Phase 1 Study of HBI0101 CAR-T in Refractory B-Cell Autoimmune Diseases

A Phase 1 Dose Escalation and Safety Study of HBI0101 CART in B-cell Mediated Refractory Autoimmune Diseases

A Phase 1 study of HBI0101 BCMA-CART in B-Cell Mediated Autoimmune Rheumatic Diseases. The goal of the study is evaluation of safety and identification of the maximum HBI0101 CART dose that may be administered safely to patients with B-cell mediated autoimmune disease.

Up to 120 subjects with B-cell mediated autoimmune rheumatic diseases will be enrolled in a single-arm, open-label, single-site Phase 1 study.

The study includes 2 parts. The first Part A is an establishment of the safety profile followed by a dose ranging, maximum tolerated dose (MTD) study and the second Part B is an extension phase to further evaluate safety at the selected safe dose.

Eligible subjects will undergo leukapheresis procedure to provide starting material for manufacturing of HBI0101 CART investigational product. Each eligible subject will receive a single dose of HBI0101 CART cells. Prior to administration of HBI0101 CART, the study subjects will undergo lymphodepletion. Following administration of HBI0101 CART the subjects will be hospitalized for several days and then will return for routine follow-up periodical visits until 48 months after infusion.

Inclusion Criteria:

1. Age: 18~80 years old; for patients aged ≥ 75 years, geriatric assessment and endorsement are required;

2. Diagnosis of B-cell mediated ARDs listed below:

   SLE patients: individuals diagnosed with SLE according to American College of Rheumatology (ACR) and/or Systemic lupus international collaborating clinics (SLICC) classification criteria, who have severe and progressive disease course reflected by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) score of 8 or more. Eligible patients must have failed to at least one of the conventional DMARDs (azathioprine, methotrexate, mycophenolate mofetil or cyclophosphamide), one of the calcineurin inhibitors (tacrolimus or cyclosporin) and one of the biologic agents (belimumab, rituximab or aniflorumab), each administered for a minimum of 3 months, or have a contraindication to, or have experienced toxicity from, any therapy within these categories. The failure is defined as:

   • lack of response per SLEDAI-2k (<4 points reduction from baseline) or no improvement in BILAG domains, or
   • disease flare per SLEDAI-2k (≥4 points increase from baseline) or new BILAG A or ≥2 new BILAG B organ scores, or intolerance or discontinuation due to adverse effects.

   SSc patients: Patients who were diagnosed with diffuse or limited cutaneous SSc according to the College of Rheumatology/European Alliance of Associations for Rheumatology (ACR-EULAR) classification criteria, with severe or rapidly progressive disease Eligible patients must meet any of the following criteria:

   • Progression of skin thickening ≥ 12 over the past 6 months or Modified Rodnan skin score (mRSS) ≥15
   • Any Medsger Disease Severity Score grade 3-4 in one major organ or grade ≥2 in two organs
   • Progressive interstitial lung disease evidenced by HRCT or FVC <80% or DLCO <80%, or evidence of pulmonary function decline, defined as an absolute FVC decline of ≥ 10% , or FVC decline of 5% -9% combined with DLCO 15%.
   • Other internal organ involvement.

   Eligible patients must have failed to at least two state-of-the-art immunosuppressive therapies including MTX, MMF, cyclophosphamide, azathioprine, nintedanib, tocilizumab or rituximab; each therapy must have been administered for a minimum of 3 months, unless discontinued due to a contraindication or toxicity. The failure is defined as:

   • lack of response in skin per mRSS (≤20% relative and ≤5 point absolute reduction from baseline) or no clinically meaningful improvement in FVC, DLCO, or other organ involved assessed by Medsger DSS, or
   • disease flare in skin per mRSS (increase in mRSS ≥20% and ≥5 points from baseline) or decline in FVC ≥10% predicted or in DLCO ≥15% predicted from baseline, other major SSc complication, or
   • intolerance or discontinuation due to adverse effects

   IIM, including dermatomyositis, anti-synthetase syndrome, immune mediated necrotizing myopathy, and polymyositis: patients must be diagnosed with IIM according to the 2017 ACR/EULAR Classification Criteria for idiopathic inflammatory myopathies.

   Eligible patients must have active disease, defined by at least one of the following:

   • CPK ≥4xULN
   • Loss of muscle strength in the weakest muscle group for less than 80% per MMT8
   • Evidence on MRI of active myositis within last 6 months
   • Evidence on EMG of active myositis within last 6 months
   • Muscle biopsy evidence of active myositis within last 6 months

   Only patients with refractory disease will be recruited, defined as previous failure to (1) at least two of five non-glucocorticoids immunosuppressive therapies and (2) either rituximab or IVIG, each administered for a minimum of 3 months, or have a contraindication to, or have experienced toxicity from, any therapy within these categories. The five non-glucocorticoids therapies considered are azathioprine, MTX, MMF, IVIG, and rituximab The failure is defined as:

   • lack of response in muscle strength per MMT-8 or CPK (<20% relative improvement) or per MRI or
   • disease flare in muscle strength per MMT-8 (≥30% decline) or CPK (≥30% rise) or objective worsening of other organ involvement per Myositis Disease Activity Assessment Tool or
   • intolerance or discontinuation due to adverse effects

   RA patients: Seropositive RA patients (positive for anti-cyclic citrullinated peptide and rheumatoid factor), diagnosed according to the 2010 ACR/EULAR classification criteria.

   Eligible patients must exhibit high disease activity (DAS28CRP ≥5.1), and be resistant to at least four conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARD) groups.

   Each patient must have previously received at least one medication from each of the mentioned groups, including

   • JAK-STAT inhibitors
   • Anti-TNF agents
   • Anti-IL6 drugs
   • Anti-CTLA4-Ig treatments, each administered for a minimum of 3 months, or have a contraindication to, or have experienced toxicity from, any therapy within these categories

   Drug resistance is defined as:

   • Inadequate clinical response measured by composite score DAS28CRP (> 3.6) or failure to reach ACR20 or
   • Disease progression measured by DAS28CRP (≥20% increase) or radiographic progression or
   • Intolerance or discontinuation due to adverse effects

   NMOSD: Patients must be diagnosis of AQP4-IgG-positive NMOSD based on the 2015 International Panel for NMOSD Diagnosis (IPND) criteria (Wingerchuk et al., 2015).

   Eligible patients must have experienced at least two relapses in the past 24 months, with at least one occurring in the preceding 12 months before screening Each patients must have previously received with inadequate disease control (one or more clinical attacks, with new MRI activity, despite adequate treatment dosing) at least one immunosuppressant for at least 6 months (azathioprine or mycophenolate mofetil) and/or Rituximab for at least 3 months and/or a targeted therapy (eculizumab, inebilizumab, or satralizumab) or must have a contraindication to such treatment.

   MS patients: must have confirmed history of diagnosis of primary progressive or secondary progressive MS .

   Eligible patients must have: Expanded Disability Status Scale (EDSS) score between 3.0 and 8.5 and evidence of disease activity, defined by either clinical progression and/or radiological finding on MRI, such as new, enhancing or enlarging lesions in the last 12 months.

   Eligible patient must have previously received at least one high efficacy drug and have been offered standard treatments and have experienced disease progression or lack of efficacy despite at least six months of treatment. These will include clinical activity (new relapse[s]), radiological activity (new or enlarging T2 lesions and/or gadolinium-enhancing lesions on MRI), or confirmed disability progression (an increase in least 1 point on the EDSS sustained for ≥6 months).

   Eligible patient must have history of treatment with anti-CD20 mAb with continuing evidence of worsening physical disability over a period of ≥6 months, with documented clinical disability progression within the year prior to inclusion, irrespective to concurrent MRI activity.

   MG patients must meet all the following criteria:

   - Confirmed diagnosis of generalized MG, supported by positive autoantibodies (anti-AChR, anti-MuSK).

   Disease Severity:

   • Myasthenia Gravis Activities of Daily Living (MG-ADL) score of ≥6, with ocular symptoms constituting less than 50% of the total score.
   • Myasthenia Gravis Foundation of America (MGFA) clinical classification of II to IV.

   Eligible patients must have Refractory Status and meet at least one of the following criteria:

   • No improvement or worsening myasthenic symptoms, with failure to achieve minimal manifestation status or meaningful improvement in MGFA class or MG-ADL score, or recurrent myasthenic exacerbations despite adequate immunosuppressive or immunomodulatory therapy for at least 6 months for all therapies and 3 months for B cell depletion therapy
   • Improvement in Post-Intervention Status (PIS), but with an MG-ADL score ≥6 persisting for at least 4 months.
   • Remission or improvement in PIS, but with ≥1 episode of disease exacerbation (MG-ADL ≥6) per year during tapering of immunotherapy medications.
   • After experiencing a myasthenic crisis, patients who undergo multiple immunotherapies (e.g., intravenous immunoglobulin, plasma exchange, high-dose intravenous methylprednisolone), thymectomy, and active infection control but still cannot be weaned off the ventilator due to MG-induced respiratory muscle weakness for more than 14 days.

   Each patient must receive stable doses of medication prior to enrollment.

   Refractory APLA patients: must have confirmed history of APLA, based on Sydney 2006 or ACR/EULAR 2023 criteria

   - Eligible patients must have medium to high-titer antiphospholipid antibodies, documented repeatedly (≥2 tests spanning 12 weeks) Eligible patients must have refractory disease: persistent or recurrent arterial thrombosis, venous thrombosis or diffuse alveolar hemorrhage despite conventional therapy with stable treatment with vitamin K antagonist anticoagulation (maintained at therapeutic stable dose keeping INR consistently within target range) and immunosuppression treatment including glucocorticoid, rituximab and Plaquenil

3. AST/ALT below 5 times the upper limit of normal, blood bilirubin below 3 times the upper limit of normal ;

4. Cardiopulmonary function is basically normal, echocardiography indicates that the ejection fraction is >45%, normal to mild pulmonary hypertension, and the oxygen saturation is above 93% in the resting state without oxygen;

5. No obvious active infection;

6. There are no contraindications for blood collection;

7. Women of child-bearing potential (WCBP), defined as a sexually mature woman who has not undergone a hysterectomy or tubal ligation or who has not been naturally postmenopausal for at least 24 consecutive months, must have a negative serum pregnancy test prior to treatment. All sexually active WCBP and all sexually active male subjects must agree to use effective methods of birth control throughout the study;

8. Voluntary participation and informed consent signed by the patient or his/her legal/authorized representative.

9. Ability and willingness to adhere to the study visit schedule and all protocol requirements

Exclusion Criteria

1. CNS disease- History of CNS or spinal cord tumor, metabolic or infectious cause of myelopathy, genetically inherited progressive CNS disorder, sarcoidosis, non-autoimmune progressive neurologic condition or PML
2. Abnormal liver function: aspartate transaminase (AST) or alanine transaminase (ALT) or glutamyl transpeptidase (GGT) or alkaline phosphatase (ALP) detection value is greater than 5 times the upper limit of normal (ULN); or total bilirubin test value greater than 3 times the upper limit of normal (ULN); Exceptional: liver function disturbance due to myositis.
3. Cardiovascular disease: Unstable angina or myocardial infarction or coronary artery bypass graft (CABG) within 6 months prior to leukapheresis/ moderate- severe pulmonary hypertension/ severe arrhythmia (ventricular tachycardia, ventricular fibrillation, high grade ventricular block) in the past 6 months; New York heart function class (NYHA) class III- Level IV or LVEF<45%.
4. Lung disease: patients with chronic lung disease with any of the following: * Oxygen saturation (SpO2) < 90% on room air * FVC≤45% of predicted or DLCO≤40% of predicted at screening. * Evidence of pulmonary hypertension as defined as estimated RVSP> 50 mmHg.
5. Muscle disease: evidence of any of the following: * Severe proximal muscle atrophy of upper or lower extremity on MRI or clinical examination. *Finding of muscular inflammation or myopathy other than the indication, such as inclusion body myositis (IBM), or cancer-associated myositis (myositis diagnosed within 2 years of cancer).
6. Other uncontrolled diseases: acute diseases (such as acute pneumonia or other infection, pulmonary embolism, diabetic ketoacidosis, acute pancreatitis, etc.) that are clinically unstable or have not been effectively controlled and are not related to indicated autoimmune diseases which in the judgment of the investigator may confound study results or place subjects at undue risk.
7. Biologics therapy: Received rituximab within 4 months of expected CAR T treatment: No plasma exchange or immunoglobulin treatment within 4 weeks prior to screening. MS patients: No high dose corticosteroid treatment in the 30 days prior to enrollment; see also section 9.1 for the list of restrictions.
8. Participated in any clinical study within 3 months prior to enrollment, or participate in other clinical investigations during the study period.
9. Previous or concurrent malignancy with the following exceptions: Adequately treated basal cell or squamous cell carcinoma, in situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to screening. A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 5 years prior to screening.
10. Transplantation: History of vital organ transplantation (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/or bone marrow transplantation.
11. Disease-specific criteria: MS/NMO patients: No disease relapse in the 30 days prior to enrollment
12. Known HIV positive status.
13. Active hepatitis B or C infection.
14. Active CMV infection
15. Pregnant or lactating women.
16. Inability to understand or follow the research protocol subject requirements.
17. Have any other clinically significant disease history or current disease that, in the judgment of the research physician, may pose a risk to the safety of the subjects, or interfere with the completion of the research procedure and the evaluation of safety and efficacy