Slides
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Developing and Delivering a New Generation of T Cell Therapies April 23, 2025 Autolus.com Investor R&D Update
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Forward looking statements These slides contain forward-looking statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as “may,” “will,” “could,” “expects,” “plans,” “anticipates,” and “believes.” These statements include, but are not limited to, statements regardingAutolus’ development of its product candidates, including the obe-cel program; the profile and potential application of obe-cel in additional disease settings; the future clinical development, efficacy, safety andtherapeutic potential of the Company’s product candidates, including progress, expectations as tothe reporting of data, conduct and timing and potential future clinical and preclinical activity and milestones; expectations regarding the initiation, design and reporting of data from clinical trials and preclinical studies; the extension of the pipeline beyond obe-cel; expectations regarding the regulatory approval process for any product candidates; the Company’s current and future manufacturing capabilities; and the Company’s anticipated cash runway. Anyforward-looking statements are based on management’s current views and assumptions and involve risks and uncertainties thatcould cause actual results, performance, or events to differ materially from those expressed or implied in such statements. These risks and uncertainties include, but are notlimited to, the risks that Autolus’ preclinical or clinical programs do not advance or result in approved products on a timely or cost effective basis or at all; the results of early clinical trials are not always being predictive of future results; the cost, timing and results of clinical trials; that many product candidates do not become approved drugs on a timely or cost effective basis or at all; the ability to enroll patients in clinical trials; and possible safety and efficacy concerns. For adiscussion of other risks and uncertainties, and other important factors, any of which could causeAutolus’ actual results to differ from those contained in the forward-looking statements, see the section titled “Risk Factors” in Autolus' Annual Report on Form 10-K filed with the Securities and Exchange Commission, or the SEC, on March 20, 2025 as well as discussions of potential risks, uncertainties, and other important factors inAutolus’ subsequent filings with the Securities and Exchange Commission. All information in this presentation is as of the date of the presentation, and Autolus undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise, except as required by law.You should, therefore,not rely on these forward-looking statements as representing the Company’s views as of any datesubsequent to the date of this presentation. Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 2
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Welcome Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 3 1. Autolus is positioned for value creation 4. Opportunity in multiple sclerosis • Medical need and treatment landscape • Planned P1 MS study 5. Early-stage pipeline outlook 6. Q&A Part 2 2. Opportunity in SLE and lupus nephritis • Medical need and treatment landscape • CARLYSLE SLE P1 data • Pivotal study in lupus nephritis 3. Q&A Part 1 Invited Guests Mark Freedman, MD University of Ottawa David Isenberg, MD University College London (UCL) Management Christian Itin, Ph.D. Chief Executive Officer Matthias Will, MD Chief Development Officer Agenda Today’s Speakers
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Autolus is positioned for value creation • Highly active, fast off-rate CD19 CAR T therapy with a well managed safety profile • First FDA-approved CAR T therapy without a REMS obligation – building on a substantial safety data base • Established infrastructure for manufacturing and commercialization • Commercial presence in key US centers – building to 60 centers in 2H 2025 • Expect to add UK and select EU countries in upcoming 12 months • Year-end 2024 cash position of $588M Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 4 Building on a strong foundation with obe-cel Roddie C, et al "Obecabtagene autoleucel in B-cell acute lymphoblastic leukemia" N Engl J Med 2024; DOI: 10.1056/NEJMoa2406526
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Momentum in the AUCATZYL® U.S. launch Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 5 High level of engagement with physicians for expanding the use of AUCATZYL in adult R/R B ALL indication 38 US Treatment Centers Authorized as of April 22, 2025 • >85% of total U.S. medical lives covered • Anticipated payor mix: approximately 60% commercial and 40% government/other Anticipated New Markets • Anticipated decision in the UK in Q2 2025; EU in 2H 2025 • Country-by-country investments and launch plans based on pricing and reimbursement assessments
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Expanding the obe-cel opportunity PLANS FOR AUTOIMMUNE DISEASE A pipeline in a product
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Obe-cel drives deep reset of the B cell compartment Results we have observed in clinical trials in B cell malignancies • High MRD-negative complete remission rate in relapsed or refractory (r/r) adult and pediatric acute B cell lymphoblastic leukemia (ALL) patients (94%)1 • Long term outcomes indicate complete removal of all malignant B cells in r/r ALL1,2,3 • Experience in non-Hodgkin lymphoma indicate high metabolic complete remission rate (88% in r/r LBCL and 95% in r/r FL)4 • Long term outcomes in patients with LBCL4 Targeted positioning of obe-cel in: • Frontline consolidation in aggressive B cell malignancies in ALL and LBCL – Aim for long term outcomes, while avoiding over-treatment • B cell mediated autoimmunity with an aim to reset the B cell compartment, and remove autoreactive antibodies and B cells – Aim for sustained effect with a one-time therapy Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 7 Combined with a favorable tolerability profile with low levels or no high- grade CRS and ICANS 1. Roddie C, et al "Obecabtagene autoleucel in B-cell acute lymphoblastic leukemia" N Engl J Med 2024; DOI: 10.1056/NEJMoa2406526 2. Ghorashian, S., Kramer, A.M., Onuoha, S. et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med 25, 1408–1414 (2019). https://doi.org/10.1038/s41591-019-0549-5 3. Roddie C, et al. J Clin Oncol 2023;41:16_suppl, 7000 4. Roddie et al, ASH 2023, Poster 2114
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B cell targeting approaches in autoimmune disease • B cell targeting antibody therapy showed a transient effect in a proportion of patients – Rituximab (CD20) – Belilumab (BAFF / BlyS) – Anifrolumab (IFNα/βR) – Obinatuzumab (CD20) • Extending targeting to include all B cell stages and plasmablasts combined with a more potent approach may improve clinical outcomes • Extending targeting to include plasma cells could impact immunization status of patients • Landmark CD19 CAR T clinical experiment by Georg Schett 1 and Andreas Mackensen at the University of Erlangen in patients with refractory autoimmune disease indicate long term outcomes in patients who have failed SoC incl. B cell targeting therapy 8 Crickx, Etienne et al. Kidney International, Volume 97, Issue 5, 885 - 893 Bone Marrow Peripheral Blood 1 Mugiakakos et al,N Engl J Med 2021, Mackensen et al. Nature Medicine 2022 Bergmann et al. Ann Rheum Dis 2023, Fischbach et al. Med 2024 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Inflammation and structural organ damage in autoimmunity • Autoimmune disease is driven by auto-reactive antibodies redirecting the immune system onto various organs and tissues. • With continued inflammatory process organs and tissues become damaged, fibrotic and over time can lose function. • An anti-inflammatory approach targeting B cells and auto-antibody producing plasmablasts or plasma cells will - if successful - remove the inflammatory auto- reactive process. • Reversibility and full recovery of a patient will largely depend on the level of tissue and organ damage and the respective organ’s ability to regenerate. CD19 CAR T therapy will be focused on severe/refractory patients. • Key elements of patient selection: – Active inflammatory disease – Limited chronicity of disease – Evidence of organ involvement – Limited extent of organ damage • Desired outcome: – Remove autoimmunity memory and antibodies – Stabilize impacted organ – Upside is improved organ function Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 9
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• High disease activity is associated with inflammatory processes • Uncontrolled inflammation leads to high chronicity due to accumulated kidney damage • Despite treatment advances including regulatory approvals of belimumab and voclosporin the goal to sufficiently improve short and long-term outcomes in patients with LN remains unmet • There are no treatment options for refractory patients • Kidneys are one of the most common organs involved in SLE - 30% – 40% are lupus nephritis patients Refractory lupus nephritis is a high unmet medical need Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 10 Clarivate/DRG Epidemiology, Arthritis Rheumatol. 2023 Apr;75(4):567-573, Arthritis & Rheumatology. 2017;69(10):2006-2017 US Treated SLE ∼350,000 Treated LN (Biopsy Confirmed) ∼110,000 Treated LN Class III-V 70,000 - 90,000 Refractory to SOC 25,000 - 35,000
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Progressive multiple sclerosis is a high unmet medical need • MS impacts approximately 1,000,000 individuals in the US1 and there is currently no known cure 1: GlobalData MS Market Forecast 2020-2030 April 2023 2:Watson, C., Thirumalai, D., Barlev, A. et al. Treatment Patterns and Unmet Need for Patients with Progressive Multiple Sclerosis in the United States: Survey Results from 2016 to 2021. Neurol Ther 12, 1961–1979 (2023). https://doi.org/10.1007/s40120-023-00532-2 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day • Around 30% of patients have progressive disease and more than half of Progressive MS patients experience disability progression despite receiving disease modifying agents 2 • Highest unmet need for patients who continue to progress despite being treated with highly effective agents for at least 6 months Relapsing Remitting MS ∼ 700,000 Primary Progressive MS ∼100,000 Secondary Progressive MS ∼ 200,000 Obe-cel focus 11
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David Isenberg, MD, FRCP , FAMS • Leading academic rheumatologist and the Emeritus Professor of Rheumatology at University College London, UK and runs UK's largest SLE clinic (> 900 patients) • Pioneering work in autoimmune diseases, especially in systemic lupus erythematosus (SLE), vasculitis and antiphospholipid syndrome • Fellow of the Royal College of Physicians and the Royal Academy of Medical Sciences • Developed disease activity and damage assessment tools for lupus and led the introduction of B-cell targeted therapy for SLE (e.g. rituximab, belimumab, ianalumab and others) • Past president of the British Society of Rheumatology (2004-2006), past chair of the British Isles Lupus Assessment Group (BILAG) and Chair of the Systemic Lupus International Collaboration Clinics (1998-2003) • Evelyn Hess Prize from the Lupus Foundation of America (2010), the Master of the American College of Rheumatology (2016) among others • Published so far 625 original articles, 325 reviews/chapters and 20 books, including the principal editorship of the Oxford Textbook of Rheumatology • Serves of several editorial boards of several major journals including the Journal of Rheumatology • Performs with the band “Lupus Dave and the Davettes” at medical events Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day University College of London
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Professor David Isenberg Emeritus Professor of Rheumatology UCL THERAPIES FOR LUPUS – WHERE ARE WE NOW? WHERE ARE WE GOING?
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A FEW MONTHS AGO, A TRAINEE SAID TO ME… “The treatment for SLE? I thought that was all sorted out now.” 14
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THE BORDER – RUSSIA/POLAND 15
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A PEASANT FAMILY STORY 16
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You know we want to be in Poland.. 17
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We couldn't stand the thought of another one of those long cold Russian winters 18
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SO THE MORAL OF THE STORY IS…. PERCEPTION 19
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History of Lupus 20
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Cohort = 920 ; Details of the first 800 – clinical (1) Sex ratio F : M = 736 : 64 Disease duration = 14.1 yr (SD=10) Ethnicities Caucasian = 448 (56%) Afro-Caribbean = 176 (22%) Asian = 106 (13%) Chinese = 42 (5%) Others = 26 (3%) The UCL Lupus Clinic 1978-2025 21
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Cohort (n= the first 800); Details – clinical (2) % % Rash 54 Arthritis 90 Photosensitivity 35 Serositis 36 Alopecia 25 Renal 30 Oral ulcers 27.5 CNS 20 The UCL Lupus Clinic 1978-2025 22
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UCL – cohort • Since 1978 – over 920 patients under long term review • Deaths n = 170 (19%) Mean age of death = 54.8 yrs [SD = 18.3] – range 17 - 95 Main causes of death = infection/vascular/cancer/active disease including renal SLE – OUTCOMES 23
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1950s – 4 yr survival ~ 50% 2025 – 15 yr survival ~ 85% SLE – OUTCOMES 24
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AND LET’S NOT FORGET MORBIDITY INCREASED RISK OF: • CVS events • Infection • Osteoporosis • Infertility • Hypertension • Other steroid side-effects e.g. cataracts 25
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Systemic Lupus Erythematosus Systemic lupus erythematosus Minor rash or arthralgia Arthritis Pleuritis Pericarditis Haematological CNS NSAIDs Antimalarials Topical steroids NSAIDs Antimalarials Low-dose steroids Severe haemolytic anaemia (Hb <7g/dl) or Thrombocytopenia (Platelets <25000) Controversial: Usually give modest steroids (~30mg/day) and relevant antipsychotic, antiepileptic drugs etc. If non-responsive Corticosteroids 20-30 mg/day If non-responsive Add Azathioprine (occasionally B cell depletion or consider Belimumab) Prednisolone 60-80mg/day + either Azathioprine or Cyclophosphamide (iv pulses or oral) If little response, B cell depletion or consider Belimumab If little response double steroids and add Azathioprine and iv Cyclophosphamide pulses If little response, B cell depletion or consider Belimumab 26
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LUPUS RENAL HISTOLOGY 27
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CURRENT THERAPY FOR LUPUS NEPHRITIS 28 • Conventionally Prednisolone is given together with: Mycophenolate/ Cyclophosphamide Or if the patient is pregnant Azathioprine • In addition, tight control of BP and the use of Hydroxychloroquine are important. • If the above approach does not work, consider Rituximab / Benlysta/ Voclosporin
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Treatment Guidelines in Lupus Nephritis • ACR 2024 guidelines recommend triple therapy for class III/IV ± V LN: • Hydroxychloroquine and RAAS backbone with 1. Glucocorticoid pulse and taper to 5 mg/d by M6 2. Mycophenolate (MPAA) 3. B-cell targeting agents (e.g. Belimumab) or calcineurin inhibitors (CNI) • Patients who fail to respond are given an alternative triple therapy • There is no recommended approach for refractory patients having failed B-cell targeting agents and CNI 29
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40-YEAR FOLLOW-UP OF A LUPUS NEPHRITIS (UCL) COHORT 30 KEY FACTS • From 1975-2015, 219 lupus nephritis pts (91% F) were followed up: • The five-year mortality rates decreased from 24.1% (1975-84) to approximately 5% currently. • Progression to end-stage renal failure occurred in 38 patients (17.4%). • A decrease in incidence among Caucasians but increased in African and Asian patients. • The outcome in LN has not changed significantly in the past thirty years. Gisca et al. Rheumatology 2021; 60: 814-22.
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Assessing Outcome in Lupus Nephritis – 40-year cohort study [1] 1975 – 1985 1986 – 1995 1996 – 2005 2006 - 2015 n = 29 50 92 48 Age at SLE diagnosis [yr] 28 23 23 26 Age at LN diagnosis [yr] 29 26 26 29 End-stage renal disease within 5 yr of LN 3% 4% 7% 4% Mortality 24% 4% 4% 3% Age at death [yr] 42 42 50 33 31Gisca, Duarte, Farinha, Isenberg. Rheumatology 2021; 60: 1814
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Assessing Outcome in Lupus Nephritis – 40-year cohort study [2] CONCLUSION Despite the changes in treatment of lupus nephritis in the past 20 years, we have reached a plateau in 5-year mortality and progression to end- stage renal disease rates; suggesting that new therapeutic and management approaches….are needed to improve outcomes… 32
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Incidence, Prevalence and Mortality of Lupus Nephritis: • Patient with incident LN [1976 - 2018] in Olmstead County Minnesota [n = 72] • Estimated prevalence ↑ from 168/100,000 [1985] to 212/100,000 [2015] • LN patients had a standardized mortality ratio of 6.33 [95% CI, 3.81 – 9.89] with no improvement in mortality gap in the last 4 decades • At 10 yrs, survival was 70%; 13% of LN patients had end-stage renal disease. 33Hocaoglu et al. A & R 2023; 75: 567-73. A…Four Decades Study Using The Lupus Midwest Network [1]
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CONCLUSION The incidence and prevalence of LN….increased in the last 4 decades. LN patients have poor outcomes with high rates of end-stage renal disease and mortality rates 6 times that of the general population. 34 Incidence, Prevalence and Mortality of Lupus Nephritis: A…Four Decades Study Using The Lupus Midwest Network [2]
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IL 6R APC T Cell B Cell Antibodies s Apoptotic Material pDC IFNα Immune stimulation Immune complexes containing nucleic acids CD22 Bly S CD20 Target pathway for SLE therapies 35 CD19
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APC T Cell B Cell Epratuzumab Rituximab Obinutuzumab Veltuzumab IPP 201101 Peptide Abatacept Fostamatinib Rontalizumab Sifalimumab pDC IFNα Immune stimulation Tocilizumab CD22 Abetimus Belimumab Atacicept IL 6R Bly S CD20 Some targeted therapies for SLE 36 Apoptotic Material Immune complexes containing nucleic acids Antibodies s CD19
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Naïve B cell CD19+ CD20+ Ig+ CD38+/- CD19+ CD20+ Ig+ CD38+ CD19+ CD20+ Ig+ CD38++ CD19+ CD20- Ig+/- CD27++ CD38++ CD19+ CD20+ CD27+ IgM/G/A+ CD38- CD19+/- CD20- Ig- CD27++ CD38+++ CD138+ CD19+ CD20+ Ig+ CD38+ Naïve activated B cell GC B cell Post GC B cellMemory B cell Plasma Cell Plasma- blast Peripheral compartmentsBone marrowStem cell Pro-B Cell CD19+ CD20- Ig- Pre-B Cell Immature B cell CD19+ CD20+ Ig- CD19+ CD20+ Ig+ B CELL DEVELOPMENT 37
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1. When everything else has failed. 2. Before using anything at all! When to Use B-cell targeting agents in SLE 38
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Regime used [with very few exceptions] Day 1 - 1g rituximab IV - 250 mg methylprednisolone IV Day 2 - 750 mg cyclophosphamide Day 14 - repeat day 1 Day 15 - repeat day 2 b. STOP - prior immunosuppressive drugs until CD19 counts return to normal. CONTINUE - hydroxychlroquine & steroids (10 mg→15mg). Long Term Follow up on the first 50 Patients Treated with B Cell Depletion 39Lu et al Arthritis Care Res , 2009, 61, 482 The UCL Experience
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Results Clinical outcome at 6 months: BILAG Full Remission n = 19 (42%) Partial remission n = 21 (47%) No improvement n = 5 (11%) 40
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Severe Sub-acute Cutaneous Lupus – Before B cell Depletion 41 Patient A
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Severe Sub-acute cutaneous Lupus Treated with B cell Depletion – Before and 1 Month Afterwards 42 Patient A
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43 Patient B (pre)
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44 Patient B (pre)
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45 Patient B (post)
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Before After With thanks to Professor Ronald Van Vollenhoven Renal biopsy appearance – Patient C 46
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BUT there were some important positives… Secondary serological endpoints • Significant reduction in anti-dsDNA antibodies and ↑ in C3 and C4 at week 52 and 78 • No new safety signals 47
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Treatment regime - Rituxilup • Steroid avoiding regime • Used in all new and relapsing lupus who are not already on steroids and who do not have cerebral lupus • Very low toxicity • Established as our first line treatment protocol 48Condon et al. Annals Rheum Dis. 2013; 72:1280-6
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Time to remission and relapse newly diagnosed LN patients In CR: • 12 wks 9 (18%) • 26 wks 16 (32%) • 52 wks 26 (52%) Time since treatment (weeks) Proportion achieving Number of patients in follow-up 50 49 42 27 CR + PR CR Relapse 49Condon et al. Annals Rheum Dis. 2013; 72:1280-6
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19.8%* OR 2.7 21.1%* OR 2.7 % of trial population 52% * p <0.0001 11.8%* OR 1.68 56% 31.7 32.4 38.8 51.5 53.5 50.6 0 20 40 60 Low C3/4 + anti–dsDNA Low C3/4 + steroid use General Pooled Placebo + SOC (n = 326) Belimumab 10 mg + SOC (n = 344) Belimumab trial subpopulation analysis: SRI Response Rate at Week 52 based on Combination of Baseline Disease Characteristics Sub-populations 50 Moran et al NEJM 2020; 382: 211-21
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Belimumab+SOC vs SOC achieving a 30% CRR @ wk 104 51 Furie et al NEJM 2020
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BLISS-LN BLISS-LN post hoc analysis Placebo (n=223) BEL (n=223) OR (95% CI) P 30%↓ eGFR-sustained 25 (11.2%) 8 (3.6%) 0.29 (0.13- 0.68) 0.004 40%↓ eGFR-sustained 15 (6.7) 4 (1.8) 0.25 (0.08- 0.78) 0.018 Rovin B et al., KI, 2022 Improvement in eGFR and Reduction of Renal Flares 52
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Voclosporin v Benlysta (for Lupus nephritis) 53 Time to UPCR < 0.5 CRR 41% vs 23% Patients with proteinuria shift from > 0.5 to <0.5. AURORA 1 BLISS-LN Resolution of Proteinuria Furie et al NEJM 2020 Rovin et al Lancet 2021
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BIOLOGICS/OTHER NEW MOLECULES IN SLE – WHERE ARE WE NOW? – 4 - New approaches for achieving B-cell depletion: 1. CD20 directed bispecifics, e.g. mosunetuzumab (no data yet) 2. Obinutuzumab [fully humanized anti-CD20] 3. Combination therapy e.g. rituximab plus Benlysta 4. CAR T-cell therapy 54
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GAZYVA (OBINUTUZUMAB) • REGENCY showed that Gazyva helped more patients achieve a complete renal response when added to standard of care • The phase III study met both primary and key secondary endpoints: CRR 46.4% vs 33.1% • NB: Only Benlysta is approved for the treatment of nephritis. 55Furie et al NEJM 2025
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HOT NEWS – REGENCY Phase III Trial Of Obinutuzumab Obinutuzumab (n = 135) Placebo (n = 136) Difference (95% CI) P Value Week 76 CRR 46.4% 33.1% 13.4% 0.02 CRR w/PT* 42.7% 30.9% 11.9% 0.04 * with prednisone taper to <7.5 mg weeks 64 and 76 56Furie et al. NEJM 2025
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BIOLOGICS/OTHER NEW MOLECULES IN SLE – WHERE ARE WE NOW? - Combination therapies Rituximab + Benlysta BEAT-LUPUS CALIBRATE BLISS-BELIEVE Renal + Non-Renal (n = 52) Renal (n = 42) Non-Renal ( n = 292) Phase IIb Phase III safety study Phase III – 3 arm study Met serological primary endpoint [↓ dsDNA] ↓ flare frequency No difference between the arms No difference between the arms 57
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CAR = Chimeric Antigen Receptor Sònia Guedán Carrió y Anna Boronat Barado Chapter 6. Monografías SEI – Elsevier. “Inmunoterapia antitumoral con linfocitos genéticamente modificados (CAR): una realidad con futuro” Antibody TcR Complex 58
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Bio-reactorPrevious conditionin g GMP production “Clean Rooms” Clinical Manag, Autologu s T-cells Vector viral vector + CAR generic construct Infusion Transduction Expansion CAR-T ATMP Defreeze \ Cryopreserve Selection / inclusion / autorization (clinical criteria) Monitoring clincal Immune follow-up Leukoapheresis Autologous donation of T-cells AUTOLOGOUS PROCEDURE CAR-T procedure (drug)
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Emerging CAR T Lupus data in early clinical experience * A case of grade 3 ICANS was also observed in Cabaletta’s Scleroderma Phase 1 trial Erlangen Cabaletta Kyverna Novartis BMS Product Various Rese-cel KYV-101 Rapca-cel BMS-986353 n 19 SLE 4 SLE & 2 LN 6 LN 11 LN 11 SLE Baseline LN Disease - Class III –V Class II-V Class III –V - CRS Yes (Gr 1 & 2) Yes (Gr 1 & 2) Yes (Gr 1 & 2) Yes (Gr 1 & 2) Yes (Gr 1 & 2) ICANS No Yes* (Gr 4) Yes (Gr 1) Yes (Gr 2) Yes (Gr 3) Efficacy 100% DORIS at month 6. No relapse (median follow up 18months) 3/4 DORIS and 1/2 complete renal responses SLEDAI-2k improved SLEDAI 2K down to <10 for all pts median 10-point reduction in SLEDAI-2K Study NCT06347718 NCT06121297 NCT05938725 NCT05798117 NCT05869955 Data EHA/EBMT 7th CAR T Meeting 2024 March 2025 Nov 2024 Dec 2024 ACR 2024 60 • Reported CAR T observations from small cohorts, largest from Schett’s • Included LN subjects had mostly NIH class II-III disease, some class V addition • CRS G2 was observed with all tested CAR T constructs in few cases • ICANS was reported for each cohort (up to G4) except for the Erlangen cohort
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G Schett;EULAR May 2023 61
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G Schett;EULAR May 2023 62
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CD19 CAR T cell therapy for SLE: an exciting advancement …. • Currently administered at specialty centers, path to outpatient administration to be further validated • Data from well designed clinical trials required to properly assess • Current evaluation in refractory patients without treatment alternatives, best use preventing end organ damage may be early on • Long term follow up for larger patient cohorts relevant to determine long term clinical and cost benefit 63
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UNMET/ONGOING NEEDS IN SLE • Earlier diagnosis of commencement of treatment. • Try to minimize the use of long-term steroids. • Patients need to be referred to specialist centres • How to manage patients who are poorly compliant. • How to manage patients with very aggressive disease responding inadequately to steroids/immunosuppressives/biologics. 64
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WHAT WOULD I BE LOOKING FOR IN A NEW AGENT TO TREAT LUPUS/LUPUS NEPHRITIS • Is it more effective than currently available therapies? • Is it safe? • How much does it cost [and how does the cost compare to the cost of currently available therapies?] 65
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CONCLUSIONS (1) • Although the outcome for SLE patients is better in 2025 than in the 1950s, major problems of morbidity and mortality remain. • Based upon a better understanding of the immunopathology, we are now producing B-cell targeting therapies addressing precisely those cells or pathways likely to be responsible for SLE. 66
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• We have clearly reached the limits with conventional therapies [steroids, Azathioprine, MMF etc]. • To improve long-term outlook we have to move to the earlier and possibly combined use of biologics or CAR T therapy. • The future is bright – we just have to get there. CONCLUSIONS (2) 67
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Autolus.com Initial results from the Phase 1 trial of obe-cel in patients with severe lupus and organ manifestation CARLYSLE Study David Isenberg, MD FRCP FAMS University College London
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Ongoing Phase 1 CARLYSLE: Obe-cel CD-19 CAR T in severe refractory systemic lupus erythematosus (SLE) Key Inclusion Criteria • Diagnosis of SLE based on (EULAR)/ (ACR) 2019 classification • Positive (ANA) (≥ 1:80), or anti-dsDNA (≥ 30 IU/mL) or anti-Smith (> ULN), anti-histone or anti-chromatin (> ULN) • Severe, refractory SLE with organ involvement Key Exclusion Criteria • Recurrent or active, severe or unstable neuropsychiatric lupus • Any acute, severe lupus-related flare that needs immediate treatment • Significant, likely irreversible organ damage related to SLE (e.g., end- stage renal disease) • Diagnosis of another non-SLE autoimmune disease (e.g. polymyositis, dermatomyositis) Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day • Dose Level 1 (n=6): 50 x 106 CAR positive T-cells • Dose Level 2 (n=6): 100 x 106 CAR positive T-cells 69
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Summary of findings from first dose cohort (n=6) at 50x106 cells • Six patients aged 19-50 years, (5 female and 1 male) • Disease history of 3 and 23 years with SLEDAI-2K scores at screening ranging from 15 to 28 • All patients had lupus nephritis class III/IV with 4/6 patients having also class V components: • Serum creatinine was elevated in 4/6 patients (ranging from 69-222 μmol/l) • Baseline eGFR was reduced in 4/6 patients (ranging from 47-161 ml/min/SA) • Baseline UPCR was elevated in all patients (ranging from 0.49 to 4.0 mg/mg (normal range <0.13)) • Other manifestations • 2/6 also had musculoskeletal manifestations • 4/6 of patients also had dermal manifestations • Prior therapies • All patients had failed prior B-cell modifying agents, none of them as immediate last therapy prior to obe-cel • 3/6 patients had failed prior calcineurin inhibitor (CNI) 70 Baseline Characteristics Data cut off 17 March 2025 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Summary of safety profile, key events 71 • No high-grade CRS, No ICANS observed, No DLTs observed • Transient hypertension, including G3, due to abnormal kidney function prior to start of therapy according to PI’s judgement nor pre-existing hypertension (3/6) Highest grade of treatment-emergent adverse event observed by patient: TEAE, Grade #1 #2 #3 #4 #5 #6 Patients, n (%) CRS - - 1 - 1 1 3 (50%) ICANS - - - - - - 0 (0%) Neutropenia 3 3 4 4 3 3 6 (100%) Anemia - - 3 3 1 3 4 (67%) Thrombocytopenia - - - 3 - - 1 (17%) Infection 2 2 3 3 1 2 6 (100%) Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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10+ point drop by M3 in SLEDAI-2K scores No immunosuppressive drugs except for maintenance doses of prednisone; tapering in all patients ongoing. 72 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day M3+ follow up M1 follow up Screening M3 M6 M8 0 5 10 15 20 25 30 GB06002 SLEDAI-2K score Screening M3 M4 0 5 10 15 20 25 30 GB01004 SLEDAI-2K score Screening M3 M4 0 5 10 15 20 25 30 GB01005 SLEDAI-2K score Screening M3 0 5 10 15 20 25 30 GB01006 SLEDAI-2K score Rash Renal Involvement Arthritis Alopecia Mucosal Ulcers Low Complement Increased DNA binding Screening M1 0 5 10 15 20 25 30 GB01007 SLEDAI-2K score Screening M1 0 5 10 15 20 25 30 GB01008 SLEDAI-2K score * • All patients benefited significantly from obe-cel • Skin: rash, alopecia and mucosal ulcers resolved by M3 • Musculoskeletal: Arthritis resolved by M1 • Complement normalized in all patients by M1 #1 #2 #3 #4 #6#5 *Kidney biopsy on month 7 showed no disease activity 72
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Three out of six patients with complete renal response within 3 months 73 Transient worsening of renal function due to hypertension and inflammatory response not due to LN per PI’s judgment ** UPCR increase caused by urinary tract infection observed on Day 27 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day CRR at M3 UPCR (normal range <0.13mg/mg) Serum creatinine (normal range 45-92umol/L) eGFR (normal range >90ml/min/SA) 1 4 0.42 (M8) 222 348 57 34 2 0.49 0.27 (M3) 69 80 161 149 3 1.32 1.87 (M3) 124 127 56 54 4 2.08 0.13 (M3) 123 92 47 62 5 2.26 0.40 (M1) 100 119 107 85 6 0.91 3.37 ** (M1) 132 165 50 47 CRR at M3 CRR at M1 D-30 Last FU D-30 Last FU D-30 Last FU
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Short Term Efficacy Outcomes – Anti-dsDNA antibodies & complement Improvement in serology was observed starting from M1 post infusion (anti-dsDNA decrease to ULN and complement normalization) 74 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day Anti-dsDNA antibodies Complement C3 • Complement C3 normalized by M1 for all patients • Anti-dsDNA improved for all by M1, normalized in 2 patients screening M1 M2 M3 M6 0 50 100 150 200 250 300 350 400 Anti-dsDNA antibodies IU/mL GB06002 GB01004 GB01005 (Normal range 0-10) GB01006 GB01007 GB01008 screening M1 M2 M3 M6 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Complement C3 g/L GB06002 GB01004 GB01005 (Normal range 0.7-1.8) GB01006 GB01007 GB01008 #1 #2 #3 #4 #5 #6 #1 #2 #3 #4 #5 #6
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Steroids tapering post obe-cel infusion in all patients post M1 75 • All patients received bridging therapy with a median steroid dose of 15mg/daily (range • 5-500mg/daily) • Following obe-cel infusion, steroids tapering below 10mg/daily occurred for all patients (no more than 10mg/daily is permitted post obe- cel infusion) • No additional SLE medications have been administered to any of the patients Steroids tapering post infusion Median dose is reported Note: Patient 007 and 008 reached 4weeks FU at data cut-off 17Mar25. They are receiving since day 1 10mg qd Day 1 M1 M2 M3 M4 M8 0 5 10 15 Steroids tapering post infusion Prednisone mg/daily GB06002 GB01004 GB01005 GB01006 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day #1 #2 #3 #4
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High CAR T peak expansion and deep B cell aplasia CAR-T Persistence B-cell Aplasia *Samples with 0 VCN are shown as 0.1 due to the log scale CAR T Cmax similar to observations in heme indications and persistence between M2 and M3 for 3/6 of patients B-cell recovery observed between M2 and M6 in 3/4 patients Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day screening LD M1 M2 M3 M6 0 50 100 150 200 B cell aplasia cells/ul GB06002 GB01004 GB01005 GB01006 GB01007 GB01008 #1 #2 #3 #4 #5 #6 76
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B cells upon recovery display primarily a naïve phenotype in all 3 pts Patient Day -5 M6 M9M3 #1 #2 #3 #4 #5 #6 No baseline sample/data available Memory DN Naive Unswitched Memory Memory DN Naive Unswitched Memory • At baseline, memory B-cells represent up to 90% of B-cell population • B-cel reconstitution occurs as early as M3 • Reconstituted B-cells are ≥90% naïve B-cells • Double negative (CD27-, IgD-) Memory B-cells are mostly eliminated • Early findings suggest a reset of B-cell population post obe-cel 77 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Conclusions from CARLYSLE study to date • Patient population studied • Patients had exhausted prior therapy options, all had B-cell depleting agent exposure, 2 also BAFF inhibitors, 3/6 also calcineurin inhibitors • Lupus nephritis: 5/6 patients had a class IV disease, 4/6 had also a class V component • Kidney function was significantly impaired (<60 ml/min/SA) in 4/6 patients • Safety • No DLTs observed in first 6 patients dosed at 50x106 cells • CRS only grade 1 (fever) observed in 3/6 patients • No ICANS • Transient neutropenia in all, anemia in 3/6 and thrombocytopenia in 1/6 patients • Transient hypertension, including G3, occurred in 5/6 patients • Efficacy • All patients benefited from obe-cel treatment including three patients with a CRR (all by M3) • Complement normalized first, and in all patients • Musculoskeletal and dermal manifestations resolved in all patients by M3 78 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Development path in lupus nephritis (LN) PLANS FOR AUTOIMMUNE DISEASE
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Development Rationale Lupus nephritis development strategy 80 Leveraging a fast to market strategy Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day • LN is assessed by quantitative lab- parameter based endpoints (CRR) vs. SLE with a composite endpoint depending on clinical assessments • Current guidelines require for Class III/IV LN triple therapy including B-cell modifier or CNI, without any treatment options for those being refractory to both • Lack of SOC for refractory LN opens the possibility to single arm trial path for initial approval • Outcome of refractory LN single arm trial serves as good predictor for RCT in earlier LN vs. SOC DL1 n=6 DL2 n=6 SLE with kidney manifestation Refractory LN n=30; [CRR=40%] RCT in LN vs. SoC SoC Obe-cel LN III/IV±V Ph1 Dose Confirmation Ph2 Single Arm Pivotal Ph3 Randomized Controlled vs SoC Initial Approval Expanded Indication
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Pivotal phase 2 study in severe refractory, active lupus nephritis 81 Trial design Single arm, open-label, multi-centre, phase 2 Sample size 30 patients Patient population • 12-65 years of age, body weight ≥ 40kg • Diagnosis of SLE based on (EULAR)/ (ACR) 2019 classification • Positive (ANA) (≥ 1:80), or anti-dsDNA (≥ 30 IU/mL) or anti-Smith (> ULN), anti-histone or anti-chromatin (> ULN) • Severe, refractory LN (ongoing active class III, IV or V (only in combination with III or IV) • Prior immunosuppressive and biologic therapies Treatment 50 x 106 CAR positive T-cells following Flu/Cy lymphodepletion Endpoints Primary: Complete Renal Response at 6 months Key Secondary: DORIS at 6 months Timing • First patient enrolled by YE 2025 • Anticipated enrolment window: 24 months • One year follow up Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day Day-5 Day 1 Monthly safety and efficacy follow-upL Leukapheresis Obe-cel Manufacturing Lymphodepletion Obe-cel Infusion Screening Cy 1000 mg/m2 Flu 25 mg/m2
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FDA interactions support registrational potential based on a single arm study in high-risk patients • Collaborative approach with the FDA in reviewing IND intending to preserve registrational potential • Defined patient population with a clear unmet medical need: ‒ Eligibility will be reviewed by independent committee (rheumatologist, nephrologist, pathologist): ‒ Definition of refractoriness for inclusion: ‒ failure of B-cell targeting agent and ‒ CNI where available in jurisdictions, or intolerance to those agents • Alignment of Complete Renal Response as primary endpoint • IND cleared in February 2025 82 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Autolus.com Questions? 83
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Mark Freedman, HBSc, MSc, MD, CSPQ, FAAN, FRCPC • Professor of Medicine (Neurology) at the University of Ottawa and Director of the Multiple Sclerosis Research Unit with 35 years of clinical experience • Senior Scientist at the Ottawa Hospital Research Institute with extensive research in molecular neurochemistry, cellular immunology and neuroimmunology related to MS • Research focused on cell-based therapies and biomarkers for MS: lead investigator in Canadian BMT study in MS and of the Canadian Mesenchymal Stem Cell Transplantation in MS study (MESCAMS) and co-director of the International Mesenchymal Stem Cell Transplantation in MS study Group • Principal investigator in >100 clinical trials for new treatments for MS • Led all versions of the Canadian Treatment Optimization Recommendations • Serves on multiple editorial boards including the Multiple Sclerosis Journal and Multiple Sclerosis and Related Disorders • Published more than 400 papers and 550 research abstracts • Past-president of the Canadian Network of MS Clinics and recent past-president of the Americas Committee for Treatment and Research in MS (ACTRIMS) • Aspired to be a race car driver but was precluded by his size (they sent him away saying they would need the “jaws of life” to extract him from the car.) Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day University of Ottawa
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Multiple Sclerosis PLANS FOR AUTOIMMUNE DISEASE
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Multiple Sclerosis: Current Understanding and Treatment Approaches Mark S. Freedman MSc MD FANA FAAN FRCPC Professor of Medicine (Neurology) University of Ottawa Sr. Scientist, The Ottawa Hospital Research Institute
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Review of some basics Diagnosis MS Classification Therapeutic approaches and results Monitoring for treatment response Unmet needs for treating progressive disease Possible role for CAR T cell therapy Objectives:
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Fundamentals of the Disease
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MS: Global Distribution Region Prevalence1 North America 140/100,000 Europe 108/100,000 East Asia 2.2/100,000 sub-Saharan Africa 2.1/100,000 Canada has one of the highest rates of MS in the world, with an estimated 100,000 (1 in 340) Canadians living with the disease2 1. Leray E, et al. Rev Neurol (Paris). 2016;172(1):3-13. 2. About MS. https://mssociety.ca/about-ms. Accessed April 20, 2018 The most common demyelinating disease with a heterogeneous prevalence worldwide1 Affects > 2 million people The global median prevalence of MS has increased from 30/100,000 in 2008 to 33/100,000 in 20131
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Epidemiology of Multiple Sclerosis (MS) Typically, the disease becomes clinically apparent between the ages of 20 and 40 years1 Mean age at onset is 31 years (range 5-67 years)2 o 3–10% of all MS cases have their first manifestations in childhood or adolescence3 Women are 2-3 times more likely than men to have MS, but men have worse outcomes4 No difference in mortality between MS patients and controls in the first 20 years of the disease 1 The overall life expectancy is reduced by 6-7 years in MS patients1 1. Leray E, et al. Rev Neurol (Paris). 2016;172(1):3-13. 2. Waldman A, et al. Lancet Neurol. 2014;13:936–48 3. Gilmour H, et al. Statistics Canada, Catalogue no. 82-003-X . January 2018 Health Reports;29(1):3-8. 4. Confavreux C, et al. N Engl J Med. 2000 Nov 16;343(20):1430-8
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Multiple Sclerosis An inflammatory demyelinating disease of the central nervous system (CNS) The pathologic hallmark: – Focal areas of myelin loss within the CNS Demyelination is accompanied by: – Variable gliosis – Inflammation – Relative axonal preservation Demyelinated lesions are commonly found in: – CNS white matter – Cortical gray matter Trapp BD, et al. The Neuroscientist. 1999;5(1):48-57 Popescu BF, Continuum (Minneap Minn). 2013;19(4 Multiple Sclerosis):901-21.
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Pathological Drivers of Progression in MS 1 4 3 2 5 Pathologies underlying MS progression1 Focal MS lesions 1 Age-related atrophy 5 Diffuse gliosis 4 Slowly expanding lesions 3 Meningeal B-cell aggregate 2 Hauser SL and Cree BAC. Am J Med, 133(12), Treatment of Multiple Sclerosis: A Review, 1380-1390 Blood, Brain Barrier
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1. Hauser SL, Cree BAC. Am J Med 2020;133:1380–90; 2. Dendrou CA et al. Nat Rev Immunol 2015;15:545–58; 3. van Langelaar J et al. Front. Immunol 2020;11:760; 4. Baker D et al. EBioMedicine 2017;16:41–50; 5. Serafini B et al. Brain Pathol 2004;14:164–74; 6. Howell OW et al. Brain 2011;134:2755–71; 7. Elliott C et al. Brain 2019;142:2787–99; 8. Preziosa P et al. Neurol Neuroimmunol Neuroinflamm 2022;9:e1139; 9. Arnold DL et al. Mult Scler 2021;27:1681–1683; 10. Liu Y et al. Eur J Nucl Med Mol Imaging 2022;49:1275–1287. White matter lesions are characterised by: • Presence of peripheral B cells, T cells, and macrophages 2–4 • Gadolinium-enhancement on MRI which indicates blood−brain barrier disruption 1 BTK inhibitors target both the adaptive and innate immune pathology2–4 Meningeal B-cell-rich aggregates are: • Persistent follicular-like structures that allow for a complex immune response in the grey matter 5,6 • Associated with aggressive clinical disease, rapid disability progression, and younger death 5,6 New BTK inhibitors are more selective5,6New BTK inhibitors are more selective5,6 Slowly expanding lesions are: • Characterised by a rim of activated microglia1,7 • Activated by B cells • Detected longitudinally on standard MRI scans 7,8 • Linked to long-term disability progression and a higher rate of brain atrophy8 • Observed in 83% of early RRMS patients9 BTK inhibitors exhibit rapid reversibility6 BTK inhibitors target both the adaptive and innate immune pathology2–4 Reactive microglia and astrocytes (gliosis) are characterised by: • Increased inflammatory cytokine production 2 • Decreased myelin density and increased axonal damage 1 • PET imaging with specific radiotracers 10 Pathologies Underlying MS Progression1
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Diagnosing the Disease
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Clinical Threshold Demyelination CIS McDonald + (MRI) MS or CIS+ (2005) “Definite” MS (McDonald or Poser 1983) Disease Parameter CDMSCISRIS Transitional MS SPMS MSMS McDonald 2010 or 2017 Evolving Diagnostic Criteria Time RIS McDonald 2024
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MS: New Nosology Primary progressive MS (PPMS) (10–15% of patients with MS) • Active* and with progression† • Active but without progression • Not active but with progression • Not active and without progression (stable disease) Secondary progressive MS (SPMS) (up to 75% progression from RRMS) Subtype Modifications Radiologically isolated syndrome • Incidental imaging findings without clinical signs or symptoms • May increase risk of developing clinical MS Clinically isolated syndrome • Not active • Active (transitioning to MS) Relapsing-remitting MS (RRMS) (65–70% of patients with MS) • Not active • Active Adapted from Ontaneda D, et al. Active* (clinical) with progression† Active (MRI/clinical) without progression Active (MRI) with progression Not active with progression Not active without progression Lublin FD, et al. Neurology. 2014;83:278–286.
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Diagnosing MS: Paraclinical Testing Paraclinical testing to: Help exclude other possible diagnoses mimicking MS Look for changes compatible with MS o MRI o Evoked potentials o CSF
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CSF Oligoclonal Bands in MS: Preferred Test is IEF-Immunoblotting No Bands OCB in CSF NOT serum OCB in CSF & Non-specific bands Non-specific bands MCB Freedman MS et al. Arch Neurol 2005; 62:865-870 Indicates MS
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MS: Pathological vs. Clinical Course of Disease Time (Years) Clinical Threshold Axonal Loss Demyelination First Clinical Attack Time Window for Early Treatment Inflammation Disease parameter Relapsing – Remitting Transitional Secondary ProgressiveCISRIS Treatment depends on WHERE in the window you think the patient is when you are initiating treatment Or advanced (silent) disease presenting late? Are you dealing with new disease presenting early? 0 2,000 4,000 6,000 8,000 10,000 12,000 Active Chronic active edge Chronic active core NAWM Control white 11,236 3,138 875 17 0.7
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The Natural History of MS
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The New Natural History of MS
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Historical Perception of MS 1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:1-18; 2. Leray E, et al. Brain. 2010;133(Pt 7):1900–13; 3. Kamm C, et al. Eur Neurol. 2014;72(3–4):132–41; 4. Lublin FD, Reingold SC. Neurology. 1996;46(4):907–11; 5. Hauser SL, Cree BAC. Am J Med. 2020;133(12):1380–90. Peripherally initiated acute inflammation mediated by B and T lymphocytes Acute focal inflammatory lesions Acute relapses Progressive diffuse neurodegeneration Disability accumulation Time Disability Relapses Disability accumulation Stage 2 Neurodegeneration; disability accumulation Stage 1 Inflammation; relapses
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Emerging MS Paradigm views MS as a Single Biological disease driven by TWO Parallel Inflammatory Pathways1-6 1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:1-18; 2. Kappos L, et al. JAMA Neurol. 2020;77:1132–40; 3. Vollmer T, et al. Neurol Clin Pract. 2021;11:342–51; 4. Lublin F, et al. Brain. 2022;145:3147–61; 5. Baker D, et al. EBioMedicine. 2017;16:41–50; 6. Bar-Or A. Semin Neurol. 2008;28:29–45. Emerging paradigm: Two parallel processes CNS- compartmentalized inflammation Peripherally- initiated inflammation MS disease course (years) 5 10 20150 “Smouldering MS” CNS-compartmentalized inflammation PIRA Peripherally-initiated inflammation RELAPSES & RAW BEGINS EARLY IN THE DISEASE COURSE Magnitude of neuronal injury & disability Figure adapted from Bar-Or A. The immunology of multiple sclerosis. Semin Neurol 2008;28:29–45. ©Georg Thieme Verlag KG. Functional brain reserve
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Peripherally Initiated and CNS-compartmentalized Inflammation Contribute to Pathologies Underlying Disability Accumulation1-4 1. Hauser SL, Cree BAC. Am J Med. 2020;133:1380–90; 2. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:1–18; 3. Bayas A, et al. Mult Scler Relat Disord. 2022;68:104166; 4. Piehl F. J Intern Med. 2021;289(6):771-791; 5. Lublin F, et al. Brain. 2022;145:3147–61; 6. Scalfari A, et al. Neurology. 2011;77:1246–52; 7. Marrie RA. Nat Rev Neurol. 2017;13:375–82. CNS-compartmentalized inflammation ‘Smouldering MS’ Cognitive & physical worsening, fatigue, reduced productivity chronic active lesions e.g. SELs, PRLs Brain atrophy PIRA Disability progression independent of relapse activity Total disability accumulation Acute focal inflammatory lesions e.g. T1 Gd+ Relapses RAW Relapse-associated worsening of Disability Peripherally initiated acute inflammation Additional patient factors5-7 Biological age Baseline brain health Comorbidities
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Need to Target BOTH Peripheral and CNS-Compartmentalized Inflammation? 1. Giovannoni G, et al. Ther Adv Neurol Disord. 2022;15:17562864211066751; 2. Hauser SL, Cree BAC. Am J Med. 2020;133(12):1380–90; 3. Kuhlmann T, et al. Lancet Neurol. 2023;22(1):78–88; 4. Piehl F. J Intern Med. 2021;289(6):771–91; 5. Calvi A, et al. Mult Scler. 2023;29(3):352–62; 6. Airas L, et al. Front Neurol. 2018;9:181; 7. Mallik S, et al. J Neurol Neurosurg Psychiatry. 2014;85(12):1396–404; 8. Absinta M, et al. Neurology. 2015;85(1):18–28. Diffuse white matter inflammation6 Meningeal inflammation8 Acute axonal damage/ demyelination and remyelination 2,7 Focal lesions4 SELs and PRLs5 Peripherally initiated CNS-compartmentalized Both peripherally initiated and CNS-compartmentalized Biological mechanisms underlying MS disease progression1–3
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EDSS: Disability Scale for MS Visual Brainstem Pyramidal Cerebellar Sensory Bowel/Bladder Mental EDSS = Composite of several Functional Subscores (KFS)
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Disease Modifying Treatment
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Predictors of a Poor Prognosis in Multiple Sclerosis Rotstein D & X Montalban Nat Rev Neurol 2019;15:287-300
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Disease Modifying Medications vs. MoA It is not known which MoA will work in any given patient Choice of Tx (modest vs. higher efficacy) depends on perception of risk for early progression vs. safety Monitoring for Tx response vital to reduce Tx inertia Yang J et al. Front Neurol doi: 10.3389/fneur.2022.824926
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Pros Safety Long term experience Disease Modifying Medications: Categories Interferon-β GA DMF Teriflunomide Fingolimod Natalizumab Ozanimod Ponesimod Siponimod (SPMS only) Alemtuzumab Cladribine Tablets Ocrelizumab Ofatumumab Teriflunomide Mitoxantrone Cyclophosphamide AHSCT (BMT) Immunomodulators Anti-Cell Trafficking Agents Cell Depleting Therapies Cons Modest efficacy Many injectable Pros Greater efficacy Onset of action quick Well tolerated Cons Opportunistic infections (PML) Cells still in body Rebound disease Long term safety unclear Pros Definitive in depleting disease causing cells Some are IRT No rebound disease Cons Opportunistic infections Secondary autoimmunity (alemtuzumab) Most cumbersome
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Monitoring for Treatment Response
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Biomarkers MRI
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MRI parameters – Brain – Spinal cord – Use of contrast – Sequences and metrics (eg. T1, T2, T2*Epi, volumetrics) Frequency Evaluation – Manual – Computer driven MRI for Monitoring
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MRI parameters – Brain – Spinal cord – Use of contrast – Sequences and metrics (eg. T1, T2, T2*Epi, volumetrics) Frequency Evaluation – Manual – Computer driven MRI for Monitoring
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Danish registry Initial Tx with moderate efficacy agent Clinically stable for ≥1 year MRI at baseline, 3 and 6 months and then q 6 months Probability of being relapse free at 4 years vs. lesion development Change in DMT based on MRI Monitoring Bsteh G et al. Neurol 2024;103:e209752.doi:10.1212/WNL.0000000000209752
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No single metric proven useful Brain atrophy (inverse of brain volume) – Gray matter atrophy vs. white matter atrophy – Cortical atrophy – Spinal cord atrophy Slowly expanding lesions (SEL) Paramagnetic rim lesions (PRLs) PET MRI for Monitoring Disease Progression
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Biomarkers Fluid Biomarkers
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What Makes an Ideal Biomarker? Biological rationale Clinical relevance Practicality Correlation with disease activity/progression Correlation with treatment effects
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Role of a Biomarker Diagnostic Used to confirm diagnosis Measures a “surrogate” Prognostic/Predictive Indicates disease trajectory in a given individual Disease Activity Biomarkers Measures inflammatory/neurodegenerative disease components Treatment Response Biomarkers Differentiate patients regarding their outcome related to efficacy and side effects (treatment responders and non-responders as well as patients with and without adverse drug reactions) Ziemssen et al. Journal of Neuroinflammation 2019;16:272
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Baseline sNfL Predicts Disability and Disease Activity 1. Disanto G, et al. Ann Neurol. 2017;81(6):857-870; 2. Thebault S, et al. Mult Scler Relat Disord. 2022;59:103535; 3. Gaetani L, et al. J Neurol. 2019;266(9):2157-2163. sNfL was associated with EDSS score1 sNfL were significantly associated with probability of relapse, MRI activity and time to cCDA2 Neurofilament light chain protein (NfL)1,3 CSF biomarker + direct contact with CNS + relatively high abundance Blood biomarker + safe, quick, and easy collection + available at different timepoints This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). © 2022 The Author(s). 0.0 2.5 5.0 7.5 EDSS sNfL (pg/ml) 5 10 20 50 100 200 300 Probability of survival0 100 200 300 400 500 Days to relapse 0 50 100 p=0.0068 0 100 200 300 400 500 Days to ≥5 new Gd lesions 0 50 100 p=0.0096 0 100 200 300 400 500 Days to cCDA 0 50 100 p=0.0020 sNfL <10 pg/mL sNfL 10–20 pg/mL sNfL >20 pg/mL
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Serum GFAP better predicts disability and disease activity1 1. Meier S, et al. JAMA Neurol. 2023;80(3):287-297; 2. Barro C, et al. Neurol Neuroimmunol Neuroinflamm. 2022;10(1):e200052; 3. Jiang X, et al. Mult Scler. 2023;29(9):1070-1079. CSF biomarker + direct contact with CNS + relatively high abundance Blood biomarker + safe, quick, and easy collection + available at different timepoints Glial fibrillary acidic protein (GFAP) 1-3 Baseline sGFAP were associated with loss of gray matter volume and prognostic capacity for future PIRA1 sGFAP were significantly associated with CDW1 Associations of sGFAP with gray and white matter atrophy1 sGFAP sNfL Estimated annualized GM atrophy per biomarker doubling (%) -0.4 -0.2 0.0 0.2 Gray matter sGFAP sNfL Estimated annualized WM atrophy per biomarker doubling (%) -0.4 -0.2 0.0 0.2 White matter No CDW (n=209) CDW (n=43) sGFAP Z score -4 -2 0 2 4 6 P <.001 P <.001 P =.002
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sNfL Predicts Non-Relapsing Progression: Following Anti-CD20 Therapy with Ocrelizumab Bar-Or A. et al. eBioMedicine 2023;93:104662
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Unmet Clinical Needs in Managing MS Progression
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CAR T-Cell Therapy in MS: Role of B Cells
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CAR T-Cell Therapy in MS: CNS Penetration
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CAR T-Cell Therapy in MS: CNS Penetration
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Conclusions Multiple Sclerosis is a condition that can be diagnosed with accuracy Numerous treatments are successful at targeting focal inflammation and reducing relapses and MRI activity but fall short on disease progression None of the current medications have been successful at targeting compartmentalized inflammation except possibly the BTKi There is a strong unmet need for CNS-penetrating therapies capable of addressing compartmentalized inflammation and stopping progression There are no successful therapies for remyelination or repair
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Development path in MS PLANS FOR AUTOIMMUNE DISEASE
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Multiple sclerosis development strategy 132 Establish Phase 1 Clinical Proof of Concept in MS 3 x 6 dose escalation design - a higher dose may be required for CNS effect Biomarker readouts to provide nearer term evidence of biological effect at 6 months + Definitive clinical outcomes based on clinical disability progression at 12 months + Initiate Phase 2/3 study in progressive MS patients exhibiting PIRA • Anticipate a randomised phase 2/3 study design as path to approval • Phase 1 clinical PoC is derisking for initiation of development in other neurology indications Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day Anticipate dosing first patient in Phase 1 trial by year end 2025
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Modified single arm, Phase 1 study in MS 133 MS patients with PIRA 6 pts. Obe-cel 100 × 106 cellsFlu/CyApheresis Week 4 Week 52 Sample size: 12-18 patients infused with obe-cel Primary endpoint: • Safety Secondary endpoints: • 12-week confirmed disability progression (CDP) at one year, composite measure of disability at one year, confirmed disability improvement • Other functional measures: cognition, fatigue, QoL • Imaging: MRI lesion counts (T1 Gd+, T2), MRI – MTR, MRI – regional brain volumes, MRI – cervical spinal cord volume, SEL, PRL) • Biomarkers (blood and CSF): OCBs, IgG index, NfL, GFAP , Kappa chains, PK Interim analysis at 6 months: • Biomarkers including OCBs, IgG index, NfL, MRI lesions, MTR, Kappa chains, PK Week 12 Week 52 V2V < 21 days PMS patients exhibiting PIRA Includes both patients with low activity or non- active disease. Both SPMS and PPMS Patients must continue to progress while on a highly efficacious therapy for at least six months (e.g. anti-CD20, S1P inhibitor) Week 24 Extension1 04 Washout Rx Goal: Tolerable safety and efficacy signal on biomarkers 6 pts. Obe-cel 50/100/200 × 106 cells Interim analysis 6 pts. Obe-cel 100/200/400 × 106 cells Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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What does good look like? • Changes in confirmed disability progression and relapse rates are expected in the follow up year and beyond • In the shorter term both fluid and imaging biomarkers may support evidence of biological effect and impact on CNS inflammation, with trends across biomarkers providing increased confidence in clinical outcomes. • Reduction in oligoclonal bands (inline with other biomarkers) is the strongest early evidence of impact on disease progression biology other than HSCT and CAR T therapy, no other treatment has had impact on OCBs 134 Early evidence of Biological Effect and Impact on CNS Inflammation Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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Initiated studies in autoimmune diseases as stepstone into new disease area SL1 (CARLYSLE) study and subsequent pivotal SL2 study in refractory lupus nephritis: • Patients treated in SL1 are representative for SL2 patient population, paving a clear path to a timely approval in patients with highest unmet medical need • Opens the opportunity to future expansions into: • Earlier lines of lupus nephritis comparing against SOC • Other adjacent indication of similar pathology in the kidney, i.e. membranous glomerulo-nephritis • Non-nephritis SLE indications MS1 is a dose escalation study designed to assess the safety and the potential of obe-cel in MS based on imaging, biomarkers and early clinical responses: • Posterchild disease to differentiate from mABs and bispecific driven approaches as obe-cel crosses the blood brain barrier • Insights will inform the path forward for MS in Progression Independent of Relapse Activity (PIRA) • Serve as a springboard into other neurological indications, e.g. NMOSD or CNS lupus Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 135
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Early stage pipeline PIPELINE IN A PRODUCT
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Translational programs with UCL 137 Product Indication Target Preclinical Phase 1 Status *UCL Collaboration § BioNTech holds option to co-fund and co-commercialise AUTO8 Multiple Myeloma CD19 & BCMA Enrolling in MM; Phase 1 in amyloidosis initiated AUTO1/22* Pediatric ALL CD19 & CD22 Initiating new cohort in Q2 2025 AUTO6NG*§ Neuroblastoma GD2 Patient dosing ongoing; preliminary data expected in 2026 AUTO4/5 TRBC1/2+ Peripheral TCL TRBC1/2 Moving back into translational research AUTO9* Acute Myeloid Leukemia CD33,123,CLL1 Preclinical work ongoing UCL collaboration provides cost-efficient approach to generate early data for future growth opportunities, following the obe-cel pathway to approval Early-stage pipeline supports long-term growth potential Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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AUTO8: BCMA & CD19 dual targeting CAR T for plasma cell diseases Proof of Concept shown in r/r Multiple Myeloma • Phase 1 MCARTY dose escalation study in RRMM • Data presented at ASH in 2023 and 2024 • No notable tox at 50 and 150 million dose levels • Response rate in line with other BCMA CAR • Improved persistence in dual CAR cohort • Initiated enrolment at 450 million dose level Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day 138 Initiating a Phase 1 study in Light Chain (AL) Amyloidosis • AL amyloidosis causes multi-organ failure from plasma cells secreting unstable proteins that deposit in organs • High unmet medical need with very few treatment options in the second line r/r setting • AUTO8 is designed to remove the disease-causing plasma cells and allow organ recovery • Clinical study open for enrolment Lee et al., ASH 2023, 2024 Enhanced function compared to other BCMA CARs NT bb2121 LCAR-B38M D8 1 10 100 1000 0 50000 100000 150000 IL-2 [BCMA-Fc] (ng/mL) IL-2 (pg/mL) NT Bb2121 (ide-cel) LCAR-B38M (cilta-cel) BMCA CAR (AUTO8) CK VH VL HNG FabCAR format Collaboration with BCMA CAR Novel FabCAR format designed to be very sensitive to low BCMA expression CD19 CAR Coupled to CD19 CAR from obe-cel to drive persistence and durability of response
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Upcoming milestones and financials Anticipated Milestone or Catalyst Anticipated Timing Notification from UK regarding approval in adult r/r ALL Q2 2025 Notification from EU regarding approval in adult r/r ALL H2 2025 Initial data from PY01 trial in pediatric ALL H2 2025 SLE Phase 1 trial presentation at medical conference Q4 2025 First patient dosed in SL2 Phase 2 trial in lupus nephritis YE 2025 First patient dosed in progressive MS Phase 1 trial YE 2025 Oncology Autoimmune The Company is well capitalized to drive the launch and commercialization of obe-cel in r/r B ALL and obtain data in the lupus nephritis potential pivotal trial. $588M as of YE 2024 139 Developing and Delivering a New Generation of T Cell Therapies | April 2025 R&D Day
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