A Phase 1 Study of Prulacabtagene Leucel (Prula-cel, Formerly ADI-001) in Autoimmune Disease

For Cohort 1: Subjects with LN:

• Clinical diagnosis of systemic lupus erythematosus (SLE) per 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria (Aringer 2019).
• Have unequivocally positive anti-nuclear antibody (ANA) test results defined as an ANA titer ≥ 1:80 (based on Hep-2 immunofluorescence assay or equivalence by enzyme-linked immunosorbent assay (ELISA), and/or positive anti-dsDNA (≥ 30 IU/mL based on ELISA.
• Historical ANA and anti-dsDNA results (defined as within the 2 years prior to enrollment) may be used for eligibility. During screening a specimen will be collected.
• Active kidney disease with biopsy-proven active LN Class III or IV (coexistent class V permitted) (per 2018 International Society of Nephrology [ISN]/Renal Pathology Society [RPS] criteria); biopsy should be performed within 6 months before enrolling in the study.
• Proteinuria (or urine protein creatinine ratio [UPCR]) > 1g / 24 hours.
• LN showing inadequate response to current standard of care, defined per 2023 EULAR/ERA-EDTA recommendations as:
• Failure following at least two lines of standard of care therapies for LN (including at least one being mycophenolate or cyclophosphamide or a biologic at doses and durations of treatment per local standard of care.
• Adequate renal function, including:
• Estimated creatinine clearance ≥ 45 mL/min as calculated using the method standard for the institution, or equivalent estimated glomerular filtration rate (eGFR) determination.
• Proteinuria ≤ 8 g/24 h or UPCR ≤ 8 in a spot urine.
• Adequate pulmonary function defined saturated oxygen (SpO2) ≥ 93% on room air.

For Cohort 1: Subjects with SLE with Extrarenal Involvement

• Clinical diagnosis of systemic lupus erythematosus (SLE) per 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria (Aringer 2019).
• Positive anti-nuclear antibody (ANA) test results and/or a positive anti-dsDNA and/or anti-Smith antibodies above the ULN.
• Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≥ 8 with a clinical SLEDAI-2K score (SLEDAI-2K not including points for anti-dsDNA and/or low complement) ≥ 6 and/or ≥ 1 British Isles Lupus Assessment Group (BILAG)-2004 Category A AND physician's global assessment of SLE disease activity score ≥ 1.5 (on a 0 to 3 visual analogue scale).
• Inadequate response in terms of active disease despite treatment with current standard of care for SLE including corticosteroids and at least 2 SLE therapy.
• Estimated creatinine clearance ≥ 60 mL/min AND Proteinuria ≤ 1 g/24 h or UPCR ≤ 1 in a spot urine.
• Adequate pulmonary function defined saturated oxygen (SpO2) ≥ 93% on room air.

For Cohort 2: Subjects with SSc

• Disease duration ≤ 6 years (from onset of first non-Raynaud manifestation)
• Subjects with diffuse cutaneous SSc, must meet both of the following criteria: mRSS ≥ 15 at screening AND one of the following within 6 months prior to screening: (i) mRSS increase of ≥ 3 units in the total mRSS, OR (ii) Involvement of 1 new body area, OR (iii) Increase in mRSS ≥ 2 units in 1 body area
• Subjects with diffuse or limited cutaneous SSc and ILD must meet both of the following criteria: ILD, defined as evidence of fibrosis on HRCT within 4 months of screening AND Progression of ILD by FVC or HRCT in previous 24 months:
• Relative decline in FVC of 10% predicted or more OR 5% to \<10% and worsening respiratory symptoms OR relative decline in FVC of 5% to \<10% and any increased extent of fibrosis on HRCT OR Worsening of respiratory symptoms and any increased extent of fibrosis on HRCT.
• Inadequate response to at least one (1) of the following medications administered at the appropriate dose for at least 3 months within 24 months prior to screening: mycophenolate mofetil or its derivatives, cyclophosphamide, tocilizumab, rituximab, azathioprine, methotrexate.
• Adequate pulmonary function, defined as Baseline FVC ≥ 45% predicted AND Baseline diffusing capacity of the lung for carbon monoxide (DLCO), corrected for hemoglobin, ≥ 40% predicted.
• Adequate renal function, defined as Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 as estimated by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Inker 2021).

For Cohort 3: Subjects with AAV

• Diagnosis of AAV defined as either GPA or MPA according to the 2012 Chapel Hill Consensus Conference definitions:
• Positive for PR3-ANCA or MPO-ANCA
• Relapsed or refractory AAV:
• Relapsed following remission after at least 1 standard-of-care immunosuppressive regimen in addition to steroids.
• Refractory after at least 1 immunosuppressive regimen in addition to steroids administered for at least 3 months.
• Severe disease (i.e., presence of one or more major AAV sign or symptom per the BVAS or ≥ 3 minor items, or at least the 2 renal items of proteinuria and hematuria due to vasculitis)
• Adequate renal function: CrCl ≥ 30 mL/min AND Proteinuria ≤ 8 g/24 hour or UPCR ≤ 8 in a spot urine.
• Adequate pulmonary function defined as saturated oxygen (SpO2) ≥ 93% on room air.

For Cohort 4: Subjects with Idiopathic Inflammatory Myopathies

• Meets the 2017 ACR/EULAR classification criteria (Lundberg 2017) for probable/definite IIM
• Muscle weakness defined as Manual Muscle Testing (MMT)-8 score \< 142/150, and ≥ 2 of the following abnormal core set measures: (i) Patient global assessment VAS ≥ 2 cm (on 10-cm VAS), (ii) Physician global assessment VAS ≥ 2 cm (10-cm VAS), (iii) HAQ-DI > 0.25 , (iv) Extra-muscular global activity VAS ≥ 2 cm (10-cm VAS)
• Active disease defined as ≥ 1 of the following signs in the past 4 months: a) Elevated serum CK or aldolase levels ≥ 3 times ULN; b) Active myositis by muscle biopsy, muscle MRI, or EMG; c) Active DM rash and CDASI >14; d) Active interstitial lung disease
• Positivity for ≥ 1 myositis-specific antibody or myositis-associated antibody at screening
• Inadequate response or intolerance/contraindication to glucocorticoids and to ≥ 2 immunosuppressants for 3 months of an immunosuppressive medication.
• Adequate renal function defined as estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 as estimated by the 2021 CKD-EPI equation.

For Cohort 4: Subjects with Stiff Person Syndrome

• Meets the 2009 criteria for diagnosis of stiff person syndrome (SPS) (Dalakas 2009): (a) Stiffness of the axial muscles, particularly the abdominal and thoraco-lumbar paraspinals, leading to hyperlordosis; (b) Superimposed painful spasms triggered by unexpected tactile or auditory stimuli; (c) Severe anxiety with task-specific phobias especially in anticipation of physically challenging tasks; (d) Electromyographic evidence of continuous motor unit activity of agonist and antagonist muscles; (e) Absence of other neurological findings that may suggest an alternative diagnosis; (f) Highly positive anti-GAD titer (> 10,000 IU/mL in serum by ELISA or detectable in CSF)
• Inadequate response or intolerance or contraindication to ≥ 1 treatment including chronic IVIG or other biologic therapy.

Exclusion Criteria:

For all Subjects:

• Presence of severe liver disease, Child-Pugh class B or C.
• Prior treatment with any gene therapy, genetically modified cell therapy, or adoptive T cell therapy.
• Autoimmune disease requiring prednisone higher than 0.5 mg/kg/day (or corticosteroid equivalent).
• Subjects unwilling to participate in an extended safety monitoring period (LTFU protocol)
• History of a clinically significant infection (including sepsis, pneumonia, bacteremia, fungal, viral and opportunistic infections) within 4 weeks prior to first dose of study drug which in the opinion of the Investigator may compromise the safety of the subject in the study.
• Radiation therapy within 1 week prior to study entry.
• Autologous stem cell transplant (auto-SCT) within 6 weeks of planned prulacabtagene leucel (prula-cel) infusion.
• History of any form of primary immunodeficiency such as severe combined immunodeficiency disease.
• History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac diseases.
• Concurrent malignancy or history of prior malignancy requiring systemic treatment. Subjects with a prior history of malignancy whose natural history or treatment does not have the potential to interfere with either the safety or efficacy assessment of the investigational regimen may be included after discussion with Sponsor or designee.
• Active acute or chronic graft-versus-host disease (GvHD) other than Grade 1 with skin involvement, or GvHD requiring immunosuppressive treatment within 4 weeks of enrollment.
• Any other acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or that, in the judgment of the investigator, would make the subject inappropriate for entry into the study.
• Concurrent opportunistic infections.
• History of severe immediate hypersensitivity reaction to any of the agents used in this study, including known hypersensitivity reaction to dimethyl sulfoxide (DMSO) or excipients of cell therapy products.
• Any condition that in the opinion of the Investigator might place the subject at unacceptable risk for participation in the study.
• Anti-HLA antibodies against all available prula-cel.

For Cohort 1: Subjects with LN

• Current or history in the past year of severe central nervous system involvement due to SLE. For subjects who have had seizures, seizure control should be such that no seizures have occurred in at least the past 6 months.
• LN pure class V, per 1028 ISN/RPS criteria (Bajema 2018).
• Presence of autoimmune disease other than LN as the main diagnosis.
• Presence of kidney impairment due to etiologies other than LN.
• Treatment with cyclophosphamide, voclosporin, belimumab, or rituximab within 5 half-lives or 2 weeks of enrollment, whichever is shorter.

For Cohort 1: Subjects with SLE with External Involvement

• Presence of significant lupus-associated renal disease and/or renal impairment.
• Current of history of Class III or IV LN per 2018 ISN/RPS criteria, presently with proteinuria > 1 g/24 h (i.e., UPCR > 1.0 in a spot urine).
• Pure Class V LN per 2018 ISN/RPS criteria.
• Current or history in the past year of severe central nervous system involvement due to SLE. For subjects who have had seizures, seizure control should be such that no seizures have occurred in at least the past 6 months.
• Treatment with an approved or investigational immunosuppressant for SLE within at least 5 half-lives or 2 weeks of enrollment, whichever is shorter.
• Presence of autoimmune diseases other than SLE as the main diagnosis.

For Cohort 2: Subjects with SSc

• Treatment with an approved or investigational agent for SSc within at least 5 half-lives or 2 weeks of enrollment, whichever is shorter.
• ILD requiring supplemental O2 therapy.
• Evidence of pulmonary arterial hypertension (PAH) as defined as estimated right ventricular systolic pressure (RVSP) of ≥ 45 mmHg or right atrial or ventricular enlargement or dilatation, unless subsequent right heart catheterization shows no PAH.
• PAH on right heart catheterization requiring specific treatment.
• Severe gastrointestinal involvement of small and large intestine requiring total parenteral nutrition; active bleeding related to gastric antral vascular ectasia.
• Renal crisis within 1 year prior to enrollment; presence of kidney impairment due to etiologies other than SSc
• Active severe central nervous system (CNS) involvement; in case of seizure history, no seizures within the past 6 months prior to enrollment.
• Presence of systemic autoimmune disease other than SSc.

For Cohort 3: Subjects with AAV

• Clinically significant CNS dysfunction in the opinion of the investigator.
• Presence of any other known systemic autoimmune disease other than GPA or MPA (subjects with well controlled thyroid disease or type 1 diabetes are eligible for the study)
• AAV with active diffuse alveolar hemorrhage.
• AAV with rapid progressive pneumonitis with significant oxygen requirements.
• Presence of kidney impairment due to etiologies other than AAV.
• Treatment with an approved or investigational agent for AAV within at least 5 half-lives or 2 weeks of enrollment, whichever is shorter.
• Solid organ transplant at any time before enrolment.
• Requires ongoing corticosteroid therapy for AAV on Study Day 0.
• Required dialysis or plasma exchange within 12 weeks prior to screening.

For Cohort 4: Subjects with Autoimmune Muscle Diseases

• Presence of inclusion body myositis.
• Presence of myopathy due to malignancy, toxic myopathy, or drug-induced myopathy with the exception of steroid- or statin-induced myopathy.