Hemophilia scenario in India- Unmet needs and way forward

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1 1 Hemophilia scenario in India- Unmet needs and way forward Dr Anupam Verma MD, PDCC Addl Professor, Transfusion Medicine SGPGI, Lucknow State Nodal Officer Hemophilia (Uttar Pradesh)

2 2 Outline Background Hemophilia Goals of treatment in Hemophilia How to achieve the therapeutic goals? Epidemiology of Hemophilia in India Current scenario of Hemophilia care in India Unmet needs Opportunities

3 Background: Hemophilia Hemophilia is a rare, X-linked congenital bleeding disorder due to deficiency of factor VIII/IX

Without appropriate treatment # : Reduced life expectancy Death Permanent disabilities Joint/bone damage Brain damage *

2010;16:20 32 # Resolution of the World Federation of Hemophilia General Assembly on the Supply of Safe High-Quality

3 3 Background: Hemophilia Hemophilia is a rare, X-linked congenital bleeding disorder due to deficiency of factor VIII/IX Characterised by profuse bleeding into joints, muscles & internal organs. Without appropriate treatment # : Reduced life expectancy Death Permanent disabilities Joint/bone damage Brain damage * Stonebraker J. S. et al. A study of variations in the reported haemophilia A prevalence around the world. Haemophilia. 2010;16:20 32 # Resolution of the World Federation of Hemophilia General Assembly on the Supply of Safe High-Quality Clotting Factor Concentrates July 15, Available from URL contents last accessed on 22 June 2015

4 4 Goals of treatment: Recommendations PWH to lead a normal life with full life expectancy as a normal human being No/little compromise on Quality of Life due to hemophilia PWH without disability No pain 1. Srivastava A et al., Haemophilia (2013), 19, e1 e47 2. Giangrande P et al., Haemophilia (2014), 20, Keeling D et al., Haemophilia (2008), 14,

5 5 How to achieve these goals? Place for Treatment Good Laboratory Sustainable funding: Government support Products for Treatment Suitable Manpower

6 Place for treatment 6 Home Rx HTCs Primary care District Central State/ Nodal Referral Medical College

7 7 Products for treatment CFC Good quality Virally safe Replacement in form of Prophylactic therapy 20,000 IU/pt/yr for episodic Tt Adequate dosing -2,16,000 -IU/Pt/yr* * Assuming 25IU/Kg thrice a week regimen for an average BW of 60 Kg 1. Srivastava A et al., Haemophilia (2013), 19, e1 e47 2. Giangrande P et al., Haemophilia (2014), 20, Factor VIII & IX bypassing agents Adequate Continued factor supply

8 8 Diagnostic services Labs that can run following services Prioritization: 1 advanced lab in each state Basic screen PT/aPTT Factor assays Identify & quantify Inhibitor screen mixing tests Inhibitor assays Bethesda/Nijmegen Prenatal Diagnosis & carrier detection

9 9 Physiotherapy Equipment Trained personnel A key goal is to help maintain mobility, muscle strength, and balance If these have been compromised, physiotherapy must restore or improve these modalities Physiotherapy advises on safe sports and exercises

Man power for comprehensive care 10 Primary Requirement Doctor (trained in bleeding disorder) Hemophilia Nurse Physiotherapist Imaging specialist (Radiologist) Add on

10 Man power for comprehensive care 10 Primary Requirement Doctor (trained in bleeding disorder) Hemophilia Nurse Physiotherapist Imaging specialist (Radiologist) Add on Requirement Orthopedician Counsellor( Psycho-social) General Surgeon Gastroenterologist Laboratory(Pathologist & Technician) Dentist Comprehensive care from a multidisciplinary team

11 11 Hemophilia Global scenario World population: 6,491,492,078 PWH: 1,78,500 Hemophilia A: 1,43,523 PWH= people with hemophilia; HA = Hemophilia A World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec 2015.

World Federation of Hemophilia Report on the annual global survey 2014.

12 12 India: Largest global burden of Hemophilia A India population: 1,236,344,631 PWH: 17,470 13, ,450 HA: 14, PWH= people with hemophilia; HA = Hemophilia A World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec 2015.

13 13 Observed (calculated at 0.9/1,00,000) and estimated (calculated at 4/1,00,000 population) prevalence of hemophilia A for states and UT of India

14 Hemophilia India : Current status Estimated PWH in India: ~75,000*/1.2 billion Diagnosis rate: ~23% Diagnosed PWH: ~17,000 Hemophilia India : Challenges Under diagnosis: Tip of iceberg has been diagnosed till date 14 Treatment for PWH FVIII/IX ~50% FFP/Cryo ~50% $ Pd CFC Recombinant 98% # CFC: 2% # PWH Persons with Hemophilia *Kar A, Phadnis S, Dharmarajan S & Nakade J. Indian J Med Res 140, July 2014, pp $ As per data communicated by Dr Cecil Ross from Hemophilia Federation (India) # World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec 2015.

15 Hemophilia India : Current scenario Estimated PWH in India: ~75,000*/1.2 billion Diagnosis rate: ~23% Diagnosed PWH: ~17,000 Treatment for PWH FVIII/IX ~50% FFP/Cryo ~50% $ Hemophilia India : Challenges >50% of diagnosed PWH are yet treated with blood products risk of infection HIV/HBV/HCV 15 Pd CFC Recombinant 98% # CFC: 2% # PWH Persons with Hemophilia *Kar A, Phadnis S, Dharmarajan S & Nakade J. Indian J Med Res 140, July 2014, pp $ As per data communicated by Dr Cecil Ross from Hemophilia Federation (India) # World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec 2015.

16 Hemophilia India : Current scenario Estimated PWH in India: ~75,000*/1.2 billion Diagnosis rate: ~23% Diagnosed PWH: ~17,000 Hemophilia India : Challenges 16 Treatment for PWH FVIII/IX ~50% FFP/Cryo ~50% $ Pd CFC Recombinant 98% # CFC: 2% # Plasma derived CFC - Limited supply / availability due to the source pooled plasma *Kar A, Phadnis S, Dharmarajan S & Nakade J. Indian J Med Res 140, July 2014, pp $ As per data communicated by Dr Cecil Ross from Hemophilia Federation (India) # World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec PWH Persons with Hemophilia

17 Hemophilia India : Requirement vs reality - Unmet medical need 17 FVIII (in millio on IU) Minimum required FVIII for preventing Disabilities for all PWH in India / year 1200 Minimum required FVIII for optimum survival for all PWH in India /year 7 Actual consumption in 2014 in India (Plasma derived + recombinant) Pd-CFC are not able to meet the minimum requirements for optimal survival or for prophylaxis as stated by WFH * *World Federation of Hemophilia Report on the annual global survey Available from URL contents last accessed on 10 Dec Giangrande P et al., Haemophilia (2014), 20,

18 Unmet medical needs: Demand supply gap 18 Recently more number of State Govt started procuring AHF Complete AHF support (21 states) Advocacy with Govt. in Progress (2 states) Advocacy to be done Adequate and affordable availability of FVIII/FIX concentrates will depend upon Indigenous Production of CFC?? Increasing demand & usage of CFC in India Not matched by supply of Pd-Factors 1. Inadequate supply 2. Intermittent supply 3. In-ordinate delay Due to limited manufacturer/ supplier

19 19 Why is there a scarcity in supply of Pd-FVIII? Low Production yield from 1 litre of plasma gm of Albumin, IU FVIII IU FIX, 3-5 gm of IVIG, 250 IU Antithrombin, 0.20 gm of alpha-1 antitrypsin, Various amounts of hyper-immune globulin products Angelis et al, Blood Transfusion 2013 Several reasons but one of these could be due to complicated manufacturing and time taken to manufacture.

20 20 Preparation of pd FVIII: Approx. time Collection of human plasma Protein fractionation Purification Stabilization & final formulation Appropriate donor selection Mandatory screen for HIV/HBV/HCV FVIII/IX is separated from pooled plasma Viral protection For adequate storage & shelf life Plasma inventory hold to exclude window period Nucleic acid testing. WFH Guide for the Assessment of clotting factor concentrates Sherwood L. Human Physiology: From Cells to Systems (8 th Ed). Brooks/Cole, CA, USA. Plasma Protein Therapeutics Association (PPTA). Accessed at on 11 July months

Fact is.shortage of blood donors. 21 Whereas the current global plasma supply is not meeting the needs of people with bleeding disorders around the world.

21 Fact is.shortage of blood donors. 21 Whereas the current global plasma supply is not meeting the needs of people with bleeding disorders around the world. Even the majority of countries that are self sufficient in fresh blood components are unable to meet their own needs for plasma-derived products from their domestic plasma collections Whereas there are no proposals anywhere in the world that would substantially alter this supply situation in the foreseeable future Resolution of the World Federation of Hemophilia General Assembly on the Supply of Safe High-Quality Clotting Factor Concentrates July 15, Available from URL contents last accessed on 6 November 2015

22 22 Plasma CFC However, achieving plasma of high quality and safety is very demanding commitment of all involved parties human resources financial expenditure Status of blood systems, and the degree of supply of the population with blood products of good quality and safety is apparently very different throughout the world Not enough plasma from whole blood donation Plasmapheresis costly, from paid donors Plasma Protein Therapeutics Association (PPTA)

Truck was heading to Mumbai to a pvt industry.

23 23 Synthetic Plasma- Fake plasma The Bathinda Police on July 21 st,2016 seized over 21,700 packets of fake blood plasma. Truck was heading to Mumbai to a pvt industry. Police claimed that plasma was mixed with refined oil, soya bean milk and egg yolk.

24 Threat of infections Unknown/Emerging viruses??? Battle against infections & struggle for blood safety are closely interrelated How to tackle? 24 Recombinant technology(r-cfc) NAT Pathogen inactivation Nanofiltration (15-35 nm) Pd-CFC

25 25 Scarcity of pd FVIII Use of FFP/Cryo O n d e m a n d FFP/Cryo Pd - CFC r-cfc *Kar A, Phadnis S, Dharmarajan S & Nakade J. Indian J Med Res 140, July 2014, pp $ As per data communicated by Dr Cecil Ross from Hemophilia Federation (India)

26 Challenges - Infection burden - Use of blood products Indian scenario Hepatitis C 30% 20% HIV Hepatitis B 30% 10% % PWH 1% 6% 0% Ghosh K, et al. Indian J Med Res 2000; 112 : Khaja MN, et al. Infection, Genetics and Evolution 6 (2006)

27 Challenges - Infection burden.. SGPGI Study 27

28 Pd FVIII: safety issues* Plasma derived Clotting factor VIII animal or human protein Infections???? 28 Solvent detergent treatment ++ No Nanofiltration Protection Hepatitis B Hepatitis C HIV Risk Hepatitis A, E ++ Parvovirus B19 ++ Prion diseases ++ * WFH Guidelines. Guidelines for the management of hemophilia. Haemophilia (2013), 19, e1 e47 Farrugia A. WFH Guide for the assessment of clotting factor concentrates.

29 Opportunities for safety: First-generation (Recombinate ) Animal- and human-derived proteins in cell culture Pasteurised human albumin used to stabilise the final product Second-generation

plasma-derived proteins are used in culture or in stabilization Although albumin has not been shown to transmit pathogens, a risk is still associated with its use because it is derived from

29 29 Opportunities for safety: First-generation (Recombinate ) Animal- and human-derived proteins in cell culture Pasteurised human albumin used to stabilise the final product Second-generation (Kogenate FS ) Animal- and human-derived proteins in the cell culture Sucrose instead of albumin as a stabiliser Third-generation (Novoeight, Advate, Refacto AF /Xyntha ) No Animal or human plasma-derived proteins are used in culture or in stabilization Although albumin has not been shown to transmit pathogens, a risk is still associated with its use because it is derived from human plasma Franchini M and Lippi G. Semin Thromb Hemostasis. 2010;36: NHF. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. 2012

30 30 India: 1 st gen recombinant FVIII rfviii First generation Components in cell culture medium Bovine albumin, Insulin, aprotinin Primary stabilizer in formulation Human albumin No Solvent detergent* No Nanofiltration* Risk of hypersensitivity reactions Risk of infection due to animal/human components * Keeling D et al., UKHCDO guideline Haemophilia (2008), 14, Boedeker BDG. Seminars in Thrombosis and Hemostasis. 2001; 27(4):

31 Reality check 31

32 Hemophilia management Unmet needs & opportunities 32 Infections Immobility Switch to 3rd generation recombinant CFC Prevent bleeding & arthropathy by prophylaxis C o s t PWH leads a normal life free of pain & disability Supply R-CFC > pd-cfc products Inhibitor more in r-cfc *Farrugia A. Guide for the assessment of clotting factor concentrates. Available in URL contents last accessed on 20 January 2015.

33 Cost Benefit Model in Hemophilia 33 Resources you need depend on the outcome you would like to see W. Schramm, 2006; modified

34 Opportunities for prophylaxis and inhibitor management Fc fusion (VIII, IX) Albumin fusion (IX, FVIIa, VWF) Half life extension PEGylation PEG Liposome Polysialysation Single chain FVIII Improves stability FVIII mimetic bispecific antibodies Alternatives to factor replacement Anti TFPI Gene Therapy Transgenic products Antithrombin RNAi Interference Kaufman RJ and Powell JS. Blood. 2013;122(22): Oldenburg J and Albert T. Haemophilia (2014), 20 (Suppl. 4), 23 28

35 Summary 35 India has the largest disease burden of hemophilia. Though it is a rare disease; the current prevalence rates represent only the tip of the iceberg. More HTCs are required with holistic management. The requirement for FVIII & FIX in India is on a steady increase and will continue to do so in near future. The government support and cost -benefit, demand-supply & inhibitor issues will govern the usage of CFC.

36 36 With support from NHM and U.P. Government Thanks

The Role of Disease Foundations in Moving Gene Transfer Forward

The Role of Disease Foundations in Moving Gene Transfer Forward Mark W. Skinner WFH President 7 April 2005 ASGT Stakeholder Meeting WFH Mission Introduce Improve Maintain Care for people with hemophilia