Transcript Nathan Visweshwar MD.,FRCP.,FRCPath.,FRCPC

Joint bleed in hemophilia - impact on
resources in developing countries
Nathan Visweshwar MD.,FRCP.,FRCPath.,FRCPC
Director, Hemophilia/Hematology Program
University of South Florida
Tampa, FL. USA
Disclosures
• Nothing to disclose
Outline
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Incidence & Prevalence
Prophylaxis Vs. On-demand
Pathogenesis of Arthropathy
Subjective Vs. Objective bleed
Role of U/S in Hemophilia
Utilization of resources
What is new in hemophilia?
A study of variations in the reported haemophilia A prevalence around the world
Haemophilia
Volume 16, Issue 1, pages 20-32, 21 OCT 2009 DOI: 10.1111/j.1365-2516.2009.02127.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2516.2009.02127.x/full#f2
• Reported hemophilia A prevalence in the early
1970s for the United Kingdom was
approximately 10 per 100 000 males versus 20
per 100 000 males in the United States
• Thirty years later the reverse is true – the
prevalence in 2006 in the United States was
reported as 8.0 per 100 000 males versus 20.7
per 100 000 males in the United Kingdom
• The literature suggests that the hemophilia A
and B incidence is the same for all populations
and racial groups
Hemophilia in developing world
• About 80% of patients with hemophilia live in
developing countries. Only 10% are registered
with HTCs
• Most of the patients in developing countries
are receiving on-demand therapy
The world Federation of Hemophilia is aiming for
“treatment for all” patients with hemophilia
Brinkhaus, Davie & Ratnoff
Coagulation Cascade
Hemophilia time-line
• 1939 – Brinkhaus identifies anti-hemophilia
factor- factor VIII as deficiency in Hemophilia
• 1952 - factor IX deficiency-Christmas disease
identified
• 1952 - thromboplastin test developed
• 1958 - Nilsson in Sweden proposes primary
prophylaxis
• 1964- coagulation cascade described
Plasma concentrates
• 1984- CDC tests on heat- treated concentrates
(HIV is heat susceptible)
• 1985- Viral inactivated factor concentrates
become available. ELISA/Western blot in use
• 1989- HCV identified
• 1991- Testing for HCV introduced
• 1995- In UK variant Creutzfeldt-Jacob disease
• 2009- Hemophilia patient with variant CJD
Recombinant proteins
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1984- factor VIII gene is cloned
1992 - recombinant factor VIII developed
1996 - recombinant VIIa approved
1997 - recombinant factor IX
1998 - gene therapy trials in humans for factor IX
deficiency
• 2014 - extended half-life product approved in
USA
• 2016 – Factor VIII mimetic bispecific Ab.
Primary prophylaxis
versus
On-Demand therapy
Manco-Johnson MJ, et al. N Engl J Med. 2007;357:535-5.
Average American life span - 76
Duration of prophylaxis
• When the prophylaxis is stopped in the adult
age group about one third of the patients
maintain healthy joints
• About one third of the patients develop
recurrent spontaneous joint bleeds – need to
continue prophylaxis
• The rest may need – factor VIII concentrate
according to the physical activity/ exercise
Financial burden to society
• In developing countries, because of the
financial constraints, primary prophylaxis with
factor VIII (costing about 300,000 US dollars) is
too expensive for an average individual
Adherence Concerns in Adolescents
for primary prophylaxis
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Repeated infusaport infection
Denial and fear of their Hemophilia
Misinformation
Distrust of the medical establishment
Lack of confidence in the effectiveness of
medications
Low self-esteem
Unstructured and chaotic lifestyles
Mood disorders and other mental illness
Lack of familial and social support
Lack of or inconsistent access to care
New Intervention
Disparity of Factor VIII level & severity
• Some patients with trough levels less than 1% do
not bleed, whereas others bleed despite trough
levels more than 3%
• Arthropathy develops in patients who have
reported few or no joint bleeds - “micro-bleeds”
can not be prevented by primary prophylaxis
• About 10-15% of severe Hemophiliacs are
without symptoms
• Nearly 50% with severe Hemophilia do not have
major joint symptoms
High incidence of ankle arthropathy in mild and moderate haemophilia A. Ling M, Heysen JP,
Duncan EM, Rodgers SE, Lloyd JV Thromb Haemost 2011; 105:261–268.
Rationale for individualizing haemophilia care Sorensen B et al. Blood Coagul Fibrinolysis 2015 Dec;26(8):849-57
On- demand treatment
• Treatment to be tailored to the individual's
clinical, pharmacokinetic and pharmacodynamic
characteristics
• Therapy be individualized and encompass all
aspects of patient care that may impact QoL
Blood Coagul Fibrinolysis - 2015 Dec;26(8):849-57
Joint pain
• What is perceived as a bleed by the patient
on-demand therapy may be pain from other
causes including pain secondary to joint
complications, including synovitis,
hemosiderin deposition, fibrosis of the joint
and osteophytes from osteoarthritis.
Synovium
Joint space
Cartilage/Menisci
Pain in Knee
Hoffa’s fat pad
Bursae
Hemophilic “Target Joint”
• 11-19 Yrs. - there is marked villus proliferation
• 20-29 Yrs. - disappearance of proliferative
changes
• >30 Yrs. - complete atrophy with flat synovium
• >40yrs. - fibrosis of the subsynovial
connective-tissue with penetration of fibrosis
to the deeper layers of the articular cartilage
occurs (Roosendaal et al., 1999).
Diagnostic accuracy of
ultrasonography – Doria et al. 2015
Only 40% have US confirmed bleed
HTCs role
• Education of bleed detection
• Evaluation of early joint changes and
appropriate management
• Preservation of musculoskeletal function
• Preservation of activities
• Effective communication between the patient,
hematologist, physical therapist and
orthopedic surgeon
Future
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Prolonged efficacy
Higher potency
Resistance to inhibitors
Resistance to inactivation
New products
Different delivery
Higher production
Extended half-life
Fusion
• Fc fusion molecules
• Albumin fusion
• PEGylation (Glyco/Site-directed/Random)
Modifying synthesis/delivery
• Single chain - fusion of heavy/light chains
• Liposomal delivery
• Polymer based delivery
Potentiation of factor concentrates
Mutation
• IX – arg338ala – 776% potency
Activation
• VIII/HC II
Increased binding
• Mutation of Gla – domain (GGA of IX-VIIa)
Post translational
• Sulfation/phosphorylation/glycosylation
Alter Immunogenicity
Change protein sequence
• tyr2105cys/arg593cys –most immunogenic
Porcine hybrid
• Factor VIII human/porcine hybrid
Prevent Inactivation
Heavy/Light chain stabilization
• by stabilizing disulfide bonds
Hybridization
• Human/HC II hybrid
Higher Production
• FVIII – A1 domain and B domain mutations
• FIX- arg338ala
- increased production in cell culture
Gene therapy
• Long-Term Safety and Efficacy of Factor IX
Gene Therapy in Hemophilia B
Amit C. Nathwani, et al.
N Engl J Med 2014; 371:1994-2004 November
20, 2014DOI: 10.1056/NEJMoa1407309
(UCH/St.Jude’s)
Emicizumab in waterfall hypothesis
- FVIII mimetic bispecific Ab.
Emicizumab
Effect of Emicizumab on Coag. screening
Factor VIII-Mimetic
Function of Humanized
Bispecific Antibody in
Hemophilia A.
Shima, Midori; Hanabusa,
Hideji; Taki, Masashi;
Matsushita, Tadashi; Sato,
Tetsuji; Fukutake, Katsuyuki;
Fukazawa, Naoki; Yoneyama,
Koichiro; Yoshida, Hiroki;
Nogami, Keiji
New England Journal of
Medicine. 374(21):20442053, May 26, 2016.
DOI:
10.1056/NEJMoa1511769
Copyright © 2016 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society.
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Emicizumab –efficacy
71% reported no
bleeding with
1mg/kg. weekly
Emicizumab
Copyright © 2016 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society.
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Intervention in hemophilia
Optimal utilization of the factor concentrates
can only be achieved by:
• Education
• Expedited physical therapy
• Evaluation of the joint for secondary
complications
• Early intervention and prenatal diagnosis
• Expectant mothers (5Es).