Shifting Paradigms in Hemophilia Care

Shifting paradigms in
hemophilia care
AD R IEN N E L EE
H EM ATO LOGY R O U N D S, O C TO BER 8 T H , 2 0 1 5
Objectives
• History and current state of hemophilia care
• Concepts in personalized prophylaxis
• Enhanced half-life factor concentrates
• Gene therapy and other new and cool stuff
• MCQ’s throughout for the fellows and trivia for fun
Hemophilia is often considered the “royal
disease” made famous by queen Victoria who
was a carrier and her affected great grandson
Alexei
What type of hemophilia did Alexei have?
1. Hemophilia A
2. Hemophilia B
3. Hemophilia C
The “Royal Disease”
Russian Royal family remains from
exumed – including Alexei, his
mother Alexandra, and sister
Anastasia
Genotyping revealed Factor 9 gene
exon 4 mutation
“Royal disease” is hemophilia B
Why is hemophilia B also known as
“Christmas disease”?
1. It was named after the doctor who discovered FIX deficiency to be a
separate entity from FVIII deficiency (hemophilia A)
2. It was first reported in the Christmas issue of the British Medical
Journal in 1952
3. The first patient discovered to have FIX deficiency was a 5 year old by
named Stephen Christmas
4. Number 1 and 3
5. Number 2 and 3
Types of hemophilia
Hemophilia A
◦ “Classical hemophilia” – deficiency in factor VIII
◦ 1 in 10,000. Approximately 2500 Canadians
◦ Represents ~80-85% of hemophilia population
Hemophilia B
◦ “Christmas disease” – deficiency in factor IX
◦ 1 in 50,000. Approximately 600 Canadians
Severity
Severity
Severe
Moderate
Mild
SSC/ISTH 2003
Factor VIII or IX level
< 1%
1-5%
>5-40%
A brief history of hemophilia
treatment
Prior to the 1940’s
◦ No treatment available
◦ Average lifespan of a person with severe hemophilia was 10 years old
1960’s – major discoveries
◦ Antihemophilic factor (AHF) concentrates created through plasma fractionation
◦ Cryoprecipitate discovered in 1964 by Judith Graham Pool
◦ Average lifespan increased to 40 years
1980’s
◦
◦
◦
◦
◦
Lyophilized plasma-derived factor concentrates were the norm
No viral inactivation steps
Average lifespan increased to 65 years
First case of AIDs in a hemophilia patient reported
FVIII gene sequenced
1990’s
◦
◦
◦
◦
◦
◦
Over 50% of hemophilia patients became infected with HIV
70% infected with hepatitis C
About 40% died of AIDS
Average lifespan dropped back down to 40 years
First recombinant FVIII concentrate produced
Plasma-derived factor concentrates solvent detergent/heat treatment for viral
inactivation became standard requirement
2000’s
◦ Recombinant FVIII and FIX concentrates readily available
2010’s – now
◦
◦
◦
◦
◦
Recombinant FVIII and FIX is standard of care
Enhanced halflife clotting factors
Non-clotting factor based therapies
Gene therapy
Average lifespan 75 years or more?
Shifts in paradigms in
hemophilia care
Before 1970’s
◦ Standard therapy in hemophilia patients – treat bleeds when they occur
◦ Prophylaxis was only for surgeries
Persons with hemophilia suffered from
debilitating arthropapathy and chronic pain.
Quality of life was poor.
Shift 1: Prophylaxis
1970’s
◦ Development of factor concentrates allowed for infusions on regular basis to
prevent bleeds
◦ Pioneered by the Swedes (Inge-Marie Nilsson)
◦ Idea was to give factor regularly to bring levels >1%; effectively making a
severe hemophilia into a milder phenotype in order to reduce the number of
spontaneous bleeds
1%
Prophylaxis
Demonstrated that when started early and administered regularly
◦ Significantly reduced bleeding
◦ Maintained excellent joints
◦ Able to lead “normal” lives
Nilsson IM. J Intern Med 1992; 232:25-32
Prophylaxis vs on-demand
Landmark trial
◦ Fewer bleeds
◦ Better joints
Manco-Johnson et. al. NEJM 2007;357:535-44
Prophylaxis: earlier the
better
Fischer K. Blood 2002;99:2337-41
Prophylaxis
World Federation of Hemophilia (WFH) Guidelines 2013
“Prophylaxis prevents bleeding and joint destruction and should be the
goal of therapy to preserve normal musculoskeletal function” (Level 2)
1990 - 2000’s:
- safe, plasma derived or recombinant factor concentrates
- home therapy/self-infusion was encouraged
- standard practice to offer prophylaxis to pediatric hemophilia patients
who still have good joints
Lots of evidence that with effective
prophylaxis: Less bleeds, healthier joints…
and ultimately QoL
Number of joint bleeds/year
18
16
14
12
10
8
6
15.6
11.5
≈-80%
17.1
≈-80%
4
2
0
2.8
Fisher et al, Haemophilia,
2002
Intermediate dose
2.9
on demand
prophylaxis
≈-90%
1.2
Gringeri et al, ESPIRIT; JTH, Manco-Johnson et al; NEJM,
2011
2007
Secondary
prophylaxis
Full dose Primary
prophylaxis
What is the average age of first joint
bleed in severe hemophilia?
1. 6 months old
2. 1.2 years old
3. 1.8 years old
4. 3 years old
5. 5 years old
What is the definition of primary
prophylaxis?
1. Regular continuous treatment started before the age of 2 and onset
of clinically evident joint disease for 52 weeks per year.
2. Regular continuous treatment started after 2 or more bleeds into
large joints and before the onset of clinically evident joint disease, for at
least 45 weeks per year.
3. Regular continuous treatment started before the 2nd clinically evident
large joint bleed joint bleed and before age of 3, for at least 45 weeks
per year.
4. Regular continuous treatment started after the onset of clinically
evident joint disease, for 52 weeks per year
Problems with prophylaxis
1. Product issues
◦ Must be administered intravenously
◦ Currently available factor concentrates have short half-lives, thus the
need for frequent infusions
◦ Major problem when venous access is an issue (e.g. in the very young
and the elderly)
◦ Ports
◦ Central access devices
◦ Risks: thrombosis, line infections, inhibitor risk
◦ Differences in the pharmacokinetic handling of factor concentrates
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
Orthopedic joint outcome study
323 severe hemophilia A patients with X-ray and PE joint scores
10% entered the study with scores of 0; of these 50% maintained joint
scores of 0 after 6 years follow up
Those who maintained joint scores of 0 had annual joint bleeds of 1.8 vs
11.2 in those who’s joint scores worsened.
Aledort. J Int Med. 1994;236:391-399
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
Van Dijk. Haemophilia 2005;11:438-43
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
◦ Variability in joint status irrespective of bleeding phenotype
? Subclinical bleeds causing occult joint
damage
? Other genetic factors causing protection
against cartilage damage
Manco-Johnson et. al. NEJM 2007;357:535-44
Valentino. JTH 2010;8:1895-1902
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
◦ Variability in joint status irrespective of bleeding phenotype
◦ Adherence issues
Full dose primary prophylaxis:
25-40U/kg 3 x per week or every other day for severe hemophilia A
That’s 156 - 178 injections per year!
Reality
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
◦ Variability in joint status irrespective of bleeding phenotype
◦ Adherence issues
Missed dose
At risk of bleeding
Problems with prophylaxis
2. Patient issues
◦ Variability in bleeding phenotype and joint status
◦ Variability in joint status irrespective of bleeding phenotype
◦ Adherence issues
Definition of being adherent: taking ≥ 80% prescribed doses
Studies
Region
Adherence
1. Manco-Johnson M. Am J Hematol. USA
1994
2. Hacker MR. Haemophilia 2001
3. Thornburg CD, Pipe S.
Haemophilia 2006
60%
4. De Moerloose P. Haemophilia
2008
80%
Europe
Not
great!
Problems with prophylaxis
2. Patient issues
◦
◦
◦
◦
Variability in bleeding phenotype and joint status
Variability in joint status irrespective of bleeding phenotype
Adherence issues
Desire for normalcy
◦ Young boys/men
◦ Want to be like peers
◦ Is FVIII > 1% good enough for these activities?
Shift 2: Personalising
prophylaxis
Patient factors
Product factors
•Bleeding phenotype
•Joint status
•Activity level
•Adherence
Patient + product
Individual PK
handling of factor
concentrates
•Time and
inconvenience of dosing
•Venous access
On average, what is the terminal halflife for FVIII and FIX concentrates?
1. FVIII 8 hours, FIX 12 hours
2. FVIII 18 hours, FIX 24 hours
3. FVIII 12 hours, FIX 18 hours
4. FVIII 12 hours, FIX 24 hours
What does “IVR or in vivo
recovery” mean?
1. The number of units of factor concentrate needed to increased a
patients factor level to 100%
2. How well the synovium recovers after factor is administered for a
joint bleed
3. The IU/dL increase in plasma factor activity level per unit of factor
infused.
4. The percent increase in plasma factor activity level per unit/kg body
weight of factor infused.
For the fellows and
residents:
1% factor activity = 1 IU/dL = 0.01 IU/mL
If the IVR for a factor concentrate is 2.0 (e.g.Kogenate), every IU/kg of
factor infused will increase the plasma factor activity by 2%.
To bring a severe HA patient (FVIII <1%) to 100% plasma factor VIII
activity level, you need to infuse 50 IU/kg of Kogenate
Dose in IU/kg = (target level in IU/dL (%) factor activity – baseline or
measured level in IU/dL (%) factor activity) ÷ IVR
Which one is correct?
1
2
3
4
pdFVIII
(e.g. Wilate
or Humate)
1.0
2.0
2.0
2.0
Average IVR
rFVIII
pdFIX
(e.g.
(e.g.
Kogenate) Immunine)
2.0
1.0
2.0
1.0
1.5
2.0
1.8
2.0
rFIX
(e.g.
Benefix)
0.8
0.8
1.0
1.0
Shift 2: personalising
prophylaxis
Not everyone NEEDS the same dose/frequency
>1%?
>20%?
>2%?
>40%?
>5%?
Shift 2: personalising
prophylaxis
Not everyone HANDLES factor concentrates the same way (PK
differences)
We assume an avg T1/2 12 hours for
all HA’s receiving FVIII concentrate.
But this not the case for all.
T1/2 range for rFVIII
6 to 25 hours
T1/2 range for rFIX
11 to 36 hours
Collins PW. Haemophilia 2011; 17:2-10
Measuring PK parameters
PK profile for any individual:
• Must measure factor level at
multiple time points (6 to 12)
• No patient wants to do this
Population PK:
• Model generated based on
algorithm to estimate an
individual’s PK profile using only a
few (2-3) time points
Problem:
• Need a pop PK model for every
factor product out there!
What PK parameters are
important and how do you
adjust?
Depends on what you and your patient are aiming to achieve
◦ Decrease the risk of spontaneous bleeds
◦ Protect from subclinical (microbleeds) because of progressive worsening in
joint status
◦ Protection during episodes of high activity (e.g. soccer practice)
Goal: Decrease the risk of
spontaneous bleeds
Troughs are important!
More time spent with levels < 1%, the more likely to have a bleed
Age 1-6
2.2% ↑ annual bleeding rate per
additional hour/wk spent w/ FVIII < 1%
Age 10-65
1.4%
Collins. JTH 2009;7:413-20
Log FVIII IU/dL
PK parameters affecting
troughs
Half-life
Long T1/2 (95th
percentile)
∆ 35 hours
Short T1/2 (5th
percentile)
Time (hours)
Log FVIII IU/dL
High IVR (95th
percentile)
∆ 9.7 hours
Low IVR (5th
percentile)
Time (hours)
◦ Individuals who have a longer T1/2
take longer to reach levels of <1%
◦ Difference between individual at 5th
percentile and 95th percentile T1/2
is about 35 hours
IVR
◦ Minimal effect on time to reach
trough
◦ Difference between individual at 5th
percentile and 95th percentile IVR is
only 9.7 hours
Dose vs Frequency
Increase dose at same frequency – achieves higher trough
Lower dose at higher frequency – able to achieve even higher trough
Troughs
Mainly affected by:
An individual’s T1/2 for the product infused
AND
Dosing frequency
Factor VIII requirements depending on
dose schedule and half-life
*†unrealistic and potentially harmful dose with post-infusion level estimated to be about
550 IU/dL
Collins PW, et al. Haemophilia 2011;17:2–10
What about peaks?
Important for:
Stopping active bleeding
Preventing bleeding during surgery
Protection from injury-related bleeding during intensive activity
Trying to achieve a specific hemostatic target and in most of these cases
this means factor levels ≥ 50%
PK parameters affecting
peaks
IVR
Dose
Goal: Protection from injury-related
bleeding during episodes of high activity
(e.g. soccer practice)
Ensure adequate dose and timing to achieve desired peak and coverage
during the time they are most active
Soccer
practice
Soccer
practice
Goal: Protect from subclinical
(microbleeds) because of progressive
worsening in joint status
time
Combination of dose and frequency that achieves greatest area under the
curve of your target factor level
Putting it all together
Adjust dosage for desired peak
Adjust dosage or frequency for desired trough
Customise of dosage and frequency for personalised prophylaxis
Example
21yo M with severe hemophilia A
Has had a several ankle bleeds but has good joint function and no
chronic joint pain
Currently on rFVIII 1500U three times a week; Mon Wed Fri
Compliant with prophylaxis but will get breakthrough bleeds on the
weekends when he is more active and playing basketball with his
friends, especially on Sundays
Trough level drawn on a Wed morning is 1.5%
Factor VIII Level
Implication of 3x weekly FVIII
prophylaxis
Collins. Haemophilia 2012;18(Suppl. 4):131-35
For FVIII:
Assuming T1/2= 12-h
Friday dose -4x regular dose for
equivalent trough level on Monday
Prophylaxis options to deal
with high physical activity on
Sundays
Higher dose on Friday
(2000 U)
Same dose every other day;
every other Sunday – levels will
be lower
Continue MWF dosing with smaller dose
(500 U) Sun to cover higher intensity
activity
Daily dosing with a smaller dose (500 U),
but achieve higher troughs with daily
peaks
What trough level should we
aim for?
1. Original observation: patients with Factor level >1% seldom have
spontaneous joint bleeds
2. Considerable heterogeneity:
- some bleed at higher trough level
- Prophylaxis in some patients are effective even if trough level <1%
Influence of baseline factor level on
frequency of joint bleeds
5
12
3
den Uijl IEM et al. Haemophilia 2011; 17: 849–853
What trough level to aim for?
Sedentary
1?
2,3,4?
Active
Sporty
5,6,7?
Extreme sports
5
12
3
den Uijl IEM et al. Haemophilia 2011; 17: 849–853
20, 30, 40?
Anticoagulation
30, 40, 50?
Shift 3: Enhanced half-life
products
Changes the prophylaxis landscape!
3 main technologies
1. Pegylation
◦ Creates “cloud” around protein
◦ Protects it against enzymatic digestion
◦ Blocks it from interacting with clearance receptors and immune effector cells
2. Fc fusion
◦
◦
◦
◦
Fusion of factor protein to Fc-portion of IgG
Takes advantage of long T1/2 of IgG
Fc molecules “recycled” in endothelial cells by binding FcR
Averts lysosomal degradation
3. Albumin fusion
◦ Also recycled from intravascular space by FcR
◦ Factor is fused to albumin via cleavable linker peptide
◦ Naturally occurring protein
Enhanced half-life products
Product
Technology
Longer acting FIX
• N9-GP
•
•
•
rFIXFc
rFIX-FP
Longer acting FVIII
• BAY-94-9027
•
•
•
•
BAX 855
•
•
N8-GP
•
•
FVIII-Fc
•
T1/2
T1/2 vs
native
FVIII/FIX
Estimated time to
1% after 50IU/kg
dose
Site-specific glycopegylation with
40 kDa PEG molecule
Fusion with Fc fragment of IgG1
Fusion with albumin
96-110
>5 fold
22Once
days every
57-83
89-96
3 fold
>5 fold
Site-specific pegylation of B
domain-deleted FVIII
Controlled pegylation of full-length
FVIII
Single site-specific glycopegylation
of B domain-truncated FVIII
B domain-deleted FVIII fused to
monomeric Fc fragment of IgG
19
1.4 fold
NA
NA
1.5 fold
NAOnce every
19
1.6 fold
3.5-7 days
6.5 days
prophylaxis
18.8-19
1.5-1.7 fold
4.9 days
3-5X
1.5X
10-20 days
10.1
days
prophylaxis
2-3 weeks
Fc-fusion FVIII or FIX vs.
native
Powell. NEJM. 2013; 369:2313-23
Mahlangu. Blood. 2014; 123(3):317-325
Using enhanced half-life
factors
Concepts remain the same
Gives us more options for personalising
Enhanced T1/2 factors: main
advantages
◦ Decreased frequency of infusions (especially for FIX longacting products)
◦ For pediatrics – less likely to need CVADs
◦ Increase adherence?
◦ Fewer breakthrough bleeds, better outcomes?
Enhanced T1/2 factors:
potential pitfalls
• Spend more time
per week below an
arbitrary level
considered
protective
• Time spent below
level spread across
day and night vs
alternate day
shorter acting
where lowest levels
occur at night when
less active
Collins. Haemophilia 2011;17:2-10
Risk of bleeding
The risk of bleeding is a complex function of many
parameters
◦
◦
◦
◦
◦
Age
Factor level
Joint health
Lifestyle
Unknown components
“Treatment must be tailored to the individual not
to the concentrate”
Longer-lasting products: T1/2 prolonged.
But what is most important – dose interval
or trough both?
Critical factor level
Critical factor level is individual. The longer they spend
below that level, the higher the risk of bleeding
10%
5%
1%
time
Scenario 1: Either dosing gives priority to
convenience (long intervals)…
10%
1%
time
Scenario 2: or it gives priority to
safety…
10%
1%
Scenario 3: or it is a compromise
between convenience and safety
10%
1%
Prophylaxis: Take home
message
Think individually and be PK-minded
Try to offer best risk/benefit ratio when implementing new
extended half-life products
Allow more time at protective levels, especially those with
active lifestyles
Beyond coagulation factors
What’s new on the horizon for hemophilia therapy?
Gene therapy
Hemophilia is an ideal candidate for gene therapy because it’s not
necessary to correct the genetic defect.
Only a small amount of coagulation factor needs to be synthesized by
the vector to improve hemostasis in severe hemophiliacs such that they
no longer require regular prophylaxis to prevent spontaneous joint
bleeds.
Much more successful for HB than HA
- FIX is a smaller gene
- more easily incorporated into a vector
Gene therapy - technique
Ohmori 2015;13(suppl 1):S13-42
Gene therapy success?
Barriers to success
1. Host immune response against AAV/viral capsid
Humoral immune response:
• Majority of adults have humoral immunity against viral capsid due to natural exposure to
wild-type AAV
• Anti-AAV antibodies impair viral transduction of FIX transgene
Innate immune response:
• MCH class I expression of viral capsid antigens by hepatocytes triggers CD8+ T cell response
• Destroys vector-transduced hepatocytes resulting in transaminitis and loss of circulating FIX
2. Vector/transgene-dose
Only single-strand of FIX cDNA available for transcription
How to improve success?
Improve safety?
◦ Reduce immunogenicity and
transaminitis
Improve efficacy?
◦ Higher circulating FIX levels
Reduce transaminitis and
increased vector transduction
1. Select patients without neutralizing
anti-AAV8 antibodies
◦ ~ 32% hemophilia patients have anti-AAV
antibodies
2. Steroids/immunosuppression
3. Block exposure to neutralizing antiAAV8 antibodies temporarily to optimize
vector transduction
Increase efficacy of FIX
expression
UNC Vector Core AAV8.FIX (AskBio009):
Production Minimizes Empty Capsids
Reduce immunogenicity = Maintain efficacy
80-90% Empty capsids
Allay et al. Hum Gene Ther. 2011;22(5):595-604.
~5-10 % Empty capsids
Slide credit: Paul Monohan
More Activity without More Vector?
FIX.R338L Variant with Increased Specific Activity (FIXPadua)
Protein (%)
Activity (%)
Thrombosis
Proband
92
776
Yes
11 Y.O. Sibling
64
551 ↑ in puberty
No  Yes
Mother
94
337
No
Father
116
123
No
Simioni et al. N Engl J Med. 2009;361(17):1671-1675.
Slide credit: Paul Monohan
FIX-Padua increases the activity of the
expressed FIX
3000
Specific Activity (U/mg)
FIXopt
R338LFIXopt
2500
2000
1500
1000
500
Normal Value 200 Units/mg
0
w1
w2
w4
w8
w12
w16
w20
w24
w28
Potential to reduce viral vector exposure
Simioni et al. N Engl J Med. 2009;361(17):1671-1675.
Slide credit: Paul Monohan
w40
Local cell-based therapy for hemophilic
arthropathy by MSCs expressing
coagulation factor
•
•
•
Therapeutic gene (FVIII or FIX) packaged into lentiviral vector that efficiently transduces MSCs
to produce FVIII or FIX.
MSC can self-renew and differentiate into various cell types that have effect on cartilage
regeneration, modulation of immune responses and inflammation, as well as expression of
coagulation factor.
Transduced MSCs expressing coagulation factor are transplanted to joint space by
athrorocentesis
Ohmori 2015;13(suppl 1):S13-42
Concept of FVIII-mimetic
bispecific antibody
(ACE910)
ACE910 supports
the interaction of
FIXa and FX,
thereby promotes
FX activation and
accelerates
coagulation
Mimics FVIIIa’s
cofactor role in
formation of tenase
complex
Features:
• Subcutaneous injection, long half-life (mean 28-34 days), low dosing frequency
• Effective irrespective of presences of FVIII inhibitors
• Not expected to induce FVIII inhibitors
Kitazawa, T et al. Nature Medicine 2012
What is the definition of 1 Bethesda
unit?
1.
The amount of an inhibitor that will neutralise 50% of 1 unit of
FVIII:C in normal plasma after 2 hour incubation at 37C.
2.
The amount of an inhibitor that will neutralise 50% of 1 unit FVIII:C
in patient plasma in 2 hours at 37C
3.
The amount of an inhibitor that will neutralise 50% of FVIII:C in a 1:1
mixing study
4.
The amount of factor concentrate needed to neutralise 50% of an
inhibitor
Isn’t hemophilia cool??
Questions?