2017 ASH ANNUAL MEETING

The Highlights of Thalassemia

Prof. Vip Viprakasit

Department of Pediatrics &

Thalassemia Center

Faculty of Medicine Siriraj Hospital

Mahidol University

THAILAND

Disclaimer

• This scientific information may include data on investigational uses of compounds/drugs that have not yet been approved by regulatory authorities.

• The opinions expressed in this presentation represent those of the speaker.

Outline

• General overview of thalassemia

• Iron overload pathophysiology

• Iron overload detection

• Update on current thalassemia management

• Novel treatment approaches

Classification of thalassaemia syndromes

Viprakasit V & Ekwattanakit S. Hem Clin N Am 2017; in press

Marrow expansion and bone disease

Extramedullary haemopoiesis and organomegaly

Ineffective erythropoiesis

α/β chain imbalance Peripheral haemolysis and gall stones

Anaemia

Organ damage (heart, liver. endocrine)

The introduction of transfusion therapy ameliorates ineffective erythropoiesis and anemia but exacerbates iron overload

Taner AT el al. Lancet 2017; Epub ahead of print.

Pathophysiology in the absence of treatment

Hypercoagulability and vascular disease

Iron overload

Without treatment iron overload is cumulative in NTDT

Iron overload in NTDT is associated with multiple extra-hepatic manifestations

Transfusional iron overload leads to multiorgan morbidity in TDT

Pituitary

Hypogonadotropic hypogonadism

Heart

Cardiomyopathy

Gonade

Hypogonadotropic hypogonadism

Bone

• Osteomalacia • Osteoporosis

Thyroid

Hypothyroidism

Parathyroid

Hypoparathyroidism

Liver

• Cirrhosis • Carcinoma

Pancreas

Diabetes

Iron overload assessment and decision making

Iron monitoring in TDT: TIF Guidelines

Iron monitoring in TDT: limited MRI access

Iron monitoring & ICT in NTDT: TIF Guidelines

Deferasirox film-coated tablets: dose-equivalent formulation of deferasirox

Once-daily oral suspension

Starting dose 20 mg/kg/day in TO IOL

and 10 mg/kg/day in NTD IOL

Multistep preparation may

conflict with daily activities

Restrictions on taking with food

Palatability issues can make

administration a challenge

Once-daily film-coated tablets

Starting dose 14 mg/kg/day in TO IOL

and 7 mg/kg/day in NTD IOL

No preparation or mixing required.

It may also be crushed and

sprinkled on soft food

May be taken with a light meal

Does not contain lactose or

sodium lauryl sulfate

Deferasirox film-coated Tablts received FDA

Approval in 2015 and EMA approval in 2016

Deferasirox FCT contains the some active ingredient As deferasirox DT but has ~ 30% lower dose, due to higher bioavailability

Patients treated with DFX FCT had a 10% greater reduction in SF compared with those treated with DFX DT

Laboratory parameter Time point Treatment N Mean SD Median Min Max

Serum ferritin (ng/mL) Baseline DFX DT 86 3023.2 1993.17 2485.0 915 8250

DFX FCT 87 3377.1 2070.46 2983.0 939 8250

EOT DFX DT 78 2820.4 2364.47 2064.0 439 16500

DFX FCT 79 2797.6 1771.13 2302.0 443 8250

Novel therapies targeting iron dysregulation

ɑ/β-Chain imbalance

Sotatercept Luspatercept

Gene therapy Gene editing

JAK2 inhibitors

↓ Differentiation

↑ Proliferation

Minihepcidins

Ineffective erythropoiesis

Anaemia

Iron overload

TMPRSS inhibitors

↑ GDF11

↓ Hepcidin

Erythroferrone

TMPRSS6

Takeaways

• Iron overload is associated with a significant risk of morbidity in both patients with NTDT and TDT, with effects on various vital organs

• Advances in detection and monitoring of iron overload by MRI now allow the assessment of specific organ loading rates to help tailor iron chelation therapy

• Available iron chelators have shown efficacy in removing iron from the liver, heart and endocrine glands at various levels of Iron overload severity

• Most recent advances in iron overload management include the introduction of a new deferasirox formulation aimed at improving adherence while data from more novel agents that target iron dysregulation are awaited

American Society of Hematology Helping hematologists conquer blood diseases worldwide

New Therapeutic Targets in Transfusion Dependent and

Non-Transfusion Dependent Thalassemia

M. Domenica Capellini

Ca Granda Foundation – Policlinico Hospital

University of Milan

Education Session in Thalassemia

ASH® Annual Meeting and Exposition

Atlanta, GA

December 9-12, 2017

TIGET-BTHAL STAGGERED STRATEGY

GROUP 1 N=3 adults

≥ 18 yrs

GROUP 2 N=3 children

8-17 yrs

GROUP 3 N=4 children

3-7 yrs

1° data safety monitoring board (DSMB) evaluation on: early safety, hematological recovery, presence of transduced cells in BM at ≥ 2 months follow-up

2° Evaluation of DSMB

March 2016 1ˢᵗ report to DSMB Approved

September 2016 2ⁿᵈ report to DSMB Approved

TIGET-BTHAL: patient and drug products BTHAL Age at GT/gender Genotype Gene therapy

dose CD34+/kg

Vector copy number (VCN^)

% Transduction efficiency (TE*)

001 31/M cod39/IVS I-110 ß0/ß+°

19.4 0.8 60

003 35/F cod39/IVS I-110 ß0/ß+°

18.4 0.7 63

004 34/M cod39/IVS I-110 ß0/ß+°

18.7 0.7 68

005 13/M IVS I-110 homoz ß+/ß+*

19.5 1.2 53

006 13/M cod39 homoz ß0/ß0

16.3 1.5 77

007 13/M IVS I-6/IVS I-110 ß+/ß+

19.5 0.7 62

008 6/M cod39 homoz ß0/ß0

19.7 1.0 59

Bthal002 failed screening *severe genotype, ß0-like. ^ VCN/cell = average vector copies per cell on day 14 CD34* bulk culture *TE:% vector positive colonies

Median 19.4 Range 16.3-19.7

Median 0.8 Range 0.7-1.5

Key primary endpoints from TIGET study (1 yrs)

• Primary endpoint: Efficacy

Reduction of transfusion requirement resulting in delayed interval between consecutive transfusions (mainly in 3 adults) up to transfusion independence (3/4 pediatrics)

• Secondary endpoint: Adequate Hb levels in patients achieving transfusion independence (end-point Hb > 9 gr/dL in adults and Hb > 10 gr/dL in children at 9, 12, 18 and 24 months): in 3 pediatric patients

Clinical Outcomes up to 3 Years Following LentiGlobinᵀᴹ Gene Therapy for

Transfusion-Dependent β-Thalassemia in the Northstar HGB-204 Study

Janet L. Kwiatkowski, Alexis A. Thompson, John E. J. Rasko, Suradej Hongeng, Gary J Schiller Usanarat Anurathapan, Marina Cavazzana, P. loy Ho, Christof von Kalle, Morris Kletzel ' Philippe Leboulch, Elliott Vichinsky, Briana Deary, Mohammed Asmal and Mark C. Walters

Northstar (HGB-ZO4) study of LentiGlobin BB305 gene therapy in TDT

• International, multi-center, Phase 1/2, open-label, single-arm study in adolescents/adults with TDT

• Primary objectives: Safety and efficacy of LentiGiobin Drug Product in TDT

• 18 treated patients (fully enrolled) - Ages 18 - 35y (n=15), 12 - 17y (n=3)

• Median follow-up: 27.4 months (min max: 17.5 - 36.5 months)

• All 18 patients have ≥ 18 months follow-up • 10 patients have completed 2-year analysis • 3 patients have 3 years follow-up

Patient and drug product characteristics N=18 patients

Patient Characteristics β⁰/β⁰ (n=8)

Non-β⁰/β⁰ (n=10)

Genotypes β⁰/β⁰ Other

- -

6 4

Age at drug product infusion median (min-max), years

23.5 (13-36)

2.5 (16-35)

Pre-study pRBC transfusion volume annualized median (min-max), mL/kg/yr

182.7 (124.4-261.3)

146.9 (139.1-234.5)

Liver Iron Concentration median (min-max), mg/g

6.3 (0.4-17.0)

5.7 (1.2-26.4)

Drug Patient Characteristics β⁰/β⁰ (n=8)

Non-β⁰/β⁰ (n=10)

Drug product VCN“ median (min max)

0.6 (0.3-1.5)

0.7 (0.3-1.1)

C034+ cells transduced"I median (min max), 96

32 (18.58)

29 (17-44)

Drug product cell dose median (min -max), C034+ cells x106/k3

11.0 (6.1-18.1)

7.1 (5.2-13.0)

VCN: vector copy number (vector copies per diploid genome) *22 drug product lots manufactured for 18 patients

Further patient and treatment characteristics have been previously reported: Thompson A, et al. ASH 2016. Abstract 1175.

Safety profile remains consistent with myeloablative conditioning N=18 patients

Non-hematologic* grade ≥ 3ᶧ AEs Reported in ≥ 2 patients DP infusion to up to 2 years follow-up

Incidence N (%)

Stomatitis 12 (67)

Febrile neutropenia 10 (56)

Veno-occlusive liver disease 2 (11)

Irregular menstruation 2 (11)

Epistaxis 2 (11)

• 9 SAEs were reported in 6 patients from DP infusion to last follow-up: - SAEs in ≥ 2 patient were: • Veno-occlusive liver disease (n=2) • Thrombosis (n=2; 1 central catheter

thrombosis, 1 intracardiac thrombus)

• No grade ≥ 3 DP-related AEs or deaths • No replication competent Ientivirus • No evidence of clonal dominance

*Hematologic AEs commonly observed post-transplant have been excluded; ᶧNo grade 4 or 5 events were reported

AE, adverse event; DP, drug product; SAE, serious adverse event

Key primary endpoints from Northstar study (3 yrs)

• 9/10 patients with non-β⁰/β⁰ genotypes are free from chronic RBC transfusions

• Median of 29 months free from chronic transfusions in 9/ 10 patients

• Peripheral VCN and Hb𝐴^(𝑇87𝑄 )production is stable up to 3 years Patients with non-β⁰/β⁰ genotypes

• 2/8 patients with β⁰/β⁰ genotypes are free from chronic RBC transfusions

• Reduction in RBC transfusion requirements in most patients with β⁰/β⁰ genotypes (volume and number)

• Not clear on reduction of LIC

HGB-207 Non-β⁰/β⁰ genotypes

Phase 3, multi-center, global study NCT02906202

• N=15 adults and adolescents • N=8 pediatric patients • Open and enrolling • 7 patients treated

Abstract 526 Oral Session: Dec 10, 5:15 PM

Next steps: Pivotal clinical studies of LentiGlobin therapy in TDT

HGB-212 β⁰/β⁰ genotypes

Phase 3, multi-center, global study NCT03207009

• N=15 adults adolescents and pediatric patients

• Open and enrolling

• 1 patients treated

Reactivation of endogenous Hb F

CRISPR-CAS 9 Disrupts the BCL11A Erythroid Enhancer

Disruption of BCL11A expression to re-express 𝛾-globin (HbF) in symptomatic patients

BCL11A gene (Chromosome 2)

β-globin locus (Chromosome 11)