Presented at the 60th American Society of Hematology (ASH) Annual Meeting – December 1-4, 2018, San Diego, CA, USA

• Allogeneic hematopoietic stem cell transplantation (HSCT) enables cure of trilineage cytopenias and prevents the occurrence of myeloid malignancies in patients with Fanconi anemia (FA)1-3

• Long-term outcomes in patients with FA who undergo HSCT can be hampered by the occurrence of squamous cell carcinoma, which represents a well-known complication of the allograft in these patients - Squamous cell carcinoma can occur with the use of total body irradiation (TBI) during the conditioning regimen and development of chronic graft-versus-host disease (cGvHD)3,4

• In patients with FA, HLA–partially matched haploidentical (haplo) HSCT has historically been associated with inferior results compared with transplant from an HLA-identical donor

• Selective depletion of αβ-T and B cells, an innovative approach of graft manipulation, has recently been shown to improve the outcomes in children with non-malignant disorders who have undergone haplo-HSCT5

- However, delayed recovery of adaptive immunity and the possible risk of life-threatening infections warrant exploration of novel strategies that are able to accelerate immune reconstitution and improve outcomes in these patients

• Rivogenlecleucel (rivo-cel, BPX-501) is an allogeneic product consisting of T cells modifi ed to express the inducible caspase-9 (iC9) safety switch (Figure 1) - The polyclonal nature of rivo-cel provides broad virus- and tumor-specifi c immunity - The iC9 safety switch, induced by dimerization through administration of rimiducid, has the unique ability to promptly and durably resolve symptoms of GvHD

Figure 1. Chemical Induction of Dimerization (CID) Molecular Switch Platform

• Figure 2 depicts rivo-cel T cells, which are: - Derived from un-mobilized donor leukapheresis - Produced in Good Manufacturing Practice facilities in Europe and the United States - Activated and expanded in culture - Transduced with the iC9 suicide gene and selected using the CD19+ marker - Cryopreserved and stored in liquid nitrogen

• Normal T-cell characteristics are maintained, including: - Broad T-cell repertoire - Antiviral and antitumor immunity

Figure 2. Rivo-cel Addresses the “T-Cell Dilemma” in Haplo-HSCT

GMPFacility

Patient

Day 0

HSCTStem cells

T cells

Rimiducid foruncontrolled

GvHD

Day 21+/- 14 days

10 days

Haploidentical Donor

iC9

No GvHDprophylaxis

Rivo-cel:Tipping the benefit / risk scale

RISKS BENEFITSRelapse Prevention – Graft vs Leukemia (GvL)

Infection Control

Engraftment

Graft vs HostDisease (GvHD)

TCR/CD19Depletion

Rivo-cel CellProcessing

Rivo-cel Addback Infusion

GMP, Good Manufacturing Practice; GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation.

BACKGROUND

Viral transductiontransfers the DNAfrom a vector into thetarget cell nucleus.

Rimiducid infusion activates signalling pathways to control T-cell function

Vector-derived DNAdirects expression ofCID and accessoryproteins.

2

3

1 VECTOR APPLICATION SPECIFICACCESSORY PROTEINS

2 CID PROTEINS

Monomeric =Inactive Proteins

SIGNALINGDOMAIN

Rimiducid dimerizesthe CID proteins, thusturning on the signalcascade.

BINDINGDOMAIN

Signal Caspase-9 (“iC9”)

Result Apoptosis (cell death)

3

Dimerized =Active Proteins

SIGNALCASCADE

1

METHODS

RESULTS

CONCLUSIONS

REFERENCES

DISCLOSURES

ACKNOWLEDGEMENTS

• To evaluate the safety and effi cacy of rivo-cel administered after αβ–T- and B-cell–depleted haplo-HSCT in pediatric patients with FA

OBJECTIVES

• In 2 multicenter, prospective phase 1/2 trials (US [NCT03301168] and EU [NCT02065869]), αβ–T- and B-cell–depleted haplo-HSCT was followed by infusion of a titrated number of donor lymphocytes genetically modifi ed with the iC9 safety switch (rivo-cel) in patients with malignant and non-malignant disorders6,7

- Data presented here are for the subset of patients with FA

• The study design is described in Figure 3

Figure 3. Study Design

a ATG was administered from Day -4 to Day -2 (12-15 mg/kg over 3 consecutive days) and rituximab at a dosage of 200mg/m2 on Day -1.

ATG, anti-thymocyte globulin (rabbit); GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; MTD, maximum tolerated dose; SoC, standard-of-care.

• For patients with FA, the conditioning regimen included: - Cyclophosphamide 1200 mg/m2 over 4 days (days −6 to −3) + fl udarabine 160 mg/m2 over 4 days (days −6 to −3) ± low-dose TBI (200 cGy as a single dose on day −1)

- Rabbit anti-thymocyte globulin (ATG) was administered for 3 consecutive days (days −4 to −2) to reduce the incidence and severity of possible immune-mediated complications (ie, graft rejection and acute or chronic GvHD)

- Rituximab 200 mg/m2 was administered on day −1 for prevention of Epstein-Barr virus–related post-transplant lymphoproliferative disease (PTLD)

• Per protocol, rivo-cel cells were to be infused on day 21 ± 14 following the allograft

• No post-transplant pharmacological GvHD prophylaxis was used

• Patients who developed visceral GvHD or were refractory to standard-of-care treatment were eligible to receive ≥ 1 dose of rimiducid - Rimiducid 0.4 mg/kg was administered over 2 hours

Statistical Analysis• Study participants with FA who received HSCT and rivo-cel infusion and had ≥ 1

follow-up assessment were included in the effi cacy-evaluable population (EEP)

• The safety-evaluable population (SEP) was defi ned as any patient who received HSCT

• Clinical cutoff: September 17, 2018

Pediatric high-risk malignancies and

non-malignant disorders

No matched donor

Haploidentical donor available

Phase I: 3+3 Design (no MTD reached)2.5 x 105, 5 x 105, 1 x 106, 2 x 106, 4 x 106 rivo-cel T cells/kg

Phase II:1 x 106 rivo-cel T cells/kg

Key Inclusion Criteria Key Exclusion Criteria• Life-threatening acute leukemia• Non-malignant disorder deemed curable by HSCT• Life expectancy > 10 weeks• Age < 18 years and > 1 month

• Active GvHD or Immunosuppressive treatment from a previous allograft• Renal or liver dysfunction• Active infection• Pregnant or breastfeeding

Fanconi anemiaa

(N=14)

αβ-T-cells and B-cell–depletedhaplo-HSCT + rivo-celNo post-HSCT GvHD prophylaxis

Rimiducid for patients who develop visceral GvHD or are refractory to SoC treatment

Outcomes: • Event-free survival• Transplant-related mortality (non-malignant)• Incidence and severity of GvHD• Time to resolution of GvHD after administration on rimiducid• Immune reconstitution

Table 1. Key Baseline and Transplant Characteristics

Characteristic Patients(n = 14)

Male/female, n (%) 4 (28.6)/10 (71.4)

Median age at HSCT (range), years 7.99 (1.84-22.12)

Conditioning regimens, n (%)

Cyclophosphamide + fl udarabine + TBI 13 (92.9)

Cyclophosphamide + fl udarabine 1 (7.1)

Donor source, n (%)

Parent 13 (92.9)

Sibling 1 (7.14)

Median HSCT dose (range)

CD34+ cell dose, × 106/kg 16 (7 - 28)

αβ-TCR cell dose, × 105/kg 0.26 (0.06 -0.90)

Median time to rivo-cel infusion (range), days 15 (13-75)

Median time to hospital discharge (range), days 22 (15-113)

HSCT, hematopoietic stem cell transplantation; TBI, total body irradiation; TCR, T-cell receptor.

Effi cacy• The median follow-up was 25.8 months (range, 0.79-44.1 months)

- Median follow-up of surviving patients was 28.2 months (range, 1.1-44.1 months)

• Probability of both overall survival (Figure 4) and disease-free survival was 92.9% (95% CI, 79.4%-100%)

• The median interval time from date of transplant to last reported transfusion was 10 days (range, 3-145 days)

• 1 patient died of a brain hemorrhage 25 days after HSCT

Figure 4. Overall Survival in Patients With FA Receiving Rivo-cel

100

80

60

40

20

0

0 200 400Days from HSCT

N=14, Events=1, Overall Survival OS, 92.9% (95% CI 79.4 – 100)

Fanconi Anemia Patients – Overall Survival

Number at Riskn=14 7 5

600 800 1000 1200Pa

tient

s (%

)

FA, Fanconi anemia; HSCT, hematopoietic stem cell transplantation; OS, overall survival.

Graft Failure• 1 patient experienced primary graft failure (7.7% [95% CI, 0-22.2%])

Graft-versus-Host Disease• Of the 13 patients evaluable for assessment, 1 developed grade 1 acute GvHD

(aGvHD) on day 61 (7.7% [95% CI, 0-22.2%])

• 2 additional cases of late-onset aGvHD developed > 100 days after HSCT; both cases were grade 2

• No cases of cGvHD developed

• No patient with FA received rimiducid for the treatment of visceral GvHD or GvHD refractory to standard-of-care treatment

Engraftment• Time to hematopoietic recovery

- Hematopoietic recovery was defi ned as neutrophils > 0.5 × 109/L for 3 consecutive days; platelet recovery was defi ned as platelet count > 20 × 109/L and without platelet support for 7 consecutive days

• The median time to neutrophil and platelet engraftment was 15 days (95% CI 12-24 days) and 11 days (95% CI 9-23 days), respectively (Figure 5)

Figure 5. Median Time to Neutrophil and Platelet Engraftment

Patie

nts

(%)

Days from HSCT

Days to Neutrophil Recovery Days to Platelet Recovery

100

80

60

40

20

00 5 10 15 20 25 30 35 40

SEP (excluding graft failures).HSCT, hematopoietic stem cell transplantation.

Immune Recovery• CD3+ and CD3+CD4+ T cell counts of > 500 cells/µL were achieved by 180 and

360 days, respectively (Figure 6A)

• Normal immunoglobulin A (IgA) and immunoglobulin M (IgM) levels were achieved by 30 and 180 days, respectively (Figure 6B)

Figure 6. Recovery of (A) CD3+ and CD3+CD4+ T-Cell Counts and (B) IgA and IgM Levels

1800

1600

2000

1400

1200

1000

800

600

400

200

0CD3 (Mean)CD4 (Mean)CD8 (Mean)

30 60

Follow-up Time (days)

Cel

ls/µ

L

CD3+

CD3+CD4+

CD3+CD8+

100 180 270 360 720

203.4921.95425.392

225.8362.09842.859

335.5130.9112.31

744.44233.7364.37

1220.2375.22638.84

1539.6590.15653.4

1773.1745.9500.01

A

B

200

175

150

125

100

75

50

25

030 60 100 180 270 360 540 720

Imm

unog

lobu

lin L

evel

(mg/

dL)

IgAIgM

Ig, immunoglobulin.

• The adoptive transfer of rivo-cel following αβ–T- and B-cell–depleted haplo-HSCT represents a novel and effective strategy for pediatric patients with FA

• The toxicity profi le observed in patients exposed to rivo-cel was manageable - No deaths related to infections occurred

• Despite the addition of rivo-cel, low rates and severity of aGvHD were observed. No cases of cGvHD occurred - Low rates of GvHD could translate into signifi cant long-term benefi t, particularly in reducing rates of squamous cell carcinoma, a known cause of morbidity and mortality after HSCT in patients with FA

1. Fanconi G. Familial constitutional panmyelocytopathy, Fanconi’s anemia (F.A.). I. Clinical aspects. Semin Hematol. 1967;4:233-240.

2. Alter BP. Fanconi’s anemia and malignancies. Am J Hematol. 1996;53:99-110.

3. Zecca M, Strocchio L, Pagliara D, et al. HLA-haploidentical T cell–depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia. Biol Blood Marrow Transplant. 2014;20:571-576.

4. Fanconi Anemia Research Fund. Fanconi anemia: guidelines for diagnosis and management, 4th ed; 2014. https://www.fanconi.org/images/uploads/other/Guidelines_4th_Edition.pdf. Accessed November 26, 2018.

5. Bertaina A et al. HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. Blood. 2014;124:822-826.

6. ClinicalTrials.gov. Study of gene modifi ed donor T-cells following TCR alpha beta positive depleted stem cell transplant. https://clinicaltrials.gov/ct2/show/NCT03301168. Accessed October 30, 2018.

7. ClinicalTrials.gov. Safety study of gene modifi ed donor T-cells following TCR alpha beta depleted stem cell transplant. https://clinicaltrials.gov/ct2/show/NCT02065869. Accessed October 30, 2018.

• Swati Naik, Susanne Baumeister, Victor M. Aquino, Annalisa Ruggeri, Daria PagliaraThere are no relevant confl icts of interest to disclose

• Melissa AldingerBellicum Pharmaceuticals

• Franco LocatelliAdvisory Board, Bellicum Pharmaceuticals

• The authors would like to acknowledge all patients and their families and caregivers for participating in this clinical trial, along with the investigators.

Sponsorship/Funding/Medical Writing:• This poster was sponsored by Bellicum Pharmaceuticals, Inc.

Third-party writing assistance was furnished by Health Interactions, Inc.Baseline Characteristics

• A total of 14 patients (EU, n = 9; US, n = 5) with FA met the EEP defi nition

• Key baseline and transplant characteristics are shown in Table 1

Safety• Among 14 patients with FA:

- 13 patients experienced ≥ 1 adverse event (AE) - 11 patients experienced more than one AE - 6 AEs were related to rivo-cel treatment (as determined by the investigator)

• Aphthous stomatitis, viral cystitis, infusion-related reaction, pollakiuria, alopecia, maculopapular rash

• All 6 AEs were grade 1 or 2

• No patients died of infectious complications

• All other noninfectious serious AEs were resolved

Administration of Rivogenlecleucel (Rivo-cel, BPX-501) Cells Following αβ–T- and B-Cell–Depleted HLA-Haploidentical HSCT in Children With Fanconi AnemiaSwati Naik,1 Susanne Baumeister,2 Victor M. Aquino,3 Annalisa Ruggeri,4 Daria Pagliara,4 Melissa Aldinger,5 Franco Locatelli4

1Texas Children’s Hospital, Houston, TX; 2Dana-Farber Cancer Institute, Boston, MA; 3UT Southwestern Medical Center, Dallas, TX; 4Sapienza, University of Rome and IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy; 5Bellicum Pharmaceuticals, Houston, TX

Abstract #4654