose of cizutamig: i. Serious (requiring hospitalization or systemic use of antimicrobials for >= 2 weeks) ii. Opportunistic (including but not limited to pneumocystis jirovecii, cytomegalovirus, toxoplasmosis, histoplasmosis, herpes zoster, as defined in Winthrop et al 2015) iii. Note: Herpes zoster is considered active and ongoing until all vesicles are dry and crusted over. iv. Recurring (including, but not limited to, herpes simplex, herpes zoster, recurring cellulitis, chronic osteomyelitis) Note: Patients with recurrent nonserious infections (eg, urinary tract infection) may be enrolled at the discretion of the investigator if it does not place patients at an increased risk of complications. 3.Receipt of or inability to discontinue any of the following excluded therapies (except dosing if indicated as recommended acute management of CRS or ICANS:a. Any of the following less than 4 weeks prior to Screening: i. Janus kinase (JAK) inhibitors, Bruton tyrosine kinase (BTK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors: eg, but not limited to tofacitinib, upadacitinib, baricitinib, deucravacitinib ii. Complement system inhibitors: eg, but not limited to eculizumab, ravulizumab, zilucoplan, iptacopan iii. Plasmapheresis or IVIg iv. Any dose of systemic corticosteroids other than budesonide b. Any of the following less than 12 weeks prior to Screening i. Anti-metabolites: eg, but not limited to mycophenolate mofetil (MMF), mycophenolate sodium, azathioprine ii. Alkylating agent: eg, but not limited to cyclophosphamide iii. Calcineurin inhibitors: eg, but not limited to cyclosporine, tacrolimus, voclosporin iv. Traditional Chinese Medicines and proprietary Chinese medicines for autoimmune disease: eg, but not limited to Tripterygium wilfordii, polyglycosides, and total glucosides of paeony v. Tumor necrosis factor (TNF) inhibitors: eg, but not limited to infliximab, adalimumab vi. Anti-cytokine (IL-1, IL-6, IL-17, IL-12/23): eg, but not limited to anakinra, tocilizumab, secukinumab, ustekinumab, risankizumab vii. Thalidomide or thalidomide derivatives viii. Neonatal fragment crystallizable receptor (FcRn) inhibitors: eg, but not limited to efgartigimod, rozanolixizumab c. Any of the following less than 24 weeks prior to Screening:i. Any dose of enteric-release budesonide ii. Anti-BAFF, anti-APRIL, and/or anti-transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI): eg, but not limited to belimumab, telitacicept iii. CD19 inhibitor: eg, but not limited to inebilizumab iv. CD20 inhibitors: eg, but not limited to rituximab, ocrelizumab, obinutuzumab v. CD38 inhibitors: eg, but not limited to isatuximab, daratumumab vi. Other cell depleting therapy, anti-CD3, anti-CD4, anti-CD5 d. CAR-T or TCE therapy directed at any antigen or BCMA-targeted therapy at any time e. Any other approved immunosuppressive medication not listed within 12 weeks or 5 half-lives prior to Screening, whichever is longer, unless approved by the medical monitor f. Participation of an investigational study involving non-biologic therapy within 4 weeks or 5 half-lives of the investigational product (IP) (whichever is greater) prior to Screening g. Participation of an investigational study involving biologic therapy within 12 weeks or 5 half-lives of the IP (whichever is greater) prior to Screening; 4.Receipt of live vaccine within 4 weeks prior to Screening; 5.Patient has kidney biopsy mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis (MEST) or mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, crescents (MEST-C) score of T2 from the Oxford IgAN classification schema. If MEST-scoring was not performed, the presence of >50% tubular atrophy/interstitial fibrosis is exclusionary. 6.Rapidly progressing glomerulonephritis with eGFR reduction ≥50% within 12 weeks of Screening; 7.Secondary IgAN (eg, chronic liver disease, celiac disease, HIV); 8.History of IgA vasculitis; 9.Presence of any concomitant autoimmune disease (including overlap syndrome) other than disease being studied and requires systemic treatment. Note: concomitant Sjogren’s syndrome is allowed. 10.History of progressive multifocal leukoencephalopathy; 11.History of primary immunodeficiency (eg, hypogammaglobulinemia) or a hereditary deficiency of the complement system; 12.Central nervous system (CNS) disease: a. Any history of neurologic disorder the investigator considers would increase the risk for the patient (including but not limited to stroke, epilepsy, CNS vasculitis, multiple sclerosis, optic neuritis, transverse myelitis, or acute or chronic demyelinating polyneuropathy, or neurodegenerative disease); 13.Have presence of 1 or more significant concurrent medical conditions per investigator judgment, including but not limited to the following: a. Diabetes b. Poorly controlled hypertension; c. Severe chronic pulmonary disease (eg, requiring oxygen therapy) or in respiratory failure d. Severe or uncontrolled cardiovascular disease requiring treatment, including any of the following: i. New York Heart Association Class III or IV congestive heart failure within 12 months prior to Screening; ii. Unstable angina within 12 months prior to Screening (even if controlled with medication); iii. Myocardial infarction within 12 months prior to Screening; iv. Pericardial tamponade within 6 months prior to Screening; v. Mean electrocardiogram (ECG) QT interval corrected by Fridericia’s formula (QTcF) >480 ms on single ECG at Screening; vi. Serious arrhythmia requiring medical treatment (excluding atrial fibrillation or paroxysmal supraventricular tachycardia);vii. Patients with pacemaker placement and condition is not stable at the discretion of the investigator. 14.Have a diagnosis or history of malignant disease within 5 years prior to Screening, with the exceptions of: a. Basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease, or b. Adequately treated cervical carcinoma in situ, with no evidence of recurrence within the 5 years prior to Screening. 15.Serious mental illness, alcohol or drug abuse, dementia, or any other condition that would impair the patient’s ability to receive the planned treatment or to understand informed consent at the study site as determined by local practice; 16.Inability to comply with protocol-mandated requirements; 17.History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins) or any constituents of cizutamig; 18.History of severe allergic or anaphylactic reactions, or intolerance to required antimicrobial prophylaxis: acyclovir/valacyclovir for herpes simplex virus/varicella zoster virus and trimethoprim-sulfamethoxazole/dapsone/atovaquone for Pneumocystis jirovecii pneumonia); 19.History of or planned organ transplant and/or autologous or allogeneic hematopoietic stem cell transplantation for the duration of the study (from Screening to patient’s last visit); or a corneal transplant within 12 weeks prior to Screening; 20.Major surgery requiring use of general anesthesia within 12 weeks prior to Screening or planned or expected major surgery during the study period (from Screening to patient’s last visit); 21.Tonsillectomy within 24 weeks prior to Screening; 22.Any serious medical condition or abnormality on clinical laboratory testing that, in the investigator’s or medical monitor’s judgment, precludes the patient’s safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results; 23.Women of childbearing potential (WOCBP) who:a. Are pregnant or breastfeeding b. Do not agree to the following starting at the time of informed consent and continuing until at least 12 weeks after the last dose of study drug: i. Refrain from donating ova ii. Using 2 forms of highly effective contraceptive methods (Section 10.4.2), including total abstinence (if consistent with the patient’s preferred usual lifestyle). Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. Note: If a female patient is using oral contraceptives, this medication should be stable for at least 12 weeks before the first dose ofcizutamig as cytokines induced by cizutamig may potentiate the adverse reactions of oral contraceptives. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity where pregnancy can occur to decrease the risk for inclusion of a patient with an early undetected pregnancy. 24.Sexually active male patients who do not agree to the following starting at the time of informed consent and continuing until at least 12 weeks after the last dose of study drug: a. Refrain from donating semen b. If sexual partners are WOCBP (defined in Section 10.4.1), use 2 forms of highly effective contraceptive methods (Section 10.4.2), including total abstinence (if consistent with the patient’s preferred usual lifestyle). Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception; 25.Individuals considered to be part of a vulnerable population (eg, incarceration).

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The result data will be uploaded to the registration agency for sharing in accordance with the law on Jan2027.

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