treatment? A Haematologists perspective Professor Cedric HERMANS MD - - PowerPoint PPT Presentation

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European Haemophilia Consortium Round Table of Stakeholders Orthopaedic Aspects in Haemophilia Care

What are the goals of treatment? A Haematologist’s perspective

Professor Cedric HERMANS MD PhD FRCP (Edin, Lon) Haemostasis and Thrombosis Unit Haemophilia Clinic Division of Haematology Cliniques Universitaires Saint-Luc Catholic University of Louvain 1200 Brussels, Belgium cedric.hermans@uclouvain.be

Speaker disclosures

Shareholder No relevant conflicts of interest to declare Grant / Research Support No relevant conflicts of interest to declare Consultant Pfizer, Bayer, Shire, Novo Nordisk, CSL Behring, Octapharma, Sobi, LFB, CAF-CDF, OctaPharma Employee No relevant conflicts of interest to declare Paid Instructor No relevant conflicts of interest to declare Speaker bureau No relevant conflicts of interest to declare Other

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THE MOST FAMOUS HAEMOPHILIA PATIENT TSARÉVITCH ALEXIS (1904-1918)

4 year-old 8 year-old 10 year-old

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HAEMOPHILIA TODAY : NOT LONGER A ROYAL DISEASE BUT A DISEASE THAT CAN BE TREATED

This young boy with severe haemophilia can now be treated safely and have a normal life.

HAEMOPHILIA

Blood Coagulation Defect Debilitating Arthropathy

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Bleeding complications in patients with haemophilia

Intra-Cranial

Hip

Ilio-psoas Muscle

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Factor Level

(%)

Phenotype

Annual bleeding rate (ABR) without Replacement Moderate

Severe

<1%

1–5% 6–24% 25–49% 50–150% >150%

Mild

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1–5 0–1

The Most Affected Joints in Haemophilia

• 90% of bleeding episodes affect MSK system
• Up to 80% in ankles, knees and elbows
• 10% of hematomas
• Begin by age 2

• Nonvital tissues express low levels
• f TF.
• These tissues appear to rely more
• n the intrinsic pathway of

coagulation to maintain hemostasis.

• This may explain why hemophilia

A and B patients exhibit spontaneous hemorrhages into skeletal muscle and joints.

Mackman N. Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22.

Why do patients with haemophilia bleed in their joints ? Haemotological reason

Elbows, knees and ankles are the most susceptibe to acute haemarthrosis « hinge joint »  synovium gets stuck in the joint Shoulders and hips are less susceptible to acute haemarthrosis

Why do patients with haemophilia bleed in their joints ? Anatomical reason

Interleukin-1 Interleukin-6 TNF-alpha

Consequence of hemarthrosis:

Inflammation and hypertrophy of the Synovium

Source: S. Lobet Source: Novo Nordisk

Musculoskeletal bleeding episodes in patients with haemophilia Features

Location Joint Muscle Reason Spontaneous Induced (trauma, physical activity) Presentation Clinically patent Suclinical

Symptomatic Asymptomatic

Clinical haemarthrosis

Large amount of blood Clinically patent

Subclinical haemarthrosis

Small amount of blood Clinically silent

Treatment of haemophilia

Replacement or substitutive therapy by regular intravenous infusions of exogenous clotting F8 or F9 to correct clotting factor deficiency in order to treat or prevent bleeding episodes Injection of missing Factor VIII or IX

Treatment of haemarthrosis should not be delayed

WITH A JOINT BLEED, TIME LOST IS JOINT AND CARTILAGE LOST

Visit our Website: http://www.hemophilie-ucl.be and discover our computer-generated movie on blood coagulation and haemophilia

The benefits of early treatment : a well-known concept in various therapeutic areas

CARDIOLOGY

Acute myocardial infarction

Saves cardiac muscle NEUROLOGY

Acute ischemic stroke

Saves neurones HAEMOPHILIA

Acute haemarthrosis

Saves cartilage

PATIENT

Education Good understanding Rapid recognition Good venous access

HEALTH CARE SYSTEM

Home-treatment Education

TREATMENT

Replacement or Bypassing

Haemostatic efficacy Convenience of use

Requirements for early treatment of bleeding episodes in patients with haemophilia

Better than early treatment, PREVENTION of haemarthrosis is the optimal option

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Ideal treatment of Severe Haemophilia : Prevention of bleeding episodes by regular infusions

Regular self-administration of F8 or F9 concentrate in order to prevent bleeding episodes (20-40 units/kg – 3x/week or 1x/2days) Time FVIII 1%

F8 correction by regular infusion

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The Concept of Prophylaxis

<1%

1–5% 6–24% 25–49% 50–150% >150%

• Patients with moderate hemophilia

(FVIII / FIX 2–5%) have much less frequent haemarthrosis than patients with severe disease (<1%)

• The rationale for prophylaxis is to

maintain FVIII / FIX >1% in order to prevent spontaneous bleeding episodes, especially haemarthrosis

• Regular infusions of FVIII

concentrates aim to convert severe into moderate

• No consensus on optimal

prophylaxis regimen

• Considering a recovery of 2, and

a half-life of 9-13 hours for currently available FVIII concentrates, 2-3 infusions per week are needed

10 % 20 % 30 % 40 % 50 % 60 %

Monday Tuesday Wednesday Thursday Friday Saturday Sunday

Factor VIII measured in blood

1 %

Infusions of concentrate

Prophylactic Treatment of Haemophilia A: Basic Principles

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Choices of Treatment Regimens and Different Ages at Which They Are Implemented

• A. Coppola. Blood transfusion, 2008.

5 10 15 20 25 30 35 40

Prevention of Life- threatening Bleeding Reduction of Progression of Arthropathy and Disability Enable Normal Activities of Daily Life and Physical Exercise Enable Practically Normal Psychosocial Development without Overprotection Primary Prophylaxis Early Secondary Prophylaxis Late Secondary Prophylaxis Secondary Prophylaxis in Adolescents and Adults Short-term Prophylaxis On-demand Treatment

Age (years)

• To all boys with severe haemophilia A/B
• Around the age of one year
• At a low dose, i.e. usually 25 U/kg
• Frequency of every 2nd day/trough guided
• Avoiding “immunological danger signals” first 20 ED
• As “prophylaxis” during first 20 ED instead of “on demand”

How should prohylaxis be started in 2017 ?

DATA SUPPORTING PROPHYLAXIS: RETROSPECTIVE AND PROSPECTIVE STUDIES

Author Outcome Prophylaxis On-Demand

Liesner et al. 19961 All bleeds/year (median) 1.5 14.7 Szucs et al. 19982 Joint bleeds/6 mos (mean) 3.1 8.8 Yee et al. 20023 Joint bleeds/year (median) 0.5 3.5 Panicker et al. 20034 Major bleeds/year (mean) 1.9 15.5 Feldman et al. 20065 (Interim results: prophylaxis only) Joint bleeds/year (mean) 1.2 N/A

N/A = not available.

• 1. Liesner et al. Br J Haematol. 1996;92(4):973-978 2. Szucs et al. Haemophilia. 1998;4(4):498-501 3. Yee et al. Haemophilia. 2002;8(2):76-82.
• 4. Panicker et al. Haemophilia. 2003;9(3):272-278 5. Feldman et al. J Thromb Haemost. 2006;4(6):1228-1236.

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Prophylaxis Reduces the Occurrence of Bleedings

Manco-Johnson M. et al, NEJM, 2007; 357:535-44.

On-demand (n=33) Prophylaxis (n=32)

Total Bleeds/year 18 1.9 Joint Bleeds/year 5 0.5

(90% less) (90% less)

PK of FVIII and the risk of haemarthrosis

Peak Trough Monday Friday Wednesday Reduced bleeding risk zone

Collins PW: Plenary lecture „Personalized Prophylaxis“ WFH congress July, 10 2012

FVIII level ( %) time Peak / time spent in reduced bleeding risk zone: Important to prevent activity related and traumatic bleeds Trough Important to prevent spontaneous break through bleeds AUC Important to prevent subclinical bleeds, maximizing the window of protection

RISKS OF STOPPING PROPHYLAXIS IN ADULTS

• Haemophiliacs do not lose the risk of joint bleeding at

the age of 18

• Switching to “on-demand” will lead to haemarthroses –

how many before haemophilic arthropathy develops ?

• Risk of losing the benefits of the financial and human

resource invested in childhood

SECONDARY PROPHYLAXIS

• Introducing prophylaxis in adulthood is

effective in reducing joint bleeding and improving joint function

Median (interquartile range) number

• f bleeds per

patient On-demand treatment* Prophylactic treatment† P value‡ Months 1–6 (n = 20) Months 7–13 (n = 19) Joint bleeds 15.0 (11–26) 0 (0–3) < 0.001 All bleeds 20.5 (14–37) 0 (0–3) < 0.001 Spontaneous bleeds 13.5 (7–29) 0 (0–1) < 0.001 Trauma bleeds 2.5 (0–9) 0 (0) < 0.001

NUMBER OF BLEEDS ON SECONDARY PROPHYLAXIS

Median observation period was 192 days. †Median observation period was 177 days. ‡Wilcoxon test.

Collins et al JTH 2009 8, 83-89

Patients receiving prophylaxis had 15.2 times fewer bleeds

Note: Median treatment duration at time of data analysis was 1.4 years; data shown are for all nondiscontinued patients who completed at least 1 study year. *On demand vs prophylaxis; adjusted for stratification variables (presence/absence of target joints and number of previous BEs). References: 1. Kempton C, et al. Presented at: XXXth International Congress of the World Federation of Hemophilia; July 8-12, 2012; Paris, France.

• 2. Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V, Rescia V, Hong W.

Randomized, controlled, parallel-group trial of routine prophylaxis versus on-demand treatment with rFVIII-FS in adults with severe hemophilia A (SPINART) [published correction appears in J Thromb Haemost. 2014;12:119–122.] J Thromb Haemost. 2013;11:1119-1127.

40.7 29.2 1.9 3.5 52.7 36.9 2.0* 4.2* P<0.001, on demand vs prophylaxis* Mean BEs, n Total BEs per year Total BEs Mean BEs, n 10 20 30 40 50 60 10 15 25 30 40 45 20 35 5 Joint BEs per year Joint BEs On demand (n=42) Prophylaxis (n=42)

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G.SM.HEM.03.2014.0146

SPINART (Secondary Prophylaxis in Adults, Randomized Trial)

One year mean efficacy results1,2

Optimal tr treatment str trategies for hemophil ilia: achievements and lim limitations of f cu current prophylactic regimens.

• Current prophylactic regimens, although very effective, do not

completely prevent joint disease in a long-term perspective.

• Joint arthropathy in primary prophylaxis develops over many years,

sometimes over a decade or even longer time periods.

• The ankle joints are the first and most severely affected joints in

those patients and thus may serve in outcome assessment as an indicator of early joint arthropathy when followed by ultrasound or magnetic resonance imaging.

• J. Oldenburg Blood. 2015 Mar 26;125(13):2038-44.

Patients with Different Lifestyle and Activity Level may need Different FVIII Trough Levels

>3% ? 10% ?

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• Based on FVIII PK parameters
• Based on bleed pattern
• (presence of target joints/joint damage)
• Tailored to activity level (sports)
• Tailored to personal circumstances
• Based on all available information
• Efficient

Hemostasis

Joint Status

Activity Level

Valentino LA. Considerations in individualizing prophylaxis in patients with haemophilia A. Haemophilia 2014 Sep; 20(5): 607-15.

Individualized prophylaxis should be

Standard prophylaxis not optimal for everybody

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Patient with an average half-life (25 IU/kg every other day) Patient with a short half-life (25 IU/kg every other day)

Time spent with FVIII plasma levels <1%

Increased risk for break through bleeds 1% 1%

FVIII level (%) FVIII level (%)

PHARMACOKINETIC DOSING

FVIII:C (U/dL)

6,000 IU/week 1,575 IU/week 770 IU/week 100 10 1 0.1 100 10 1 0.1 100 10 1 0.1 3 6 9 12 15 18 Time (days) 2000 IU, 3 times a week 450 IU, every 2 days 110 IU, daily

Carlsson et al. Eur J Haematol 1993;51:247–52.

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« ZERO » bleed world

A new ambition in haemophilia therapy Not only an issue of treatment availability and intensity Only achievable with major collaboration of the patient and his family

Aiming for zero bleeds

Lifetime joint bleeds Joint scores

Normal joints Moderate damage Substantial damage

Joint health Patient impact

Patient–doctor relationship

Funk M et al. Haemophilia 2002; 8:98–103.

4 or more 3 0–2 Physical examination 3–7 0–2 X-ray 7–12 0–3 MRI 3–8 2

Which FVIII Trough Levels are needed for Zero Joint Bleeds?

Den Uijl et al. Haemophilia 2011; 6: 849-53

3% 12%

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Correlation of endogenous FVIII level and annual number of joint bleeds

INTEGRATION OF REAL WORLD-DATA COLLECTION,

TAILORED CARE AND PATIENT EMPOWERMENT

Personalized Medicine 1. PK profiling 2. Bleeding risk profiling 1. Bleeding phenotype 2. Target joints 3. Joint status 4. Work and sport activity 5. Lifestyle 6. Compliance 3. Bleeding recognition Patient Empowerment 1. Disease and treatment understanding (adherence) / psychological support 2. Shared treatment and goals decision making (GAS) 3. Life-style and activity adjustment 4. Promotion of self-management

Real-World Data Collection Treatment tracking (recording of bleeding episodes and factor consumption) Outcome tracking

Patient-centric prophylaxis

Adapted from Gringeri A, Doralt J, Valentino LA, Crea R, Reininger AJ. Expert Rev Pharmacoecon Outcomes Res. 2016 Jun;16(3):337-45.

Haematological treatment of hemophilia

TODAY TOMORROW Compensation of defective production of FVIII or FIX "Cure" Factor replacement therapy with plasma-derived or recombinant concentrates Gene therapy Non-factor replacement / Disruptive therapy Endogenous production of natural/unmodified FVIII or FIX

Could IL-1 blockers prevent blood-induced joint damage in hemophilia ?

• It would be ideal if there were oral

drugs which could be taken soon after a joint bleed for a short period

• f time during the period

associated with damaging inflammatory responses along with CFC replacement to prevent further bleeding.

• This could be particularly

significant for the vast majority of patients in the world who do not have access to prophylaxis with CFC. Srivastava A. Blood. 2015 Nov 5;126(19):2175-6.

Antibodies to block TNF-a / IL-1 antiangiogenesis drugs

Impact of innovation on haemophilia care

More efficient treatments Persistent control of FVIII or FIX deficiency Cure of the disease No BLEEDS More time and resources for assessing and following non- bleeding consequences of haemophilia

CONCLUSION

• The goal / ambition of the haematological treatment of

haemophilia should be a complete abolition of all bleeding episodes and a full preservation of the musculo- skeletal system

• This is now achievable with current treatment options in

a large proportion but not all patients with severe haemophilia

• The focus should be on patients with an Annual Bleeding

Rate (ABR) > 0 . In these patients, different strategies should be implemented to better control their disease.

Thank you for your attention