What's new in Hematology: Thalassemia. Vip Viprakasit

1. AUBHO-2015
Vip Viprakasit, MD, DPhil (Oxon)
Thalassaemia Center & Department of Paediatrics
Faculty of Medicine Siriraj Hospital
Mahidol University
Bangkok, THAILAND
“What ‘s new in Hematology: Thalassemia”

2. Agenda
• A new Guideline for TDT-TIF 2014
• A new information on current management
- What’s new!! on iron chelators
• A new future treatment on horizon
- New approach and new paradigm shift
- New diagnosis & future

3. Agenda
• A new Guideline for TDT-TIF 2014
• A new information on current management
- What’s new!! on iron chelators
• A new future treatment on horizon
- New approach and new paradigm shift
- New diagnosis & future

4. The TIF Thalassemia Management
Guidelines in a nutshell
• Published and endorsed by the Thalassaemia International
Federation (TIF), Nicosia, Cyprus
• Currently in its 3rd edition (published in 2014 since 1980s’)
• Current edition exclusive to transfusion-dependent
thalassemia (TDT)
− Guidelines for the management of non-transfusion-dependent
thalassemia (NTTD) published separately in 2013
• Ed. Taher A, Vichinsky E, Musallam KM, Cappellini MD, Viprakasit V
• Guidelines mainly targeting HCPs
− Separate guidelines published for
• emergency care
• Nursing staff

5. More importantly…
Moving from
independent expert
opinion
To evidence-based
practice

6. Evolving change in the direction of
thalassemia management
Looking at the total patient
population
Looking at the individual
patient
Considering the patient
status today
Considering the patient
journey until today
Managing iron overload
Managing an iron overload
profile
Treating a patient Supporting a human
Acting as a physician Acting as a team

7. IOL, iron overload; TIF, Thalassaemia International Federation.
Management of IOL: TIF 2014 guidelines
Prevention
of IOL
Rescue/
removal of
liver IOL
Rescue/
prevention
of cardiac
IOL
Emergency
chelation

8. Agenda
• A new Guideline for TDT-TIF 2014
• A new information on current management
- What’s new!! on iron chelators
• A new future treatment on horizon
- New approach and new paradigm shift
- New diagnosis & future

9. Liver iron load above 7 mg/g dw increases the risk
of complications in TDT
1. Olivieri NF N Engl J Med 1999;341:99–109; 2. Taher AT et al. Blood 2012;120:970–977.
Homozygous
hemochromatosis
Estimate for NTDT 2
(based on data from Study 2209)
Age (years)
LIC(μg/gwetwt)
TDT
LIC(mg/gdw)
Increased risk of iron-related morbidity1Normal LIC
15,000
10,000
5000
0
0 10 20 30 40 50
0
10
20
30
40
50

10. Liver enzyme concentrations increase at LIC
>15 mg Fe/g dw
Jensen PD et al. Blood 2003;101:91-96.
AST,U/L
16.8Femg/gdrywt
Liver iron, µmol Fe/g
SF, µg/L
240
200
160
120
80
40
0
0 100 200 300 400 600500
240
200
160
120
80
40
0
0 100 200 300 400 600500
100
10
100 1000 10,000
100
10
100 1000 10,000
ALT,U/L
R2=0.55
P<0.0001
R2=0.62
P<0.0001

11. In summary, liver complications in TDT
are becoming more prominent
Voskaridou E et al. Ann Hematol 2012;91:1451–1458.
0
5
10
15
20
25
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Heart disease
Liver disease
Year of death
Patients,n
The number of deaths due to cardiac problems has decreased, while the
number of deaths due to liver disorders has increased during the last decade

12. DFX+DFO therapy improved cardiac T2* in
severe myocardial IOL
Aydinok Y et al. Blood. 2015 May 1. pii: blood-2014-07-586677
Gmean cardiac T2* and mean LIC over 1 year
6
7
8
9
10
BL Month 6 Month 12
10
15
25
30
35
20
GmeancardiacT2*(ms)
MeanLIC(mgFe/gdrywt)
LICCardiac T2*
33.43
24.05
18.25
7.68
7.167.03
Absolute change in LIC from BL:
−14.30 ± 11.92 Fe/g dry wt
46% improvement
T2* Gmean ratio:
1.09 [95% CI 1.04, 1.15]
9% improvement
In highly iron-overloaded patients, DFX+DFO improved cardiac T2*
Hyperion study in patients with severe myocardial siderosis (n = 52)
Cardiac T2*
LIC

13.  Compared to current formulation
– more bioavailable: 14 mg DFX FCT equals 20 mg of
DFX DT
– lower biovariability and more limited food effect
 Different posology
– tablets of 90, 180, and 360 mg DFX FCT corresponding
to 125, 250, and 500 mg tablets DFX DT
 No lactose in DFX FCT: improved GI safety?
– to be evaluated in the 2201 trial
DFX DT, deferasirox dispersible tablets (Exjade®);
DFX FCT, deferasirox film-coated tablets, “new formulation”.
New deferasirox formulation:
film-coated tablets (FCT)

14. AE, adverse event;
GI, gastrointestinal. Available from: clinicaltrials.gov/ct2/show/NCT02125877?term=deferasirox&rank=31. Accessed March 2015.
F2201 trial evaluates the safety
(and efficacy) of deferasirox FCT
 Primary objective: to evaluate the overall safety, measured as frequency and severity of
AEs and changes in laboratory values in patients with TDT or MDS (IPSS-R Very low, Low,
or Intermediate risk)
 Secondary objectives (both formulations)
– selected GI AEs
– pharmacokinetics
– patient-reported outcomes (satisfaction, palatability, and GI symptoms)
– patient compliance (using pill count and a daily diary)
Screening
(including wash out)
14 days
Deferasirox DT
taken as per local label (n = 75)
Follow-up
Follow-up
Deferasirox FCT
taken with or after food (n = 75)
24 weeks
24 weeks
1 month
1 month
Randomization

15. Basel, March 30, 2015 - Novartis announced today that the US Food and Drug Administration
(FDA) has approved JadenuTM (deferasirox) tablets, a new oral formulation of Exjade®
(deferasirox) tablets for oral suspension, for the treatment of chronic iron overload due to
blood transfusions in patients 2 years of age and older, and chronic iron overload in non-
transfusion-dependent thalassemia syndromes (NTDT) in patients 10 years of age and
older. Jadenu is the only once-daily oral iron chelator that can be swallowed whole.

16. Future Questions for Iron Chelation Therapy in 2015
• Can we start iron chelation in children younger than 2 yrs.
• Should we stop ICT when SF < 500 ng/dL
• How low we can go with ICT: 300 vs 100 ng/dL
• Considering ICT in other underlying diseases: CDA, AA, MDS etc.
• Difficult to treat patients with IOL: a newer and better ICT
• Role of ICT in the future paradigms of thalassemia treatment

17.  SP-420 development is based
on deferitrin
– orally available
– modified to reduce toxicity
 More effective iron chelator
than existing (in animal trials)
– better chelating efficiency
– improved bioavailability
– higher tissue levels, esp.
cardiac and pancreatic
– reduced renal toxicity
 Improved formulation
SP-420: a new generation oral iron chelator

18.  Primary objectives: safety and efficacy of SP-420
 SP-420 dose TBD; pending phase 1b results (trial NCT02274233)
 Deferasirox dose - as currently used / prescribed by investigator
– if treatment-naive, in accordance with the prescribing information
Proposed phase 2 study design
RANDOMIZE
SP-420 Dose A mg/kg QD
n = 40
SP-420 Dose A mg/kg QD
SP-420 Dose B mg/kg
n = 40
SP-420 Dose B mg/kg
Deferasirox
n = 20
Extended period
(weeks 25–48), SP-420
Primary treatment period
(weeks 1–24)
patients≥14years
oldwithTDT

19. • Derivative of desazadesferrithiocin
• Polyethers chosen to increase hydrophilicity
• Very high affinity and selectivity for iron
• Orally bioavailable
• FBS0701 chosen for pharmacological,
pharmacokinetic and toxicity profile
• Iron chelating efficiency 23% in primates
FBS0701: A New Promising Drug?
Rienhoff et al. Haematologica 2011;96:521–5; Hahn et al. J Am Chem Soc 1990;112:1854–60; Anderegg &
Raeber J Chem Soc Chem Commun 1990;17:1194–6; Bergeron et al. J Med Chem. 2008; 51: 3913–23

20. FBS0701/Ferrikin/SH602/Deferithiozine

21. Agenda
• A new Guideline for TDT-TIF 2014
• A new information on current management
- What’s new!! on iron chelators
• A new future treatment on horizon
- New approach and new paradigm shift
- New diagnosis & future

22. Ineffective Erythropoiesis

23. RBC Hemolysis: Oxidative stress

24. Stress vs ineffective erythropoiesis
Normal
Stress
erythropoiesis
Ineffective
erythropoiesis
Iron limited erythropiesis
Hyperactivation of Jak-2 kinase

25. Controls over erythroid lineage development

26. ActRIIB, activin receptor type Iib. Suragani R, et al., Nat Med. 2014;20:408-14.
ACE-536 and ACE-536: selective
human ActRII receptor ligand TRAP
ActRIIB receptor
(only inhibition
of GDF11)
Fc domain of
human IgG1
antibody
ACE-536
luspatercept
ActRIIA receptor
(inhibits activin A,
B, GDF11)
Fc domain of
human IgG1
antibody
ACE-011
sotatercept

27. * s.c. injection once every 3 weeks.
25 patients: 18 NTDT; 7 TDT.
NTDT, non-transfusion-dependent thalassaemia; TDT, transfusion-dependent thalassaemia.
Porter J, et al. EHA 2014. Haematologica.
2014;99 Suppl 1:abstract S662.
Phase 2a interim results: sotatercept* improves
anaemia and has a favourable safety profile
Sotatercept increased Hb levels in NTDT patients, decreased transfusion
requirement in TDT patients, and has a favourable safety profile
0
20
40
60
80
100
≥ 1 g/dL increase ≥ 2 g/dL increase
0.1 mg/kg (n = 6)
0.3 mg/kg (n = 6)
0.5 mg/kg (n = 6)
0.75 mg/kg (n = 4)
Maximum change in Hb during the first 9 weeks
Sotatercept
Patients(%)
Maximum change in Hb in
NTDT patients during the first 9 weeks
Interim data as of 7 February 2014.
Hb values are not included if measured within 2 weeks after transfusion.
0
20
40
60
80
100
≥ 20% reduction ≥ 50% reduction
0.1 mg/kg (n = 2)
0.3 mg/kg (n = 3)
0.5 mg/kg (n = 2)
0.75 mg/kg (n = 3)
Sotatercept
Reduction in transfusion
burden in TDT patients
Change in transfusion burdenb
Interim data as of 7 February 2014.
a Transfusion burden evaluated up to the last known efficacy record,
adjusted to 168 days.
b Change in transfusion burden (units/168 days) from baseline.
a

28. *s.c. injection once every 3 weeks for up to 5 doses with a 2-month follow-up.
24 patients: 20 NTDT; 4 TDT.
Piga A, et al. EHA 2014. Haematologica.
2014;99 Suppl 1:abstract S664.
Phase 2 preliminary results: luspatercept*
improves anaemia in NTDT and TDT
0
20
40
60
80
100
Hb ≥ 1 g/dL Hb ≥ 2 g/dL
0.2 mg/kg (n = 6)
0.4 mg/kg (n = 6)
0.6 mg/kg (n = 5)
0.8 mg/kg (n = 3)
Patients(%)
Luspatercept increased Hb levels in NTDT patients, decreased transfusion
requirement in TDT patients, and has a favourable safety profile
Maximum change in Hb in NTDT

29.  RBC morphology before (A) and after (B) 6 months of
treatment with sotatercept 0.5 mg/kg in a 55-year-old
Cypriot–Greek male
– baseline Hb was 8.7 g/dL
– Hb at 6 months was 11.8 g/dL
Porter J, et al. EHA 2014. Haematologica.
2014;99 Suppl 1:abstract S662.
Results: RBC morphology before
and after sotatercept treatment
A B

30.  30-year-old male, non-transfusion-dependent thalassaemia intermedia
 Baseline Hb 9.2 g/dL
 History of lower limb ulcers since 2011
– leg ulcer healing noticed 2 weeks after first dose of ACE-536 (0.4 mg/kg)
– 2nd dose delayed due to unrelated bone marrow hypoplasia
– leg ulcer substantially resolved after 6 weeks on treatment
– patient received a total of 4 doses; maximum Hb on study 10.6 g/dL
Piga A, et al. EHA 2014. Haematologica.
2014;99 Suppl 1:abstract S664.
Patient 0203 – leg ulcer
ACE-536 β-thalassaemia phase 2 clinical trial
Pre-treatment After 6 weeks ACE-536
Study day
1 22 43 64 85

31.  Care
– prevention of complications: Improving ICT
– early control of complications through a rigorous
follow-up and treatment
– control of ineffective erythropoiesis: Jak-2, Activin inh.
 Cure
– SCT: Haploidentical
– gene therapy
Future landscape of
haemoglobinopathic treatment

32. Our Lab team
Acknowledgement: Vip’s team at Siriraj Hospital