U.S. patent application number 10/416055 was filed with the patent office on 2004-02-19 for method for treating hemophilia b.
Invention is credited to Bishop, Paul D., Ohrstrom, Jan, Rose, Lynn M..
Application Number | 20040033947 10/416055 |
Document ID | / |
Family ID | 31716023 |
Filed Date | 2004-02-19 |
United States Patent
Application |
20040033947 |
Kind Code |
A1 |
Ohrstrom, Jan ; et
al. |
February 19, 2004 |
Method for treating hemophilia b
Abstract
Use of factor XIII for treating hemophilia B. A patient having
hemophilia B is treated by administering factor XIII generally in
conjunction with factor IX.
Inventors: |
Ohrstrom, Jan; (Mercer
Island, WA) ; Rose, Lynn M.; (Seattle, WA) ;
Bishop, Paul D.; (Fall City, WA) |
Correspondence
Address: |
James M Bogden
Attorney for Applicants
ZymoGenetics Inc
1201 Eastlake Avenue East
Seattle
WA
98102
US
|
Family ID: |
31716023 |
Appl. No.: |
10/416055 |
Filed: |
May 7, 2003 |
PCT Filed: |
November 8, 2001 |
PCT NO: |
PCT/US01/47144 |
Current U.S.
Class: |
424/94.5 ;
514/13.7 |
Current CPC
Class: |
A61K 38/4846 20130101;
A61K 38/36 20130101; A61K 38/4846 20130101; A61K 38/36 20130101;
A61K 38/45 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/12 |
International
Class: |
A61K 038/37 |
Claims
What is claimed is:
1. A method for treating hemophilia B in an individual comprising
administering factor XIII to said individual.
2. The method of claim 1 wherein the factor XIII is administered at
a dosage of 0.45 U/kg to raise the factor XIII by 1%.
3. A method for treating hemophilia B comprising administering
factor XIII in conjunction with factor IX.
4. The method of claim 3 wherein the factor XIII is administered at
a dosage of 0.45 U/kg to raise the factor XIII by 1%.
5. The use of factor XIII for the production of a medicament for
the treatment of hemophilia B.
Description
BACKGROUND OF THE INVENTION
[0001] Hemophilia B is an inherited disorder of blood coagulation
characterized by a permanent tendency to hemorrhage due to a defect
in the blood coagulation mechanism. Hemophilia B is caused by a
deficiency in factor IX. Factor IX is a single-chain, 55,000 Da
proenzyme that is converted to an active protease (factor IXa) by
factor XIa or by the tissue factor VIIa complex. Factor IXa then
activates factor X in conjunction with activated factor VIII.
Hemophilia B occurs in 1 in 30,000 male births. Since the disease
displays X-linked recessive inheritance, females are very rarely
affected.
[0002] Hemophilic bleeding occurs hours or days after injury, can
involve any organ, and, if untreated may continue for days or
weeks. This can result in large collections of partially clotted
blood putting pressure on adjacent normal tissues and can cause
necrosis of muscle, venous congestion, or ischemic damage to
nerves.
[0003] Hemophilia B is treated by administering to the patient
either recombinant or plasma-derived factor IX.
[0004] However, there are times when treating such patients with
factor IX produces less than satisfactory results, and hemorrhaging
continues. Thus, there is a need to develop additional therapies
for treating hemophilia B.
DESCRIPTION OF THE INVENTION
[0005] The present invention fills this need by administering to
patients with hemophilia B factor XIII in conjunction with factor
IX, and by administering to patients afflicted with hemophilia B
factor XIII in conjunction with factor IX.
[0006] The teachings of all of the references cited herein are
incorporated in their entirety by reference.
[0007] Hemophilia B is heterogeneous in both its clinical severity
and molecular pathogenesis. Clinical severity roughly correlates
with the level of factor IX activity. In severe hemophilia B, the
patient will have less than 1% normal factor IX in his plasma
(about 0.1 U/ml of plasma). Once a bleeding disorder has been
determined to be present, the physician must determine what is the
cause of the disorder. For diagnostic purposes, the hemostatic
system is divided into two parts: the plasma coagulation factors,
and platelets. With the exception of factor XIII deficiency, each
of the known defects in coagulation proteins prolongs either the
prothrombin time (PT), or partial thromboplastin time (PTT), or
both of these laboratory-screening assays. A PT is performed by
addition of a crude preparation of tissue factor (commonly an
extract of brain) to citrate-anticoagulated plasma, recalcification
of the plasma, and measurement of the clotting time. A PTT assay is
performed by the addition of a surface-activating agent, such as
kaolin, silica, or ellagic acid, and phospholipid to
citrate-anticoagulated plasma. After incubation for a period
sufficient to provide for the optimal activation of the contact
factors, the plasma is recalcified and the clotting time measured.
The name of the PTT assay emanates from the phospholipid reagents
being originally derived from a lipid-enriched extract of complete
thromboplastin, hence the term partial thromboplastin. The PTT
assay is dependent on factors of both the intrinsic and common
pathways. The PTT may be prolonged due to a deficiency of one or
more of these factors or to the presence of inhibitors that affect
their function. Although its commonly stated that decreases in
factor levels to approximately 30% of normal are required to
prolong the PTT, in practice the variability is considerable in
sensitivity of different commercially available PTT reagents to the
various factors. In fact, the levels may vary from 25% to 40%. See,
Miale J B: Laboratoiy Medicine-Hematology. 6.sup.th Ed., (CV Mosby,
St. Louis, Mo., 1982). If the PT and PTT are abnormal, quantitative
assays of specific coagulation proteins are then carried out using
the PT or PTT tests and plasma from congenitally deficient
individuals as substrate. The corrective effect of varying
concentration of patient plasma is measured and expressed as a
percentage of normal pooled plasma standard. The interval range for
most coagulation factors is from 50 to 150 percent of this average
value, and the minimal level of most individual factors needed for
adequate hemostasis is 25 percent.
[0008] Dosage in Factor IX Replacement Therapy
[0009] One unit of factor IX is defined as the amount of factor IX
activity present in 1 ml of pooled normal human plasma and is
equivalent to 100% activity. The dose of factor IX needed to
achieve a desired level of activity can be calculated based on
estimation of the patient's plasma volume and knowledge of factor
IX kinetics.
[0010] Plasma volume may be estimated as 5% of body weight or 50
ml/kg body weight. Thus the plasma volume of a 70 kg patient is
approximately 3,500 ml. By definition, for such a patient to have
100% factor IX activity, 1 U/ml of plasma or a total of 3,500 U of
factor IX must be present in this plasma volume. If severe
hemophilia B is present, it may be assumed that the initial factor
IX activity is zero. Thus, to obtain 100% activity, at least 3,500
U of factor IX must be administered. Because of rapid
redistribution into the extravascular space and adsorption onto
endothelial cells of vessel walls, however, only about 50% of the
infused factor IX remains in circulation after a short period.
Therefore, to obtain 100% activity, the initial dose should be
about 7,000 U of factor IX. To generalize to any size patient with
any initial factor IX level and any desired target level, infusion
of 1 U/kg of body weight of factor IX will raise the factor IX
level approximately 1%. For example, a dose of 1,750 U would raise
a 50-kg patient from a starting factor IX level of 15% to a target
of 50% activity.
[0011] After its initial rapid redistribution, factor IX has a
second phase half-life of approximately 18-24 hours. Because the
variability in this measurement is significant, it is best
determined in each individual patient to allow proper dosing. Based
on these data, the factor IX level of a patient raised to 100%
activity would be expected to decay to 50% by approximately 24
hours after infusion of the initial dose. A second bolus one-half
the amount of the first should then raise the level from 50% to
100%. Factor IX is commonly administered in boluses every 12-24
hours. For the recombinant factor IX, BENEFFIX.RTM., Genetics
Institute, Cambridge, Mass., the number of factor IX International
Units (IU) to be administered should be the percentage of factor IX
increase desired multiplied by 1.2 IU/kg of body weight.
[0012] Factor IX is produced by a number of companies in both a
recombinant and plasma-derived formulations. Among these are the
following: BENEFIX.RTM. (recombinant product produced by Genetics
Institute, Cambridge, Mass.), MONOINE.RTM. Concentrate (Centeon,
King of Prussia, Pa.), ALPHANINE.RTM. SD (Alpha Therapeutic Corp.
Los Angeles, Calif.), BEBULNE VH IMMUNO.RTM. (Immuno, Rochester,
Minn.), KONYNE 80.RTM. (Bayer Corporation, Biological, West Haven,
Conn.), PROPLEX T.RTM. (Baxter Healthcare, Glendale, Calif.) and
PROFILNINE SD.RTM. (Alpha Corporation).
[0013] Treatment of Hemophilia B with Factor IX and Factor XIII
[0014] The method of the present invention improves upon the
above-described treatment of hemophilia B by administering factor
XIII in conjunction with factor IX. The factor XIII can be
administered at any time alone or at the same time as factor IX
either to stop a hemorrhage or for prophylaxis.
[0015] Factor XIII, also known as fibrin-stabilizing factor,
circulates in the plasma at a concentration of 10-20 mg/ml. The
protein exists in plasma as a tetramer comprised of two A subunits
and two B subunits. Each subunit has a molecular weight of 85,000
Da, and the complete protein has a molecular weight of
approximately 330,000 Da. Factor XIII catalyzes the cross-linkage
between the .gamma.-glutamyl and .epsilon.-lysyl groups of
different fibrin strands. The catalytic activity of factor XIII
resides in the A subunits. The B subunits act as carriers for the A
subunits in plasma factor XIII. Recombinant factor XIII can be
produced according to the process described in European Patent No.
0 268 772 B1. See also U.S. Pat. No. 6,084,074. The level of factor
XIII in the plasma can also be increased by administering a factor
XIII concentrate derived from human placenta called
FIBROGAMMIN.RTM. (Aventis Corp.) or by administration of
recombinant factor XIII.
[0016] A pharmaceutical composition comprising factor XIII can be
formulated according to known methods to prepare pharmaceutically
useful compositions, whereby the therapeutic proteins are combined
in a mixture with a pharmaceutically acceptable carrier. A
composition is said to be a "pharmaceutically acceptable carrier"
if its administration can be tolerated by a recipient patient. A
suitable pharmaceutical composition of factor XIII will contain 1
mM EDTA, 10 mM Glycine, 2% sucrose in water. An alternative
formulation will be a factor XIII composition containing 20 mM
histidine, 3% wt/volume sucrose, 2 mM glycine and 0.01% wt/vol.
polysorbate, pH 8. The concentration of factor XIII should
preferably be 1-10 mg/mL, more preferably about 5 mg/mL.
[0017] Other suitable carriers are well known to those in the art.
See, for example, Gennaro (ed.), Remington's Pharmaceutical
Sciences, 19th Edition (Mack Publishing Company 1995).
[0018] Administration of Factor XIII
[0019] Factor XIII can be administered intravenously,
intramuscularly or subcutaneously to treat hemophilia B. When
administering therapeutic proteins by injection, the administration
may be by continuous infusion or by single or multiple boluses. The
levels of factor XIII in an individual can be determined by assays
well known in the art such as the BERICHROM.RTM.0 F XIII assay
(Dade Behring Marburgh GmbH, Marburg, Germany). The normal adult
has an average of about 45 ml of plasma per kg of body weight. Each
liter of blood has 1000 units (U) of factor XIII. The amount of
factor XIII administered should be enough to bring an individual's
level of factor XIII in the plasma to 100% of normal plasma or
slightly above to 1-5% above normal, A dose of 0.45 U/kg would
raise the level of factor XIII by about 1% compared to normal. One
unit of factor XIII is about 10 .mu.g of recombinant factor XIII,
which contains only the dimerized A subunit. Thus, to raise the
level of factor XIII by 1%, one would administer about 4.5 .mu.g of
the A2 subunit per kilogram weight of the individual. So to raise
the level 30% of normal, one would administer 13.5 U/kg. For a 75
kg individual this would be about 1,012.5 U. Some patients may have
consumptive coagulopathies that involve factor XIII losses. In such
cases, a higher dosing (e.g., 1-2 U/kg-%) or multiple dosing of
factor XIII (e.g., 1-2 U/kg-%-day) may be required.
* * * * *