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Sana Biotechnology Changing the Possible for Patients Recent data
confirm Sana's hypoimmune platform (HIP) overcomes allogeneic rejection in people Transplanted HIP-modified pancreatic islets overcome allogeneic and autoimmune rejection in type 1 diabetes We believe T1D result generalizable across
many cell types and patient populations HIP technology provides foundation for multiple drugs across multiple large therapeutic areas Type 1 diabetes - SC451 B-cell mediated autoimmune diseases (lupus, vasculitis, others) -
SC291 Blood cancers - SC262 Fusogen platform proof of concept for in vivo CAR T cells Potential for potent CAR T cells with no conditioning chemotherapy and opportunity to transform the autoimmune landscape Balance sheet allows
Overcoming allogeneic immune rejection has been key limitation in
transplant and cellular medicine Allogeneic cell rejection Sana's hypoimmune approach ~75 years of transplants - immune rejection remains the largest problem Blocks innate Blocks adaptive immune system immune system
Lifelong immunosuppression is current standard 1 2 3 Disruption of MHC Class I & Overexpression of Genome modification efforts to date have II expression CD47 generally been incomplete Autologous therapies have limited scalability
and are only available for a small number of cell types - MHC I + CD47 Healthy donor Hypoimmune Sana has published and/or presented cells cells positive data with the HIP platform showing - MHC II the ability to overcome allogeneic rejection
Type 1 diabetes (T1D) remains a significant unmet need Improvement in
glycemic control reduces microvascular complications T1D is an autoimmune destruction of insulin-producing pancreatic beta 1 but increases the risk of hypoglycemia cells and leads to lifelong insulin therapy requirement 8.4M people WW
have T1D, and incidence is increasing. Prevalence is expected to double over next 15 years 80% of individuals with T1D are from high-income countries Insulin therapy has been transformative, but not curative T1D leads to more
than a decade shorter life expectancy despite significant advances such as continuous glucose monitoring, insulin pumps, and novel forms of insulin Complications directly related to hyperglycemia include microvascular (retinopathy,
nephropathy, neuropathy) and macrovascular (coronary artery disease, heart attacks, stroke, wound healing, and amputations) issues At the other extreme, severe hypoglycemia can be rapidly fatal 1 Diabetes Control and Complications Trial
Advancing toward a cure for broad T1D population T1D is a disease of
missing pancreatic beta cells 1 2 Primary islet transplants provide Stem-cell derived islets provide The Goal: long-term glucose control, but: a scalable supply, but: A single treatment with Supply is an issue long-term normal blood glucose
Still requires chronic Requires chronic without immunosuppression immunosuppression Immunosuppression or insulin therapy 3 Eliminate the need for Abbreviations: T1D, type 1 diabetes. immunosuppression 2020-2025 Sana
Potential clinical validation of hypoimmune islet cells in T1DM patients
IST Design Trial at Uppsala University Hospital 1 2 3 Primary human HIP-modified islet cells transplanted in type 1 diabetes patients Intramuscular administration in forearm No immunosuppression Transplant into HIP gene
All primary and secondary endpoints met Primary and Secondary Endpoints:
Data Summary Endpoints D7 D14 D21 D28 Safety (no AE/SAE related to drug) Cell survival/function (C-peptide) Not performed Graft visibility (MRI) (as per protocol) Adaptive immune evasion Innate immune evasion 2020-2025 Sana Biotechnology. All
Stable C-peptide demonstrates survival and function of cells after HIP
islet cell transplantation Basal C-peptide in peripheral blood 15 11.4 11.3 12 10.2 9.7 9 6 3 0 Baseline D7 D14 D21 D28 Summary: No detectable C-peptide before transplantation; present and stable C-peptide observed after transplantation. Baseline:
Increased C-peptide levels with a mixed meal tolerance test (MMTT)
highlight survival and function Before transplantation Day 28 20 17.2 17.0 16.3 15 13.4 12.1 10 10.5 5 0 0 30 60 90 120 Time (min) Summary: Before transplantation, C-peptide is below detection limit during MMTT. 28 days after UP421 transplantation,
C-peptide is present and stimulated by MMTT. Baseline: Below limit of detection (LOD).Sensitivity: 0.48 pmol/L. Standard deviation represent technical triplicates. C-peptide analyzed in plasma samples. 2020-2025 Sana Biotechnology. All rights
Day 28 MRI: Further evidence of graft survival MR T2-STIR-weighted
trans images showing signal in musculus brachioradialis after injection of UP421 Arrows indicate the location of some examples of injected cells D28 MRI showing several punctual signals at the site of graft injection, no inflammation and no safety/
pathological related observations The MR T2-STIR-weighted sequence is sensitive to water and fluid and is a fat suppression technique to suppress the high signal from fat. Abbreviations: STIR, short TI inversion recovery. 2020-2025 Sana
The drug product's mixed cell population allows detailed immune
analysis Donor islet cells contain wild type & double knockout cells as well as HIP cells Donor Immune analysis using patient's (recipient) immune cells after transplantation + CD47 HLA I HIP islet cells T cells HLA II
Donor-specific antibodies CD47 HLA I Natural killer cells dKO islet cells HLA II Whole blood CD47 HLA I WT islet cells HLA II Abbreviations: dKO, double knock-out; HIP, hypoimmune; WT, wild type. 2020-2025 Sana Biotechnology.
Unmodified islet cells: Do not evade T cell or B cell immune response
WT islet cells WT islet cells WT islet cells Patient's T cells are activated and kill WT Patient's B cells produce donor-specific CD47 HLA I islet cells with peak at 7 days after transplant antibodies (switch from IgM to IgG at D14) 800
200 685 576 600 150 128 HLA II 457 98 400 100 85 301 67 60 200 50 21 0 0 Baseline D7 D14 D21 D28 Baseline D7 D14 D21 D28 200 Baseline D28 1.5 1.5 150 129 125 1.0 1.0 88 100 no killing 61 62 0.5 0.5 50 killing 0.0 0.0 0 10 20 30 40 50 10 20 30 40 50
dKO islet cells: Evade B and T cell responses but are killed by NK
cells dKO islet cells dKO islet cells dKO islet cells dKO islet cells No killing of HLA deficient cells No binding of donor-specific Patient's NK cells are killing CD47 HLA I by patient's T cells antibodies to HLA deficient cells HLA
I/II deficient cells (due to "missing-self") 800 200 Baseline 1.5 600 150 HLA II 1.0 400 100 61 62 61 62 59 0.5 200 50 killing 20 23 21 23 20 0 0 0.0 10 20 30 40 50 Baseline D7 D14 D21 D28 BL D7 D14 D21 D28 Hours -0.5 Baseline D28 200
D28 1.5 1.5 1.5 150 1.0 1.0 1.0 no killing no killing 100 0.5 0.5 0.5 60 60 60 61 59 killing 50 0.0 0.0 0.0 10 20 30 40 50 10 20 30 40 50 10 20 30 40 50 0 Hours Hours Hours -0.5 -0.5 -0.5 BL D7 D14 D21 D28 Abbreviations: BL, baseline.
HIP islet cells: Evade T cell, B cell, and NK cell immune responses HIP
islet cells HIP islet cells HIP islet cells HIP islet cells No killing of HIP islet cells No binding of donor-specific No killing of HIP islet cells + CD47 HLA I by patient's T cells antibodies to HIP islet cells by patient's NK cells
800 200 Baseline 1.5 600 150 HLA II 1.0 400 100 63 62 61 60 59 no killing 0.5 200 50 22 21 20 21 23 0 0 0.0 10 20 30 40 50 Baseline D7 D14 D21 D28 BL D7 D14 D21 D28 Hours -0.5 Baseline D28 200 D28 1.5 1.5 1.5 150 1.0 1.0 1.0 no killing no killing no
Normalized Cell Index IgG MFI IgM MFI Normalized Cell Index Normalized Cell Index
HIP islet cells overcome patient's allogeneic and autoimmune barrier
still image before movie D7 sample: PBMC (containing all immune cell populations) Donor islet cells with NK cells plus serum (containing antibodies and complement) killing assay editing profile in column title Target: WT islet cell Target: HLAI/II
still image after movie 2020-2025 Sana Biotechnology. All rights
SC451: A drug for the broad T1D population Make hypoimmune islet
Manufacture Deliver as a 1 2 3 cells from stem cells at scale single therapy Graft site + CD47 MHC I MHC II SC451 program - HIP stem cell-derived islet cell therapy delivered with no immunosuppression 2020-2025 Sana Biotechnology. All
Four major challenges to realizing the vision of SC451 1 2 3 4
Overcoming immune Differentiating PSCs into Generating a gene- Manufacturing enough rejection without islet cells at a purity, modified MCB from a GMP- product to treat the immunosuppression potency, and yield to compliant PSC line that is patients
that need it enable clinical trial dosing genetically stable and We believe this challenge We are working on remains so after gene has now been solved Many groups have done this the challenges of editing and differentiation successfully and so has
HIP-modified PSC differentiated islet cells transplanted into muscle
persist & control blood glucose in mice for >15 months PSCs differentiated into HIP-modified PSC HIP-modified PSC islets persist islets at high purity islets produce human and control blood glucose (non-fasted blood glucose*) c-peptide** in
vivo (performed at week 51) iPSC-islets Diabetic (STZ) control 600 ULOQ 2000 400 1500 Insulin Diabetic 1000 200 500 0 0 4 8 12 16 20 24 52566064 0 STZ Time post-transplant (weeks) Pre- Post- glucose glucose Maintain normoglycemia (64+ weeks)
Secrete c-peptide in response to glucose Retain strong expression of hCD47 Diabetic threshold at 250 mg/dL; data reported as mean S.E.M. **plasma human c-peptide after 5 hr fast (pre) and 30 min after I.P. 3 g/kg dextrose bolus
B-cells drive autoimmune disease in millions of patients >75
different types of autoimmune disorders with underlying B cell pathology and high unmet need SLE NMDAR encephalitis Vasculitis (granulomatosis Thrombocytopenic purpura with polyangiitis & microscopic
Amyloidosis >5M polyangiitis) Systemic sclerosis 1 patients Neuromyelitis optical spectrum Autoimmune hemolytic anemia B-cell mediated Pemphigus Chronic immune demyelinating autoimmune Relapsing and
polyradiculoneuropathy diseases progressive MS Immune-mediated necrotizing Rheumatoid arthritis myopathy Lupus nephritis Membranous nephropathy Lupus Foundation of America Sj gren's syndrome
estimates over a million people 2 have lupus in the US 1 2 Sana internal analysis; SciVida Autoimmune Factbook 2023, U.S; www.lupus.org/resources/how-many-people-have-lupus-in-the-united-states. 2020-2025 Sana Biotechnology. All rights
Autologous CAR Ts have shown curative potential; allogeneic cells have
inherent advantages Autologous CAR T CD19 Autologous CAR T treatment has Challenges 1 delivered long term, drug-free remissions Difficult to scale SLEDAI-2K Urinary Protein Excretion Prescription-to-infusion time over 4 weeks
Patients must be taken off anti-inflammatory drugs for apheresis and treatment Allogeneic CAR T Promise Scalable Available to patients off-the-shelf No apheresis Allogeneic CAR Ts are the future 1 Muller F et al, NEJM 2024,
Sana's T cell manufacturing process provides high yields of
successfully edited cells SC291: Highly efficient editing of cells Product ready when the patient needs it 1 100s of autoimmune patient batches/manufacturing run + CD47 + CAR MHC I ~85% full knock-out of MHC class I and II MHC II >99.5% TCR
SC291 can be safely administered and results in deep, dose-dependent
B-cell depletion in oncology Deep B-cell depletion seen in NHL patients ARDENT Safety Data (N=16) 5000 Dose Level 3 Dose Level 4 300-006 (M5) 300-012 1000 300-007 (M3) No cases of Grade 2 or higher CRS 103-002 (D28) 500 300-008 (M3) 3
cases of Grade 1 CRS 300-010 (M3) 100 50 No cases of ICANS 40 1 case of Grade 1 IEC-HS 30 20 10 LLOQ 0 D-5 D0 D1 D3 D6 D8 D10 D13 D16 D21 D28 M2 M3 M4 M5 Timepoint Data cutoff Nov 2024. Abbreviations: CRS, cytokine release syndrome;
SC291: GLEAM Phase 1 trial goals are to understand safety, dose, and
early efficacy Allogeneic HIP CAR T cell + CD47 Key features of Phase 1 trial (GLEAM) Patients with refractory systemic lupus erythematosus and ANCA-associated MHC I vasculitis + CD19 CAR Dose escalation study MHC II
Potential to expand beyond these indications over time SC291 granted Fast Track designation in relapsed/refractory SLE TCR Trial enrolled first patients in 2024 An effective allogeneic CAR T offers potential to transform outcomes
Sana is pursuing in vivo engineering of CAR T cells using a fusosome
vector system Delivery Expression Function Transduction of CD8 T cells Transgene integration and CAR expression Targeted cell killing B cell T cell Target cell killing CAR CAR Transgene T cell amplification for CAR expression CAR T cell Fusosome 2 1
Fusosome technology: Cell-specific in vivo delivery Sana approach:
Potent and cell-specific in vivo delivery demonstrated with SG299 in
GLP tox study 4 NHPs at each dose received single SG299 injection Potent transduction of No off-target transduction detected in + circulating CD8 T cells hepatocytes or gonadal cells Low dose High dose 0 -1 10 10 ON-TARGET Low dose Achieved in the
absence of High dose -1 CAR-mediated amplification 10 (CAR is not NHP-reactive) -2 10 -2 10 -3 10 LOQ -3 NO LIVER NO TESTIS 10 OFF-TARGET OFF-TARGET -4 10 LOD 0 10 20 30 40 60 80 100 Day Avg SEM plotted. Note that any values BLOQ are not
right lobe Lung caudal Lymph node draining CD8+ lymph node Spleen CD8+ spleen Heart ventricle Injection site Kidney left Kidney right Large intestine Pancreas Small intestine Testis Thymus Tonsils Heart atrium Spinal cord cervical Brain + CAR Vector
Copy Per CD8 T Cell CAR Vector Copy Per Cell
Surrogate SG299 with additional component leads to T cell transduction,
CAR expansion, and B-cell depletion Surrogate SG299 transduces T cells & expresses a CAR that recognizes NHP B cells + + CD8 CAR cells expand in circulation Deep B-cell depletion achieved in peripheral blood Control NHP 1 NHP 2 Control n=3 NHP 1
Study shows B cell clearance in lymph nodes without lymphodepletion
SC262: Targets growing population of patients with inadequate response
to CD19 therapy CD19 CAR T relapsed patients represent CD22 CAR T is a promising approach to 1 5 large and growing unmet need treat CD19 therapy failure Autologous CD22 CAR T results in >50% CR rate in Estimated ~12,000 CD19 CAR failure
DLBCL patients B cell malignancy patients treated with High rates of non relapse mortality reported in long 2 CD19 CAR T in 2027 term follow up of autologous CD22 CAR T-treated Estimated ~35-40% patients Potential of ~7,500 of CAR T
patients CAR T failures 6 with durable High rate of CRs also seen in CD19 failure ALL patients 2 annually in 2027 4 complete responses Median survival of ~5 months post-CD19 3 CAR T therapy failure = 1,000 people 1 2 US, EU5, and
Japan. Clarivate DRG NHL Market Forecast Nov 2021; 2027 Forecast is 2L+ LBCL patients; internal analysis of secondary EPI data. 3 4 5 ;5 6 Di Blasi et al. Blood.2022; DESCAR-T registry. DiBlasi et al. Blood. 2022: 2024 ASH Kramer et al. 2022 ASH
SC262: VIVID Phase 1 trial goals are to understand safety, dose, and
early efficacy Allogeneic HIP CAR T cell + CD47 Key features of Phase 1 trial (VIVID) CD19 CAR T exposed patients with relapsed and/or refractory NHL MHC I + CD22 CAR Starting dose of 90 million CAR T cells MHC II Expect
We anticipate meaningful clinical data in multiple diseases in 2025 and