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Today's Agenda AGENDA TOPIC SPEAKER Steven Nichtberger, MD
CABA-201 Overview Chief Executive Officer Lessons from Oncology: Expanding CAR T Carl H. June, MD Director of the Center for Cellular Immunotherapies, Penn Medicine Cell Therapies into Autoimmunity CABA-201 Clinical and Translational Data David
Chang, MD, MPH, FACR TM Chief Medical Officer from the RESET Clinical Program Steven Nichtberger, MD Conclusions Chief Executive Officer Q&A 3
CABA-201: CD19-CAR T specifically designed for autoimmunity 1,3
Cabaletta's CD19 binder with similar in vitro & in vivo activity to construct used in academic studies Clinical data reported by IASO using 4 licensed CD19 binder in oncology Fully human anti-CD19 binder Similar binding affinity &
biologic activity to FMC63, 1,2 with binding to the same epitopes Fully human binder Evaluated as dual-CAR combined with CD22 binder with standard Flu/Cy preconditioning Data reported in ~20 patients to date 4-1BB costimulatory domain B cell
leukemia and lymphoma in IIT in China Same co-stim. domain as used in academic studies CD3- signaling domain Safety data supports autoimmune development 5 CABA-201 IIT - Investigator-initiated trial; Flu/Cy -
Fludarabine/Cyclophosphamide 1. Peng, Binghao J, et al. "Preclinical specificity and activity of CABA-201, a fully human 4-1BB containing CD19 CAR T therapy for treatment-resistant autoimmune disease." Poster presented at: American
Society Gene and Cell Therapy 26th Annual Meeting; 2023 May 19; Los Angeles, CA. 2. Dai, Zhenyu, et al. Development and functional characterization of novel fully human anti CD19 chimeric antigen receptors for T cell therapy. Journal
of Cellular Physiology 236.8 (2021): 5832-5847. 3. M ller, Fabian, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease-A Case Series with Follow-up. New England Journal of Medicine 390.8 (2024): 687-700. 4. Evaluated as part of CT120, a
dual-CD19xCD22 CAR T product candidate under development by Nanjing IASO Biotherapeutics, Co., Ltd. (IASO Bio). 5. Transmembrane domain in CABA-201 is CD8 vs. TNFRSF19 (Troy) utilized in the academic construct. The two transmembrane domains
have not been shown to have a significant difference in function or 4 IFN- production in preclinical studies. The CD8 transmembrane domain is employed in tisagenlecleucel.
RESET clinical program for CABA-201, a CD19-directed CAR T Multiple
autoimmune diseases evaluated in distinct disease cohorts across five clinical trials Phase 1/2 Pivotal Program Trial Preclinical Dermatomyositis Rheumatology Anti-synthetase syndrome Neurology RESET-Myositis IMNM Dermatology Contains cohort(s)
without preconditioning Juvenile Myositis Pediatric Indication Lupus Nephritis FTD RESET-SLE CABA-201 Non-Renal SLE 4-1BB CD19-CAR T Skin + Organ Cohort RESET-SSc Skin Cohort AChR-Ab pos. gMG RESET-MG AChR-Ab neg. gMG 2 Mucocutaneous & mucosal
pemphigus vulgaris RESET-PV RESET - REstoring SElf-Tolerance; IMNM - Immune-mediated necrotizing myopathy; SLE - Systemic lupus erythematosus; Ab - Antibody; AChR - Acetylcholine receptor; gMG - Generalized
myasthenia gravis 5 1. FDA Fast Track Designation received in dermatomyositis, SLE and lupus nephritis, systemic sclerosis, mucosal pemphigus vulgaris, and MuSK-Ab positive MG.
1 Expanding clinical site footprint across RESET program TM 16 patients
enrolled and 10 patients dosed across RESET studies, with 40 actively recruiting U.S. sites TM Clinical development expanding to Europe in 2025 with EMA CTA authorization for CABA-201 received for RESET-SLE Gerwin Winter appointed as
SVP and Head of International at Cabaletta Bio SLE sites Myositis sites SSc sites MG sites PV sites TM RESET Program Upcoming Milestone: 2025: Data permitting, anticipate meeting with FDA regarding potential registrational trial designs for
CABA-201 6 1. Data per clinicaltrials.gov as of November 12, 2024, as compared to companies with actively recruiting U.S. clinical sites for autoimmune cell therapy trials under company-sponsored INDs.
Lessons from Oncology: Expanding CAR T Cell Therapies into Autoimmunity
Success of CAR T in oncology established over decades B cell cancer
experience with CAR T informs use in autoimmune patients 1987 1994 2003 2017 1 First CAR design First report of CAR T cells First anti-CD19 First CAR T cell therapy approved by FDA 2 5 7 killing tumor cells in mice CAR reported (tisagenlecleucel)
1994 1998 2004 2021 First clinical trial of First CD28- First 4-1BB- Early report of CAR T cell CAR T for HIV costimulated CAR costimulated CAR therapy for autoimmune 3 4 6 8 initiated reported reported disease in humans 9 Multiple types of
cell therapies are in Phase 1/2 studies, with the majority being autologous CAR T cell therapy 10 ~800 ongoing CAR T trials, with the majority in the US and China Experience in oncology has established foundation for application in
autoimmune disease 1. Kuwana Y, et al. Biochem Biophys Res Commun. 1987;149(3):960-968. 2. Moritz D, et al. Proc Natl Acad Sci USA. 1994;91:4318-4322. 3. Roberts MR, et al. Blood. 1994;84(9):2878-2889. 4. Krause A, et al. J Exp Med.
1998;188:619-626. 5. Brentjens RJ, et al. Nat Med. 2003;101(4):1637-1644. 6. Imai C, et al. Leukemia. 2004;18:676-684. 7. O'Leary MC, et al. Clin Cancer Res. 2019;25(4):1142-146. 8. Mougiakakos D, et al. N Engl J Med. 2021;385(6):567-569. 9.
Krishnamurthy A, et al. Wells Fargo, November 2017. 10. Clinicaltrials.gov. Accessed November 14, 2024. 8 https://clinicaltrials.gov/search?intr=chimeric%20antigen%20receptor.
Considerations for CAR T therapy in cancer and autoimmunity 1 Factors
that predict adverse events and relapse differ in patients with autoimmune diseases Cancer Autoimmune disease Risk of side effects related to target B cell burden (including 1-5 CAR CRS and ICANS) T cell Healthy cells Risk of treatment failure due
to Necrotic 1,2 cell mutational load (antigen escape) Cancer cells T reg Risk of permanent B cell aplasia 2 Fibroblast due to prior bone marrow damage TME Diseased cell Risk of environmental barriers Cancer (DLBCL) Healthy B cells for CAR T cell
infiltration 7 ~10 trillion cells 300 billion cells Anticipated risk of 1-5 1,6 High risk Lower Risk suboptimal outcomes 1 Images adapted from Baker DJ, et al. 2023. TME, tumor microenvironment. 1. Baker DJ, et al. Nature. 2023;619(7971):707-715. 2.
Sterner RC, Sterner RM. Blood Cancer J. 2021;11(4):69. 3. Breyanzi. Prescribing information; 2024. 4. Yescarta. Prescribing information; 2024. 5. 9 Kymriah. Prescribing information; 2022. 6. M ller F, et al. N Engl J Med. 2024;390(8):687-700.
7. Sender, R et al. PNAS 2023 e2308511120.
Potential adverse events after CAR T cell therapy in cancer Physician
experience in oncology has established algorithms for routine management of common AEs 1 CRS/ICANS assessment parameters Measures alterations in speech, Fever orientation, handwriting, attention, ICE score 2 & receptive aphasia Hypogamma- CRS
events globulinemia Consciousness with ICANS CRS Hypotension Graded 1-4 Graded 1-4 Seizure depending on depending on severity & severity & manifestations manifestations and/or Motor findings Hypoxia Cytopenias & neutropenias,
ICANS events increasing risk of ICP/cerebral edema infection Managing CRS & ICANS events 3 CRS: Tocilizumab +/- steroids & supportive care 4 ICANS: Steroids, supportive care and anti-seizure medications when appropriate 5-8
Seizure prophylaxis is a routine part of some CAR T therapy administration protocols 9 10 11 Image adapted from Bonifant CL, et al. 2016, Verdun N and Marks P. 2024, Adkins S, et al. 2019. AE, adverse event; CAR, chimeric antigen receptor;
CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; ICE, immune effector cell encephalopathy; ICP, intracranial pressure 1. Lee DW, et al. Biol Blood Marrow Transplant. 2019;25(4):625-638. 2. Herr MM,
et al. Biol Blood Marrow Transplant. 2020;26(11):e271-e2744. 3. Zhang Y, et al. J Clin Med. 2023;12(19):6124. 4. Jain MD, et al. Blood. 2023;141(20):2430-2442. 5. The EBMT/EHA CAR-T Cell Handbook. Available at:
www.ebmt.org/sites/default/files/2022-02/2022_Book_TheEBMTEHACAR-TCellHandbook.pdf (accessed 10 October 2022). 6. Pensato U, et al. J Neurol. 2023;270(5):2659-2673. 7. Pensato U, et al. Neurol Sci. 2024;45(8):4007-4014. 8. Mackensen A,
et al. Nat Med. 2022;28(10):2124-2132. 9. Bonifant CL, et al. Mol Ther Oncolytics. 2016;3:16011. 10. Verdun N, Marks P. N Eng J Med. 2024;390(7):584-586. 11. Adkins S. J Adv Pract Oncol. 2019;10(suppl 3):21-28.
CABA-201 Clinical and Translational Data TM from the RESET Clinical
Autoimmune disease patients face substantial unmet medical needs 1-4
Despite therapies with chronic broad immunosuppression, mortality is increased, and quality of life is reduced* Systemic lupus Myositis Systemic sclerosis erythematosus 6 Chronic inflammation often leads to Progressive, multi-organ
damage Progressive skin and organ fibrosis, which 1 permanent tissue damage often leads to irreversible lung, cardiac and 2 ~40% develop lupus nephritis with 25% risk kidney damage 7,8 Progressive weakness, pain, dysphagia,
and of death or ESKD within 10 years extramuscular manifestations are also 9 Average survival from diagnosis is ~12 years 5 common Patients are seeking a drug-free, symptom-free life; 10 physicians also prioritize prevention of end-organ
damage *Compared with the general population ESKD, end-stage kidney disease 1. Lundberg IE, et al. Nat Rev Dis Primers. 2021;7(1):86. 2. Allanore Y, et al. Nat Rev Dis Primers. 2015;1:15002. 3. Zen M, et al. Eur J Intern Med. 2023;112:45-51.
4. Refai RH, et al. Sci Rep. 2024;14(1):5234. 5. Suh J, Amato AA. Muscle Nerve. 2024;70(2):166-172. 6. Murimi-Worstell IB, et al. BMJ Open. 2020;10(5):e031850. 7. Anders HJ, et al. 12 Nat Rev Dis Primers. 2020;6(1):7. 8. Hoover PJ, Costenbader
KH. Kidney Int. 2016;90(3):487-492. 9. Mayes MD. Rheum Dis Clin North Am. 2003;29(2):239-254. 10. Golder, et al. Lupus. 2018;27(3): 501-506
TM Key inclusion and exclusion criteria in RESET clinical program
Designed to evaluate the safety and tolerability of CABA-201 in subjects with active, refractory disease 1-3 Key inclusion criteria Evidence of active disease despite prior or current treatment with standard of care RESET-Myositis
RESET-SLE RESET-SSc Age 18 and 65 with an SLE diagnosis Age 18 and 75 with a diagnosis of IIM Positive ANA or anti-dsDNA at screening Age 18 and 70 with a limited or diffuse
(ASyS, DM, or IMNM) SLE (non-renal): active, moderate to severe SSc diagnosis Presence of at least one MSA SLE, SLEDAI-2K 8; pure class V LN patients Evidence of significant skin, pulmonary, eligible for this cohort
JIIM: Age 6 and 17 with presence of at least renal, or cardiac involvement one MSA or MAA LN: active, biopsy-proven LN class III or IV ( class V) 1-3 Key exclusion criteria B cell-depleting agent within
prior 3-6 months; Previous CAR T therapy and/or HSCT Presence of kidney disease other than LN Cancer-associated myositis Severe lung or cardiac impairment Current symptoms of severe, progressive, or
Significant lung or cardiac impairment uncontrolled pulmonary or cardiac disease ASyS, antisynthetase syndrome; CAR, chimeric antigen receptor; DM, dermatomyositis; HSCT, hematopoietic stem cell transplantation; IIM, idiopathic inflammatory
myopathy; JIIM, juvenile idiopathic inflammatory myopathy; LN, lupus nephritis; MAA, myositis-associated antibody; MSA, myositis-specific antibodies; SLEDAI-2k, SLE disease activity index 2000; SSc, systemic sclerosis. 1. ClinicalTrials.gov.