the highlights of thalassemiatsh.or.th/file_upload/files/thalassemia - refresher course 2018... ·...
TRANSCRIPT
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)