What is new in the management of Thalassemia in 2019?

Thalassemia and sickle cell disease (SCD) are disorders of hemoglobin that affect millions of people
worldwide. The carrier states for these diseases arose as common, balanced polymorphisms during
human history because they possibly afforded protection against severe forms of malaria. These
complex, multisystem diseases demand comprehensive, multidisciplinary and lifelong system of care.
While the emphasis should be on prevention, let us try to get an idea as to what medical science has
to offer in the near future in terms of management as we commemorate World Thalassemia Day on
8th May.

Gene Therapy
On 29th March 2019, European Medicines Agency (EMA) has recommended granting a marketing
authorization in the European Union for a genetically modified product for beta-thalassemia.
Zynteglo® (LentiGlobin vector BB305) is intended for adult and adolescent patients 12 years and older
who need regular blood transfusions to manage their disease and have no matching donor for a stem
cell transplant. Zynteglo® is a new therapeutic option for patients for whom a related donor for stem
cell transplantation is not available. Using a lentiviral viral vector, it adds functional copies of a
modified β-globin gene into a patient’s own stem cells, thereby addressing the underlying genetic
cause of the disease. Zynteglo should only be administered in a qualified treatment centre by a
physician with experience instem cell transplantation and in the treatment of patients with beta-
thalassemia.In the two main studies to demonstrate the effects of Zynteglo® it was shown that the
majority of patients who do not have a β0/β0 genotype treated with Zynteglo® no longer needed
regular blood transfusions. The most common side effects were thrombocytopenia, abdominal pain,
non-cardiac chest pain, pain in the extremities, dyspnea and hot flush. Since Zynteglo® addresses an
unmet medical need, it benefited from PRIME, EMA’s platform for early and enhanced dialogue with
developers of promising new drugs.

The potential of gene therapy to address the root cause of thalassemias, rather than simply alleviating
their symptoms, and to provide long-term therapeutic effects after a single administration may bring
hope for a curative treatment for many affected patients. Gene therapy by gene addition has made
great strides forward since the discovery of the regulatory elements that control β-globin
transcription, the advent of LVs, the development of preclinical globin vectors, and the proof-of-
principle of efficacy in mouse models. In particular, this vector (LentiGlobin vector BB305) and current
protocol appear consistently therapeutic for TDT patients with βE/β0, the genotype responsible for
approximately half of all TDT. Phase III trials are currently being undertaken at 3 centers in USA,
France, Germany, Greece, Italy and UK on behalf of Bluebird Bio. The implementation of gene therapy
in clinical practice for TDT and SCD will ultimately depend on long-term benefit/risk/cost ratios, which
will be carefully evaluated over the next few years.

Gene Editing
A Phase I/II Study to Assess the Safety, Tolerability, and Efficacy of ST-400 for Treatment of
Transfusion-Dependent Beta-Thalassemia (TDT) is currently being undertaken at 5 centers in USA by
Sangamo Therapeutics. This thalassemia gene therapy clinical trial aims to assess the effectiveness of
ST-400 on transfusion-dependent beta-thalassemia (TDT). ST-400 is a type of investigational therapy
that consists of gene edited cells. ST-400 is composed of the patient's own blood stem cells which are
genetically modified in the laboratory using Sangamo's zinc finger nuclease (ZFN) technology to
disrupt a precise and specific sequence of the enhancer of the BCL11A gene (which normally
suppresses fetal hemoglobin production in erythrocytes). This process is intended to boost fetal
hemoglobin (HbF), which can substitute for reduced or absent adult (defective) hemoglobin. ST-400
is then infused back into the patient after receiving conditioning chemotherapy to make room for the
new cells in the bone marrow, with the aim of producing new erythrocytes with increased amounts of
HbF. Patient receives a transfusion of edited blood stem cells. Ultimately, this approach aims to boost
the production with the aim of producing new erythrocytes with increased amounts of HbF. The
primary objective is to understand safety and tolerability of ST-400, and secondary objectives are to
assess the effects on HbF levels and transfusion requirements.

Precision gene editing by homology-directed repair (HDR) within the HBB locus, using engineered
nucleases and donor templates, is theoretically an ideal method for repairing the patient’s
Hematopoietic Stem Cells (HSCs) safely and ensuring optimal beta-globin expression. However, low
rates of HDR in HSCs, the inefficient delivery of nucleases and templates, potential off/oncotarget
cleavage, and the low engraftment potential of HSCs with repaired genes are all issues that need to be
addressed further before this approach can be translated into clinical practice. In addition, the very
large number of mutations (>200 for Beta-Thal) observed in patients would require an equally large
number of HDR products receiving regulatory and market approval, unless one focuses only on the
most common genotypes.

Activator of the red cell isoform of pyruvate kinase (PK-R)

In RBCs, ATP is generated through glycolysis and pyruvate kinase-R is involved in the final step of ATP
production. β-thal intermedia (Non Transfusion Dependent Thalassemias, NTDT) RBCs show 3-fold
faster glucose metabolism compared to controls. Under oxygenation/deoxygenation condition, β-thal
major and β-thal /HbE RBCs show reduced ATP content compared to healthy RBCs. AG-348 is an
Allosteric activator of the red cell isoform of pyruvate kinase (PK-R). AG-348 binds at PK-R enzyme
dimer-dimer interface to promote active tetramer. AG-348 increases ATP levels in healthy volunteers
(NCT02149966).

In β thalassemic mice, AG-348:

• Reduces ineffective erythropoiesis, extramedullar erythropoiesis, Erfe expression and ROS levels

• Increases Hb levels, reduces reticulocyte count and circulating erythroblasts

• Significantly increases RBC survival

• Reduces liver iron overload and increases Hamp

AG-348 might represent a novel therapeutic approach in clinical management of anemia in β

thalassemic syndromes.

Study AG348-C-010 is a phase 2 multicenter study to evaluate the efficacy, safety, pharmacokinetics,
and pharmacodynamics of treatment with AG-348 in adult participants with non-transfusion-
dependent thalassemia (NTDT). This study will include a 24-week core period followed by a 2-year
extension period for eligible participants. Approximately 17 participants with NTDT will be enrolled.
The initial dose of AG-348 will be 50 milligrams (mg) twice daily (BID) with one potential dose-level
increase to 100 mg BID, at the Week 6 visit based on the participant's safety and hemoglobin (Hb)
concentrations. Agios Pharmaceuticals, Inc has started the study in USA, Canada and UK.

Luspatercept
Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the
treatment of anemias with ineffective erythropoiesis. In beta-thalassemia, imbalanced production of
alpha and beta globin chains in erythroid precursors inhibits late-stage erythroid differentiation,
leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Luspatercept
promotes late-stage erythroid differentiation, corrects ineffective erythropoiesis, and reduces alpha
globin aggregates, hemolysis, and disease complications including iron overload in a beta-thalassemia
mouse model.

Luspatercept treatment for up to 3 months was well-tolerated, increased Hb levels in NTD patients,
and decreased transfusion requirement in TD patients with beta-thalassemia. Both TD and NTD
patients also had decreases in LIC, and healing of leg ulcers occurred in 3 of 3 patients. These
treatment effects represent a significant reduction in disease burden for patients with beta-
thalassemia. Phase 3 studies of luspatercept in beta-thalassemia are planned.

A Phase 2, double-blind, randomized, placebo-controlled, multicenter study is being conducted by

Celgene Corporation in multiple countries to determine the efficacy and safety of luspatercept (ACE-
536) versus placebo in adults with non-transfusion dependent beta (β)-thalassemia. The study is
divided into the Screening Period, Double-blind Treatment Period (DBTP) and Post-Treatment Follow-
up Period (PTFP). It is planned to randomize approximately 150 subjects at a 2:1 ratio of luspatercept
versus placebo.

Hepcidin
Iron overload is a significant complication in patients with thalassemia. LJPC-401, a synthetically
produced peptide identical to endogenous human hepcidin, is being developed as a therapeutic
intervention for iron overload in these conditions.

A Study With LJPC-401 for the Treatment of Myocardial Iron Overload in Adult Patients With
Transfusion-Dependent Beta Thalassemia is being conducted at 31 study locations by La Jolla. LJPC-
401 was well tolerated at single doses between 4 and 20 mg (the highest dose tested), and at doses
of 10 mg twice weekly in healthy adults, and resulted in decreases in serum iron levels compared with
baseline. Serum ferritin increased over the time course of observations, consistent with an increased
distribution of iron into the macrophage compartment, secondary to decreased iron egress into the
plasma transferrin compartment. No treatment-emergent serious adverse events were reported. One
subject discontinued treatment due to a TEAE (exacerbation of pre-existing atopic dermatitis) two
days after initial 10 mg dose. No trends were observed in clinical laboratory data, vital signs, ECGs, or
concomitant medications. No subjects tested positive for antibodies specific to LJPC-401.These results
warrant further research in longer-term studies.

Fetal Hemoglobin Induction Treatment with Metformin

Fetal Hemoglobin Induction Treatment Metformin (FITMet) study is a dose escalation, pilot study for
subjects with sickle cell anemia (SCA) disease and non-transfusion dependent thalassemia (NTDT) to
determine if metformin has a beneficial effect on the treatment and quality of life of SCA and NTDT
patients. There are two arms in the study. Group A: Hydroxyurea + Metformin in Subjects who are
currently taking Hydroxyurea as part of standard of care and have sickle cell anemia. Group B:
Metformin in Subjects who are not taking Hydroxyurea as part of standard of care and have non-
transfusion dependent thalassemia or sickle cell anemia. No results have been published till now.

Unfortunately none of these trials are being conducted in India, and hence we have no idea as to how
Indians with thalassemia would get the benefit of futuristic therapies in the real life scenario. For our
country, prevention of births of thalassemics should be our priority by generating awareness and
creating infrastructure for screening and prenatal diagnosis whenever required. The theme of World
Thalassemia Day this year is : “Universal access to quality thalassaemia healthcare services: Building
bridges with and for patients.” Let no thalassemic suffer because of lack of optimum and safe blood
transfusion and adequate iron chelation and management by a comprehensive care team.