Download The Future is Here, Longer Acting Products

The future is here:
long-acting products
Dr. Paul Giangrande
Oxford Haemophilia and Thrombosis Centre
&
Nuffield Department of Clinical Medicine
University of Oxford
[email protected]
Novel products:
• Clinical trials well under way and more planned to
start soon
• Development wholly based on recombinant
technology
• Products under development include:
–
–
–
–
–
–
Biosimilars (copies of current products)
Long-acting factor VIII
Long-acting factor IX
Porcine (pig) factor VIII
Activated factor VII analogues
Anti-TFPI antibodies
Novel products:
• I am confident that at least some of these
products will be available within 3-5 years
• Potential to change clinical practice radically
• Success not guaranteed: several
failures/problems encountered already
– FVIII and pegylated liposomes (Bayer)
– TFPI inhibitor (Baxter)
– Recombinant FIX (Ipsen/Inspiration)
– Long-acting factor VII & vatreptacog (NovoNordisk)
• Need for vigilance for unexpected problems
Current therapy:
• Factor VIII has half life of around 12 hours
• Factor IX has half life of around 18 hours
• Prophylaxis involves self-treatment two or
three times a week
• Factor levels still far from normal for most
of the week
• Trough level of just 1% currently regarded
as satisfactory
• Cost of products is the limiting factor
An example of decline in factor VIII level over time:
Factor
VIII
level
(%)
Time (hours)
Typical troughs and peaks seen with
prophylaxis:
Collins PW et al. Haemophilia 17: 2-10 (2011)
Risk of break through bleeds on
prophylaxis:
Collins PW et al. Thromb. & Haemost. 7: 413-420 (2009)
What is our goal?
Skinner M. Haemophilia 18 (Suppl. 4): 1-12 (2012)
• FVIII level of 1% “wholly insufficient”
• Trough level of 15% “ideal” but
“unattainable in short term due to cost”
• “Improving patient quality of life should
drive treatment decisions, not economics”
• “Moving forward incrementally to higher
baseline levels of 3 or 5% would be a step
in the right direction”
Pegylation:
When attached to a drug, polyethylene glycol (PEG)
polymer chains can sustain bioavailability by protecting the drug
molecules from immune responses and other
clearance mechanisms. In an aqueous medium, the long, chainlike PEG molecule is heavily hydrated and
in rapid motion. This motion causes the PEG to sweep
out a large volume and prevent the interference of other
molecules.
N9-GP (GlycoPegylated
rFIX)
•
Based on rFIX
•
Half-life prolongation with the
aim to provide
•
treatment of acute bleeds
with a single dose
•
at least a once-weekly
prophylaxis regimen
•
Designed using innovative
specific glycoPEGylation
technology
•
PEG attached to specific Nglycan sites with FIX activation
peptide
•
No modification of the peptide
sequence
•
Activated to native FIXa in
normal way
N9-GP
Activation
at site of injury
FIXa
Source: Østergaard et al. Blood 2011
Summary of N9-GP study:
Negrier C et al. Blood 118: 2695-2701 (2011)
•
•
•
•
16 subjects: ≥18 years; FIX ≤ 2; ≥150 ED
Dose rFIX (N9-GP): 25-100 IU/kg
T½ 93 hours (5 fold longer than current FIX)
Incremental recovery was 94% higher than
rFIX and 20% higher than plasma-derived FIX
• No inhibitors
• One severe allergic reaction
FIX (U/mL)
Summary profiles comparing N9-GP to previous FIX –
normalised to 50 U/kg
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Treatment
N9-GP
rFIX
pdFIX
0 10 20 30 40 50 60 70 80 90 100110120130140150160170
Time (hours)
1
week
Summary plot for N9-GP – log scale until 4 weeks
10.000
Treatment
FIX (U/mL)
25 U/kg
50 U/kg
1.000
100 U/kg
0.100
0.03 U/mL
0.010
0.01 U/mL
1 week
0.001
0
50
100
150
200
2
weeks
250
300
350
4
weeks
400
450
500
550
600
650
700
Time (hours)
Two weeks after dosing, four patients had received FIX treatment as on-demand or
prophylaxis. Four weeks after dosing, nine patients had received FIX treatment. FIX
activity values from these patients were excluded from the pharmacokinetic evaluation
after two or four weeks depending on the time when they received their FIX treatment.
Comparison of derived PK parameters between N9-GP and previous FIX
(normalised to 50 U/kg)
N9-GP
Mean
(N=15)
rFIX
Mean
(N=7)
pdFIX
Mean
(N=8)
Ratio
N9-GP/FIX
t1/2 (hours)
92.7
19.3
17.8
5.00
Incremental
Recovery (U/dL per
U/kg)
1.33
0.69
1.12
1.53
(1.94 ; 1.20)
CL (mL/hour/kg)
0.70
6.99
5.48
0.11
Vz (mL/kg)
94.2
195
141
0.57
Time to 1% activity
(days)
22.5
4.5
4.0
Time to 3% activity
(days)
16.2
2.8
2.7
PK Parameters
N9-GP study:
• ‘Paradigm’ is the name for the portfolio of
clinical trials with this agent
• Phase III study already started
• No further allergic reactions: around 50
subjects have received product so far
• Surgical study has started: protocol
envisages just 3-4 injections to cover
major surgery
• Paediatric studies also planned
N8-GP (GlycoPegylated rFVIII)
•
Designed to provide
treatment with less frequent
dosing
•
Based on full-length rFVIII
•
Comparable one stage and
chromogenic assay results
•
Designed using innovative
specific glycoPEGylation
technology with a
40K-PEG
•
No modification of the
peptide
•
Preliminary results suggest
extension of half-life by 1.6
compared to normal factor
VIII
N8-GP
Activation
at site of injury
FVIIIa
Source: Stennicke et al. WFH 2010
Endocytosis and FcRn:
• Antibodies and albumin survive for a long time in
the blood stream: half-life of many days
• This is because of “recycling” which takes place in
the cells lining blood vessels (“endothelial cells”)
• Antibodies taken up into endothelial cells can either
be released back into the circulation, or if they are
not bound they will be destroyed
• A special receptor called FcRn is involved in the
process
Endocytosis and FcRn:
• This ability of FcRn to bind and release
albumin and antibodies back into the
bloodstream is a form of recycling and allows
them to outlive other proteins circulating in
the bloodstream
• Therapeutic molecules attached to antibody
molecules may also have half-lives extended
by endothelial recycling:
– Examples include romiplostin and etanercept
– Biogen Idec have developed linked FVIII and
FIX molecules linked to antibody molecules
FIXFc Monomer
X
FI
H
H
CH2
CH2
CH3
CH3
Product consists of a Fc-fusion construct that links
a single copy of the drug to the Fc region on an antibody.
Optimized to bind to Fc receptors (FcRn) in the endothelial
cells that line the blood vessels, “recycling” the drug to
increase its circulating half-life.
Summary of rFIXFc study:
Shapiro AD et al. Blood 119: 666-672 (2012)
• 14 subjects: ≥18 years; FIX ≤ 2; ≥150 ED
• Dose rFIXFc: 1-100 IU/kg
• Samples taken out to 240 hours (10 days):
also at 12 and 14 days after 100 iu/kg
• Mean activity terminal t½ 56.7 hours (≈ 3 fold
longer than current FIX products)
• No inhibitors or allergic reactions
• Six subjects reported bleeds between 9 and
28 days after infusion
Fc-fusion molecules:
• Study in dogs and mice documented ≈2 fold
extension of FVIII half-life
Dumont JA et al. Blood 119: 3024-3030 (2012)
• Results of A-LONG study suggest 1.7 fold
extension of FVIII T½ in humans
Powell JS et al. Blood 119: 3031-3037 (2012)
• Could these products help induce immune
tolerance or even reduce risk of inhibitor
development in the first place?
Lei TC Blood 105: 4865-4870 (2005)
• Do these molecules cross the placenta?
Albumin fusion products
Schulte S. Thrombosis Research 128 (Suppl. 1) S9-S12 (2011):
• Marketed as “natural alternative” to PEG,
which is not entirely biodegradable
• DNA construct encoding both target protein
and albumin in a single recombinant molecule
• Short linker in between to avoid problems due
to steric hindrance and ensure retention of
maximum potency
Albumin fusion products:
• Phase 1 study completed in 19 subjects
with FIX-FP using 25, 50 and 75 iu/kg
• T½ 91.5 hrs (5.3 fold extension)
• 7 fold increase in AUC
• Trough levels of 7.4% and 2.5% at days 7
and 14 after 25 iu/kg
• Problem of steric hindrance with FVIIa-FP:
starting dose needs to be 1000 µg/kg
• Phase 1 study has begun: 6 fold increase
in T½ anticipated
The factor VIII gene:
Single-chain factor VIII (CSL627):
• Most of B-domain and 4 amino acids of
adjacent A3 domain deleted (amino acids
765-1652 of full length molecule)
• Covalent link between heavy and light
chains prevents dissociation
• Binding site for VWF also modified to
increase affinity twofold
• Very preliminary data suggest T½ extension
of 1.6 fold
• Clinical trials now underway
Why is it more difficult to
prolong half-life of factor VIII?
• Clear difference noted with various methods
used (pegylation, Fc fusion, albumin)
• 2 vs. 5 fold difference in extension
• Difference attributed to role of VWF
• In FVIII and VWF knockout mice, it is
possible to extend T½ of rVIII-Fc fivefold
compared to normal factor VIII
• Similar observation with pegylated FVIII
Porcine factor VIII for patients with
inhibitors:
• Previous product derived from porcine plasma
(Hyate:C) withdrawn in 1996
• Pig factor VIII similar to human factor VIII in
structure so works almost as well in humans
• Differences in structure protect it against rapid
inactivation by antibodies against human factor VIII
• Recombinant porcine factor VIII (Baxter) now
undergoing phase 3 clinical trials in acquired and
congenital haemophilia with inhibitors
• Potential problem is antibody formation after
repeated administration (e.g. surgery)
The role of TFPI:
Tissue Factor Pathway Inhibitor
Tissue Factor Pathway Inhibitor (TFPI):
•
•
•
•
•
•
•
Serine protease inhibitor protein
Encoded on chromosome 2q
Associated with lipoproteins in plasma
≈10% located in platelets
Heparin enhances activity
TFPI inhibits TF-FVIIa complex
Do inhibitors of TFPI have a possible role as
adjunctive therapy in haemophilia?
Inhibition of TFPI and haemophilia:
• Fucoidan is a non-anticoagulant
sulphated polysaccharide
• Inhibits TFPI
• Accelerates clotting time of human
haemophilic plasma in test tube
• Clinical trial of similar agents being
explored as oral therapy to help
prevent bleeding in patients with
haemophilia
Inhibition of TFPI and haemophilia:
TFPI inhibitors:
• Blocking of Tissue Factor Pathway
Inhibitor (TFPI) may facilitate
haemostasis initiated by FVIIa/TF
•
Thereby compensating for impaired
FIX/FVIII-dependent coagulation
• mAb2021 is antibody developed by
NovoNordisk against Kunitz 2 domain
of TFPI
• Grown in serum free CHO cells
• Liquid formulation designed for
injection with injector pen
• Anti-TFPI monoclonal antibody may
become a potential subcutaneous
prophylaxis treatment option for all
haemophilia patients without the risk
of development of inhibitors to FVIII
and FIX
• Phase 1 trial of NovoNordisk product
already completed
• BAX499 (Baxter) is an aptamer with
similar effect, also undergoing clinical
trials
Principal conclusions:
• Gene therapy will ultimately offer a
permanent cure for haemophilia
• Longer-acting factor concentrates are a
much more realistic early goal
• Activity of coagulation factors can be
extended by various technologies: e.g.
– Pegylation
– Binding to immunoglobulin molecules
– Genetic fusion with albumin
• Much easier to extend duration of action of
factor IX compared to factor VIII