Recoding in Action
Q3 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
Tremendous Progress in Challenging Times
Programs and Pipeline
ide-cel updated data at ASCO; BLA resubmitted
Clarity on accelerated US regulatory path for SCD (Updated data at EHA)
Key 2021 milestones tracking: EU TDT ramp, ide-cel launch, US TDT, ALD & SCD filings & pipeline emergence
2022
THE GENE THERAPY
PRODUCTS COMPANY
Patient∞Impact
Operation Plan
Optimized BMS collaboration & $200M rights monetization
Revised operating plan by over $500M through mid-2022
Extended cash runway into 2023
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):
- Non-β0/β0: 90% of patients achieving TI
Northstar-3(HGB-212):
- 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):
- Non-β0/β0: All patients treated o 89% successfully achieved TI
Northstar-3(HGB-212):
- 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
Ready to treat patients in Germany
pending COVID-19 environment
Ongoing engagement with payers in additional EU markets supports access and reimbursement by end of 2020
Plan to pursue expanded label to
include patients with β0/β0 genotypes
and pediatrics
US: Clear Path
Updated data reinforce confidence in pursuing initial approval for patients with TDT and all genotypes
Learnings from FDA engagement
leveraged across programs
US BLA Submission Planned for mid-
2021 (Q2/Q3)
9
preparing to serve patients in Europe
Apheresis Personnel | Cell Lab Personnel | Transplant Personnel (ATC) | Manufacturer |
Apheresis | Apheresis | Cell Lab | Transplant | Transplant | Transplant | Transplant | bbb Manufacturing |
Coordinator | Operator | Operator | Coordinator | Nurse | Physician | Administrator | Logistics |
launch expectations
1 drug product manufacturing
- Optimal patient experience through a seamless delivery network
- Steady country by country launch with progressive build
- Get the model right for long term success
- Advance value-based payment over time reimbursement
Munich, Germany
initial launch focus
- Germany
- Italy
- UK
- France
10
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 | 11 |
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*
- Accelerated development 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; | 12 |
data as of March 3, 2020
Sickle Cell Disease:
Totality of the clinical data validates transformative clinical results
ASH 2019
Early clinical benefit:
- 99% mean reduction in VOC and ACS
Group C patients:
-
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:
-
99.5% mean reduction in VOC and ACS
More patients; more follow-up:
- 25 patients; 14 patients with ≥6 months follow up and ≥4 VOC/ACS at baseline
Consistent results across multiple markers:
- Continued improvements in hemolysis markers, HbAT87Q levels and pancellular expression
Clarity on U.S. regulatory path:
- Based on HGB-206 Group C
13
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 14
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 | 15 |
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 | 16 |
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 | 17 |
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 | 18 |
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 | 19 |
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
- 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
- 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 | 20 |
vaso-occlusive crisis |
Updated, accelerated plan based on compelling VOE data
HGB-206 Group C | HGB-210 |
Sickle Cell Disease, history of vaso-occlusive
events (VOEs) over 24 months
Ongoing Phase 1/2, single arm, multi-center,
U.S. 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
Sickle Cell Disease, history of VOEs over
24 months
Phase 3, single arm, multi-center,
global study
- Primary Endpoint: HbAT87Q and Total Hb
- Key Secondary Endpoint:
- Reduction in severe VOEs
HGB-206 Group C: Basis of | Primary endpoint: | HGB-210: Serving as |
1. BLA submission in 2H 2021 | 2.VOEs | 3.confirmatory study |
21
21
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 submitted July 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, | 22 |
Blood 2014 (PomDex) | |
Multiple Myeloma - ide-cel:
Broad oncology strategy and development program supported by clinical data
BCMA Program
BMS Alignment
- U.S. 50/50 co-co
- Ex-U.S.BMS wholly-owned
Regulatory path enabling near-term launch:
- BLA submitted
- 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:
- CAR+ T cell persistence observed up to 1yr with meaningful detectable vector
- mPFS of 12.1 months at 450x106 dose o KarMMa N=128; CRB-401 N=67
23
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 | 24 |
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
25
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 | 26 |
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.27 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, | 28 |
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. | 29 |
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 | 30 |
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 | 31 |
Ide-cel is being developed in collaboration with Bristol-Myers Squibb |
Revised BMS Collaboration: Aligned to Support ide-cel Commercialization
shared commitment
- U.S. co-promote/co-develop intact
- KarMMa development program underway in earlier lines
manufacturing alignment
• BMS to manufacture vector ex- U.S. over time
• bluebird to continue U.S. vector manufacturing
monetization
- bluebird to receive $200m for ex- U.S. milestones and royalties
32
Cerebral Adrenoleukodystrophy - From Tragedy to Hope
2009
R E C O D E
Enhanced Construct
&
Manufacturing
EPNS: 2019
- 15/17 patients alive and MFD-free at 24 months follow up and continue to be MFD-freewith up to 5 years of follow-up
- 32 total patients treated
Data as of April 25, 2019
2020
- 2H 2020 anticipated MAA submission
- Newborn screening active in 14 US states; several pilot programs in EU
Science 2009 | 33 |
Lenti-D treatment halts CALD disease progression
October 4, 2017
N Engl J Med 2017; 377:1630-1638
All patients who were alive and MRD-free at 24 months follow up (15/17; 88%) continue to be MFD-free with up to 5 years of follow-up
- 32 patients have been treated with Lenti-D with a median follow-up time of 21.2 months
- 14 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
Enrollment completed in Starbeam study Phase 3 ALD-104 study currently enrolling
Data as of April 25, 2019
34
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
35
pipeline overview
- Dev is led by Dana-Farber/Boston Children's Cancer and Blood Disorders Center
- Dev is led in collaboration with Bristol Myers Squibb
- Dev is led by Fred Hutch Cancer Research Institute
- Dev is led by University of North Carolina
- Dev is led by Seattle Children's Research Institute
Severe Genetic Diseases
Oncology
LENTI-DTM
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 | 36 | ||||||||||||||||
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
37
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 38
2020-2021: BLUE is Prepared and On Track for the Catalysts Ahead
Regulatory
Clinical
Updates
Commercial
- Foundation Building
2020 | 2021 | |
LentiGlobin SCD Regulatory Update | ||
| LentiGlobin SCD U.S. BLA submission (2H) | |
Ide-cel (bb2121) MM U.S. BLA submission | ||
| LentiGlobin TDT U.S. BLA submission (Q2/Q3) | |
Lenti-D CALD EU MAA Submissions | ||
| Lenti-D CALD U.S. BLA submission (mid-year) | |
- Ide-cel(bb2121) KarMMa data at ASCO,
CRB-401 by EOY | | Ide-cel KarMMa studies progressing and evolving |
SCD: HGB-206 data at EHA, EOY | ||
| Building and evolving clinical data set on | |
TDT: HGB-207,HGB-212 Data at EHA | SGD programs | |
Lenti-DALD-102 data update by EOY | ||
ZYNTEGLO Access and Reimbursement | ||
| Ide-cel U.S. launch underway | |
established in additional EU countries | ||
| ZYNTEGLO geographic expansion | |
ZYNTEGLO first commercial patients | ||
| LentiGlobin TDT U.S. launch ready and SCD | |
treated (2H) | ||
Ide-cel U.S. launch ready | gearing up | |
39
Attachments
- Original document
- Permalink
Disclaimer
Bluebird Bio Inc. published this content on 11 August 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 18 August 2020 18:40:00 UTC