U.S. patent application number 11/953955 was filed with the patent office on 2008-06-12 for method for treating a pulmonary hypertension condition.
Invention is credited to Christopher Dufton, Michael J. Gerber.
Application Number | 20080139593 11/953955 |
Document ID | / |
Family ID | 39092031 |
Filed Date | 2008-06-12 |
United States Patent
Application |
20080139593 |
Kind Code |
A1 |
Gerber; Michael J. ; et
al. |
June 12, 2008 |
METHOD FOR TREATING A PULMONARY HYPERTENSION CONDITION
Abstract
A method for treating a pulmonary hypertension condition such as
pulmonary arterial hypertension (PAH) in a subject comprises
administering to the subject a therapeutically effective amount of
ambrisentan, wherein, at baseline, time from first diagnosis of the
condition in the subject is not greater than about 2 years.
Inventors: |
Gerber; Michael J.; (Denver,
CO) ; Dufton; Christopher; (Nederland, CO) |
Correspondence
Address: |
HARNESS, DICKEY, & PIERCE, P.L.C
7700 Bonhomme, Suite 400
ST. LOUIS
MO
63105
US
|
Family ID: |
39092031 |
Appl. No.: |
11/953955 |
Filed: |
December 11, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60869667 |
Dec 12, 2006 |
|
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Current U.S.
Class: |
514/274 |
Current CPC
Class: |
A61P 11/00 20180101;
A61K 31/53 20130101; A61K 31/505 20130101; A61K 31/519 20130101;
A61P 9/12 20180101; A61P 9/00 20180101; A61K 31/4985 20130101 |
Class at
Publication: |
514/274 |
International
Class: |
A61K 31/505 20060101
A61K031/505; A61P 9/12 20060101 A61P009/12; A61P 9/00 20060101
A61P009/00 |
Claims
1. A method for treating a pulmonary hypertension condition in a
subject, comprising administering a therapeutically effective
amount of ambrisentan to the subject, wherein, at baseline, time
from first diagnosis of the condition in the subject is not greater
than about 2 years.
2. The method of claim 1, wherein the pulmonary hypertension
condition comprises pulmonary arterial hypertension (PAH).
3. The method of claim 2, wherein the PAH comprises idiopathic PAH,
familial PAH or PAH associated with another disease or
condition.
4. The method of claim 2, wherein the PAH at baseline is of at
least WHO Class II.
5. The method of claim 1, wherein, at baseline, time from first
diagnosis of the condition in the subject is not greater than about
0.5 years.
6. The method of claim 1, wherein the subject experiences at least
one of (a) adjustment of one or more hemodynamic parameters
indicative of improvement of the pulmonary hypertension condition
towards a more normal level versus baseline; (b) increase in
exercise capacity versus baseline; (c) lowering of Borg dyspnea
index (BDI) versus baseline; (d) improvement of one or more quality
of life parameters versus baseline; and/or (e) movement to a lower
WHO functional class.
7. The method of claim 6, wherein mean pulmonary arterial pressure
(PAP) is lowered by at least about 3 mmHg versus baseline.
8. The method of claim 6, wherein mean PAP is lowered by at least
about 5 mmHg versus baseline.
9. The method of claim 6, wherein exercise capacity is increased as
measured by an increase of at least about 10 m in 6-minute walking
distance (6MWD).
10. The method of claim 6, wherein exercise capacity is increased
as measured by an increase of at least about 20 m in 6MWD.
11. The method of claim 6, wherein BDI is lowered by at least about
0.5 index point versus baseline.
12. The method of claim 6, wherein BDI is lowered by at least about
1 index point versus baseline.
13. The method of claim 1, wherein the ambrisentan is administered
orally once a day.
14. The method of claim 13, wherein the ambrisentan is administered
in a daily dosage amount of about 1 mg to about 25 mg.
15. The method of claim 13, wherein the ambrisentan is administered
in a daily dosage amount of about 2.5 mg to about 10 mg.
16. The method of claim 1, wherein the ambrisentan is administered
for a treatment period of at least about one month.
17. The method of claim 16, wherein the treatment period is at
least about three months.
18. The method of claim 1, wherein the ambrisentan is administered
in monotherapy.
19. The method of claim 1, wherein the ambrisentan is administered
in combination therapy with a second active agent effective for
treatment of the pulmonary hypertension condition or a condition
related thereto.
20. The method of claim 19, wherein the second active agent
comprises at least one drug selected from the group consisting of
prostanoids, phosphodiesterase-5 (PDE5) inhibitors, endothelin
receptor antagonists (ERAs) other than ambrisentan, calcium channel
blockers, diuretics, anticoagulants, oxygen and combinations
thereof.
21. A method for providing an improved prognosis for a subject
having a pulmonary hypertension condition, the method comprising
administering to the subject ambrisentan at a dose and frequency
and for a treatment period effective to provide (a) a reduction in
probability of a clinical worsening event during the treatment
period, and/or (b) a reduction from baseline in serum brain
natriuretic peptide (BNP) concentration, wherein, at baseline, time
from first diagnosis of the condition in the subject is not greater
than about 2 years.
22. The method of claim 21, wherein, at baseline, time from first
diagnosis of the condition in the subject is not greater than about
0.5 years.
23. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
of at least about 25% in probability of a clinical worsening event
during the treatment period.
24. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
of at least about 50% in probability of a clinical worsening event
during the treatment period.
25. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
of at least about 80% in probability of a clinical worsening event
during the treatment period.
26. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
of at least about 50% in probability of death, lung
transplantation, hospitalization for pulmonary arterial
hypertension, atrial septostomy or an aggregate thereof during the
treatment period.
27. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
from baseline of at least about 15% in BNP concentration.
28. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
from baseline of at least about 25% in BNP concentration.
29. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are effective to provide a reduction
from baseline of at least about 50% in BNP concentration.
30. The method of claim 21, wherein the pulmonary hypertension
condition comprises PAH.
31. The method of claim 30, wherein the subject has idiopathic
PAH.
32. The method of claim 30, wherein the subject has non-idiopathic
PAH.
33. The method of claim 32, wherein the non-idiopathic PAH is
secondary to scleroderma, systemic lupus erythematosus, anorexigen
use or HIV infection.
34. The method of claim 30, wherein the PAH at baseline is of at
least WHO Class II.
35. The method of claim 21, wherein the subject at baseline has at
least one of (a) mean PAP of at least about 25 mmHg at rest or at
least about 30 mmHg while exercising, (b) pulmonary vascular
resistance (PVR) of at least about 3 mmHg/L/min, and/or (c)
pulmonary capillary wedge pressure (PCWP) or left ventricle end
diastolic pressure (LVEDP) not greater than about 15 mmHg.
36. The method of claim 35, wherein the subject the subject at
baseline has all three of (a) mean PAP of at least about 25 mmHg at
rest or at least about 30 mmHg while exercising, (b) PVR of at
least about 3 mmHg/L/min, and (c) PCWP or LVEDP not greater than
about 15 mmHg.
37. The method of claim 21, wherein the subject at baseline has
mean PAP at rest of at least about 40 mmHg.
38. The method of claim 21, wherein the ambrisentan is administered
orally once a day.
39. The method of claim 38, wherein the ambrisentan is administered
in a daily dosage amount of about 1 mg to about 25 mg.
40. The method of claim 38, wherein the ambrisentan is administered
in a daily dosage amount of about 2.5 mg to about 10 mg.
41. The method of claim 21, wherein the treatment period is at
least about one month.
42. The method of claim 21, wherein the treatment period is at
least about three months.
43. The method of claim 21, wherein the ambrisentan is administered
in monotherapy.
44. The method of claim 21, wherein the ambrisentan is administered
in combination therapy with a second active agent effective for
treatment of the pulmonary hypertension condition or a condition
related thereto.
45. The method of claim 44, wherein the second active agent
comprises at least one drug selected from the group consisting of
prostanoids, phosphodiesterase-5 (PDE5) inhibitors, endothelin
receptor antagonists (ERAs) other than ambrisentan, calcium channel
blockers, diuretics, anticoagulants, oxygen and combinations
thereof.
46. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are additionally effective to improve
pulmonary function of the subject over baseline as measured by at
least one of exercise capacity and/or BDI.
47. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are additionally effective to enhance
quality of life of the subject over baseline as measured by an
increase in one or more parameters in an SF-36.RTM. health
survey.
48. The method of claim 47, wherein an increase of at least about 1
point is observed in one or more parameters in the survey.
49. The method of claim 21, wherein the dose, frequency and period
of ambrisentan administration are additionally effective to
maintain or improve WHO functional class.
50. The method of claim 21, wherein the subject is female.
51. The method of claim 21, wherein the subject is male and
fertility of the subject is not substantially compromised.
52. A method for prolonging life of a subject having a pulmonary
hypertension condition, comprising administering to the subject
ambrisentan at a dose and frequency and for a treatment period
effective to increase life expectancy, from a time of initiation of
treatment, by at least about 30 days, wherein, at baseline, time
from first diagnosis of the condition in the subject is not greater
than about 2 years.
53. A method for extending time to clinical worsening in a subject
having a pulmonary hypertension condition, comprising administering
to the subject ambrisentan at a dose and frequency and for a
treatment period effective to decrease the probability of a
clinical worsening event by at least about 25%, wherein, at
baseline, time from first diagnosis of the condition in the subject
is not greater than about 2 years.
54. A method for treating a pulmonary hypertension condition in a
reproductively active male subject, the method comprising
administering a therapeutically effective amount of ambrisentan to
the subject, wherein fertility of the subject is not substantially
compromised.
55. A method for treating PAH in a subject, comprising
administering a therapeutically effective amount of ambrisentan to
the subject, wherein the PAH is associated with one or more of (a)
a congenital heart defect, (b) portal hypertension, (c) use of a
drug or toxin other than an anorexigen, (d) thyroid disorder, (e)
glycogen storage disease, (f) Gaucher disease, (g) hereditary
hemorrhagic telangiectasia, (h) hemoglobinopathy, (i)
myeloproliferative disorder, (j) splenectomy, (k) pulmonary
veno-occlusive disease or (l) pulmonary capillary
hemangiomatosis.
56. A method for treating a pulmonary hypertension condition
classified in WHO Groups 2-5 in a subject, comprising administering
a therapeutically effective amount of ambrisentan to the
subject.
57. The method of claim 56, wherein the condition comprises
left-sided atrial or ventricular heart disease and/or left-sided
valvular heart disease.
58. The method of claim 56, wherein the condition is associated
with one or more of chronic obstructive pulmonary disease (COPD),
interstitial lung disease, sleep-disordered breathing, an alveolar
hypoventilation disorder, chronic exposure to high altitude, a
developmental abnormality, thromboembolic obstruction of proximal
and/or distal pulmonary arteries, a non-thrombotic pulmonary
embolism, sarcoidosis, histiocytosis X, lymphangiomatosis, and/or
compression of pulmonary vessels.
Description
[0001] This application claims the benefit of U.S. provisional
application Ser. No. 60/869,667, filed Dec. 12, 2006, incorporated
in its entirety herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods useful for treating
a subject having a pulmonary hypertension condition, and for
improving clinical outcome in such a subject.
BACKGROUND OF THE INVENTION
[0003] Pulmonary hypertension (PH) has been previously classified
as primary (idiopathic) or secondary. Recently, the World Health
Organization (WHO) has classified pulmonary hypertension into five
groups: [0004] Group 1: pulmonary arterial hypertension (PAH);
[0005] Group 2: PH with left heart disease; [0006] Group 3: PH with
lung disease and/or hypoxemia; [0007] Group 4: PH due to chronic
thrombotic and/or embolic disease; and [0008] Group 5:
miscellaneous conditions (e.g., sarcoidosis, histiocytosis X,
lymphangiomatosis and compression of pulmonary vessels).
See, for example, Rubin (2004) Chest 126:7-10.
[0009] Pulmonary arterial hypertension (PAH) is a serious,
progressive and life-threatening disease of the pulmonary
vasculature, characterized by profound vasoconstriction and an
abnormal proliferation of smooth muscle cells in the walls of the
pulmonary arteries. Severe constriction of the blood vessels in the
lungs leads to very high pulmonary arterial pressures. These high
pressures make it difficult for the heart to pump blood through the
lungs to be oxygenated. Patients with PAH suffer from extreme
shortness of breath as the heart struggles to pump against these
high pressures. Patients with PAH typically develop significant
increases in pulmonary vascular resistance (PVR) and sustained
elevations in pulmonary artery pressure (PAP), which ultimately
lead to right ventricular failure and death. Patients diagnosed
with PAH have a poor prognosis and equally compromised quality of
life, with a mean life expectancy of 2 to 5 years from the time of
diagnosis if untreated.
[0010] Endothelin-1 (ET-1) is the primary member of a family of
potent vasoconstrictor peptides, which are known to play an
essential role in mammalian cardiovascular physiology. ET-1 is
synthesized de novo and released from endothelial cells in response
to a variety of factors, including angiotensin II, catecholamines,
cytokines, hypoxia and shear stress. Two receptor subtypes,
endothelin receptor type A (ET.sub.A) and endothelin receptor type
B (ET.sub.B), mediate the effects of ET-1. In humans, the ET.sub.A
receptor is preferentially expressed in vascular smooth muscle
cells and is primarily responsible for the vasoconstrictive effects
of ET-1. In contrast, ET.sub.B receptors are found mainly in the
vascular endothelium, and their activation results in
vasodilatation via production of nitric oxide and prostacyclin. The
ET.sub.B receptor is also involved in regulation of circulating
concentrations of ET-1, through effects on endothelin converting
enzyme (ECE-1) expression, and the synthesis and reuptake of ET-1
by endothelial cells.
[0011] Ambrisentan is a non-sulfonamide, propanoic acid-class
endothelin receptor antagonist (ERA) with high affinity (.about.12
pM) for the ET.sub.A receptor. Bosentan, a non-selective,
sulfonamide-class ERA, is approved for treatment of PAH in patients
with WHO functional class III or IV symptoms. Sitaxsentan is
another sulfonamide-class ERA that is selective for the ET.sub.A
receptor. Sitaxsentan is currently under review for market
authorization as a PAH therapeutic.
[0012] Myogen, Inc. News Release, Dec. 4, 2003
(http://www.pmewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/12-
-04-2003/0002069898&EDATE=) announced completion of a Phase II
trial of ambrisentan in PAH and initiation of Phase III trials. The
release stated that the Phase III trials would evaluate 2.5 mg, 5.0
mg and 10.0 mg oral dosages of ambrisentan administered once a day,
and would have as a primary efficacy endpoint exercise capacity,
which measures the change from baseline in 6-minute walk distance
(6MWD) compared to placebo, and secondary endpoints including Borg
dyspnea index (BDI), WHO functional class and a quality of life
assessment.
[0013] Myogen, Inc. News Release, Jan. 8, 2004
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759080&highlight=) announced patient enrollment in phase III
clinical trials of ambrisentan for treatment of PAH. According to
the news release, phase II trials had demonstrated a statistically
significant and clinically meaningful increase in the primary
efficacy endpoint (exercise capacity measured by 6MWD) in all four
ambrisentan dose groups tested.
[0014] Myogen, Inc. News Release, Feb. 16, 2004
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759478&highlight=) announced upcoming presentation of detailed
results of the phase II study of ambrisentan in PAH, at the
American Thoracic Society (ATS) 2004 International Conference.
(Rubin (2004) "Ambrisentan Improves Exercise Capacity and Clinical
Measures in Pulmonary Arterial Hypertension", ATS May 21-26,
2004.)
[0015] Myogen, Inc. News Release, May 24, 2004
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759469&highlight=) reported improvements in 6MWD, BDI and WHO
functional classification seen in the Phase II study. Additionally,
the news release mentioned suitability of ambrisentan for
once-a-day dosing.
[0016] Myogen, Inc. News Release, Feb. 10, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759971&highlight=) announced that two abstracts describing
effects of ambrisentan in patients with PAH were selected for
presentation at ATS 2005 in San Diego. (Galie (2005) "Ambrisentan
Long-Term Safety and Efficacy in Pulmonary Arterial Hypertension
1-Year Follow-Up", ATS May 23, 2005; Frost (2005) "Ambrisentan
Improves 6MWD Comparably for WHO Class II and III PAH Patients,"
ATS May 22, 2005.) It was stated that one-year data demonstrated
that ambrisentan produced a significant and durable benefit on
exercise capacity and other clinical measures of PAH and that WHO
Class II and III PAH patients have significant and comparable
improvement in exercise capacity, suggesting that the effects of
ambrisentan are not limited by the "ceiling effect" in patients
with less severe PAH symptoms.
[0017] Myogen, Inc. News Release, May 19, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759658&highlight=) reported initiation of a clinical trial to
evaluate ambrisentan in patients with PAH who have previously
discontinued bosentan or sitaxsentan therapy due to liver function
test (LFT) abnormalities, specifically elevated serum
aminotransferase concentrations.
[0018] Myogen, Inc. News Release, May 23, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759656&highlight=) reported further data presented by Galie
(2005) ATS 2005, cited above, which were stated to show
improvements in a 6-minute walking test (6MWT) accompanied with
improved levels of dyspnea (breathlessness) for WHO Class II and
III patients. The release reported a one-year survival rate of 92%
for patients with idiopathic PAH as compared to an NIH registry
predicted survival of 74%.
[0019] Myogen, Inc. News Release, Jul. 21, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
759650&highlight=) announced completion of enrollment of 187
patients in ARIES-2, one of the two Phase III clinical trials of
ambrisentan in patients with PAH. The news release reported that
ARIES-1 evaluates doses of 5.0 mg and 10.0 mg of ambrisentan
administered orally once daily, while ARIES-2 provides 2.5 mg and
5.0 mg dosages. The release stated that the results of the Phase II
clinical trial of ambrisentan in patients with PAH demonstrated
significant improvements in 6MWD, BDI and WHO functional class,
durable efficacy with long-term use and a possible survival
benefit, comparable efficacy in WHO Functional Class 2 and Class 3
patients, selectivity for the endothelin type-A receptor, dose
flexibility, true once-daily dosing, no drug interactions (no p450
induction or inhibition), and low incidence and severity of
potential liver toxicity that does not appear to be dose
related.
[0020] Myogen, Inc. News Release, Nov. 10, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
781654&highlight=) announced the expectation that ARIES-2
results would be reported in December of that year.
[0021] Rubin et al. (2005) Future Cardiol. 1(4):1-8 reported
improvement of the mean 6MWD for all patients after 12 weeks of
ambrisentan treatment, with a mean increase from baseline of 36
meters. The authors reported that similar improvements in 6MWD were
observed for patients with WHO Functional Class II and III
symptoms, indicating that the effects of ambrisentan may not be
limited by a "ceiling effect" in less advanced PAH patients, as has
been reported for sitaxsentan. Additionally, the authors reported
that clinically meaningful improvements were also seen in BDI and
WHO functional class.
[0022] Galie et al. (2005) J. Am. Coll. Cardiol. 46(3):529-535
reported results of a randomized dose-ranging study examining
efficacy and safety of ambrisentan in patients with PAH. The
authors reported an increase in exercise capacity in patients with
idiopathic PAH as well as in patients with PAH due to other
etiologies and for patients in WHO Functional Class II as well as
those in WHO Functional Class III.
[0023] PAH afflicts approximately 200,000 patients worldwide.
Improved drug therapies to treat pulmonary hypertensive disorders
such as PAH are needed in the art. Further, methods for enhancing
the clinical outcome for patients having pulmonary hypertension
conditions would be highly desirable.
SUMMARY OF THE INVENTION
[0024] There is now provided a method for treating a pulmonary
hypertension condition in a subject, comprising administering a
therapeutically effective amount of ambrisentan to the subject,
wherein, at baseline, time from first diagnosis of the condition in
the subject is not greater than about 2 years.
[0025] There is further provided a method for providing an improved
prognosis for a subject having a pulmonary hypertension condition,
comprising administering to the subject ambrisentan at a dose and
frequency and for a treatment period effective to provide (a) a
reduction of at least about 25% in probability of a clinical
worsening event during the treatment period, and/or (b) a reduction
from baseline of at least about 15% in serum brain natriuretic
peptide (BNP) concentration; wherein, at baseline, time from first
diagnosis of the condition in the subject is not greater than about
2 years.
[0026] There is still further provided a method for prolonging life
of a subject having a pulmonary hypertension condition, comprising
administering to the subject ambrisentan at a dose and frequency
and for a treatment period effective to increase life expectancy,
from a time of initiation of treatment, by at least about 30 days;
wherein, at baseline, time from first diagnosis of the condition in
the subject is not greater than about 2 years.
[0027] There is still further provided a method for extending time
to clinical worsening in a subject having PAH, comprising
administering to the subject ambrisentan at a dose and frequency
and for a treatment period effective to decrease the probability of
a clinical worsening event by at least about 25%; wherein, at
baseline, time from first diagnosis of the condition in the subject
is not greater than about 2 years.
[0028] There is still further provided a method for treating a
pulmonary hypertension condition in a reproductively active male
subject, the method comprising administering a therapeutically
effective amount of ambrisentan to the subject, wherein fertility
of the subject is not substantially compromised.
[0029] Any of the above methods is applicable to any pulmonary
hypertension condition recognized in the WHO classification,
including pulmonary arterial hypertension (PAH) as classified in
WHO Group 1.
[0030] There is still further provided a method for treating PAH in
a subject, comprising administering a therapeutically effective
amount of ambrisentan to the subject, wherein the PAH is associated
with one or more of (a) a congenital heart defect such as a
systemic-to-pulmonary shunt or Eisenmenger's syndrome, (b) portal
hypertension, (c) use of a drug or toxin other than an anorexigen,
(d) thyroid disorder, (e) glycogen storage disease, (f) Gaucher
disease, (g) hereditary hemorrhagic telangiectasia, (h)
hemoglobinopathy, (i) myeloproliferative disorder, (j) splenectomy,
(k) pulmonary veno-occlusive disease and/or (l) pulmonary capillary
hemangiomatosis.
[0031] There is still further provided a method for treating a
pulmonary hypertension condition classified in WHO Groups 2-5 in a
subject, comprising administering a therapeutically effective
amount of ambrisentan to the subject.
[0032] Other embodiments, including particular aspects of the
embodiments summarized above, will be evident from the detailed
description that follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 provides Kaplan-Meier curves for time to clinical
worsening of PAH from the study described in Example 1.
[0034] FIG. 2 provides Kaplan-Meier curves for time to clinical
worsening of PAH from the study described in Example 2.
DETAILED DESCRIPTION
[0035] The present invention is based in part on a finding, in
placebo-controlled clinical trials, that ambrisentan is effective
for treatment of a pulmonary hypertension condition, more
specifically pulmonary arterial hypertension (PAH), in subjects
wherein the condition is relatively recently diagnosed. In the
above-referenced presentation by Rubin (2004) at ATS 2004, subjects
treated with ambrisentan were reportedly characterized at baseline
by a mean time since diagnosis of 3.2.+-.3.8 years. In the absence
of placebo control, it is not possible to determine how these
subjects might have fared had they not been given the benefit of
ambrisentan therapy.
[0036] It is noted, however, that a prediction based on the
National Institutes for Health (NIH) registry is that only 74% of
patients having a diagnosis of idiopathic PAH survive for 1 year
(above-referenced presentation by Galie (2005) at ATS 2005). A
cohort of patients that have survived with the disease for a longer
period of time may not be representative of patients with more
recent diagnosis, as that cohort may be inadvertently biased in
favor of individuals better able to survive for a prolonged
period.
[0037] The sooner treatment can begin after diagnosis, the better.
Accordingly, in a first embodiment of the invention, a method for
treating a pulmonary hypertension condition in a subject comprises
administering a therapeutically effective amount of ambrisentan to
the subject, wherein, at baseline, time from first diagnosis of the
condition in the subject is not greater than about 2 years, for
example not greater than about 1.5 years, not greater than about 1
year, not greater than about 0.75 year or not greater than about
0.5 year. In one aspect of the first embodiment, administration of
ambrisentan can begin substantially immediately, for example within
about one month or within about one week, upon diagnosis.
[0038] This method does not in any way negate ambrisentan therapy
for subjects having a longer history of the condition. However, it
recognizes that early intervention is advantageous. Benefits of the
method to subjects having recent diagnosis (and poor prognosis
without early intervention as exhibited, for example, in the NIH
registry mentioned above) have now been quantified for the first
time. Illustratively, in the placebo-controlled study described in
Example 1 below, the median number of years for which PAH was
present at baseline was 0.38 for subjects receiving placebo, 0.43
years for subjects receiving 2.5 mg ambrisentan daily, and 0.26
years for subjects receiving 5 mg ambrisentan daily. In the
placebo-controlled study described in Example 2 below, the median
number of years for which PAH was present at baseline was 0.54 for
subjects receiving placebo, 0.33 years for subjects receiving 5 mg
ambrisentan daily, and 0.60 years for subjects receiving 10 mg
ambrisentan daily.
[0039] Except where otherwise indicated herein, the term "baseline"
herein means a time immediately prior to initiation of treatment
with ambrisentan.
[0040] The term "diagnosis" herein means recognition by a physician
or clinician of a pulmonary hypertension condition, for example
PAH, in the subject, by any means whether or not such diagnosis is
confirmed by hemodynamic evaluation. In one aspect of the first
embodiment, diagnosis is confirmed hemodynamically, for example in
the case of PAH by presence of one or more, more typically two or
all three of the following: [0041] (a) mean pulmonary arterial
pressure (PAP) not less than about 25 mmHg at rest or not less than
about 30 mmHg while exercising; [0042] (b) pulmonary vascular
resistance (PVR) not less than about 3 mmHg/liter/minute; [0043]
(c) pulmonary capillary wedge pressure (PCWP) or left ventricle end
diastolic pressure (LVEDP) not greater than about 15 mmHg. The
pulmonary hypertension condition diagnosed, and treated by the
method of the first embodiment, can comprise any one or more of the
conditions recognized according to the World Health Organization
(WHO) or Venice (2003) classification (see, for example, Rubin
(2004) Chest 126:7-10): [0044] Group 1: Pulmonary arterial
hypertension (PAH) [0045] 1.1 idiopathic PAH [0046] 1.2 familial
PAH [0047] 1.3 PAH associated with: [0048] 1.3.1 collagen vascular
disease [0049] 1.3.2 congenital systemic-to-pulmonary shunts
(including Eisenmenger's syndrome) [0050] 1.3.3 portal hypertension
[0051] 1.3.4 HIV infection [0052] 1.3.5 drugs and toxins [0053]
1.3.6 other (thyroid disorders, glycogen storage disease, Gaucher
disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies,
myeloproliferative disorders, splenectomy) [0054] 1.4 PAH
associated with significant venous or capillary involvement [0055]
1.4.1 pulmonary veno-occlusive disease (PVOD) [0056] 1.4.2
pulmonary capillary hemangiomatosis (PCH) [0057] 1.5 persistent
pulmonary hypertension of the newborn [0058] Group 2: Pulmonary
hypertension with left heart disease [0059] 2.1 left-sided atrial
or ventricular heart disease [0060] 2.2 left-sided valvular heart
disease [0061] Group 3: Pulmonary hypertension associated with lung
diseases and/or hypoxemia [0062] 3.1 chronic obstructive pulmonary
disease (COPD) [0063] 3.2 interstitial lung disease [0064] 3.3
sleep-disordered breathing [0065] 3.4 alveolar hypoventilation
disorders [0066] 3.5 chronic exposure to high altitude [0067] 3.6
developmental abnormalities [0068] Group 4: Pulmonary hypertension
due to chronic thrombotic and/or embolic disease [0069] 4.1
thromboembolic obstruction of proximal pulmonary arteries [0070]
4.2 thromboembolic obstruction of distal pulmonary arteries [0071]
4.3 non-thrombotic pulmonary embolism (tumor, parasites, foreign
material) [0072] Group 5: Miscellaneous (sarcoidosis, histiocytosis
X, lymphangiomatosis, compression of pulmonary vessels (adenopathy,
tumor, fibrosing mediastinitis))
[0073] In one aspect, the pulmonary hypertension condition
comprises PAH (WHO Group 1), for example idiopathic PAH, familial
PAH or PAH associated with another disease or condition.
[0074] Pulmonary hypertension at baseline can be mild, moderate or
severe, as measured for example by WHO functional class, which is a
measure of disease severity in patients with pulmonary
hypertension. The WHO functional classification is an adaptation of
the New York Heart Association (NYHA) system and is routinely used
to qualitatively assess activity tolerance, for example in
monitoring disease progression and response to treatment (Rubin
(2004) Chest 126:7-10). Four functional classes are recognized in
the WHO system: [0075] Class I: pulmonary hypertension without
resulting limitation of physical activity; ordinary physical
activity does not cause undue dyspnea or fatigue, chest pain or
near syncope; [0076] Class II: pulmonary hypertension resulting in
slight limitation of physical activity; patient comfortable at
rest; ordinary physical activity causes undue dyspnea or fatigue,
chest pain or near syncope; [0077] Class III: pulmonary
hypertension resulting in marked limitation of physical activity;
patient comfortable at rest; less than ordinary activity causes
undue dyspnea or fatigue, chest pain or near syncope; [0078] Class
IV: pulmonary hypertension resulting in inability to carry out any
physical activity without symptoms; patient manifests signs of
right-heart failure; dyspnea and/or fatigue may be present even at
rest; discomfort is increased by any physical activity.
[0079] In one aspect of the first embodiment, the subject at
baseline exhibits pulmonary hypertension (e.g., PAH) of at least
WHO Class II, for example WHO Class II or Class III.
[0080] In another aspect, the subject at baseline exhibits mean PAP
at rest of at least about 30 mmHg, for example at least about 35,
at least about 40, at least about 45 or at least about 50 mmHg.
[0081] The term "treatment" herein encompasses one or more of the
following: [0082] (a) adjustment of one or more hemodynamic
parameters towards a more normal level, for example lowering mean
PAP or PVR, or raising PCWP or LVEDP, versus baseline; [0083] (b)
improvement of pulmonary function versus baseline, for example
increasing exercise capacity, illustratively as measured in a test
of 6-minute walking distance (6MWD), or lowering Borg dyspnea index
(BDI); [0084] (c) improvement of one or more quality of life
parameters versus baseline, for example an increase in score on at
least one of the SF-36.RTM. health survey functional scales; [0085]
(d) general improvement versus baseline in the severity of the
condition, for example by movement to a lower WHO functional class;
[0086] (e) improvement of clinical outcome following a period of
treatment, versus expectation in absence of treatment (e.g., in a
clinical trial setting, as measured by comparison with placebo),
including improved prognosis, extending time to or lowering
probability of clinical worsening, extending quality of life (e.g.,
delaying progression to a higher WHO functional class or slowing
decline in one or more quality of life parameters such as
SF-36.RTM. health survey parameters), and/or increasing longevity;
and/or [0087] (f) adjustment towards a more normal level of one or
more molecular markers that can be predictive of clinical outcome
(e.g., plasma concentrations of endothelin-1 (ET-1), cardiac
troponin T (cTnT) or B-type natriuretic peptide (BNP)).
[0088] Except where otherwise indicated herein, a "therapeutically
effective amount" of ambrisentan is an amount (typically a daily
amount administered over the course of a period of treatment)
sufficient to provide any one or more of the effects mentioned
above. Preferably the amount administered does not exceed an amount
causing an unacceptable degree of adverse side effects.
[0089] What constitutes a therapeutically effective amount can vary
depending on the particular pulmonary hypertension condition to be
treated, the severity of the condition, body weight and other
parameters of the individual subject, and can be readily
established without undue experimentation by the physician or
clinician based on the disclosure herein. Typically, a
therapeutically effective amount will be found in the range of
about 1 to about 25 mg/day, for example about 2 to about 15 mg/day,
about 2.5 to about 10 mg/day, or about 2.5, about 3, about 3.5,
about 4, about 4.5, about 5, about 6, about 7, about 8, about 9 or
about 10 mg/day.
[0090] Such an amount can be administered each day, for example in
individual doses administered once, twice, or three or more times a
day. However, dosages stated herein on a per day basis should not
be construed to require administration of the daily dose each and
every day. For example, if the ambrisentan is provided in a
suitably slow-release form, two or more daily dosage amounts can be
administered at a lower frequency, e.g., as a depot every second
day to once a month or even longer. Most typically and conveniently
for the patient, ambrisentan is administered once a day, for
example in the morning.
[0091] The ambrisentan can be administered for an extended
treatment period. Typically, the longer the treatment continues,
the greater and more lasting will be the benefits. Illustratively,
the treatment period can be at least about one month, for example
at least about 3 months, at least about 6 months or at least about
1 year. In some cases, administration can continue for
substantially the remainder of the life of the subject.
[0092] In this and other embodiments, ambrisentan can be
administered by any suitable route including oral, rectal,
intranasal, intrapulmonary (e.g., by inhalation) or parenteral
(e.g., intradermal, transdermal, subcutaneous, intramuscular or
intravenous) routes. Oral administration is most convenient for the
majority of subjects and can occur independently of meal times,
i.e., with or without food.
[0093] The ambrisentan can be administered in monotherapy or in
combination therapy as described in greater detail hereinbelow.
[0094] In various aspects of the first embodiment, the subject
experiences, during or following the treatment period, at least one
of [0095] (a) adjustment of one or more hemodynamic parameters
indicative of the pulmonary hypertension condition towards a more
normal level versus baseline; [0096] (b) increase in exercise
capacity versus baseline; [0097] (c) lowering of BDI versus
baseline; [0098] (d) improvement of one or more quality of life
parameters versus baseline; and/or [0099] (e) movement to a lower
WHO functional class.
[0100] Any suitable measure of exercise capacity can be used; a
particularly suitable measure is obtained in a 6-minute walk test
(6MWT), which measures how far the subject can walk in 6 minutes,
i.e., the 6-minute walk distance (6MWD).
[0101] The Borg dyspnea index (BDI) is a numerical scale for
assessing perceived dyspnea (breathing discomfort). It measures the
degree of breathlessness after completion of the 6 minute walk test
(6MWT), where a BDI of 0 indicates no breathlessness and 10
indicates maximum breathlessness.
[0102] In various aspects of the first embodiment, the ambrisentan
can be administered in an amount effective to adjust one or more
hemodynamic parameters indicative of the pulmonary hypertension
condition towards a more normal level. In one such aspect, mean PAP
is lowered, for example by at least about 3 mmHg, or at least about
5 mmHg, versus baseline. In another such aspect, PVR is lowered. In
yet another such aspect, PCWP or LVEDP is raised.
[0103] In various aspects of the first embodiment, the ambrisentan
can be administered in an amount effective to improve pulmonary
function versus baseline. Any measure of pulmonary function can be
used; illustratively 6MWD is increased or BDI is lowered.
[0104] In one such aspect, 6MWD is increased from baseline by at
least about 10 m, for example at least about 20 m or at least about
30 m. In many instances, the method of the present embodiment will
be found effective to increase 6MWD by as much as 50 m or even
more.
[0105] In another such aspect, BDI, illustratively as measured
following a 6MWT, is lowered from baseline by at least about 0.5
index points. In many instances, the method of the present
embodiment will be found effective to lower BDI by as much as 1
full index point or even more.
[0106] The SF-36.RTM. health survey provides a self-reporting,
multi-item scale measuring eight health parameters: physical
functioning, role limitations due to physical health problems,
bodily pain, general health, vitality (energy and fatigue), social
functioning, role limitations due to emotional problems, and mental
health (psychological distress and psychological well-being). The
survey also provides a physical component summary and a mental
component summary. For further detail see, for example, Ware:
SF-36.RTM. Health Survey Update,
http://www.sf-36.org/tools/sf36.shtml.
[0107] In various aspects of the first embodiment, the ambrisentan
can be administered in an amount effective to improve quality of
life of the subject, illustratively as measured by one or more of
the health parameters recorded in an SF-36.RTM. survey. For
example, an improvement versus baseline is obtained in at least one
of the SF-36 physical health related parameters (physical health,
role-physical, bodily pain and/or general health) and/or in at
least one of the SF-36 mental health related parameters (vitality,
social functioning, role-emotional and/or mental health). Such an
improvement can take the form of an increase of at least 1, for
example at least 2 or at least 3 points, on the scale for any one
or more parameters.
[0108] The ambrisentan can be administered in monotherapy or in
combination therapy with one or more additional drugs, for example,
as described in greater detail hereinbelow.
[0109] In a second embodiment of the invention, a method is
provided for improving the prognosis for a subject having a
pulmonary hypertension condition. The method of this embodiment
comprises administering to the subject ambrisentan at a dose and
frequency and for a treatment period effective to provide (a) a
reduction in probability of a clinical worsening event during the
treatment period, and/or (b) a reduction from baseline in serum
brain natriuretic peptide (BNP) concentration, wherein, at
baseline, time from first diagnosis of the condition in the subject
is not greater than about 2 years.
[0110] Time from first diagnosis, in various aspects of the second
embodiment, can be, for example, not greater than about 1.5 years,
not greater than about 1 year, not greater than about 0.75 year or
not greater than about 0.5 year. In one aspect of the second
embodiment, administration of ambrisentan can begin substantially
immediately, for example, within about one month or within about
one week, upon diagnosis.
[0111] In the method of the second embodiment, the ambrisentan is
administered at a dose and frequency and for a period of treatment
sufficient to provide one or both of the effects mentioned above.
Preferably the dose administered does not exceed an amount causing
an unacceptable degree of adverse side effects. The dose
administered can vary depending on the particular pulmonary
hypertension condition to be treated, the severity of the
condition, body weight and other parameters of the individual
subject, and can be readily established without undue
experimentation by the physician or clinician based on the
disclosure herein.
[0112] Typically, a suitable daily dose will be found in the range
of about 1 to about 25 mg/day, for example about 2 to about 15
mg/day, about 2.5 to about 10 mg/day, or about 2.5, about 3, about
3.5, about 4, about 4.5, about 5, about 6, about 7, about 8, about
9 or about 10 mg/day. Such an amount can be administered each day,
for example in individual doses administered once, twice, or three
or more times a day. However, dosages stated herein on a per day
basis should not be construed to require administration of the
daily dose each and every day. For example, if the ambrisentan is
provided in a suitably slow-release form, two or more daily dosage
amounts can be administered at a lower frequency, e.g., as a depot
every second day to once a month or even longer. Most typically and
conveniently for the patient, ambrisentan is administered once a
day, for example in the morning.
[0113] In the method of the second embodiment, the treatment period
is long enough for the stated effect to be produced. Typically, the
longer the treatment continues, the greater and more lasting will
be the benefits. Illustratively, the treatment period can be at
least about one month, for example at least about 3 months, at
least about 6 months or at least about 1 year. In some cases,
administration can continue for substantially the remainder of the
life of the subject.
[0114] In various aspects of the second embodiment, the ambrisentan
can be administered in monotherapy or in combination therapy as
described in greater detail hereinbelow.
[0115] In a particular aspect of the second embodiment, the method
is effective to provide a reduction of at least about 25%, for
example at least about 50%, at least about 75% or at least about
80%, in probability of a clinical worsening event during the
treatment period.
[0116] Clinical worsening event (CWEs) include death, lung
transplantation, hospitalization for the pulmonary hypertension
condition, atrial septostomy, initiation of additional pulmonary
hypertension therapy or an aggregate thereof. Therefore, the
present embodiment provides a method effective to provide a
reduction of at least about 25%, for example at least about 50%, at
least about 75% or at least about 80%, in probability of death,
lung transplantation, hospitalization for pulmonary arterial
hypertension, atrial septostomy and/or initiation of additional
pulmonary hypertension therapy during the treatment period.
[0117] Time to clinical worsening of the pulmonary hypertension
condition is defined as the time from initiation of a ambrisentan
treatment regime to the first occurrence of a CWE.
[0118] In another particular aspect of the second embodiment, the
method is effective to provide a reduction from baseline of at
least about 15%, for example at least about 25%, at least about 50%
or at least about 75%, in BNP concentration.
[0119] The pulmonary hypertension condition according to the second
embodiment can comprise any one or more of the conditions in the
WHO or Venice (2003) classification described above. In one aspect
of the second embodiment, the condition comprises PAH (WHO Group
1), for example idiopathic PAH, familial PAH or PAH associated with
another disease.
[0120] In various aspects of the second embodiment, the subject at
baseline exhibits PH (e.g., PAH) of at least WHO Class II, for
example Class II, Class III or Class IV as described above.
[0121] In a more particular embodiment, the subject at baseline has
a resting PAP of at least about 30 mmHg, for example at least about
35 mmHg or at least about 40 mmHg.
[0122] In various aspects of the second embodiment, the subject can
experience, during or following the treatment period, at least one
of [0123] (a) adjustment of one or more hemodynamic parameters
indicative of improvement of the pulmonary hypertension condition
towards a more normal level versus baseline; [0124] (b) improvement
in pulmonary function; illustratively an increase in exercise
capacity or lowering of BDI versus baseline; [0125] (c) improvement
of one or more quality of life parameters versus baseline; and/or
[0126] (d) maintenance of or movement to a lower WHO functional
class.
[0127] For example, in one aspect the subject can experience
improvement in pulmonary function versus baseline. Any measure of
pulmonary function can be used; illustratively 6MWD is increased or
BDI is lowered.
[0128] In one such aspect, 6MWD is improved from baseline by at
least about 10 m, for example, at least about 20 m or at least
about 30 m. In many instances, the method of the present embodiment
will be found effective to increase 6MWD by as much as 50 m or even
more.
[0129] In another such aspect, BDI, illustratively as measured
following a 6MWT, is lowered from baseline by at least about 0.5
point. In many instances, the method of the present embodiment will
be found effective to lower BDI by as much as 1 full index point or
even more.
[0130] In another aspect, the subject can experience improvement in
quality of life, illustratively as measured by one or more of the
health parameters recorded in an SF-36.RTM. survey. For example, an
improvement versus baseline can be obtained in at least one of the
SF-36 physical health related parameters (physical health,
role-physical, bodily pain and/or general health) and/or in at
least one of the SF-35 mental health related parameters (vitality,
social functioning, role-emotional and/or mental health). Such an
improvement can take the form of an increase of at least 1, for
example at least 2 or at least 3 points, on the scale for any one
or more parameters.
[0131] In another aspect, the subject can experience maintenance or
improvement in WHO functional class.
[0132] In a third embodiment, a method is provided for prolonging
the life of a subject having a pulmonary hypertension condition,
comprising administering to the subject ambrisentan at a dose and
frequency and for a treatment period effective to increase life
expectancy, from a time of initiation of treatment, by at least
about 30 days, wherein, at baseline, time from first diagnosis of
the condition in the subject is not greater than about 2 years.
Variants and illustrative modalities of this method are as set
forth for the second embodiment above.
[0133] In a fourth embodiment, a method is provided for extending
time to clinical worsening in a subject having a pulmonary
hypertension condition, comprising administering to the subject
ambrisentan at a dose and frequency and for a treatment period
effective to decrease the probability of a clinical worsening event
by at least about 25%, wherein, at baseline, time from first
diagnosis of the condition in the subject is not greater than about
2 years. Variants and illustrative modalities of this method are as
set forth for the second embodiment above.
[0134] In any of the methods described hereinabove, the subject can
be male or female. For example, ambrisentan can be administered to
a female subject according to any of the above methods, including
the indicated variants and illustrative modalities thereof.
Alternatively, ambrisentan can be administered to a male subject,
for example a reproductively active male subject, according to any
of the above methods, including the indicated variants and
illustrative modalities thereof.
[0135] In a fifth embodiment, a method is provided for treating a
pulmonary hypertension condition in a reproductively active male
subject, the method comprising administering a therapeutically
effective amount of ambrisentan to the subject, wherein fertility
of the subject is not substantially compromised. "Not substantially
compromised" in the present context means that spermatogenesis is
not substantially reduced by the treatment and that no hormonal
changes are induced that are indicative of or associated with
reduced spermatogenesis. Male fertility can be assessed directly,
for example, by sperm counts from semen samples, or indirectly by
changes in hormones such as follicle stimulating hormone (FSH),
luteinizing hormone (LH), inhibin B and testosterone.
[0136] In accordance with the fifth embodiment of the invention,
administration of ambrisentan as described hereinabove, including
the indicated variants and illustrative modalities of such
administration, has generated no evidence of an adverse effect on
male fertility as directly or indirectly assessed.
[0137] In a sixth embodiment, a method is provided for treating PAH
in a subject, comprising administering a therapeutically effective
amount of ambrisentan to the subject, wherein the PAH is associated
with one or more of (a) a congenital heart defect, (b) portal
hypertension, (c) use of a drug or toxin other than an anorexigen,
(d) thyroid disorder, (e) glycogen storage disease, (f) Gaucher
disease, (g) hereditary hemorrhagic telangiectasia, (h)
hemoglobinopathy, (i) myeloproliferative disorder, (j) splenectomy,
(k) pulmonary veno-occlusive disease and/or (l) pulmonary capillary
hemangiomatosis. Variants and illustrative modalities of this
method are as set forth hereinabove.
[0138] In a seventh embodiment, a method is provided for treating a
pulmonary hypertension condition classified in WHO Groups 2-5 in a
subject, comprising administering a therapeutically effective
amount of ambrisentan to the subject. Variants and illustrative
modalities of this method are as set forth hereinabove.
[0139] In one aspect of the seventh embodiment, the condition
comprises left-sided atrial or ventricular heart disease and/or
left-sided valvular heart disease.
[0140] In another aspect of the seventh embodiment, the condition
is associated with one or more of chronic obstructive pulmonary
disease (COPD), interstitial lung disease (ILD), sleep-disordered
breathing, an alveolar hypoventilation disorder, chronic exposure
to high altitude, a developmental abnormality, thromboembolic
obstruction of proximal and/or distal pulmonary arteries, a
non-thrombotic pulmonary embolism, sarcoidosis, histiocytosis X,
lymphangiomatosis, and/or compression of pulmonary vessels.
[0141] In all the above embodiments of the invention, the
ambrisentan can be administered in monotherapy.
[0142] Alternatively, the ambrisentan can be administered in
combination therapy with a second active agent effective for the
treatment of the pulmonary hypertension condition or a condition
related thereto. When ambrisentan is administered concomitantly,
one of skill in the art can readily identify a suitable dose for
any particular second active agent from publicly available
information in printed or electronic form, for example on the
internet. Illustratively and without limitation, the ambrisentan
can be administered with a second active agent comprising at least
one drug selected from the group consisting of prostanoids,
phosphodiesterase inhibitors (especially phosphodiesterase-5 (PDE5)
inhibitors), endothelin receptor antagonists (ERAs) other than
ambrisentan, calcium channel blockers, diuretics, anticoagulants,
oxygen and combinations thereof.
[0143] Examples of drugs useful in combination therapy with
ambrisentan are classified and presented in several lists below.
Some drugs are active at more than one target; accordingly certain
drugs may appear in more than one list. Use of any listed drug in a
combination is contemplated herein, independently of its mode of
action.
[0144] A suitable prostanoid can be illustratively selected from
the following list:
[0145] beraprost
[0146] cicaprost
[0147] epoprostenol
[0148] iloprost
[0149] NS-304
[0150] PGE.sub.1
[0151] prostacyclin
[0152] treprostinil
[0153] A suitable PDE5 inhibitor can illustratively be selected
from the following list:
[0154] sildenafil
[0155] tadalafil
[0156] vardenafil
[0157] An ERA other than ambrisentan can illustratively be selected
from the following list:
[0158] atrasentan
[0159] BMS 193884
[0160] bosentan
[0161] CI-1020
[0162] darusentan
[0163] S-0139
[0164] SB-209670
[0165] sitaxsentan
[0166] TA-0201
[0167] tarasentan
[0168] TBC-3711
[0169] VML-588
[0170] ZD-1611
[0171] A suitable calcium channel blocker can illustratively be
selected from the following list:
[0172] Aryklalkylamines [0173] bepridil [0174] clentiazem [0175]
diltiazem [0176] fendiline [0177] gallopamil [0178] mibefradil
[0179] prenylamine [0180] semotiadil [0181] terodiline [0182]
verapamil
[0183] Dihydropyridine Derivatives [0184] amlodipine [0185]
aranidipine [0186] barnidipine [0187] benidipine [0188] cilnidipine
[0189] efonidipine [0190] elgodipine [0191] felodipine [0192]
isradipine [0193] lacidipine [0194] lercanidipine [0195] manidipine
[0196] nicardipine [0197] nifedipine [0198] nilvadipine [0199]
nimodipine [0200] nisoldipine [0201] nitrendipine [0202] NZ 105
[0203] Piperazine Derivatives [0204] cinnarizine [0205] dotarizine
[0206] flunarizine [0207] lidoflazine [0208] lomerizine
[0209] Unclassified [0210] bencyclane [0211] etafenone [0212]
fantofarone [0213] monatepil [0214] perhexyline
[0215] Particularly suitable calcium channel blockers include
amlodipine, diltiazem, felodipine, isradipine, nicardipine,
nifedipine, nisoldipine, verapamil and combinations thereof.
[0216] A suitable diuretic can illustratively be selected from the
following list:
[0217] Organomercurials [0218] chlormerodrin [0219] chlorothiazide
[0220] chlorthalidone [0221] meralluride [0222] mercaptomerin
sodium [0223] mercumatilin sodium [0224] mercurous chloride [0225]
mersalyl
[0226] Purines [0227] pamabrom [0228] protheobromine [0229]
theobromine
[0230] Steroids [0231] canrenone [0232] oleandrin [0233]
spironolactone
[0234] Sulfonamide Derivatives [0235] acetazolamide [0236] ambuside
[0237] azosemide [0238] bumetanide [0239] butazolamide [0240]
chloraminophenamide [0241] clofenamide [0242] clopamide [0243]
clorexolone [0244] disulfamide [0245] ethoxzolamide [0246]
furosemide [0247] mefruside [0248] methazolamide [0249] piretanide
[0250] torsemide [0251] tripamide [0252] xipamide
[0253] Thiazides and Analogs [0254] althiazide [0255]
bendroflumethiazide [0256] benzthiazide [0257]
benzylhydrochlorothiazide [0258] buthiazide [0259] chlorthalidone
[0260] cyclopenthiazide [0261] cyclothiazide [0262] ethiazide
[0263] fenquizone [0264] hydrochlorothiazide [0265]
hydroflumethiazide [0266] indapamide [0267] methyclothiazide [0268]
metolazone [0269] paraflutizide [0270] polythiazide [0271]
quinethazone [0272] teclothiazide [0273] trichlormethiazide
[0274] Uracils [0275] aminometradine
[0276] Unclassified [0277] amiloride [0278] Biogen BG 9719 [0279]
chlorazanil [0280] ethacrynic acid [0281] etozolin [0282]
isosorbide [0283] Kiowa Hakko KW 3902 [0284] mannitol [0285]
muzolimine [0286] perhexyline [0287] Sanofi-Aventis SR 121463
[0288] ticrynafen [0289] triamterene [0290] urea
[0291] In some embodiments, the diuretic if present comprises a
thiazide or loop diuretic. Thiazide diuretics are generally not
preferred where the patient has a complicating condition such as
diabetes or chronic kidney disease, and in such situations a loop
diuretic can be a better choice.
[0292] Particularly suitable thiazide diuretics include
chlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide,
metolazone, polythiazide and combinations thereof. Particularly
suitable loop diuretics include bumetanide, furosemide, torsemide
and combinations thereof.
[0293] A suitable anticoagulant can illustratively be selected from
the following list:
[0294] acenocoumarol
[0295] ancrod
[0296] anisindione
[0297] bromindione
[0298] clorindione
[0299] coumetarol
[0300] cyclocumarol
[0301] dextran sulfate sodium
[0302] dicumarol
[0303] diphenadione
[0304] ethyl biscoumacetate
[0305] ethylidene dicoumarol
[0306] fluindione
[0307] heparin
[0308] hirudin
[0309] lyapolate sodium
[0310] pentosan polysulfate
[0311] phenindione
[0312] phenprocoumon
[0313] phosvitin
[0314] picotamide
[0315] tioclomarol
[0316] warfarin
[0317] Where the pulmonary hypertension condition is associated
with an underlying disease (for example CTD, HIV infection, COPD or
ILD), ambrisentan can optionally be administered in combination
therapy with one or more drugs targeting the underlying
condition.
[0318] When ambrisentan is used in combination therapy with one or
more drugs, the ambrisentan and at least one drug can be
administered at different times or at about the same time (at
exactly the same time or directly one after the other in any
order). The ambrisentan and the second active drug can be
formulated in one dosage form as a fixed-dose combination for
administration at the same time, or in two or more separate dosage
forms for administration at the same or different times.
[0319] Separate dosage forms can optionally be co-packaged, for
example in a single container or in a plurality of containers
within a single outer package, or co-presented in separate
packaging ("common presentation"). As an example of co-packaging or
common presentation, a kit is contemplated comprising, in separate
containers, ambrisentan and at least one drug useful in combination
with the ambrisentan. In another example, the ambrisentan and the
at least one drug useful in combination therapy with the
ambrisentan are separately packaged and available for sale
independently of one another, but are co-marketed or co-promoted
for use according to the invention. The separate dosage forms can
also be presented to a patient separately and independently, for
use according to the invention.
[0320] Typically at least the ambrisentan is provided in an orally
deliverable formulation, for example a formulation adapted for oral
delivery of a ambrisentan dose of about 1 to about 600 mg/day,
e.g., about 10 to about 300 mg/day. The ambrisentan formulation can
be adapted for any suitable frequency of administration, but in one
embodiment is adapted for once a day oral administration.
[0321] In one embodiment at least one of the drugs other than
ambrisentan in the combination is provided in an orally deliverable
formulation; for example, each of the drugs can be so provided, and
each of the drugs can be in a formulation adapted for once a day
oral administration. Each of the drugs other than ambrisentan is
typically present in the combination in an amount providing an
adequate to full dose of the drug. One of skill in the art can
readily identify a suitable dose for any particular drug from
publicly available information in printed or electronic form, for
example on the internet.
[0322] Any two or more drugs in the combination can optionally be
coformulated to provide a fixed dose combination. For example, the
ambrisentan can be coformulated with any one or more of the other
drugs in the combination.
[0323] Mention of a particular drug or second active agent in the
present specification and claims will be understood, except where
the context demands otherwise, to include pharmaceutically
acceptable salts, esters, prodrugs, metabolites, racemates and
enantiomers of the drug, to the extent that such salts, esters,
prodrugs, metabolites, racemates or enantiomers exist and are
therapeutically effective.
EXAMPLES
[0324] The following examples are merely illustrative, and do not
limit this disclosure in any way. Reference is made in the examples
to statistical analysis and statistical significance of results.
Such reference is made in the interest of full disclosure and does
not constitute admission that statistical significance is a
prerequisite for patentability of any claim herein. Reference is
also made to "primary" and "secondary" endpoints or objectives of
particular clinical trials. These endpoints or objectives should
not necessarily be considered "primary" or "secondary" with respect
to the present invention.
[0325] Examples 1 and 2 relate to Phase III clinical trials known
as ARIES-2 and ARIES-1, respectively. Certain results and other
information relating to these trials have been mentioned in the
following news releases and presented at various conferences as
announced in some of these news releases. Each of the documents
individually cited immediately below is incorporated by reference
in its entirety herein without admission that any such document
represents prior art to the present invention.
[0326] Myogen, Inc. News Release, Dec. 12, 2005
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
794738&highlight=).
[0327] Myogen, Inc. News Release, Feb. 13, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
815989&highlight=).
[0328] Myogen, Inc. News Release, Mar. 2, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
824548&highlight=) and ATS May 19-24, 2006 presentation
announced therein.
[0329] Myogen, Inc. News Release, Apr. 10, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
840536&highlight=).
[0330] Myogen, Inc. News Release, May 3, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
851641&highlight=).
[0331] Myogen, Inc. News Release, May 8, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
853198&highlight=).
[0332] Myogen, Inc. News Release, May 24, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
860158&highlight=) and ATS 2006 presentation by Olschewski
announced therein.
[0333] Myogen, Inc. News Release, Aug. 7, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
892987&highlight=).
[0334] Myogen, Inc. News Release, Sep. 5, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
902050&highlight=) and World Congress of Cardiology (Sep. 2-6,
2006, Barcelona, Spain) presentation by Galie announced therein;
also abstract of Galie presentation at
http://cic.escardio.org/AbstractDetails.aspx?id=41830&eevtid=15.
[0335] Myogen, Inc. News Release, Oct. 10, 2006
(http://investor.myogen.com/phoenix.zhtml?c=135160&p=irol-newsArticle&ID=-
913787&highlight=) and CHEST 2006 presentation by Oudiz
announced therein.
[0336] Myogen June 2006 presentation available at
library.corporate-ir.net/library/13/135/135160/items/203236/Junepresentat-
ion.pdf.
Example 1
Summary
[0337] The primary objective of this study was to determine the
effect of ambrisentan on exercise capacity in subjects with PAH.
The secondary objectives of this study were to evaluate effects of
ambrisentan on other clinical measures of PAH, as well as safety
and tolerability of the study drug.
[0338] Study drug was provided in round, biconvex, oral tablets
that were identical in appearance. Three strengths of active study
drug, containing 1 mg, 2.5 mg or 5 mg of ambrisentan, were used in
this study. All study drug was packaged in blister cards. Subjects
were instructed to take study drug once daily (q.d.) by mouth
(p.o.) in the morning, with or without food.
[0339] The maximum study duration was up to 14 weeks from the time
of initial screening procedures to the final study visit (Week 12).
Screening procedures were performed a maximum of 2 weeks prior to
the first dose of study drug. The maximum duration of study drug
treatment was 12 weeks.
[0340] Placebo was indistinguishable from active treatment.
Methods Example 1
Patients
[0341] The number of subjects enrolled was 192 at 41 investigative
sites.
[0342] Men and women, 18 years of age or older, with idiopathic
PAH, PAH associated with connective tissue disease (CTD), e.g.,
mixed CTD, CREST syndrome, systemic sclerosis (scleroderma),
overlap syndrome or systemic lupus erythematosus, or PAH associated
with anorexigen use or HIV infection were enrolled in this study.
Subjects were to have a documented mean PAP .gtoreq.25 mmHg, PVR
>3 mmHg/L/min, and PCWP or LVEDP <15 mmHg. Subjects must have
been able to walk a distance of at least 150 m but no more than 450
m during 2 consecutive 6MWTs to be eligible for inclusion in the
study.
Study Design and Treatment
[0343] After a 2 week screening period, eligible subjects were
stratified based on the underlying etiology of PAH (idiopathic or
non-idiopathic) and were randomized to 1 of 3 treatment groups
(placebo, 2.5 mg or 5 mg ambrisentan) in a ratio of 1:1:1. One
blinded dose reduction was permitted during the 12-week treatment
period in the event of study drug intolerance (e.g., 5 mg to 2.5
mg, 2.5 mg to 1 mg, placebo to placebo). Subjects received a daily
dose of 1 mg ambrisentan only if they reduced from the 2.5 mg dose
group. Subjects were assessed for efficacy and safety at monthly
intervals.
[0344] Due to the placebo-controlled design of this study, there
was a 1 in 3 chance that a subject did not receive ambrisentan for
a period of 12 weeks. Therefore, after a minimum treatment period
of 4 weeks, subjects who met 2 or more of the following predefined
early escape criteria may have been removed from the study: [0345]
(a) a decrease from baseline of at least 20% in 6MWD; [0346] (b) an
increase of 1 or more WHO functional class; [0347] (c) worsening
right ventricular failure (e.g., as indicated by increased jugular
venous pressure, new or worsening hepatomegaly, ascites or
peripheral edema); [0348] (d) rapidly progressing cardiogenic,
hepatic or renal failure; and/or [0349] (e) refractory systolic
hypotension (systolic blood pressure <85 mmHg).
[0350] Subjects receiving placebo who were removed from the study
due to 2 or more early escape criteria were eligible to enter a
long-term extension study, and receive active treatment with
ambrisentan.
[0351] Serum levels of alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, gamma-glutamyl
transpeptidase (GGT) and total bilirubin were closely monitored in
all subjects throughout the study. Female subjects of childbearing
potential were required to undergo monthly pregnancy tests and to
use a double method of contraception to reduce risk of pregnancy
during the course of the study. Male subjects were required to
undergo complete semen and hormone analyses to evaluate potential
effects of ambrisentan on male fertility.
[0352] After completion of the 12-week study, subjects were
eligible to enroll into the long-term extension study.
Efficacy Assessments
[0353] The primary efficacy endpoint was change from baseline in
6MWD evaluated after 12 weeks of treatment compared to placebo.
[0354] The secondary efficacy endpoints included: [0355] (a) time
to clinical worsening of PAH, as defined by the time from
randomization to the first occurrence of death, lung
transplantation, hospitalization for PAH, atrial septostomy, study
discontinuation due to addition of other PAH therapeutic agents, or
study discontinuation due to 2 or more early escape criteria;
[0356] (b) change from baseline measured after 12 weeks of
treatment compared to placebo in: [0357] (i) WHO functional class;
[0358] (ii) SF-36.RTM. health survey physical functioning scale;
[0359] (iii) BDI immediately following exercise; and/or [0360] (iv)
an assessment of the safety and tolerability of the study drug; and
[0361] (c) change from baseline measured after 12 weeks of
treatment compared to placebo in plasma levels of ET-1, cTnT and
BNP.
Safety Assessments
[0362] All adverse effects (AEs) reported during the course of the
study were reported and summaries of all AEs were prepared showing
frequencies and percentages of: [0363] (a) subjects with at least 1
AE; [0364] (b) subjects with possibly or probably drug-related AEs;
[0365] (c) subjects with at least 1 serious AE (SAE); [0366] (d)
subjects with an AE leading to study discontinuation; and [0367]
(e) subjects who died.
[0368] Liver function test (LFT) assessments were separately
summarized by severity relative to the upper limit of normal (ULN)
for ALT, AST, alkaline phosphatase and total bilirubin.
[0369] For subjects who were on anticoagulants at any point during
the study (regular visit or between visits), coagulation tests
(prothrombin time (PT), partial thromboplastin time (PTT) and
international normalized ratio (INR)) were completed. In addition
to summary statistics by study visit, changes in PT and INR were
examined relative to changes in warfarin-type anticoagulant dose.
These analyses focused on the values at Week 0 and Week 12 and the
percentage change from Week 0 to Week 12.
[0370] The results of semen samples and their normality or
abnormality were assessed by an independent male fertility expert
and summarized through frequency counts and percentages by
treatment. Descriptive statistics for male hormone data were
prepared by treatment for the Week 0 and Week 12 visits when data
were collected. Change from Week 0 to Week 12 was determined. The
male fertility hormone results were analyzed in combination with
the semen sample results by a second independent male fertility
expert.
[0371] Frequency counts and percentages were used to summarize
frequency of normal, abnormal but not clinically significant, and
abnormal and clinically significant electrocardiogram (ECG) results
for each scheduled assessment time by treatment. All ECG data were
digitally recorded and analyzed by a central reader. The following
variables were analyzed: heart rate, RR and PR intervals, QRS
duration, QT interval, QTcB, QTcF and ECG diagnostic variables.
Descriptive statistics were used to summarize ECG results by
treatment group and by week of ECG assessment.
[0372] Descriptive statistics for vital signs were reported for
each scheduled assessment time by treatment and for the change from
pre-dose Week 0 to each subsequent scheduled assessment by
treatment.
Statistical Methods
[0373] A test of the null hypothesis of no treatment group
difference in change from baseline in 6MWD with 62 subjects per
group had approximately 90% power to detect an average
placebo-adjusted treatment effect of 35 m based on a 2-sample
t-test and a standard deviation of 55 m.
[0374] The intention-to-treat (ITT) population was defined as all
randomized subjects who received at least 1 dose of study drug. For
the ITT population, subjects were considered as belonging to their
randomized treatment group, regardless of the actual treatment
received.
[0375] The safety population was defined as all randomized subjects
who received at least 1 dose of study drug. Subjects were
considered as belonging to a treatment group according to the
highest actual treatment dose received. Any subject who received 5
mg ambrisentan on any day was included in the 5 mg group for safety
analyses in the entire study. Any subject who received 2.5 mg
ambrisentan on any day and never received 5 mg ambrisentan on any
day was included in the 2.5 mg group for safety analyses in the
entire study. Otherwise, any subject who received only placebo was
included in the placebo group for safety analyses in the study.
[0376] The primary efficacy endpoint was the change from baseline
in 6MWD evaluated after 12 weeks of treatment compared to placebo,
where the last observation was carried forward. Baseline 6MWD was
defined as the mean 6MWD of the last two 6MWTs prior to
randomization.
[0377] Change from baseline for Weeks 4, 8 and 12 in each of the
two ambrisentan treatment groups were compared to placebo. The mean
change was reported with 2-sided 95% confidence intervals (CIs)
calculated by normal theory. The primary comparison was the change
from baseline to Week 12. The Wilcoxon rank sum test stratified by
idiopathic and non-idiopathic PAH subjects was used for inference.
A fixed sequence approach was used to control the type I error rate
accounting for the two comparisons. The higher dose was first
compared to placebo. Because the p-value from the Wilcoxon ranlc
sum test was less than 0.05 for the 5 mg ambrisentan group, the
difference was considered significant, and the lower dose was
compared to placebo, again at the full 0.05 .alpha.-level.
[0378] The two ambrisentan dose groups were also combined and
compared to the placebo group. A p-value was reported, but for
descriptive purposes only, with no impact on the fixed sequence
procedure used for comparing the two individual dose groups to the
placebo group.
[0379] If both ambrisentan dose groups were superior to placebo for
the primary endpoint, evaluation of the secondary endpoints was
done by combining the subjects from the two dose groups for
comparison to the placebo group. However, if only the 5 mg group
was significant for the primary endpoint, evaluation of the
secondary endpoints was done only for that dose group. Secondary
endpoint analyses were stratified by idiopathic and non-idiopathic
PAH subjects.
[0380] The two most important secondary endpoints, time to clinical
worsening of PAH and change in WHO functional class, were compared
to placebo using a weighted version of Hommel's extension of the
Simes test, with an overall .alpha. of 0.05. Time to clinical
worsening was assigned a weight of 80% while change in WHO
functional class received 20% of the weight. These two tests served
as a gatekeeper, allowing the physical functioning scale of the
SF-36.RTM. health survey to be tested if at least one of the first
two secondary endpoints was significant. Lastly, the BDI was tested
conditional on a significant result from the test of the SF-36.RTM.
physical functioning scale.
[0381] Analyses of ET-1, cTnT, and BNP plasma levels were performed
both for change from baseline (treatment effect) and baseline
impact on efficacy. Descriptive statistics were presented for the
change from pre-dose Week 0 to Week 12 by treatment.
Results Example 1
Patients Study Population
[0382] Disposition of randomized subjects is shown in Table
1.1.
TABLE-US-00001 TABLE 1.1 Subject disposition (% of randomized
subjects) 2.5 mg 5 mg Combined Placebo ambrisentan ambrisentan
ambrisentan (N = 65) (N = 64) (N = 63) (N = 127) Randomized 65
(100.0) 64 (100.0) 63 (100.0) 127 (100.0) Completed 54 (83.1) 58
(90.6) 58 (92.1) 116 (91.3) Withdrew 11 (16.9) 6 (9.4) 5 (7.9) 11
(8.7) Reasons for withdrawal: Adverse 3 (4.6) 1 (1.6) 3 (4.8) 4
(3.1) event Clinical 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) status did not
improve or deteriorated Withdrawal 0 (0.0) 3 (4.7) 1 (1.6) 4 (3.1)
of consent Early escape 7 (10.8) 2 (3.1) 1 (1.6) 3 (2.4)
[0383] A total of 192 subjects, with a mean age of 50.9 years,
received at least 1 dose of study drug and were included in the ITT
and safety populations. A majority of the subjects enrolled were
female (74.5%) and Caucasian (84.9%). Approximately half (51.6%) of
the subjects were residents of western Europe or Israel. The
remainder of subjects was evenly distributed throughout eastern
Europe (24.0%) and South America (24.5%).
[0384] The number of years that PAH was present prior to
participation in the study was calculated from the date that PAH
was diagnosed until the date that informed consent was signed. For
subjects who had a diagnosis of PAH confirmed at the screening
visit for this study, the number of years of PAH present prior to
this study was set to zero. The mean number of years that PAH was
present prior to participation in this study was similar for the
placebo (2.3.+-.4.22 years) and 5 mg (2.9.+-.6.10 years) groups but
longer than that of the 2.5 mg (1.2.+-.1.93 years) group. The
median number of years that PAH was present was less than 1 year
for each treatment group: placebo, 0.38 years; 2.5 mg, 0.43 years;
5 mg, 0.26 years.
[0385] Of the subjects enrolled, 65% had a diagnosis of idiopathic
PAH prior to enrollment, and 35% had PAH associated with CTD,
anorexigen use or HIV infection (collectively designated
non-idiopathic PAH herein); idiopathic and non-idiopathic PAH
subjects were equally distributed between the treatment groups.
Nearly all of the subjects had either WHO functional class II
(44.8%) or class III (51.6%) symptoms. The mean (.+-.standard
deviation (SD)) baseline 6MWD for all subjects was 348.4.+-.84.46
m.
[0386] In general, demographic and baseline characteristics of the
subjects participating were well balanced between the treatment
groups. There was a difference in baseline 6MWD between subjects
with WHO functional class II and WHO class III symptoms for both
the placebo and combined ambrisentan groups: class II, 372.0 m and
379.1 m and class III, 330.2 m and 328.2 m, respectively.
[0387] The most frequently used concomitant medications were
furosemide (37.0%), acenocoumarol (28.6%) and spironolactone
(25.0%). There did not appear to be any differences in concomitant
medication use across the treatment groups.
Efficacy of Ambrisentan
[0388] Change in 6MWD from baseline to Week 12 in the ITT
population is shown in Table 1.2.
TABLE-US-00002 TABLE 1.2 Change in 6MWD, meters 2.5 mg 5 mg
Combined Placebo ambrisentan ambrisentan ambrisentan Baseline 6MWD,
342.7 347.3 355.3 351.3 mean (SD) (85.93) (83.81) (84.45) (83.89)
Week 12 6MWD, 332.6 369.6 404.7 387.0 mean (SD) (130.42) (128.31)
(99.45) (115.80) Change from -10.1 +22.2 +49.4 +35.7 baseline to
(93.79) (82.67) (75.36) (79.99) Week 12, mean (SD)
[0389] The primary efficacy endpoint was statistically significant
for both doses of ambrisentan compared to placebo. The
placebo-adjusted improvement in mean 6MWD at Week 12 was +59.4 m
(95% CI: +29.6 to +89.3 m; p <0.001) for the 5 mg group and
+32.3 m (95% CI: +1.5 to +63.1 m; p=0.022) for the 2.5 mg group.
For subjects in the placebo group, mean 6MWD showed a decrease from
baseline (-10.1 m). For subjects receiving ambrisentan, improvement
in 6MWD compared to placebo was observed as early as Week 8, and by
Week 12 there was evidence of a dose response.
[0390] The key secondary endpoint of time to clinical worsening of
PAH demonstrated that ambrisentan (combined ambrisentan group)
significantly delayed the time to clinical worsening of PAH
compared to placebo (p <0.001). In the placebo group, 21.5% of
subjects experienced an event of clinical worsening compared to
4.7% and 4.8% of subjects in the 2.5 mg and 5 mg dose groups,
respectively. Furthermore, the hazard ratio demonstrated an 80%
reduction in the probability of clinical worsening occurring at any
given time for a subject receiving ambrisentan, when compared to
placebo.
[0391] The time to clinical worsening of PAH is displayed in FIG. 1
as a Kaplan-Meier event-free curve through Week 12 for each
treatment group in the ITT population.
[0392] A summary of events defining clinical worsening by treatment
group is presented in Table 1.3.
TABLE-US-00003 TABLE 1.3 Clinical worsening events (% of ITT
population) 2.5 mg 5 mg Combined Placebo ambrisentan ambrisentan
ambrisentan Event (N = 65) (N = 64) (N = 63) (N = 127) Death 3
(4.6) 2 (3.1) 0 (0.0) 2 (1.6) Lung trans- 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) plantation Hospitaliza- 9 (13.8) 3 (4.7) 2 (3.2) 5 (3.9) tion
for PAH Atrial 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) septostomy Study
with- 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) drawal due to addition of PAH
treatment Escape criteria 7 (10.8) 2 (3.1) 1 (1.6) 3 (2.4) Total
subjects 14 (21.5) 3 (4.7) 3 (4.8) 6 (4.7) with .gtoreq.1 event
[0393] Of the 9 (13.8%) subjects in the placebo group hospitalized
for PAH, 5 were hospitalized for right heart failure or worsening
right heart failure. Comparatively, 5 (3.9%) subjects receiving
ambrisentan were hospitalized for PAH, of whom 1 (in the 5 mg dose
group) was hospitalized for worsening right heart failure.
[0394] There were a total of 6 deaths reported during this study or
within 30 days of the last dose of study drug. In the placebo
group, 4 (6.2%) subjects died, and 2 (3.1%) subjects in the 2.5 mg
dose group died. No subjects receiving 5 mg ambrisentan died during
the 12-week study. Five of the 6 deaths were captured as clinical
worsening events; 3 (4.6%) placebo subjects and 2 (3.1%) subjects
receiving 2.5 mg ambrisentan died prior to completion of the
12-week treatment period. The sixth subject who dies was in the
placebo group. This subject was hospitalized for clinical worsening
of PAH, and the date of hospitalization was captured as the date of
clinical worsening for this subject. The subject discontinued the
study via the early escape procedure and subsequently died.
[0395] Change in WHO functional class from baseline to Week 12 in
the ITT population is shown in Table 1.4.
TABLE-US-00004 TABLE 1.4 Change in WHO functional class (% of ITT
population) 2.5 mg 5 mg Combined Change (no. Placebo ambrisentan
ambrisentan ambrisentan of classes) (N = 65) (N = 64) (N = 63) (N =
127) -2 0 (0.0) 0 (0.0) 1 (1.6) 1 (0.8) -1 11 (16.9) 10 (15.6) 8
(12.7) 18 (14.2) no change 42 (64.6) 51 (79.7) 52 (82.5) 103 (81.1)
+1 10 (15.4) 2 (3.1) 2 (3.2) 4 (3.1) +2 2 (3.1) 1 (1.6) 0 (0.0) 1
(0.8)
[0396] A statistically significant difference between treatment
groups in the change in WHO functional class was not observed at
Week 12. However, a more than 4-fold greater percentage of subjects
in the placebo group (18.5%) deteriorated by at least 1 WHO class
compared to subjects in the combined ambrisentan group (3.9%).
[0397] The percentage of subjects at least maintaining their
baseline WHO functional class at Week 12 was 81.5% in the placebo
group, 95.3% in the 2.5 mg dose group and 96.8% in the 5 mg dose
group.
[0398] Change in SF-36.RTM. health survey parameters from baseline
to Week 12 is shown in Table 1.5.
TABLE-US-00005 TABLE 1.5 Change in SF-36 .RTM. health survey
parameters, mean (SD) 2.5 mg 5 mg Combined Parameter Placebo
ambrisentan ambrisentan ambrisentan Physical functioning -0.20
(7.14) +3.86 (7.14) +2.96 (6.81) +3.41 (6.96) Role-physical -0.15
(10.04) +5.87 (11.72) +7.61 (10.41) +6.74 (11.07) Bodily pain -0.24
(12.02) +2.34 (11.87) +0.46 (9.99) +1.40 (10.96) General health
+1.37 (6.24) +3.84 (6.71) +4.95 (8.05) +4.40 (7.40) Vitality -0.01
(9.11) +4.07 (9.12) +5.21 (8.79) +4.64 (8.94) Social functioning
+2.45 (10.54) +4.55 (9.72) +4.85 (11.89) +4.70 (10.81)
Role-emotional -1.58 (14.25) +3.11 (12.90) +8.15 (14.43) +5.63
(13.86) Mental health +2.53 (10.79) +4.98 (9.70) +4.03 (10.13)
+4.50 (9.88) Physical component summary -0.15 (7.29) +3.78 (7.63)
+2.97 (7.79) +3.38 (7.69) Mental component summary +1.27 (11.29)
+4.05 (10.30) +6.28 (11.64) +5.17 (11.00)
[0399] A statistically significant increase was observed for the
combined ambrisentan group (3.41.+-.6.96) in the physical
functioning scale of the SF-36.RTM. health survey compared to
placebo (-0.20.+-.8.14, p=0.005). Improvements in the physical
functioning scale were also demonstrated for both the 2.5 mg and 5
mg dose groups compared to placebo. Furthermore, increases were
observed in several other SF-36.RTM. scales including
role-physical, general health, vitality and role-emotional
scales.
[0400] A statistically significant improvement in BDI was observed
at Week 12 for the combined ambrisentan group, with a
placebo-adjusted BDI of -1.1 (95% CI: -1.8 to -0.4; p=0.019).
Improvements in BDI were observed for both the 2.5 mg and 5 mg dose
groups compared to placebo. For subjects in the placebo group, mean
BDI increased (worsened) from baseline by +0.82. In contrast, in
the 2.5 mg and 5 mg ambrisentan dose groups mean BDI decreased
(improved) from baseline (-0.20 and -0.36, respectively).
[0401] At Week 12, the geometric mean percent change in plasma ET-1
decreased by 4% (95% CI: 0.68 to 1.36) in the placebo group;
whereas the geometric mean percent change in plasma ET-1 increased
from baseline by 19% (95% CI: -12% to 61%; p=0.193 versus placebo)
in the 2.5 mg group and by 72% (95% CI: 32% to 125%; p=0.004 versus
placebo) in the 5 mg group. The change from baseline was
substantially greater than placebo for the 5 mg group, but not for
the 2.5 mg group.
[0402] At baseline, approximately 90% of plasma cTnT concentrations
were below the level of quantification (0.01 ng/ml). Changes in
cTnT concentrations during the 12-week study were minor and not
remarkably different from zero.
[0403] At Week 12, the geometric mean percent change plasma BNP
increased by 13% (95% CI: -6% to 36%) in the placebo group. In
contrast, the geometric mean plasma BNP decreased from baseline by
29% (95% CI: -44% to -9%; p=0.002 versus placebo) in the 2.5 mg
group and by 30% (95% CI: -47% to -9%; p=0.002 versus placebo) in
the 5 mg group. The decrease from baseline was substantially
greater than placebo for the 2.5 mg group and the 5 mg group.
Efficacy by Subgroup
[0404] Improvements in 6MWD were observed for both WHO functional
class I/II and WHO functional class III/IV subjects at Week 12. For
the class I/II subgroup, the placebo-adjusted 6MWD increase from
baseline at Week 12 was +44.1 m and +67.7 m for the 2.5 mg and 5 mg
dose groups, respectively. For the class III/IV subgroup, the
placebo-adjusted 6MWD increase from baseline at Week 12 was +17.6 m
and +51.8 m for the 2.5 mg and 5 mg dose groups, respectively.
[0405] Improvements in 6MWD at Week 12 were observed in both
ambrisentan dose groups for the idiopathic PAH subgroup and in the
5 mg dose group for the non-idiopathic PAH subgroup. For the
idiopathic PAH subgroup, the placebo-adjusted 6MWD increase from
baseline at Week 12 was +56.3 m and +75.7 m for the 2.5 mg and 5 mg
dose groups, respectively. For the non-idiopathic PAH subgroup, the
placebo-adjusted 6MWD change from baseline at Week 12 was -12.6 m
and +29.5 m for the 2.5 mg and 5 mg dose groups, respectively.
[0406] Improvements in 6MWD at Week 12 were observed in both
ambrisentan dose groups for the female subjects. For female
subjects, the placebo-adjusted 6MWD increase from baseline at Week
12 was +42.5 m and +75.7 m for the 2.5 mg and 5 mg dose groups,
respectively. For male subjects, the placebo-adjusted 6MWD change
from baseline at Week 12 was +6.8 m and +2.7 m for the 2.5 mg and 5
mg dose groups, respectively.
[0407] Improvements in 6MWD at Week 12 were observed in both
ambrisentan dose groups for the eastern European and South American
populations and in the 5 mg dose group for the western
European/Israel population. For the eastern European subgroup, the
placebo-adjusted 6MWD increase from baseline at Week 12 was +66.1
and +88.0 m for the 2.5 mg and 5 mg dose groups respectively. For
the South American subgroup, the placebo-adjusted 6MWD increase
from baseline at Week 12 was +50.5 and +79.5 m for the 2.5 mg and 5
mg dose groups respectively. For the western European/Israel
subgroup, the placebo-adjusted 6MWD increase from baseline at Week
12 was +3.0 and +39.4 m for the 2.5 mg and 5 mg dose groups,
respectively.
Safety Results
[0408] A summary of adverse events recorded is shown in Table
1.6.
TABLE-US-00006 TABLE 1.6 Global summary of adverse events (% of
safety population) 2.5 mg 5 mg Combined Placebo ambrisentan
ambrisentan ambrisentan Subjects (N = 65) (N = 64) (N = 63) (N =
127) with at least 52 (80.0) 47 (73.4) 46 (73.0) 93 (73.2) 1 AE
with at least 22 (33.8) 19 (29.7) 21 (33.3) 40 (31.5) 1 related AE
with at least 15 (23.1) 8 (12.5) 6 (9.5) 14 (11.0) 1 SAE with an AE
6 (9.2) 3 (4.7) 4 (6.3) 7 (5.5) leading to study dis- continuation
who discon- 7 (10.8) 2 (3.1) 1 (1.6) 3 (2.4) tinued the study via
early escape who died 4 (6.2) 2 (3.1) 0 (0.0) 2 (1.6)
[0409] During this 12-week study, 80.0% of the subjects in the
placebo group experienced at least 1 AE. Similarly, 73.4% of
subjects in the 2.5 mg dose group and 73.0% of subjects in the 5 mg
dose group experienced at least 1 AE during the study.
[0410] Overall, more subjects in the placebo group compared to the
ambrisentan groups prematurely discontinued from the study due to
death, SAEs, AEs, and/or the early escape procedure.
[0411] In general, more AEs were assessed as moderate and severe in
the placebo group (43.1% and 18.5%, respectively) compared to the
combined ambrisentan group (26.8% and 7.9%, respectively).
[0412] None of the 127 subjects who received ambrisentan developed
any elevated serum aminotransferase concentrations
>3.0.times.ULN, compared to 1 subject in the placebo group, and
there were no notable mean changes from baseline at Week 12 for
serum ALT and AST, and no differences between treatment groups.
Furthermore, there was a notable decrease in mean total bilirubin
and mean alkaline phosphatase that appeared to be
dose-dependent.
[0413] Mean uric acid increased at Week 12 in the placebo group
(+34.1 .mu.mol/l); whereas there was a substantial mean decrease in
uric acid (-19.1 .mu.mol/l) in the combined ambrisentan group.
[0414] The analysis of male fertility hormones in combination with
a limited number of subjects (n=6) providing serial semen samples
did not suggest that ambrisentan was associated with an adverse
effect on male reproductive potential.
[0415] More specifically, changes over baseline in follicle
stimulating hormone (FSH) concentration at Week 12 were small,
ranging from -0.25 IU/liter (placebo group) to +0.58 IU/liter (2.5
mg dose group). Although the baseline FSH concentrations for the
placebo and 5 mg dose groups (7.6.+-.8.34 IU/liter and 7.6.+-.5.69
IU/liter, respectively) suggest possibility of some spermatogenic
dysfunction prior to the first dose of study drug, the changes
observed during the study were unlikely to be of substantial
clinical relevance.
[0416] Minor increases in luteinizing hormone (LH) concentration,
ranging from 0.16 to 0.58 IU/liter, were observed in all treatment
groups, with no apparent difference between groups.
[0417] Increases from baseline in mean inhibin B concentration at
Week 12 were observed for the placebo group (139.6.+-.95.34 pg/ml)
and the 5 mg dose group (131.2.+-.98.77 pg/ml), but a decrease was
observed in the 2.5 mg dose group (-43.2.+-.36.52 pg/ml).
Therefore, changes in inhibin B were not dose-dependent. Based on
expert opinion, none of the mean inhibin B concentrations measured
at baseline and Week 12 indicated presence or development of
spermatogenic dysfunction.
[0418] Subjects in the placebo group had a minor increase
(0.66.+-.3.904 nmol/l) in testosterone concentration over the
12-week study; however, testosterone concentrations decreased in an
apparently dose-dependent manner in subjects receiving ambrisentan
(2.5 mg, -0.09.+-.4.595 nmol/l; 5 mg, -2.61.+-.6.962 nmol/l. The
data were variable and the median values indicated little change.
Furthermore, the Week 12 data did not represent a decrease below
the lower range of normal (10.41 nmol/l).
Discussion Example 1
[0419] The ambrisentan treatment benefit observed by the primary
and secondary endpoints of this study was robust, internally
consistent, and clinically relevant.
[0420] Both doses demonstrated a statistically significant and
clinically relevant improvement in 6MWD that was associated with a
significant decrease in BDI. The improvement in 6MWD was nearly
twice as large in the 5 mg dose group compared to the 2.5 mg dose
group, and improvements in 6MWD were consistently dose-responsive
for most subgroups evaluated. Furthermore, plasma BNP, a molecular
marker that has been shown to decrease in patients with PAH who
demonstrate improvements in 6MWD or hemodynamics, was substantially
reduced with ambrisentan treatment. Ultimately, these symptomatic
improvements resulted in a patient's self-assessment of an overall
better quality of life, as measured by statistically significant
improvements in several scales of the SF-36.RTM. health survey.
[0421] In addition to the symptomatic improvements observed for
exercise capacity and dyspnea, there was a more than 4-fold greater
percentage of subjects in the placebo group who deteriorated by at
least 1 WHO class compared to subjects in the ambrisentan groups.
Furthermore, there was a significant decrease in disease
progression for subjects receiving ambrisentan compared to placebo
as measured by the time to clinical worsening endpoint. This was
associated with an 80% decrease in the risk of clinical worsening
over the 12-week study for the ambrisentan group compared to
placebo. The delay in disease progression was also apparent by the
lower number of subjects in the ambrisentan treatment groups
compared to placebo for each of the following safety categories:
death, SAEs, AEs leading to discontinuation and early escapes.
Finally, the most frequent AE observed in this study was right
ventricular failure, an indicator of disease progression, which was
reported in more than 3 times the percentage of subjects in the
placebo group compared to the combined ambrisentan treatment
group.
[0422] In general, ambrisentan was well tolerated, as demonstrated
by the lack of dose reduction and AEs leading to discontinuation.
The most frequent AEs of clinical concern observed for subjects
receiving ambrisentan were headache and palpitations. For the most
part, these events were mild in severity and did not lead to study
discontinuation. Peripheral edema, which has been reported
frequently with other ERAs was observed at a similar or lower
frequency in the ambrisentan groups compared to placebo. None of
the 127 subjects that received ambrisentan developed elevated serum
aminotransferase concentrations >3.times.ULN, and there were no
increases in mean ALT or AST concentrations for either ambrisentan
dose group. Furthermore, there appeared to be a dose-dependent
decrease in mean total bilirubin and mean alkaline phosphatase.
Decreases in hemoglobin concentration were observed early in the
study and did not decrease further with continued treatment.
[0423] In conclusion, the treatment benefits observed for the
primary and secondary endpoints of this study were robust,
internally consistent, and clinically relevant. Ambrisentan was
well tolerated, was associated with a manageable safety profile,
and delayed disease progression, indicating a positive
risk-to-benefit profile.
Example 2
Summary
[0424] The primary objective of this study was to determine the
effect of ambrisentan on exercise capacity in subjects with
pulmonary arterial hypertension (PAH). The secondary objectives of
this study were to evaluate effects of ambrisentan on other
clinical measures of PAH, as well as safety and tolerability of the
study drug.
[0425] Study drug was provided in round, biconvex, oral tablets
that were identical in appearance. Three strengths of active study
drug containing 2.5 mg, 5 mg or 10 mg of ambrisentan were used in
this study. All study drug was packaged in blister cards. Subjects
were instructed to take study drug once daily (q.d.) by mouth
(p.o.) in the morning, with or without food.
[0426] The maximum study duration was up to 14 weeks from the time
of initial screening procedures to the final study visit (Week 12).
Screening procedures were performed a maximum of 2 weeks prior to
the first dose of study drug. The maximum duration of study drug
treatment was 12 weeks.
[0427] Placebo was indistinguishable from active treatment.
Methods Example 2
Patients
[0428] The number of subjects enrolled was 202 at 46 investigative
sites.
[0429] Men and women, 18 years of age or older, with idiopathic
PAH, PAH associated with CTD, e.g., mixed CTD, CREST syndrome,
systemic sclerosis (scleroderma), overlap syndrome or systemic
lupus erythematosus, or PAH associated with anorexigen use or HIV
infection were enrolled in this study. Subjects were to have a
documented mean PAP >25 mmHg, PVR >3 mmHg/L/min, and PCWP or
LVEDP <15 mmHg. Subjects must have been able to walk a distance
of at least 150 m but no more than 450 m during 2 consecutive 6MWTs
to be eligible for inclusion in the study.
Study Design and Treatment After a 2 week screening period,
eligible subjects were stratified based on the underlying etiology
of PAH (idiopathic or non-idiopathic) and were randomized to 1 of 3
treatment groups (placebo, 5 mg or 10 mg ambrisentan) in a ratio of
1:1:1. One blinded dose reduction was permitted during the 12-week
treatment period in the event of study drug intolerance (e.g., 10
mg to 5 mg, 5 mg to 2.5 mg, placebo to placebo). Subjects received
a daily dose of 2.5 mg ambrisentan only if they reduced from the 5
mg dose group. Subjects were assessed for efficacy and safety at
monthly intervals.
[0430] Due to the placebo-controlled design of this study, there
was a 1 in 3 chance that a subject did not receive ambrisentan for
a period of 12 weeks. Therefore, after a minimum treatment period
of 4 weeks, subjects who met 2 or more of the following predefined
early escape criteria may have been removed from the study: [0431]
(a) a decrease from baseline of at least 20% in 6MWD; [0432] (b) an
increase of 1 or more WHO functional class; [0433] (c) worsening
right ventricular failure (e.g., as indicated by increased jugular
venous pressure, new or worsening hepatomegaly, ascites or
peripheral edema); [0434] (d) rapidly progressing cardiogenic,
hepatic or renal failure; and/or [0435] (e) refractory systolic
hypotension (systolic blood pressure <85 mmHg).
[0436] Subjects receiving placebo who were removed from the study
due to 2 or more early escape criteria were eligible to enter a
long-term extension study, and receive active treatment with
ambrisentan.
[0437] Serum levels of alanine aminotransferase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase, gamma-glutamyl
transpeptidase (GGT) and total bilirubin were closely monitored in
all subjects throughout the study. Female subjects of childbearing
potential were required to undergo monthly pregnancy tests and to
use a double method of contraception to reduce risk of pregnancy
during the course of the study. Male subjects were required to
undergo complete semen and hormone analyses to evaluate potential
effects of ambrisentan on male fertility.
[0438] After completion of the 12-week study, subjects were
eligible to enroll into the long-term extension study.
Efficacy Assessments
[0439] The primary efficacy endpoint was change from baseline in
6MWD evaluated after 12 weeks of treatment compared to placebo.
[0440] The secondary efficacy endpoints included: [0441] (a) time
to clinical worsening of PAH, as defined by the time from
randomization to the first occurrence of death, lung
transplantation, hospitalization for PAH, atrial septostomy, study
discontinuation due to addition of other PAH therapeutic agents, or
study discontinuation due to 2 or more early escape criteria;
[0442] (b) change from baseline measured after 12 weeks of
treatment compared to placebo in: [0443] (i) WHO functional class;
[0444] (ii) SF-36.RTM. health survey physical functioning scale;
[0445] (iii) BDI immediately following exercise; and/or [0446] (iv)
an assessment of the safety and tolerability of the study drug; and
[0447] (c) change from baseline measured after 12 weeks of
treatment compared to placebo in plasma levels of ET-1, BNP and
cTnT.
Safety Assessments
[0448] All adverse effects (AEs) reported during the course of the
study were reported and summaries of all AEs were prepared showing
frequencies and percentages of: [0449] (a) subjects with at least 1
AE; [0450] (b) subjects with possibly or probably drug-related AEs;
[0451] (c) subjects with at least 1 serious AE (SAE); [0452] (d)
subjects with an AE leading to study discontinuation; and [0453]
(e) subjects who died.
[0454] Liver function test (LFT) assessments were separately
summarized by severity relative to the upper limit of normal (ULN)
for ALT, AST, alkaline phosphatase and total bilirubin.
[0455] For subjects who were on anticoagulants at any point during
the study (regular visit or between visits), coagulation tests (PT,
PTT and INR) were completed. In addition to summary statistics by
study visit, changes in PT and INR were examined relative to
changes in warfarin-type anticoagulant dose. These analyses focused
on the values at Week 0 and Week 12 and the percentage change from
Week 0 to Week 12.
[0456] The results of semen samples and their normality or
abnormality were assessed by an independent male fertility expert
and summarized through frequency counts and percentages by
treatment. Descriptive statistics for male hormone data were
prepared by treatment for the Week 0 and Week 12 visits when data
were collected. Change from Week 0 to Week 12 was determined. The
male fertility hormone results were analyzed in combination with
the semen sample results by a second independent male fertility
expert.
[0457] Frequency counts and percentages were used to summarize
frequency of normal, abnormal but not clinically significant, and
abnormal and clinically significant ECG results for each scheduled
assessment time by treatment. All ECG data were digitally recorded
and analyzed by a central reader. The following variables were
analyzed: heart rate, RR and PR intervals, QRS duration, QT
interval, QTcB, QTcF and ECG diagnostic variables. Descriptive
statistics were used to summarize ECG results by treatment group
and by week of ECG assessment.
[0458] Descriptive statistics for vital signs were reported for
each scheduled assessment time by treatment and for the change from
pre-dose Week 0 to each subsequent scheduled assessment by
treatment.
Statistical Methods
[0459] A test of the null hypothesis of no treatment group
difference in change from baseline in 6MWD with 62 subjects per
group had approximately 90% power to detect an average
placebo-adjusted treatment effect of 35 m based on a 2-sample
t-test and a standard deviation of 55 m.
[0460] The intention-to-treat (ITT) population was defined as all
randomized subjects who received at least 1 dose of study drug. For
the ITT population, subjects were considered as belonging to their
randomized treatment group, regardless of the actual treatment
received.
[0461] The safety population was defined as all randomized subjects
who received at least 1 dose of study drug. Subjects were
considered as belonging to a treatment group according to the
highest actual treatment dose received. Any subject who received 10
mg ambrisentan on any day was included in the 10 mg group for
safety analyses in the entire study. Any subject who received 5 mg
ambrisentan on any day and never received 10 mg ambrisentan on any
day was included in the 5 mg group for safety analyses in the
entire study. Otherwise, any subject who received only placebo was
included in the placebo group for safety analyses in the study.
[0462] The primary efficacy endpoint was the change from baseline
in 6MWD evaluated after 12 weeks of treatment compared to placebo,
where the last observation was carried forward. Baseline 6MWD was
defined as the mean 6MWD of the last two 6MWTs prior to
randomization.
[0463] Change from baseline for Weeks 4, 8 and 12 in each of the
two ambrisentan treatment groups were compared to placebo. The mean
change was reported with 2-sided 95% confidence intervals (CIs)
calculated by normal theory. The primary comparison was the change
from baseline to Week 12. The Wilcoxon rank sum test stratified by
idiopathic and non-idiopathic PAH subjects was used for inference.
A fixed sequence approach was used to control the type I error rate
accounting for the two comparisons. The higher dose was first
compared to placebo. Because the p-value from the Wilcoxon rank sum
test was less than 0.05 for the 5 mg ambrisentan group, the
difference was considered significant, and the lower dose was
compared to placebo, again at the full 0.05 .alpha.-level.
[0464] The two ambrisentan dose groups were also combined and
compared to the placebo group. A p-value was reported, but for
descriptive purposes only, with no impact on the fixed sequence
procedure used for comparing the two individual dose groups to the
placebo group.
[0465] If both ambrisentan dose groups were superior to placebo for
the primary endpoint, evaluation of the secondary endpoints was
done by combining the subjects from the two dose groups for
comparison to the placebo group. However, if only the 10 mg group
was significant for the primary endpoint, evaluation of the
secondary endpoints was done only for that dose group. Secondary
endpoint analyses were stratified by idiopathic and non-idiopathic
PAH subjects.
[0466] The two most important secondary endpoints, time to clinical
worsening of PAH and change in WHO functional class, were compared
to placebo using a weighted version of Hommel's extension of the
Simes test, with an overall .alpha. of 0.05. Time to clinical
worsening was assigned a weight of 80% while change in WHO
functional class received 20% of the weight. These two tests served
as a parallel gatekeeper, allowing the physical functioning scale
of the SF-36.RTM. health survey to be tested if at least one of the
first two secondary endpoints was significant. Lastly, the BDI was
tested conditional on a significant result from the test of the
SF-36.RTM. physical functioning scale.
[0467] Additional measures of interest included change from
baseline measured after 12 weeks of treatment compared to placebo
in ET-1, BNP and cTnT.
Results Example 2
Patients Study Population
[0468] Disposition of randomized subjects is shown in Table
2.1.
TABLE-US-00007 TABLE 2.1 Subject disposition (% of randomized
subjects) 5 mg 10 mg Combined Placebo ambrisentan ambrisentan
ambrisentan (N = 67) (N = 67) (N = 68) (N = 135) Randomized 67
(100.0) 67 (100.0) 68 (100.0) 135 (100.0) Completed 57 (85.1) 63
(94.0) 63 (92.6) 126 (93.3) Withdrew 10 (14.9) 4 (6.0) 5 (7.4) 9
(6.7) Reasons for withdrawal: Adverse 1 (1.5) 1 (1.5) 1 (1.5) 2
(1.5) event Withdrawal 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) of consent
Treatment 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) with other PAH thera-
peutic agents Other 1 (1.5) 2 (3.0) 1 (1.5) 3 (2.1) Early escape 4
(6.0) 0 (0.0) 2 (2.9) 2 (1.5)
[0469] A total of 201 subjects, with a mean age of 50.1 years,
received at least 1 dose of study drug and were included in the ITT
and safety populations. A majority of the subjects enrolled were
female (83.6%) and Caucasian (69.2%). More than two-thirds (68.7%)
of the subjects were residents of the U.S.; the others were
distributed in Central and South America (20.9%) and the rest of
the world (10.4% in Australia, Austria, Hungary and Italy).
[0470] The number of years that PAH was present prior to
participation in the study was calculated from the date that PAH
was diagnosed until the date that informed consent was signed. For
subjects who had a diagnosis of PAH confirmed at the screening
visit for this study, the number of years of PAH present prior to
this study was set to zero. The mean number of years that PAH was
present prior to participation in this study was slightly longer
for the placebo (2.14.+-.3.63 years) than for the 5 mg
(1.86.+-.4.36 years) and 10 mg (1.40.+-.2.39 years) groups. The
median number of years that PAH was present was less than 1 year
for each treatment group: placebo, 0.54 years; 5 mg, 0.33 years; 10
mg, 0.60 years.
[0471] Of the subjects enrolled, 63% had a diagnosis of idiopathic
PAH prior to enrollment, and 37% had PAH associated with CTD,
anorexigen use or HIV infection; idiopathic and non-idiopathic PAH
subjects were equally distributed between the treatment groups.
Nearly all of the subjects had either WHO functional class II
(32.3%) or class III (58.2%) symptoms at baseline; only a small
percentage of subjects had WHO class I (2.5%) or IV (7.0%) symptoms
at baseline. The mean (.+-.standard deviation (SD)) baseline 6MWD
for all subjects was 341.0.+-.75.80 m, and the mean baseline BDI
was 3.8.+-.2.02.
[0472] In general, demographic and baseline characteristics of the
subjects participating were well balanced between the treatment
groups. However, there were more class IV subjects in the 5 mg
(9.0%) and 10 mg (10.4%) dose groups than in the placebo group
(1.5%). There was also a difference in baseline 6MWD between WHO
class I/II and WHO class III/IV subjects for both the placebo and
combined ambrisentan groups: class I/II, 377.5 m and 372.0 m; and
class III/IV, 320.6 m and 324.6 m, respectively.
[0473] The most frequently used concomitant medications were
furosemide (47.3%), warfarin sodium (36.8%) and oxygen (26.4%).
Minor differences were observed between dose groups in the use of
concomitant medications.
Efficacy of Ambrisentan
[0474] Change in 6MWD from baseline to Week 12 in the ITT
population is shown in Table 2.2.
TABLE-US-00008 TABLE 2.2 Change in 6MWD, meters 5 mg 10 mg Combined
Placebo ambrisentan ambrisentan ambrisentan Baseline 6MWD, 341.9
339.6 341.5 340.5 mean (SD) (73.47) (76.68) (78.28) (77.20) Change
from -7.8 +22.8 +43.6 +33.2 baseline to (78.88) (82.98) (65.91)
(75.37) Week 12, mean (SD)
[0475] The primary efficacy endpoint was statistically significant
for both doses of ambrisentan compared to placebo. The
placebo-adjusted improvement in mean 6MWD at Week 12 was +51.4 m
(95% CI: 26.6 to 76.2; p <0.001) for the 10 mg group and +30.6 m
(95% CI: 2.9 to 58.3; p=0.008) for the 5 mg group. For subjects in
the placebo group, the mean 6MWD decreased from baseline (-7.8 m).
For subjects receiving ambrisentan, improvement in 6MWD compared to
placebo was observed as early as Week 4, and by Week 8 there was
evidence of a dose response.
[0476] The secondary endpoint of time to clinical worsening of PAH
demonstrated that ambrisentan (combined ambrisentan group) did not
significantly delay the time to clinical worsening of PAH compared
to placebo. However, twice as many subjects in the placebo group
(n=6) had an event of clinical worsening compared to each of the
ambrisentan dose groups (3 subjects each in the 5 mg and 10 mg dose
groups). Furthermore, the hazard ratio showed a 50% reduction in
the probability of clinical worsening occurring at any given time
for a subject receiving ambrisentan, when compared to placebo.
[0477] The time to clinical worsening of PAH is displayed in FIG. 2
as a Kaplan-Meier event-free curve through Week 12 for each
treatment group in the ITT population. The Kaplan-Meier curve
decreases sharply in the 10 mg dose group after 12 weeks due to a
single event that occurred after most subjects had completed the
study.
[0478] A summary of events defining clinical worsening by treatment
group is presented in Table 2.3.
TABLE-US-00009 TABLE 2.3 Clinical worsening events (% of ITT
population) 5 mg 10 mg Combined Placebo ambrisentan ambrisentan
ambrisentan Event (N = 67) (N = 67) (N = 68) (N = 135) Death 2
(3.0) 1 (1.5) 1 (1.5) 2 (1.5) Lung trans- 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0) plantation Hospitaliza- 2 (3.0) 2 (3.0) 2 (3.0) 4 (3.0) tion
for PAH Atrial 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) septostomy Study 1
(1.5) 0 (0.0) 1 (1.5) 1 (0.7) discontinua- tion due to addition of
PAH treatment Escape 3 (4.5) 0 (0.0) 2 (3.0) 2 (1.5) criteria Total
subjects 6 (9.0) 3 (4.5) 3 (4.5) 6 (4.5) with .gtoreq.1 event
[0479] Of the 2 (3.0%) subjects in the placebo group hospitalized
for PAH, 1 was hospitalized for right heart failure and 1 for right
ventricular failure. Comparatively, 4 (3.0%) subjects receiving
ambrisentan were hospitalized for PAH, of whom 2 (1 each in the 5
mg and 10 mg dose groups) were hospitalized for worsening right
heart failure, and the other 2 for increased shortness of breath
with increased peripheral edema (5 mg) and worsening PAH with
severe peripheral edema (10 mg).
[0480] There were a total of 4 deaths reported during this study or
within 30 days of the last dose of study drug. In the placebo
group, 2 (3.0%) subjects died, and 1 (1.5%) subject each in the 5
mg and 10 mg dose groups died. All 4 deaths were captured as
clinical worsening events.
[0481] Change in WHO functional class from baseline to Week 12 in
the ITT population is shown in Table 2.4.
TABLE-US-00010 TABLE 2.4 Change in WHO functional class (% of ITT
population) 5 mg 10 mg Combined Change (no. Placebo ambrisentan
ambrisentan ambrisentan of classes) (N = 67) (N = 67) (N = 68) (N =
135) -2 1 (1.5) 1 (1.5) 5 (7.5) 6 (4.5) -1 15 (22.4) 18 (26.9) 15
(22.4) 33 (24.6) no change 40 (59.7) 47 (70.1) 44 (65.7) 91 (67.9)
+1 11 (16.4) 1 (1.5) 3 (4.5) 4 (3.0) +2 0 (0.0) 0 (0.0) 0 (0.0) 0
(0.0)
[0482] The combined ambrisentan group demonstrated a clinically
relevant improvement in WHO functional class at Week 12 compared to
placebo (p=0.036); similar trends were observed for each
ambrisentan treatment group. Due to the multiple comparisons
procedure, a statistically significant improvement compared to
placebo could not be stated for this secondary endpoint. However, a
more than 5-fold greater percentage of subjects in the placebo
group (16.4%) deteriorated by at least 1 WHO class compared to
subjects in the combined ambrisentan group (3.0%). In addition, a
3-fold greater percentage of subjects in the combined ambrisentan
group (4.5%) had an improvement of 2 WHO classes compared to
subjects in the placebo group (1.5%).
[0483] The percentage of subjects at least maintaining their
baseline WHO functional class at Week 12 was 83.6% in the placebo
group, 98.5% in the 5 mg dose group and 95.5% in the 10 mg dose
group.
[0484] Change in SF-36.RTM. health survey parameters from baseline
to Week 12 is shown in Table 2.5.
TABLE-US-00011 TABLE 2.5 Change in SF-36 .RTM. health survey
parameters, mean (SD) 5 mg 10 mg Combined Parameter Placebo
ambrisentan ambrisentan ambrisentan Physical functioning +2.31 .+-.
7.65 +3.86 .+-. 7.14 +4.52 .+-. 7.16 +4.10 .+-. 8.39 Role-physical
+2.81 .+-. 11.36 +4.22 .+-. 10.52 +6.67 .+-. 10.35 +5.45 .+-. 10.47
Bodily pain +0.22 .+-. 10.70 -1.43 .+-. 13.21 +2.26 .+-. 12.22
+0.42 .+-. 12.81 General health +1.94 .+-. 7.50 +0.08 .+-. 8.45
+3.25 .+-. 8.81 +1.66 .+-. 8.74 Vitality +2.38 .+-. 10.06 +2.38
.+-. 10.06 +5.03 .+-. 10.07 +3.71 .+-. 10.11 Social functioning
+2.31 .+-. 11.60 +1.11 .+-. 13.63 +4.11 .+-. 11.77 +2.61 .+-. 12.78
Role-emotional +2.84 .+-. 12.63 +1.41 .+-. 13.95 +2.98 .+-. 17.37
+2.19 .+-. 15.71 Mental health +0.27 .+-. 8.09 +0.81 .+-. 9.67
+1.55 .+-. 12.66 +1.18 .+-. 11.23 Physical component summary +1.82
.+-. 9.25 +1.88 .+-. 8.68 +4.79 .+-. 7.90 +3.34 .+-. 8.40 Mental
component summary +1.56 .+-. 9.00 +0.50 .+-. 10.50 +2.11 .+-. 13.17
+1.30 .+-. 11.89
[0485] An increase in the physical function scale of the SF-36.RTM.
Health Survey was observed in the combined ambrisentan group at
Week 12 (4.10.+-.8.39); however, this increase was not
significantly different from placebo (2.31.+-.7.65). For most of
the SF-360 scales there was a general trend of greater increases
for the 10 mg group compared to the 5 mg and placebo groups.
[0486] A clinically relevant improvement in BDI was observed at
Week 12 for the combined ambrisentan group, with a placebo-adjusted
BDI of -0.6 (95% CI: -1.2 to 0.0; p=0.017). Dose-dependent
improvements in BDI were also observed for both the 5 mg and 10 mg
dose groups compared to placebo. Due to the multiple comparisons
procedure, a statistically significant improvement compared to
placebo could not be stated for this secondary endpoint.
[0487] At Week 12, the geometric mean percent change in plasma ET-1
increased by 34% (95% CI: 11% to 63%) in the placebo group. The
geometric mean percent change in plasma ET-1 increased from
baseline by 96% (95% CI: 53% to 151%; p=0.019 versus placebo) in
the 5 mg group and by 48% (95% CI: 19% to 84%; p=0.169 versus
placebo) in the 10 mg group. The change from baseline was
substantially greater than placebo for the 5 mg group, but not for
the 10 mg group.
[0488] At baseline, approximately 90% of plasma cTnT concentrations
were below the level of quantification (0.01 ng/ml). Changes in
cTnT concentrations during the 12-week study were minor and not
remarkably different from zero.
[0489] At Week 12, the geometric mean percent change in plasma BNP
increased by 9% (95% CI: -16% to 41%) in the placebo group. In
contrast, the geometric mean percent change in plasma BNP decreased
from baseline by 30% (95% CI: -43% to -14%; p=0.002 versus placebo)
in the 5 mg group and by 45% (95% CI: -57% to -29%; p <0.001
versus placebo) in the 10 mg group. The decrease from baseline was
substantially greater than placebo for the 5 mg group and the 10 mg
group.
Efficacy by Subgroup
[0490] Improvements in 6MWD were observed for both WHO functional
class I/II and class III/IV subjects at Week 12, however, a
slightly greater improvement was observed for class III/IV
subjects. For the class I/II subgroup, the placebo-adjusted 6MWD
increase from baseline at Week 12 was +25.6 m and +42.0 m for the 5
mg and 10 mg dose groups, respectively. For the class III/IV
subgroup, the placebo-adjusted 6MWD increase from baseline at Week
12 was +34.1 m and +56.9 m for the 5 mg and 10 mg dose groups,
respectively.
[0491] Improvements in 6MWD at Week 12 were observed in both
ambrisentan dose groups for the idiopathic PAH subgroup and in the
10 mg group for the non-idiopathic PAH subgroup. There was greater
improvement observed in subjects with idiopathic PAH than in
subjects with non-idiopathic PAH. For the idiopathic PAH subgroup,
the placebo-adjusted 6MWD increased from baseline at Week 12 by
+42.9 m and +56.9 m for the 5 mg and 10 mg dose groups,
respectively. For the non-idiopathic PAH subgroup, the
placebo-adjusted 6MWD increase from baseline at Week 12 was +10.2 m
and +43.0 m, for the 5 mg and 10 mg dose groups, respectively.
[0492] Improvements in 6MWD at Week 12 were observed in both
ambrisentan dose groups for female subjects. The placebo-adjusted
6MWD increased from baseline at Week 12 by +30.9 m and +57.7 m for
the 5 mg and 10 mg dose groups, respectively. For male subjects,
the placebo-adjusted 6MWD increase from baseline at Week 12 was
+19.9 m and +13.1 m for the 5 mg and 10 mg dose groups,
respectively.
[0493] Subjects not receiving calcium channel blockers (CCBs)
during the study demonstrated an improvement in 6MWD at Week 12
compared to placebo after receiving ambrisentan, with a
placebo-adjusted increase from baseline of +38.7 m and +67.9 m for
the 5 mg and 10 mg dose groups, respectively. Subjects receiving
CCBs during the study also had an improvement in 6MWD compared to
placebo after receiving ambrisentan, with a placebo-adjusted
increase from baseline of +15.1 m and +19.6 m for the 5 mg and 10
mg dose groups, respectively.
[0494] Subjects not receiving supplemental oxygen demonstrated an
improvement in 6MWD at Week 12 compared to placebo that was similar
to the overall study population. Subjects in the placebo group who
received supplemental oxygen during the study had a decrease (-25.5
m) from baseline in mean 6MWD at Week 12; whereas subjects in the 5
mg (+21.1 m) and 10 mg (+48.0 m) groups had notable increases from
baseline in mean 6MWD.
Safety Results
[0495] A summary of adverse events recorded is shown in Table
2.6.
TABLE-US-00012 TABLE 2.6 Global summary of adverse events (% of
safety population) 5 mg 10 mg Combined Placebo ambrisentan
ambrisentan ambrisentan Subjects (N = 67) (N = 67) (N = 67) (N =
134) with at least 56 (83.5) 56 (83.6) 53 (79.1) 109 (81.3) 1 AE
with at least 21 (31.3) 34 (50.7) 29 (43.3) 63 (47.0) 1 related AE
with at least 7 (10.4) 4 (6.0) 7 (10.4) 11 (8.2) 1 SAE with an AE 4
(6.0) 2 (3.0) 2 (3.0) 4 (3.0) leading to study dis- continuation
who discon- 4 (6.0) 0 (0.0) 2 (3.0) 2 (1.5) tinued the study via
early escape who died 2 (3.0) 1 (1.5) 1 (1.5) 2 (1.5)
[0496] During this 12-week study, 83.5% of the subjects in the
placebo group experienced at least 1 AE. Similarly, 83.6% of
subjects in the 5 mg dose group and 79.1% of subjects in the 10 mg
dose group experienced at least 1 AE during the study.
[0497] Overall, more subjects in the placebo group compared to the
ambrisentan groups prematurely discontinued from the study due to
death, SAEs, AEs, and/or the early escape procedure. A greater
percentage of subjects in the placebo group (6.0%) met the criteria
for early escape, compared to subjects in the combined ambrisentan
group (1.5%).
[0498] In general, a similar percentage of AEs were assessed as
severe in the placebo and 10 mg groups (19.4% and 17.9%,
respectively), whereas a lower percentage of AEs were assessed as
severe in the 5 mg group (6.0%). A similar percentage of AEs were
assessed as moderate in the placebo and 10 mg groups (38.8% and
37.3%, respectively), whereas a higher percentage of AEs were
assessed as moderate in the 5 mg group (50.7%). The most frequent
AE in the combined ambrisentan group was peripheral edema, and most
events were assessed as mild or moderate.
[0499] None of the 134 subjects who received ambrisentan developed
any elevated serum aminotransferase concentrations >3.times.ULN,
compared to 2 subjects in the placebo group. Further, there were no
notable mean changes from baseline at Week 12 for serum ALT and
AST, and no differences between treatment groups.
[0500] The changes in total bilirubin at Week 12 were shown to be
substantially decreased in the 10 mg and combined ambrisentan
groups, compared to placebo. The changes in alkaline phosphatase at
Week 12 were shown to be substantially decreased in the 5 mg, 10 mg
and combined ambrisentan groups, compared to placebo.
[0501] Mean decreases in hemoglobin concentration were observed at
Week 12 for both ambrisentan dose groups compared to placebo
(placebo, 0.15 g/dl; 5 mg, -0.83 g/dl; 10 mg, -0.93 g/dl). The
decreases were observed early (Week 4) in the study and did not
decrease further with continued treatment.
[0502] Ambrisentan had no effect on PT, INR or weekly warfarin-type
anticoagulant dose.
[0503] Mean uric acid decreased slightly over the 12-week study in
the placebo group (-6.5 .mu.mol/liter); whereas a substantial
decrease was observed for the 5 mg (-21.5 .mu.mol/liter) and 10 mg
(-53.3 .mu.mol/liter) groups that appeared to be
dose-dependent.
[0504] The analysis of male fertility hormones in combination with
a limited number of subjects (n=12) providing serial semen samples
did not suggest that ambrisentan was associated with an adverse
effect on male reproductive potential.
[0505] More specifically, changes over baseline in follicle
stimulating hormone (FSH) concentration at Week 12 were small,
ranging from +0.52 IU/liter (placebo group) to +1.83 IU/liter (10
mg dose group). Although the FSH concentrations at Week 12 for the
placebo and 5 mg dose groups (8.14.+-.2.49 IU/liter and
9.23.+-.7.21 IU/liter, respectively) suggest possibility of some
spermatogenic dysfunction, the changes observed during the study
were unlikely to be of substantial clinical relevance.
[0506] Changes in luteinizing hormone (LH) concentration at Week 12
were small: placebo, -0.07.+-.4.72 IU/liter; 5 mg, -0.15.+-.2.21
IU/liter; 10 mg, +1.28.+-.10.63 IU/liter.
[0507] Changes from baseline in mean inhibin B concentration at
Week 12 were similar across treatment groups: placebo,
+13.2.+-.73.55 pg/ml; 5 mg, -4.5.+-.28.00 pg/ml; 10 mg,
-7.6.+-.50.97 pg/ml. Based on expert opinion, none of the mean
inhibin B concentrations measured at baseline and Week 12 indicated
presence or development of spermatogenic dysfunction.
[0508] Changes from baseline in testosterone concentration at Week
12 were -2.825.+-.7.20 nmol/l for the placebo group, -0.099.+-.3.48
for the 5 mg dose group, and -0.099.+-.3.48 for the 10 mg dose
group. Based on expert opinion, these data suggest that ambrisentan
did not cause a negative effect on testosterone concentration in
this study population.
Discussion Example 2
[0509] This study demonstrated that both the 5 mg and 10 mg dose of
ambrisentan administered once daily provided statistically
significant and clinically relevant improvements in exercise
capacity and symptoms in subjects with PAH. The improvements in
6MWD were evident within 4 weeks and appeared dose-dependent by
Week 8. At Week 12, the increase in 6MWD was nearly twice as large
in the 10 mg dose group compared to the 5 mg dose group.
Improvements in 6MWD were observed in most subgroups and, in
general, appeared to be dose-dependent. Clinically relevant
improvements in 6MWD were observed in subjects with WHO functional
class I/II and class III/IV symptoms. Both doses also demonstrated
clinically relevant treatment benefits for several secondary
endpoints, including WHO functional class and BDI, as well as a
notable reduction in plasma BNP.
[0510] Ambrisentan was well tolerated as indicated by the lack of
dose reduction and AEs leading to premature discontinuation as well
as more subjects in the placebo group discontinued due to death,
SAEs, AEs, early escape, right heart failure, and/or worsening PAH.
The most clinically important AEs observed in this study were
peripheral edema, headache and nasal congestion. For the most part,
these events were mild in severity and none led to study
discontinuation. Serum aminotransferase abnormalities, which have
been observed and treatment-limiting for other ERAs, were not
observed in any subjects receiving ambrisentan. Furthermore, there
were no increases in mean ALT and AST and there were notable
decreases in mean total bilirubin and alkaline phosphatase in
subjects receiving ambrisentan. Decreases in hemoglobin
concentration were observed early in the study and did not decrease
further with continued treatment.
[0511] In conclusion, the treatment benefits observed for the
primary and secondary endpoints of this study were robust,
internally consistent, and clinically relevant. Ambrisentan was
well tolerated and was associated with a manageable safety profile,
indicating a positive risk-to-benefit profile.
Example 3
[0512] The trials described in Examples 1 and 2 enrolled subjects
from a population having PAH including idiopathic PAH and PAH
associated with CTD, anorexigen use or HIV infection. Patients with
pulmonary hypertension due to other etiologies were generally
excluded. However, the efficacy and safety of ambrisentan observed
in this classic PAH population, and the need for effective therapy
in pulmonary hypertension associated with other conditions, merits
evaluation in these non-traditional groups. Therefore, a further
study is conducted to evaluate safety and efficacy of ambrisentan
in both classic PAH patients (WHO Group 1) and in an expanded
pulmonary hypertension patient population (WHO Groups 3 and 4).
[0513] This expanded population includes subjects having idiopathic
and familial PAH; PAH associated with collagen vascular disease,
congenital systemic-to-pulmonary shunts, HIV infection, drugs and
toxins, thyroid disorders, glycogen storage disease, Gaucher
disease and splenectomy; pulmonary hypertension associated with
chronic obstructive pulmonary disease (COPD), interstitial lung
disease (ILD), sleep-disordered breathing and alveolar
hypoventilation disorders; and pulmonary hypertension due to
thromboembolic obstruction of proximal and/or distal pulmonary
arteries. Four groups are of particular interest in this study:
[0514] (a) PAH associated with congenital heart defects, including
Eisenmenger's syndrome; [0515] (b) PAH associated with HIV
infection; [0516] (c) pulmonary hypertension associated with ILD;
and [0517] (d) pulmonary hypertension associated with COPD.
[0518] Subjects having pulmonary hypertension associated with ILD
or COPD must demonstrate a degree of pulmonary hypertension that is
disproportionate to the severity of the underlying disease.
Subjects with ILD must have total lung capacity >60% of
predicted normal, mean PAP >35 mmHg, and PVR >3.5 mmHg/I/min
(280 dyne.sec/cm.sup.5). Subjects with COPD must have forced
expiratory volume in 1 second >50% of predicted normal, mean PAP
>35 mmHg, and PVR >3.5 mmHg/I/min (280
dyne.sec/cm.sup.5).
[0519] The study is designed to evaluate improvements compared to
baseline for the overall study population and for key subgroups of
interest. The study also examines safety and tolerability of
ambrisentan in a broad population of subjects with pulmonary
hypertension.
[0520] The target population includes men and women, 18 years or
older, with pulmonary hypertension as defined by the WHO clinical
classification. Subjects must have a documented history of
pulmonary hypertension and be able to walk at least 150-450 meters
in a 6MWT.
[0521] Subjects who have discontinued bosentan or sitaxsentan
therapy due to aminotransferase abnormalities or lack of efficacy
are eligible for this study. Subjects currently receiving chronic
prostanoid therapy and/or an oral PDE-5 inhibitor are also eligible
for this study.
[0522] All subjects must have a documented mean PAP .gtoreq.25
mmHg, PVR >3 mmHg/1/min, and PCWP or LVEDP <15 mmHg. Subjects
with ILD or COPD must meet the additional or stricter requirements
stated above.
[0523] All hemodynamic data represent resting pressures and must be
assessed no more than 1 year (52 weeks) prior to the screening
visit. All pulmonary function tests must be assessed no more than 3
months (12 weeks) prior to the screening visit.
[0524] Certain etiology subgroups are of particular interest.
Therefore, this study enrolls a minimum of 18 subjects in the
following etiology subgroups: [0525] (a) PAH associated with
congenital heart defects, including Eisenmenger's syndrome; [0526]
(b) PAH associated with HIV infection; [0527] (c) pulmonary
hypertension associated with ILD; and [0528] (d) pulmonary
hypertension associated with COPD.
[0529] This study also enrolls a minimum of 30 PAH (WHO Group 1)
subjects receiving concomitant sildenafil therapy at baseline.
[0530] Enrollment continues (up to a maximum of 200 subjects) until
the enrollment goals for each of the etiology subgroups, as well as
the sildenafil subgroup, have been met.
[0531] The primary objective of this study is to evaluate effect of
ambrisentan on exercise capacity in a broad population of subjects
with pulmonary hypertension. Secondary objectives are to evaluate
effects of ambrisentan on other clinical measures of pulmonary
hypertension, long-term treatment success and survival. In
addition, safety and tolerability of ambrisentan will be evaluated.
Efficacy and safety will be evaluated in the overall study
population and in various subgroups.
[0532] Anecdotal evidence suggests that patients with non-classical
pulmonary hypertension may respond more slowly to therapy than the
classical PAH population; therefore, the primary analysis of
efficacy is evaluated after 24 weeks of treatment. Eligible
subjects receive 5 mg ambrisentan once daily for the first 24
weeks. One dose reduction is permitted during the 24-week
fixed-dose treatment period if a subject is not tolerating study
drug (e.g., 5 mg to 2.5 mg). After the initial 24-week treatment
period, investigators are allowed to adjust study drug dose as
clinically indicated (available doses are 2.5 mg, 5 mg and 10
mg).
[0533] Subjects are monitored with clinical laboratory tests every
4 weeks throughout the study. These safety laboratory tests may be
performed at a local phlebotomy laboratory or at the investigator
clinic. In addition, the investigator assesses each subject for
safety and efficacy at Week 4, Week 12 and Week 24. Following Week
24, subjects are assessed for safety and efficacy every 24
weeks.
[0534] Subjects who have received stable sildenafil treatment for
at least 4 weeks are permitted to enroll in this study and continue
receiving sildenafil in combination with ambrisentan. Subjects who
are not receiving sildenafil treatment prior to enrollment are
permitted to initiate concomitant sildenafil treatment; however,
prior to addition of concomitant sildenafil treatment,
investigators must conduct at least one 6MWT after the subject has
received 10 mg q.d. ambrisentan for a minimum of 4 weeks.
Up-titration to 10 mg q.d. ambrisentan is allowed at any time after
the Week 24 visit; therefore, concomitant sildenafil treatment may
be added after 28 weeks of ambrisentan monotherapy. Furthermore,
addition of concomitant sildenafil treatment requires that a
subject meet two or more of the following predefined criteria:
[0535] (a) a decrease from baseline of at least 20% in 6MWD; [0536]
(b) an increase of 1 or more WHO functional class; and/or [0537]
(c) worsening right ventricular failure (e.g., as indicated by
increased jugular venous pressure, new or worsening hepatomegaly,
ascites or peripheral edema).
[0538] The efficacy endpoints of 6MWD, WHO functional class, BDI
and BNP must be assessed immediately prior to initiation of
sildenafil treatment to establish baseline efficacy prior to
combination therapy.
[0539] Concomitant administration of an approved prostanoid
treatment (i.e., i.v. epoprostenol, i.v. or subcutaneous
treprostinil, or i.v. or inhaled iloprost) is permitted at any time
after the Week 12 visit. The efficacy endpoints of 6MWD, WHO
functional class, BDI and BNP must be assessed immediately prior to
initiation of prostanoid treatment to establish baseline efficacy
prior to combination therapy.
[0540] Trough (pre-dose) and peak (2-hour) PK samples are collected
at Week 0 and Week 4 to assess ambrisentan plasma concentrations.
For subjects on concomitant sildenafil therapy, trough (pre-dose)
and peak (1-hour) samples are collected at Week 0 and Week 4 to
assess sildenafil and N-desmethylsildenafil plasma
concentrations.
[0541] Male subjects complete semen and hormone analyses to
evaluate potential effects of ambrisentan on male fertility.
[0542] The primary endpoint of this study is the change from
baseline in 6MWD at Week 24 for all subjects.
[0543] Secondary endpoints include: [0544] (a) clinical worsening
of pulmonary hypertension, as defined by time from initiation of
ambrisentan treatment to the first occurrence of death, lung
transplantation, hospitalization for pulmonary hypertension, atrial
septostomy, addition of chronic prostanoid treatment, or study
withdrawal due to the addition of other clinically approved
therapeutic agents for pulmonary hypertension; [0545] (b) change
from baseline in: [0546] (i) WHO functional class; [0547] (ii)
SF-36.RTM. health survey; [0548] (iii) BDI immediately following
exercise; and/or [0549] (iv) BNP; [0550] (c) monotherapy treatment
status, as defined by time from initiation of ambrisentan treatment
to addition of sildenafil, iloprost, treprostinil or epoprostenol
to ongoing ambrisentan treatment; [0551] (d) failure-free treatment
status, as defined by time from initiation of active treatment to
the first occurrence of death, lung transplantation, or study
withdrawal due to addition of other clinically approved therapeutic
agents for pulmonary hypertension; and [0552] (e) long-term
survival, as defined by time from initiation of ambrisentan
treatment to death.
[0553] Incidence and severity of adverse events associated with
ambrisentan treatment, including elevations in AST and ALT
>3.times.ULN, are evaluated for all subjects, as well as for key
etiology subgroups, and concomitant sildenafil or prostanoid
treatment.
[0554] All patents and publications cited herein are incorporated
by reference into this application in their entirety.
[0555] The words "comprise", "comprises", and "comprising" are to
be interpreted inclusively rather than exclusively.
* * * * *
References