CABA-201 for Systemic Sclerosis

CABA-201 is an autologous T cell product that is genetically engineered to specifically target B cells via the expression of a CD19 specific chimeric antigen receptor (CAR) containing a 41BB-CD3 intracellular costimulatory and T cell activation domains. Previous studies utilizing a one-time administration of an autologous CD19 CAR T cell therapy using a similar 41BB-CD3 containing construct have been well tolerated and led to deep and transient B cell depletion while inducing a significant clinical response in patients with SSc, systemic lupus erythematosus, and myositis. Thus, CD19 CAR T treatment has the potential to become an effective treatment for SSc. This study will evaluate CABA-201, an autologous CD19 CAR T product, for the treatment of patients with SSc.

Inclusion Criteria:

1. Able to provide informed consent.

2. Age ≥18 and ≤75 years of age.

3. Diagnosis of limited or diffuse SSc as defined by the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria.

4. Disease duration ≤7 years from first non-Raynaud’s phenomenon symptom.

5. Inadequate response or intolerance to at least two immunomodulatory medications in the past to treat SSc. Subjects must have been treated with at least two of the following medications for a duration of at least 12 weeks to be eligible: azathioprine, corticosteroids, CY, hydroxychloroquine, intravenous immunoglobulin, Janus kinase (JAK) inhibitors, mycophenolate mofetil or mycophenolic acid, methotrexate, rituximab, and/or tocilizumab.

6. Documented evidence of significant skin, pulmonary, renal, or cardiac involvement defined as meeting ≥1 of the below (note: Severe Skin Cohort subjects must meet the criteria for skin involvement only; Organ Cohort subjects must meet the criteria for either renal, cardiac, or pulmonary involvement and may or may not meet the skin involvement criteria):

• Skin involvement (‘a’ or ‘b’):

a. modified Rodnan Skin Score (mRSS) 15-35 at Screening with Health Assessment Questionnaire Disability Index (HAQ-DI) of >1.0 or elevated erythrocyte sedimentation rate or C reactive protein (CRP) AND disease duration ≤5 years which is rapidly progressive (defined as a 5 unit increase in mRSS over a 12-month period)

b. mRSS >35 with HAQ-DI of >1.0 AND either elevated erythrocyte sedimentation rate or CRP AND disease duration ≤7 years

• Renal involvement: history of renal crisis that is not active at time of Screening. Serum creatinine must be stable (with no increases ≥20%) for a minimum of 24 weeks post-renal crisis at the time of the Screening Visit.

• Cardiac involvement: the condition must be clinically stable with or without medication, and non-scleroderma related cardiac disorders must have been reasonably excluded (≥1 of the following):

a. New York Heart Association (NYHA) Class I or II heart disease which is well controlled (see Appendix 2)

b. Atrial or ventricular arrhythmias

c. 2nd or 3rd degree atrioventricular block

d. Myocarditis

• Pulmonary involvement (either ‘a’ or ‘b’):

a. (1) Forced vital capacity (FVC) >55% and <80% predicted or hemoglobin adjusted diffusing capacity of the lung for carbon monoxide (DLCO) >45% and <80% predicted AND (2) interstitial lung disease (ILD) by high-resolution computed tomography of the chest

b. Rapidly progressive fibrosing ILD as defined by 2 of the 3 criteria occurring within the past year and with no alternative explanation:

i. Worsening respiratory symptoms confirmed by the Investigator

ii. Physiological evidence of disease progression by either: 1. Absolute decline in FVC ≥5% predicted within 1 year of follow-up 2. Absolute decline in DLCO adjusted for hemoglobin ≥10% predicted within 1 year of follow-up

iii. Radiological evidence of disease progression (one or more):

1. Increased extent or severity of traction bronchiectasis and bronchiolectasis

2. New ground-glass opacity with traction bronchiectasis

3. New fine reticulation

4. Increased extent or increased coarseness of reticular abnormality

5. New or increased honeycombing

6. Increased lobar volume loss

7. The subject is an appropriate candidate for the study, in the opinion of the Investigator who has considered the potential benefits of other available therapies.

8. Have received all recommended vaccinations per Centers for Disease Control and Prevention (CDC) or institutional guidelines for immunocompromised individuals before or during Screening. • If required, live vaccines must be administered at least 6 weeks prior to the first Preconditioning Visit. • Non-live vaccines should be administered to subjects at least 2 weeks prior to the start of study drug infusion. If possible, non-live vaccines should also be administered at least 2 weeks prior to leukapheresis.

9. Clinical stability based upon the judgement of the Investigator.

10. If subject is currently receiving standard immunomodulatory therapy, the therapy must have been initiated at least 12 weeks prior to Screening and on a stable dose for at least 8 weeks prior to the Screening Visit, except for dose reduction due to safety or tolerability. Refer to Section 4.2 (Exclusion Criteria 11) regarding therapies that require discontinuation prior to Screening.

11. Women of reproductive potential must agree to use 2 acceptable methods of birth control from Screening to a minimum of 52 weeks after the CABA-201 infusion. Acceptable contraception methods include intrauterine device, hormone-based contraception, and barrier method (e.g., condom, diaphragm, or cervical cap) with spermicide.

12. Sexually active men, both reproductively competent and vasectomized (who do not have confirmation of infertility by laboratory testing), who are to receive CABA-201 are required to use condoms with spermicide from Screening until at least 52 weeks after CABA-201 infusion. Males of reproductive potential must also agree not to donate sperm from Screening to at least 52 weeks after the CABA-201 infusion.

Exclusion Criteria

1. Systemic sclerosis-like illness or a primary diagnosis of rheumatic AD other than SSc, including but not limited to rheumatoid arthritis, SLE, polymyositis, dermatomyositis, systemic vasculitis, Sjögren’s syndrome, anti-synthetase syndrome, or mixed connective tissue disease as determined by the Investigator. Secondary Sjögren’s or scleroderma myopathy is allowed.

2. Significant pulmonary dysfunction, defined as any of the following:

a. Resting oxygen saturation <92% without supplemental oxygen

b. FVC ≤55% predicted

c. DLCO adjusted for hemoglobin of ≤45% predicted

3. Significant pulmonary arterial hypertension (PAH), defined as mean pulmonary artery pressure ≥25 mmHg at rest on right heart catheterization (RHC).

• Subjects who have had a RHC demonstrating significant PAH within 12 months of Screening are ineligible.

• A screening echocardiogram will be performed on all other subjects, and a RHC will be required if any of the following echocardiographic findings suggestive of PAH are identified:

o Peak tricuspid regurgitation velocity >2.8 m/sec

o Elevated right ventricular systolic pressure

o Abnormality of right atrial size, shape, or wall thickness

o Abnormality of right ventricular size, shape, or wall thickness

o Abnormal septal wall shape

4. Significant cardiac disease, including any of the following:

a. Unstable angina or myocardial infarction or coronary artery bypass graft within 24 weeks prior to leukapheresis

b. Uncontrolled clinically significant arrhythmia

c. Clinical evidence of congestive heart failure NYHA Class III or IV (see Appendix 2)

d. Moderate to severe left ventricular dysfunction (left ventricular ejection fraction <45% on Screening echocardiogram)

e. Prior insertion of a pacemaker or cardioverter-defibrillator

5. Significant renal disease, including any of the following:

a. Estimated glomerular filtration rate <60 mL/min/1.73m2 using the Chronic Kidney Disease-Epidemiology Collaboration formula

b. Scleroderma renal crisis in the last 24 weeks

c. Glomerulonephritis or overlap syndromes

6. Clinical evidence for active aspiration as determined by the Investigator.

7. Alanine aminotransferase, aspartate aminotransferase, or bilirubin >2 times the upper limit of normal.

8. Documented history of seizures, encephalopathy, or cerebral edema.

9. Active gastric antral vascular ectasia (GAVE, “watermelon stomach”) at Screening esophagogastroduodenoscopy (EGD). Subjects who have a documented negative EGD within 24 weeks of Screening or subjects who have successfully been treated for GAVE (as documented by post-treatment EGD within 24 weeks) are eligible.

10. Hematologic abnormality as defined below:

a. Absolute lymphocyte count <300 cells/µL

b. Absolute neutrophil count <1,000 cells/µL

c. Platelet count <80,000 cells/µL

d. Hemoglobin <8.0 g/dL

11. Subjects who have been given:

a. Prednisone at dose of >10 mg/day within 2 weeks prior to Screening

b. Prednisone 1 mg/kg/day or its equivalent for concurrent illness such as asthma for >5 days on >2 occasions during the previous 24 weeks

c. Rituximab or other B cell-depleting agents within 24 weeks prior to Screening, or within 12 weeks if there are laboratory results indicating presence of CD19+ B cells

d. Abatacept within 8 weeks of Screening

e. Tumor necrosis factor inhibitors within 12 weeks of Screening

f. Leflunomide within 8 weeks of Screening

g. Therapeutic pheresis within 4 weeks of Screening

h. Any investigational agent within 4 weeks or 5 half-lives, whichever is longer

12. Known malignancy or a history of malignancy within 5 years, with exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix.

13. Planned major surgery during the study evaluation period.

14. Contraindications to leukapheresis.

15. History of anaphylactic or severe systemic reaction to FLU, CY, or any of their metabolites.

16. Positive test for human immunodeficiency virus, hepatitis C antibody, hepatitis B surface antigen, or evidence of active or chronic tuberculosis at Screening.

17. Active infection requiring medical intervention at Screening.

18. Any inflammatory autoimmune disorder other than SSc requiring immunomodulatory therapies.

19. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, neurological, or cerebral disease including severe and uncontrolled infection such as sepsis and opportunistic infections.

20. Previous CAR T cell therapy.

21. Prior solid organ (heart, liver, kidney, lung) transplant or hematopoietic stem cell transplant.

22. Pregnant or lactating women.

23. Unable or unwilling to comply with the protocol.