Bluebird bio : Corporate Presentation - November 2020

Recoding in Action

Q4 2020

NASDAQ: BLUE

1

forward-looking statements

These slides and the accompanying oral presentation contain forward-looking statements and information. The use of words such as "may," "might," "will," "should," "expect," "plan," "anticipate," "believe," "estimate," "project," "intend," "future," "potential," or "continue," and other similar expressions are intended to identify forward-looking statements. For example, all statements we make regarding the initiation, timing, progress and results of our preclinical and clinical studies and our research and development programs, our ability to advance product candidates into, and successfully complete, clinical studies, the timing or likelihood of regulatory filings and approvals, and the timing and likelihood of entering into contracts with payors for value-based payments over time or reimbursement approvals, and our commercialization plans for approved products are forward looking. All forward-looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. These statements are also subject to a number of material risks and uncertainties that are described in our most recent quarterly report on Form 10-Q, as well as our subsequent filings with the Securities and Exchange Commission. Any forward-looking statement speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.

2

Must Beat the Odds.

Period.

CARE DEEPLY

The	The
Why	How

BE HUMAN

3

Our 2022 Vision

ZYNTEGLO (beti-cel) for TDT

• • 2019 EU Approval
• 2021 US BLA Submission

2022

THE GENE THERAPY PRODUCTS COMPANY

Lenti-D(eli-cel) for CALD

• 2021 EU Approval
• 2021 BLA Submission

LentiGlobin (bb1111) for SCD	Patient∞Impact	ide-cel (bb2121) for Multiple
Myeloma
 2022 US BLA Submission
 2021 US Approval

4

Transfusion-Dependentβ-Thalassemia - reimagined future

2010

R E C O D E

Vector Potency &

Manufacturing

Enhancement

EHA 2020

• Northstar-2(HGB-207): All patients treated, 89% TI
• Northstar-3(HGB-212): 85% of patients have been off transfusions for > 6 months

• EU Approved 2019
• US rolling BLA initiated 2019

Nature 2010	5

Transfusion-dependentβ-thalassemia (TDT):

patients achieving transfusion independence across genotypes and ages

ASH 2019

Northstar-2(HGB-207):

1. Non-β0/β0: 90% of patients achieving TI

Northstar-3(HGB-212):

1. β0/β0 and IVS-I-110: 2 patients evaluable for TI, achieve TI

EHA 2020

Achieving and maintaining transfusion independence (TI) across ages and genotypes

Northstar-2(HGB-207):

1. Non-β0/β0: All patients treated o 89% successfully achieved TI

Northstar-3(HGB-212):

1. β0/β0 and IVS-I-110:85% of patients have been off transfusions for > 6 months

Compelling data supports commercial path

6

Northstar-2:Non-β0/β0 patients achieving & maintaining transfusion independence

91% (20/22) of patients with >3 months of follow-up	Median unsupported total Hb is ≥ 11.5 g/dL
have stopped pRBC transfusions

 89% (17/19) of evaluable patients achieved primary endpoint: transfusion
independence
 Patient 2 and Patient 20 had 46% and 16% reduction in pRBC transfusion volume,
respectively, from 6 months to last follow-up
§Patient's total Hb level at Month 22 was 13.4 g/dL. Following a planned orthopedic surgery, the patient had blood loss, which
required 1 pRBC transfusion; pRBC, packed red blood cell.
Data as of 7 April 2020	Data as of 3 March 2020	7
Median, min, max depicted

Northstar-3: β0/β0 patients continue to show compelling results

Transfusion status in patients with

≥ 3 months follow-up

TI Evaluable Patients

^

• 85% (11/13) of patients have been off transfusions for > 6 months; prior to beti-cel infusion, these patients required 11 - 39.5 transfusions/year
• Patient 4 and Patient 8 continue to receive pRBC transfusions and had an 80% and 31% reduction in number of transfusions, respectively

Total Hb and HbAT87Q over time in patients who have not received a transfusion in > 60 days

• As transduced HSCs engraft and produce mature RBCs, HbAT87Q levels increase and stabilize approximately 6 - 9 months after beti-cel infusion

^Patient < 12 years old at consent; *Indicates pRBC transfusion in prior 60 days. Data as of 7 April 2020	Median, min, max depicted; Unsupported total Hb level is defined as Hb without any red blood cell
	transfusions within 60 days. Hb, hemoglobin. Data as of 3 March 2020	8

Robust data supports commercial path forward

EU: Ready to Go

First commercial patients pending in

Germany

Ongoing engagement with payers in additional EU markets supports access and reimbursement in early 2021

Plan to pursue expanded label to

include patients with β0/β0 genotypes

and pediatrics

US: Clear Path

Plan to seek approval for all patients

with TDT, including all ages and

genotypes

Learnings from FDA engagement

leveraged across programs

US BLA Submission Planned for

mid-2021

9

Establishing Promising Access & Value Foundation

EU Launch Readiness

First ever at-riskvalue-based agreement signed with multiple Sick Funds in Germany (~50-70%of patients in Germany covered)

Team in place in Zug, UK, France, Italy, Germany, and Nordic Markets Qualified Treatment Centers and manufacturing ready in Germany

U.S. Launch Readiness

Team in place for U.S. commercialization

Payers (Commercial) - Actively engaging to enable access & value-based payment over time at launch

Policy (State & Federal) - Focused on enabling value-based payment over time in commercial and for Medicaid markets to drive access

Distribution - Establishing customized distribution model to serve QTC & payer needs

Market and Patient Engagement

Disease Education and outreach in place

Patient Advocacy education and initiative support

S T R O N G F O U N D A T I O N F O R M I N G

10

Sickle Cell Disease - Daring to Dream

2017

c		R E C O D E
		Pre-Tx Transfusions
	More Thorough Conditioning
		Higher Cell Dose
		Higher VCN

EHA 2020

99.5% reduction in annualized rate of VOC + ACS*

• Development plans under accelerated approval underway

New England Journal of Medicine 2017	*HGB-206 Group C patients with history of VOCs and ACS who had ≥ 6 months of follow-up;	11

data as of March 3, 2020

Sickle Cell Disease:

Totality of the clinical data validates transformative clinical results

ASH 2019

Early clinical benefit:

1. 99% mean reduction in VOC and ACS

Group C patients:

1. 17 patients; 9 patients with
   ≥6 months follow up and ≥4
   VOC/ACS at baseline

Improvement in key markers of hemolysis

EHA 2020

Magnitude of clinical benefit:

1. 99.5% mean reduction in VOC and ACS
   More patients; more follow-up:

1. 25 patients; 14 patients with ≥6 months follow up and ≥4 VOC/ACS at baseline

Consistent results across multiple markers:

1. Continued improvements in hemolysis markers, HbAT87Q levels and pancellular expression

Clarity on U.S. regulatory path:

1. Based on HGB-206 Group C, primary endpoint of complete resolution of VOEs

12

Sickle cell disease is characterized by high morbidity and early mortality

High levels of

HbS in RBCs

Vaso-occlusion

Hemolysis

↓O2 HbS
polymerization
& sickling	Vasculopathy

Complications
Vaso-occlusive	Anemia
pain
Cerebral
vasculopathy/	Retinopathy
stroke
Acute chest	Pulmonary
syndrome	hypertension
Hepato-splenic	Cardiovascular
sequestration	complications
Priapism	Kidney disease
Sudden death	Leg ulcers

Organ failure

Osteonecrosis

> 50% of patients with SCD die before 45 years of age1

1. Hassell K., Am J Prev Med 2010; CNS, central nervous system; Hb, hemoglobin; RBC, red blood cell 13

HGB-206 Group C: Patients infused to support BLA submission

		Consented*
Screen failure	N=51
N=7	Plerixafor Mobilization &
		Apheresis
Discontinued†	N=40
N=3
		DP Manufacture Completed
		N=36
Discontinued ‡	LentiGlobin		DP Infused
N=25
N=1		Median follow-up: 12.1 months
		(min - max, 2.8 - 24.8 months)

Cell Collection Pending

N=4

DP Manufacture

Pending

N=1

Transplant

Pending

N=11

* Currently active, not recruiting; † 1 withdrew consent, 1 at investigator discretion, 1 mobilization failure; ‡ 1 death	Data as of 3 March 2020	14
DP, drug product

HGB-206 Group C: 99.5% mean reduction of annualized rate of VOCs + ACS post-LentiGlobin treatment

LentiGlobin for SCD treatment

pre-IC	*
Total number of events over 2 years
Median (min - max)	24 months prior to Informed Consent	Duration (months) of follow-uppost-DP
annualized VOC+ACS rate	4 (2 - 14)	0 (0 - 0.8)

Total number of events over 2 years post-DP

• No ACS or serious VOCs occurred in any Group C patient post-LentiGlobin treatment to date (2.8 - 24.8 months follow-up)
• One previously reported non-serious Grade 2 VOC was observed in 1 patient ~ 3.5 months post-LentiGlobin treatment

Investigator-reported AEs of VOC or ACS are shown; Patients with ≥ 4 VOC/ACS at baseline before IC and with ≥ 6 months of follow-uppost-DP infusion are included

ACS, acute chest syndrome; CI, confidence interval; DP, drug product; IC, informed consent; VOC, vaso-occlusive crisis	Data as of 3 March 2020	15

HGB-206 Group C: Median HbS ≤60% and HbAT87Q ≥40% at ≥6 months post- LentiGlobin treatment

% represents median Hb fraction as % of total Hb; Hb, hemoglobin; * Number of patients with data available

Data as of 3 March 2020

16

HGB-206 Group C: Decrease in hemolysis markers post-LentiGlobin treatment

Reticulocyte Counts

Lactate Dehydrogenase

Total Bilirubin

Median (Q1, Q3) depicted; Dot-dash lines denote lower and upper limits of normal values; * Number of patients with data available Data as of 3 March 2020	17

Average proportion of RBCs containing βA-T87Q from LentiGlobin-treated patients is ≥70% by month 6 and ~90% by month 18

• Single RBC western assay was performed in subset of HGB-206 Group C patient samples

• Median (min - max) HbAT87Q/RBC was 15.3 (11.7 - 20)† pg in patients with ≥ 6 months follow-up, which is comparable to the 13 - 18 pg of HbA/RBC in individuals with sickle cell trait‡ and higher than 10 pg of HbF/RBC in those with HPFH§

Mean & SD are depicted; Reducing HbS to < 30% is recommended by guidelines for exchange RBC transfusions for patients with SCD (indicated by dashed line);* Pre-conditioning sample does not contain any βA-T87Q , signal is due to error rate of multiples; † Calculated as (% HbAT87Q of total Hb/% RBCs containing βA-T87Q) x MCH; ‡ Calculated to 13-18 pg/RBC using 50% HbA/RBC for the lower end

of the range and 60% HbA/RBC for the upper end of the range; § Estimated in Steinberg MH et al., Blood. 2014;123(4):481-5.	Data as of 3 March 2020	18
HPFH, hereditary persistence of fetal hemoglobin; MCH, mean corpuscular hemoglobin; RBCs, red blood cells; SD, standard deviation

HGB-206 Group C: Safety profile post-LentiGlobin infusion

Non-hematologic ≥ Grade 3 AEs	N=25
Post-DP infusion in ≥ 2 patients*	n (%)
Stomatitis	15	(60)
Febrile neutropenia	11	(44)
Increased ALT	3 (12)
Increased AST	3 (12)
Increased GGT	3 (12)
Increased total bilirubin	3 (12)
Nausea	3 (12)
Premature menopause	2	(8)
Upper abdominal pain	2	(8)
Serious AEs
Post-DP infusion in ≥ 2 patients
Nausea	2	(8)
Opioid withdrawal syndrome	2	(8)
Vomiting	2	(8)

• Hematologic AEs commonly observed post-transplantation have been excluded; AE, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase

• 3 patients with DP-related AEs (all nonserious and ≤ Grade 2)†
• No cases of veno-occlusive liver disease
• No graft failure
• No vector-mediated RCL and no insertional oncogenesis
• One death, unlikely related to LentiGlobin: A 27-year-old patient with history of VOC/ACS, pulmonary hypertension, and venous thrombosis died ~20 months post-treatment after sudden onset of shortness of breath followed by cardiac arrest

• Post-DP:No VOCs/ACS (vs 28 episodes in 2 years pre-study); no sickle- related adverse events or ≥ Grade 3 AEs

• 1. At last study visit, Hb was 13.9 g/dL, with HbAT87Q 36% and HbS 56%
• Autopsy showed no evidence of pulmonary embolism, stroke or clinically significant sickling
• 1. Death was due to CV disease, with findings of cardiomegaly, cardiac fibrosis and pulmonary congestion
• Per PIs, pre-existingSCD-related cardiac disease and pulmonary hypertension may have been contributing factors

• 1 pt with Grade 2 nonserious neutropenic fever on study day 10 (resolved on study day 18); 1 pt with post-DP infusion Grade 2 AEs of nail discoloration and constipation as well as Grade 1 AEs of runny nose and cough. This pt also had 3 AEs with onset pre-DP infusion (nonserious Grade 2 alopecia, Grade 1 vomiting and Grade 1 fatigue) which were initially assessed as DP-related, but attribution was changed to not DP-related after datacut date; 1 pt with 1 event of nonserious Grade 2 back pain

ACS, acute chest syndrome; CV, cardiovascular; DP, drug product; Hb, hemoglobin; PIs, principal investigators; RCL, replication competent lentivirus; VOC,	Data as of 3 March 2020	19
vaso-occlusive crisis

Updated plan for accelerated approval based on compelling VOE data

HGB-206 Group C	HGB-210
Sickle Cell Disease, history of vaso-occlusive	Sickle Cell Disease, history of VOEs over
events (VOEs) over 24 months	24 months
Ongoing Phase 1/2, single arm, multi-center,	Ongoing Phase 3, single arm, multi-center,
U.S. study	global study
N=41 (Group C)

• Primary Endpoint: Complete resolution of severe VOEs
• Key Secondary Endpoint:
• • HbAT87Q and total Hb
• ≥ 12 years of age - ≤ 50 years of age

• Primary Endpoint: HbAT87Q and Total Hb
• Key Secondary Endpoint:
• • Reduction in severe VOEs

Anticipated late 2022 US BLA

1. submission enabled by FDA alignment on clinical and CMC packages

Primary endpoint:	HGB-210: Serving as
2.VOEs	3.confirmatory study

20

20

Multiple Myeloma - changing what's possible

Standard of Care*

Standard of Care

• ~4 months PFS
• ~30% ORR

• ~3% CR

R E C O D E

BCMA Target &

Next-Gen CAR

ine	ASCO 2020

• mPFS of 12.1 months at 450x106 dose
• CAR+ T cell persistence observed up to 1yr
• KarMMa N=128; CRB-401 N=67

2020

• U.S. BLA accepted for Priority Review September 2020
• Ongoing studies in 3L, 2L and 1L (Newly Diagnosed)

*Lonial et al, Lancet 2016 (Dara); Siegel et al, Blood 2012 (Kyprolis); Hajek et al,
Leukemia 2017 (Kyprolis); Chari et al, NEJM 2019 (Selinexor); Richardson et al,	21
Blood 2014 (PomDex)

Multiple Myeloma - ide-cel:

Broad oncology strategy and development program supported by clinical data

BCMA Program

BMS Alignment

1. U.S. 50/50 co-co

1. Ex-U.S.BMS wholly-owned

Regulatory path enabling near-term launch:

1. BLA submitted

1. MAA submission accepted

Broad clinical development program enabling potential expansion into earlier lines

ASCO 2020

KarMMa Data

Mature and consistent data demonstrate deep and durable responses:

1. CAR+ T cell persistence observed up to 1yr with meaningful detectable vector

1. mPFS of 12.1 months at 450x106 dose o KarMMa N=128; CRB-401 N=67

22

Advancing into earlier lines of therapy and continuing to innovate

lines of therapy

front line setting phase 1 study open

2nd line phase 2 study open

2-4 prior lines phase 3 study open

4th line+ pivotal study

Basis of U.S. BLA

Submission

bb21217 next-gen anti- BCMA CAR T study ongoing

Multiple Myeloma

phase 1

phase 2

phase 3

KarMMa-4

KarMMa-2

KarMMa-3

KarMMa

CRB-402

Studies ongoing in partnership with BMS

23

KarMMa: heavily pretreated, refractory patient population

Characteristics		Ide-cel Treated
	(N=128)

	Age, median (range), y				61 (33−78)
	Male, %				59
				0		45
	ECOG PS, %		1		53
				2		2
				I		11
	R-ISS Stage,* %		II		70
				III		16
	High-risk cytogenetics [del(17p), t(4;14), t(14;16)],† %	35
	High tumor burden (≥50% BMPCs), %				51
	Tumor BCMA expression (≥50% BCMA+),‡ %				85
	Extramedullary disease, %				39
	Time since initial diagnosis, median (range), y			6 (1−18)
	No. of prior anti-myeloma regimens, median (range)			6 (3−16)
	Prior autologous SCT, %		1		94
		>1		34
	Any bridging therapies for MM, %				88
	Refractory status, %		Anti-CD38Ab-refractory		94
			Triple-refractory		84

• Patients were heavily pretreated, refractory to last line per IMWG criteria, and mostly refractory to all 3 major MM drug classes
• The majority had high tumor burden and more than one third had extramedullary disease and high-risk cytogenetics
• Tumor BCMA expression identified by IHC in all patients
• Most patients (88%) received bridging therapy during CAR T cell manufacturing
• • Only 4% of patients responded (4 PR, 1 VGPR) to bridging therapy

24

CAR+ T cell expansion, persistence, and peak exposure

CAR+ T Cell Expansion and Persistence

Median Concentration, copies/μg

Time

		Total (n=127)			300 × 106 cells (n=69)
		150 × 106 cells (n=4)			450 × 106 cells (n=54)
			Mo 1	Mo 3	Mo 6	Mo 9	Mo 12
Evaluable patients, n	118	100	49	27	11
Patients with detectable	117 (99)	75 (75)	29 (59)	10 (37)	4 (36)
vector, n (%)

Peak Vector Copies in Responders (≥PR) vs

Nonresponders (<>

μg	107
copies/,	106
max	105
C	104

Nonresponders	Responders
(n=34)	(n=93)

• Median peak CAR+ T cell expansion was at 11 d
• Median expansion increased at higher target doses with overlapping profiles
• Peak exposure higher in responders than nonresponders
• Durable persistence was observed up to 1 y

Data cutoff: 19 April 2019. Pharmacokinetic (PK) analysis population (N=127). One patient died on day 4 and had no evaluable PK samples and was	25
therefore excluded. Error bars represent interquartile range. BL, baseline; Cmax, maximum concentration; LLOQ, lower limit of quantitation; M, month.

82% ORR and 39% CR rate at 450 x 106 dose level

Response, %

100

80

60

40

20

0

CR/sCR and MRD-negative CR/sCR and MRD not evaluable

VGPR

PR		ORR=69%
		24
ORR=50%
25	CRR	4
	14
	25%
25		26

	ORR=82%
	28	ORR=73%
	CRR	26
	CRR
CRR	39%
29%	11	33%
	7
	26	20
	17	21

CAR+ T cells:	150 × 10⁶	300 × 10⁶
(n=4)	(n=70)

450 × 10⁶	Ide-cel Treated
(n=54)	(N=128)

• Primary (ORR >50%) and key secondary (CRR >10%) endpoints met in the ide-cel treated population
• • ORR of 73% (95% CI, 65.8−81.1; P<0.0001*)
  • CRR (CR/sCR) of 33% (95% CI, 24.7−40.9; P<0.0001)
• Median time to first response of 1.0 mo (range, 0.5−8.8); median time to CR of 2.8 mo (range, 1.0−11.8)
• Median follow-up of 13.3 mo across target dose levels
• All patients with CR or sCR and were evaluable for MRD, were MRD-negative

Data cutoff: 14 Jan 2020. MRD-negativedefined as <10-5 nucleated cellsby next generationsequencing. Only MRD valueswithin 3 moof achievingCR/sCRuntilprogression/death(exclusive) were considered.

Valuesmay not add up due to rounding.26 CR/sCR, completeresponse/stringentCR; CRR, CR rate; MRD, minimalresidualdisease; ORR, overall responserate (≥PR); PR, partialresponse; VGPR, very good PR. *P value at theprimary datacutoff with sameORR and 95% CI.

mDOR of 11.3 mo at 450 × 106 dose; mDOR of 19 mo in patients achieving CR/sCR

DOR by Target Dose

DOR by Best Response

Median (95% CI), mo

	1.0					150 × 10⁶	NR (2.8−NE)
					300	× 10⁶	9.9 (5.4−11.0)
DOR						450 × 10⁶	11.3 (10.3−11.4)
0.8
for
Probability	0.6
0.4
	0.2
	0
	0	2	4	6	8	10	12	14	16	18	20	22

1.0	CR/sCR	Median (95% CI), mo
19.0	(11.3−NE)
	VGPR	10.4	(5.1−11.3)
	PR	4.5 (2.9−6.7)
0.8

0.6

0.4

0.2

0

0

2

4

6

8

10

12

14

16

18

20

22

						Time, months												Time, months
At risk, N													At risk, n
150 × 106	2	2	1	1	1	1	1	1	1	1	0		CR/sCR	42	42	40	39	36	34	18	13	10	4	1	0
300 × 106	48	45	35	29	24	21	14	12	11	3	1	0	VGPR	25	24	21	17	15	14	4	2	2	0	0
450 × 106	44	42	39	35	31	29	7	2	0	0	0		PR	27	23	14	9	5	3	0	0	0	0	0

• Durable responses were observed across all target doses; DOR increased with depth of response

Data cutoff: 14 Jan 2020. CR/sCR, complete response/stringent CR; DOR, duration of response; NE, not estimable; NR,	27
not reached; PR, partial response; VGPR, very good PR.

mPFS of 12.1 months at 450 x 106 dose level; mPFS of 20.2 months in patients with a CR/sCR

PFS Probability

1.0

0.8

0.6

0.4

0.2

0

PFS by Target Dose

Median (95% CI), mo

150 × 106 2.8 (1.0−NE)

300 × 106 5.8 (4.2−8.9)

450 × 106 12.1 (8.8−12.3)

0

2

4

6

8

10

12

14

16

18

20

22

PFS by Best Response

																																								Median (95% CI), mo
																																								CR/sCR: 20.2 (12.3−NE)
1.01																																								VGPR: 11.3 (6.1−12.2)
																																							PR: 5.4 (3.8−8.2)
0.8																																								Nonresponders: 1.8 (1.2−1.9)
0.6
0.4
0.2

0

0

2

4

6

8

10

12

14

16

18

20

22

					Time, months												Time, months
At risk, N													CR/sCR	42	42	42	40	39	37	26	16	11	8	4	0
150 × 106	4	2	1	1	1	1	1	1	1	1	1	0	VGPR	25	25	22	20	16	14	8	3	2	0	0
300 × 106	70	56	42	33	29	24	17	14	11	7	2	0	PR	27	16	10	9	5	1	0	0	0	0	0
450 × 106	54	44	40	36	34	31	17	4	1	0	0		Nonresponders	34	8	83	70	64	56	35	19	13	8	4	0

• PFS increased with higher target dose; median PFS was 12 mo at 450 × 106 CAR+ T cells

• PFS increased by depth of response; median PFS was 20 mo in patients with CR/sCR

Data cutoff: 14 Jan 2020. NE, not estimable; PFS, progression-free survival.

28

Safety profile consistent with known toxicities of CAR T therapy

CRSNeurotoxicity

- Ide-cel was tolerable across the dose range

Ide-cel Treated

(N=128)

≥1 CRS event, n (%)	107 (84)
Max. grade (Lee
Criteria)*	100 (78)
1/2
5 (4)
3
1 (<1)
4
1 (<1)
5
Median onset, d	1 (1−12)
(range)
Median duration, d	5 (1−63)
(range)
Tocilizumab, n (%)	67 (52)
Corticosteroids, n	19 (15)
(%)

Ide-cel Treated

(N=128)

≥1 NT event, n (%)	23	(18)
Max. grade
(CTCAE)*	12 (9)
1
7	(5)
2
4	(3)
3
Median onset, d	2 (1−10)
(range)
Median duration, d	3 (1−26)
(range)
Tocilizumab, n (%)	3	(2)
Corticosteroids, n	10 (8)
(%)

- Grade ≥3 CRS or iiNT ≤6% at target dose of 450 × 106 CAR+

T cells

- CRS frequency increased with dose, but mostly low grade

- Cytopenias were common; not dose related

- Infections (including bacterial, viral, fungal) were common

(69%); not dose-related

- 5 deaths (4%) within 8 wk of ide-cel infusion (2 following

disease progression, 3 from AEs) and 1 from an AE within 6

mo of ide-cel infusion

Data cutoff: 14 Jan 2020; CRS, cytokine release syndrome, iiNT, investigator identified neuotoxicity

29

ide-cel (bb2121) - Positive Pivotal Data at ASCO

mPFS
(months)
			12.1
				8.8
4		5.8
2.8
SoC	150 x 106	300 x 106	450 x 106	All Doses

Heavily pretreated population

• Median 6 prior lines of therapy, 94% refractory to anti-CD38, 84% triple refractory
• All patients were refractory to their last treatment (progression during or within 60 days of last therapy)

Deep and durable responses across dose levels

• mPFS of >12mo at the 450 x 106 dose
• All patients who had CR or sCR, who were evaluable for minimal residual disease (MRD), were MRD-negative
• Durability is consistent across doses

	150 x 106	300 x 106	450 x 106	All Doses
	CAR+ T cells	CAR+ T cells	CAR+ T cells
	(N=128)
	(N=4)	(N=70)	(N=54)
ORR, n (%)	2 (50.0)	48 (68.6)	44 (81.5)	94 (73.4)
CR/sCR, n (%)	1 (25.0)	20 (28.6)	21 (39)	42 (33)
Median DoR, mo	---	9.9	11.3	10.7

Safety consistent with the Ph1 data

• Gr ≥ 3 CRS and iiNT were reported in <6% of subjects at each target dose
• CRS and iiNT of any grade occurred in 83.6% and 18% of patients, respectively

iiNT: investigator identified neurotoxicity	30
Ide-cel is being developed in collaboration with Bristol-Myers Squibb

Cerebral Adrenoleukodystrophy - From Tragedy to Hope

2009

R E C O D E

Enhanced Construct

&

Manufacturing

ALD-102 EBMT: 2020

• 20/23 patients alive and MFD-free at 24 months follow up, all continue to be MFD-free with up to 5 years of follow-up
• 32 total patients treated

Data as of January 2020

2020

• EU MAA accepted in October 2020
• Newborn screening active in 19 US states; several pilot programs in EU

Science 2009	31

eli-cel(Lenti-D) treatment halts CALD disease progression

October 4, 2017

N Engl J Med 2017; 377:1630-1638

ALD-102: all patients who were alive and MRD-free at 24 months follow up (20/23; 87%) continue to be MFD-free with up to 5 years of follow-up

• 32 patients have been treated with eli-cel with a median follow-up time of 30.0 months
• 9 patients are still on study with less than 24 months of follow-up and show no evidence of MFDs
• Three patients did not or will not meet the primary efficacy endpoint; two patients withdrew from the study at investigator discretion, and one experienced rapid disease progression early on- study resulting in MFDs and death.

Safety profile consistent with autologous transplantation

• No GvHD, no graft rejection or graft failure

Enrollment completed in ALD-102 Starbeam study Phase 3 ALD-104 study currently enrolling

Data as of January 2020

32

R&D BLUE style: what do we work on?

Core Research Principles

Programs with the	Diseases with	Targets with Human
Potential to Transform	Definitive Endpoints	Genetic and/or
Patient Lives	of Clinical Success	Functional Validation

We tackle diseases with
a clear unmet medical		Clinical success should		Biology may be complex
need based on the		be objective,		but the role of the target
magnitude of impact and		measurable, un-		in the disease must be
not necessarily the		incremental, and rapid		definitive
number of patients

Disruptive Solutions to the Problems that Need to be Solved

We don't do incremental science. We take on the big problems that, if successful, will disrupt our field

33

pipeline overview

1. Dev is led by Dana-Farber/Boston Children's Cancer and Blood Disorders Center
2. Dev is led in collaboration with Bristol Myers Squibb
3. Dev is led by Fred Hutch Cancer Research Institute
4. Dev is led by University of North Carolina
5. Dev is led by Seattle Children's Research Institute

Severe Genetic Diseases

Oncology

ELI-CEL

PRODUCT CANDIDATE

LENTIGLOBINTM

PRODUCT CANDIDATE FOR TRANSFUSION-DEPENDENTβ-THALASSEMIA (TDT)

LENTIGLOBINTM

PRODUCT CANDIDATE FOR SICKLE CELL DISEASE (SCD)

BCL11A shRNA(mir)1

MPSI GENE THERAPY APPROACH

MULTIPLE UNDISCLOSED

P R E C L I N I C A L	P H A S E 1	P H A S E 2

Cerebral Adrenoleukodystrophy (Starbeam, ALD-102)

Cerebral Adrenoleukodystrophy (ALD-104)

TDT Non-β0/β0 genotypes (Northstar-2,HGB-207)

TDT, including β0/β0 genotypes (Northstar-3,HGB-212)

SCD (HGB-210)

PH 1/2

SCD (HGB-206)

PH 1

Sickle Cell Disease

PRE-C

Hurler Syndrome

PRE-C

Undisclosed

P H A S E 3

PH 2/3

PH 2/3

IDE-CEL (BB2121)2

PH 3	A P V D I N
T H E E U
PH 3

BB21217 2

PH 2/3

MCC1 TCR 3

UNC ONCOLOGY TARGET CAR 4

MAGE-A4 TCR

DUAL B-CELL CAR

DARIC MULTI-TARGET5

MULTIPLE UNDISCLOSED

P R E C L I N I C A L

P H A S E 1

P H A S E 2

P H A S E 3

PH 1

Multiple Myeloma First Line (KarMMa-4)

PH 2

Multiple Myeloma Second Line (KarMMa-2)

PH 3

Multiple Myeloma Third Line (KarMMa-3)

PH 2

Multiple Myeloma Fourth Line+ (KarMMa)

PH 1

CRB-401: Multiple Myeloma ≥3 Prior Lines

PH 1

CRB-402: Multiple Myeloma ≥3 Prior Lines

PH 1

Merkel Cell Carcinoma

PRE-C

Solid Tumors

PRE-C

MAGE A4 Positive Solid Tumors

PRE-C

Diffuse Large B-Cell Lymphoma

PRE-C

Acute Myeloid Leukemia

PRE-C

Undisclosed

34

bb21217: PI3K inhibition during manufacturing drives increase in long-lived,memory-like T cells

TN	TSCM	TCM	TEM	TEFF
cell	cell	cell	cell	cell

Terminally Differentiated

No Self Renewal

Short-lived

T cell Plasticity

Self Renewal

Long-lived

Hypothesis: Increasing long-lived,memory-like T cell subsets in the drug product may result in enhanced persistence of functional anti-BCMA CAR T cells in vivo

35

Diffuse Large B-Cell Lymphoma -Triple Threat Approach

1

2		50,000
	(pg/mL)	40,000
	30,000
	IFNγ	20,000
	10,000
		0

No	Target	Target	Target
Target	1	2	1 & 2

3

L A Y E R

dual-CAR targeting

signal

extension

signal

amplification

P U R P O S E

prevent escape

enhance T cell

activation

improve T cell

persistence

E A C H L AY E R I N F O R M S 1 : M A N Y P L AT F O R M

Copyright bluebird bio 36

2020-2021: BLUE is Prepared and On Track for the Catalysts Ahead

Regulatory

Clinical

Updates

Commercial

• Foundation Building

2020 Complete

• LentiGlobin SCD Regulatory Update
• Ide-cel(bb2121) MM U.S. BLA submission
• Eli-celCALD EU MAA Submission
• Ide-cel(bb2121) KarMMa data at
  ASCO
• SCD: HGB-206 data at EHA
• TDT: HGB-207,HGB-212 Data at
  EHA
• Eli-celALD-102 data update by EOY
• SCD: HGB-206 data at EHA
• SCD First patients treated with sLVV
• ZYNTEGLO Launch in Germany

2020 Upcoming

• SCD: HGB-206 data by end of year
• Ide-celCRB-401 data by end of year
• bb21217 CRB-402 data by end of year

• ZYNTEGLO first commercial patients treated
• Ide-celU.S. launch ready

2021

• LentiGlobin TDT U.S. BLA submission (mid-year)
• Eli-celCALD U.S. BLA submission (mid-year)
• Ide-cel(bb2121) MM U.S. approval
• Ide-celKarMMa studies progressing and evolving
• Building and evolving clinical dataset on SGD programs
• ZYNTEGLO Access and Reimbursement established in additional EU countries
• Ide-celU.S. launch underway
• ZYNTEGLO geographic expansion
• LentiGlobin TDT U.S. launch ready and SCD gearing up