It describes about the current standards, recent developments and upcoming therapies for the treatment of sickle cell disease. it also tell regarding the current government initiatives to eliminate the disease in near future.

1. Sickle cell disease: Newer treatments
Will India be Sickle free by 2047?
Dr Pritish Chandra Patra
Associate Professor
IMS & SUM Hospital
Bhubaneswar

2. Epidemiology
• Worldwide-
• 300,000-400,000 newborns with SCD per year
• Majority in Sub-Saharan Africa
• Mortality rate among newborns to 5-year-olds is 75%
• India is the second-largest hub of SCD after Africa
• Overall prevalence of 4.3%
Bhalla N et al. Allogeneic hematopoietic stem cell transplantation to cure sickle cell disease: A review. Front Med (Lausanne), 2023
Kato, G., Piel, F., Reid, C. et al. Sickle cell disease. Nat Rev Dis Primers 4, 18010 (2018)

3. What is sickle cell disease?
Genetic disease Abnormal HbS
Homozygous HbSS disease
Compound heterozygous HbS disease
Red cell alterations HbS polymerization (↓O2)
↓Deformability
Sickling
↑Fragility
Vascular alterations Intravascular hemolysis
Chronic vascular inflammation
Endothelial activation
Leukocyte/platelet alterations
Organ alterations Eventual widespread organ damage
Kato, G., Piel, F., Reid, C. et al. Sickle cell disease. Nat Rev Dis Primers 4, 18010 (2018)

4. What is sickle cell disease?
Manifestations and complications
Acute Hemolytic anemia
Painful vaso-occlusive episodes
Stroke
Acute chest syndrome
Infections
Chronic Pulmonary hypertension
Hepatic complications
Kidney disease
Retinopathy
Avascular necrosis
Kato, G., Piel, F., Reid, C. et al. Sickle cell disease. Nat Rev Dis Primers 4, 18010 (2018)

5. Morbidity Heterogeneous in severity
Acute/chronic complications
Poor quality of life
Mortality High mortality- especially in LIC
Median survival- 42yr M & 48yr F
India
High maternal mortality
Social context Growing initiatives to address SCD
Why to study sickle cell disease?
• ICMR-
• 20% of children with SCD die by age of 2yr
• 30% of children in tribal community die before
adulthood
Newborn screening for sickle cell disease: Indian experience. Roshan Colah et al, 2018

6. Timeline of drug development
SCD first reported
1st drug approved for SCD
(Hydroxyurea)
L-glutamine
Crizanlizumab
Voxelotor
New in pipeline
88 years 20 years
1910 1998
2017
2019
Gene therapy
2023

7. Current therapies for SCD
• Pharmacologic therapy
• Hydroxyurea
• Newer agents- Crizanlizumab, Voxelotor, L-glutamine
• Transfusion therapy
• Therapy with curative intent
• Hematopoietic stem cell transplantation
• Gene/gene editing therapy

8. Basic pathophysiology of vaso-occlusion in SCD:
A chronic inflammatory disease
Torres et al, Stem Cell Reports 2022; 17(7): 1509-1535

9. The vicious cycle
HbS polymerisation/
Sickling
Vaso-occlusive process
Intravascular hemolysis
Inflammation

10. Pathophysiological-based approaches to inhibit VOC in SCD
Upstream pharmacotherapeutic approaches
Inhibitors of HbS polymerization
• Hydroxyurea: ↑HbF
• Voxelotor: (Oxbryta: GBT440), modulator of Hb O2 affinity (FDA 2019)
• Phase 3 HOPE trial: Sustained increase in HbF levels from baseline
• ↑ in Hb level & ↓ anemia and hemolysis
• × No improvement in VOC episodes
• Phase 1 trial for GBT601 (next generation therapy)
• Mitapivat, Etavopivat: Erythrocyte pyruvate kinase activator
• Phase 2/3 trails- FDA approved for hemolytic anemia (PK deficiency)
• Phase 1 trial for SCD: Mitapivat- ↑Hb concentrations, restored the thermostability of PKR, ↑ its activity and ↓2,3-DPG levels
in sickle RBCs  ↑affinity of Hb to oxygen  ↓ Hb polymerization.
• Vichinsky E et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug
8;381(6):509-519.
• Pilo F, Angelucci E. Mitapivat for sickle cell disease and thalassemia. Drugs Today (Barc). 2023 Mar;59(3):125-134.
• Al-Samkari H, van Beers EJ. Mitapivat. A novel pyruvate kinase activator, for the treatment of hereditary
hemolytic anemias. Ther Adv Hematol. 2021 Dec 21;12:20406207211066070. x

11. Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches
Counter hemolysis
Counter oxidative stress
Nitric oxide repletion/cGMP amplification
Anti-inflammatory
Anti-adhesion
Anti-platelet
Anti-microbiota

12. Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches
• Counter hemolysis
• Haptoglobin: Hemoglobin binding protein (pre-clinical)
• Hemopexin: Heme-binding protein
• Phase 1 trial, CSL889, plasma derived hemopexin

13. Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches
• Anti-oxidants
• Anti-inflammatory
• L-glutamine (FDA: Endari)
• Nrf2 activators: IMR-261
• (Nrf2: nuclear factor erythroid-2 related factor)
• Anti-microbiota
• Penicillin V
• Broad spectrum antibiotics
• Rifaximin
• Probiotics
• Reduction in nuclear activation
• Improvement in inflammation related organ damage
• Some clinically relevant improvement in clinical trials
Niihara Y et al. A phase 3 trial of l-glutamine in sickle cell disease. N Engl J Med. (2018) 379:226–35.

14. • Anti-adhesion
• Crizanlizumab (SelG1), (FDA- Adakveo/Ryverna): SUSTAIN trial and STAND trial
• Anti P-selectin mAb
• Rivipansel (GMI-1070):
• Pan selectin inhibitor- no significant difference in time to discharge in RCT
• Tinzaparin/Sevuparin:
• Modified heparins- anti-inflammatory, anti-aggregation, and anti-adhesive properties- no significant benefit in RCT
• Poloxamer 188:
• Non-ionic surfactant- ↓ blood viscosity and cell-cell interactions, ↓ duration of VOC episodes
• No significant improvement during VOC episodes in RCT
Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches

15. • Targeting cellular adhesion
• Crizanlizumab (Adakveo, Ryverna)
• Inclacumab (Phase 3)
Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches

16. Excessive intravascular release of lysed
cellular contents from damaged RBCs in
SCA can activate the inflammasome
Inflammasome-
a multiprotein oligomer promoting
maturation and secretion of
proinflammatory cytokines, including IL-1β
Canakinumab (anti IL-β1)
No significant reduction in pain
Randomised double blind phase 2 trial

17. Nitric Oxide repletion/cGMP amplification
PDE9 inhibitors: IMR-687 (Tovinontrine)
Guanylyl cyclase agonists
Hydroxyurea
Pathophysiological-based approaches to inhibit VOC in SCD
Downstream pharmacotherapeutic approaches
Nitric Oxide (NO) / cGMP pathway in SCD
NO/cGMP signaling
Elevated HbF
Inhibits leukocyte adhesion

18. Inflammatory molecule as a target in SCD: cGMP amplification
Almeida Et Al, Bood, 4 October 2012 Volume 120-14
Nitric Oxide (NO) / cGMP pathway in SCD Phosphodiesterase (PDE) enzymes
• Degrade cyclic nucleotides (cGMP/cAMP)
• PDE inhibition can amplify intracellular cyclic nucleotides
• PDE9- highly expressed in leukocytes/ RBCs of SCD patients
• PDE9- expression is predominantly in hematopoietic
cells/brain
PDE inhibitors/PDE9i
• IMARA: IMR 687 (Tovinontrine)
• Guanylyl cyclase agonist: Olinciguat

19. Various other modalities
• Increase HbF-
• Epigenetic changes- HDAC, Decitabine
• Immunomodulatory drugs- Pomalidomide
• Increasing RBC hydration-
• senicapoc, memantine
• Gardos channel inhibitor-
• Clotrimazole
• Increasing oxygen delivery-
• Sanguinate (pegylated bovine carboxyhemoglobin)
• Decreasing neutrophil interactions
• IVIG
• Decreasing oxidative stress-
• Cathepsin B inhibitor, L-arginine
• And……..

20. New uses of Hydroxyurea in SCD
• 1st FDA and EMA approved therapy for SCD
• Standard of care for preventing VOC
• ↓ hospitalization, VOC, ACS, transfusion
frequency, mortality
• Inexpensive
Hydroxyurea therapy for SCD
• ↑ HbF
• ↓ leukocyte numbers
• NO donor
• NO formation occurs with in 30 mins of oral
administration of HU in humans
Acute benefits?

21. Clinical evidence of acute effects of Hydroxyurea (HU)
• Mouse model
• Acute HU oral or IV significantly reduces vaso-occlusive like
process
• HU exerts its effects trough NO/cGMP pathway
• Acute HU administration with a cGMP amplifier (PDE9i)
improves survival in mouse model
• Acute HU reduces hemolysis related inflammation in
mouse model
• Effect in acute VOC?
• Human trial
• HELPS study
Conran N et al. Br J Haematol. 2022 Oct;199(1):153-1

22. • Hydroxyurea in the Emergency Room to Lessen Pain in Sickle Cell Crisis (HELPS) study
• Phase II, single-centre, randomized, open-label interventional study
• Primary objective- evaluating the safety of the administration of up to three moderate-
to-high daily doses of HC in HbSS patients during the acute phase of VOE
management.
• Conclusion-
• Administration of up to 3 consecutive daily doses of ~30mg/kg HU to SCD patients
during acute VOC episodes is feasible and safe.

23. Allo HSCT for SCD
• The only curative modality
• Newer modalities-
• Gene/gene editing therapy

24. Breaking News

25. Casgevy: Exagamglogene autotemcel
Lyfgenia: lovotibeglogene
autotemcel

26. India

27. Elimination: Is it at all possible?
• Can we treat these large bunch either with SCT or gene therapy?
• how long will it take?
• how much burden will it be on society/country/state?
• how much financial burden will it be?
• Can we prevent it?
• The Cyprus story of thalassemia
• Screening- pre-marital/pre-conception/pre-natal…etc.
• The govt program- NSCEM

29. NSCM 2022 & NSCEM 2023
• The Ministry of Health and Family Welfare in India has identified SCD as a disease of national importance.
• The Indian National Sickle Cell Mission (NSCM), launched in November 2022, aims to lower the prevalence
of SCD through a coordinated strategy that includes widespread screening, raising awareness, and creating a
national SCD registry.
• Recently, the Indian government has launched National Sickle Cell Anemia Elimination Mission (NSCEM)
2023, which “aims to eradicate sickle cell anemia from India in a mission mode by 2047”.
• This will include awareness creation, universal screening of seventy million people in the age group of 0–40
years in tribal areas, and premarital counseling through collaborative efforts of central and state
governments (National Health Mission 2023; National Sickle Cell Anemia Elimination Mission 2023).
• It may be a herculean task to “eradicate” SCD by 2047 in India, but with timely action such as awareness,
carrier screening programs, and genetic counseling, the SCD burden can be greatly reduced in the Indian
population (Sinha et al. 2020).

30. Odisha

31. Summary
• HU is the primary therapy to prevent these complications in children and adults with Hb SS and Hb
Sβ0 thalassemia.
• HU provides a myriad of well-documented clinical benefits, making it the first choice for children and
adults with Hb SS and Hb Sβ0 thalassemia.
• However, HU has limitations, and not all individuals with SCD benefit from it.
• Additional therapies are needed for those who don’t tolerate HU / don’t get benefit from HU.
• Newer FDA-approved therapies may further reduce VOCs, improve anemia, and/or reduce hemolysis,
but none of them have been demonstrated to provide a cure for the disease.
• Additionally, some have- high costs and requirement for i.v. or s.c. administration.
• Cure- Allo SCT  Gene/gene editing therapy
• Prevention is better than cure- NSCEM 2023

32. Towards
a
Sickle free society
Thank You