U.S. patent application number 17/736571 was filed with the patent office on 2022-08-18 for once-daily treatment of pulmonary fibrosis.
This patent application is currently assigned to GALECTO BIOTECH AB. The applicant listed for this patent is GALECTO BIOTECH AB. Invention is credited to Paul FORD, Anders PEDERSEN, Hans SCHAMBYE.
Application Number | 20220257628 17/736571 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-18 |
United States Patent
Application |
20220257628 |
Kind Code |
A1 |
SCHAMBYE; Hans ; et
al. |
August 18, 2022 |
ONCE-DAILY TREATMENT OF PULMONARY FIBROSIS
Abstract
A compound of formula (I) for use in a method for treatment of
pulmonary fibrosis in a human including administering, with a dry
powder inhaler, once-a-day to the narrowest parts of the lung
tissue of the human an amount of the compound of formula (I)
effective to treat the pulmonary fibrosis.
Inventors: |
SCHAMBYE; Hans; (Virum,
DK) ; PEDERSEN; Anders; (Lyngby, DK) ; FORD;
Paul; (West Sussex, GB) |
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Applicant: |
Name |
City |
State |
Country |
Type |
GALECTO BIOTECH AB |
Copenhagen N |
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DK |
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Assignee: |
GALECTO BIOTECH AB
Copenhagen N
DK
|
Appl. No.: |
17/736571 |
Filed: |
May 4, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15572660 |
Nov 8, 2017 |
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PCT/EP2015/060456 |
May 12, 2015 |
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17736571 |
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International
Class: |
A61K 31/7056 20060101
A61K031/7056; A61K 31/055 20060101 A61K031/055; A61K 31/4192
20060101 A61K031/4192; A61P 11/00 20060101 A61P011/00; A61K 9/00
20060101 A61K009/00 |
Claims
1. A method for treatment of pulmonary fibrosis in a human
comprising administering once-a-day to the narrowest parts of the
lung tissue of the human an amount of a compound of formula (I)
##STR00005## effective to treat said pulmonary fibrosis, wherein
the administration is carried out by a dry powder inhaler.
2. The method of claim 1, wherein the compound of formula (I) is
bis
(3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl)-.beta.-D-galactopyranos-
yl)-sulfane as the free form.
3. The method of claim 1, wherein the pulmonary fibrosis is
Idiopathic pulmonary fibrosis (IPF).
4. The method of claim 1, wherein the administration is carried out
by a monodose dry powder inhaler, such as the RS01 Monodose Dry
Powder Inhaler (Plastiape).
5. The method of claim 4, wherein the monodose dry powder inhaler
is a RS01 Monodose Dry Powder Inhaler.
6. The method of claim 1, wherein the once daily amount is from
0.15 mg to 50 mg of the compound of formula I.
7. The method of claim 1, wherein the treatment is chronic
treatment.
8. The method of claim 1, wherein the once daily amount is present
in a suitable particle size selected from a mean mass aerodynamic
diameter (MMAD) between 0.1 and 20 .mu.m.
9. The method of claim 1, wherein the compound of formula I is
administered neat or together with a pharmaceutically acceptable
additive.
10. The method of claim 9, wherein the pharmaceutically acceptable
additive is a carrier.
11. The method of claim 10, wherein the carrier is lactose.
Description
STATEMENTt REGARDING PRIOR DISCLOSURES by the INVENTOR or a JOINT
INVENTOR under 37 C.F.R .sctn. 1.77(b)(6)
[0001] Summary of Results of Phase Ia data with respect to TD139
was presented in an on-line Review, Feb. 28, 2015, week of March,
p. 16, BioCentuty by Galecto Biotech AB. A copy of the publication
will be submitted in an information Disclosure Statement, pursuant
to the guidance of 78 Fed. Reg. 11076 (Feb. 14, 2013). The summary
of results of said Phase Ia data was obtained from the
inventors.
TECHNICAL FIELD
[0002] The present invention relates to a compound of formula, (I)
for use in a method for treatment of pulmonary fibrosis in a human,
such as Idiopathic pulmonary fibrosis. The invention also relates
to pharmaceutical compositions comprising the compound of formula
(I) for use in a method for treatment of pulmonary fibrosis in a
human. Furthermore the present invention relates to a method for
treatment of pulmonary fibrosis in a human. Moreover, the present
invention relates to a dry powder inhaler device for administration
of a compound of formula (I) once-a-day to the narrowest parts of
lung tissue of a human.
BACKGROUND ART
[0003] Idiopathic pulmonary fibrosis (IPF) represents a massive
worldwide health burden. It is a chronic condition of unknown
etiology in which repeated acute lung injury causes progressive
fibrosis resulting in destruction of lung architecture,
deteriorating lung function with consequent respiratory failure and
death. Although idiopathic pulmonary fibrosis (IPF) is the
archetypal and most common cause of lung fibrosis, numerous
respiratory diseases can progress to pulmonary fibrosis, and this
usually signifies a worse prognosis. The median time to death from
diagnosis is 2.5 years and the incidence and prevalence of IPF
continues to rise. It remains one of the few respiratory conditions
for which there are no effective therapies, and there are no
reliable biomarkers to predict disease progression. The mechanisms
resulting in pulmonary fibrosis are unclear but centre around
aberrant wound healing as a consequence of repetitive epithelial
injury from an as yet unknown cause. IPF is characterized by
fibroblastic foci containing fibroblasts/myofibroblasts which show
increased activation response to fibrogenic cytokines such as
transforming growth factor-.beta.1 (TGF-.beta.1), There is a big
unmet need for drugs for treatment of Idiopathic pulmonary
fibrosis.
SUMMARY OF THE DISCLOSURE
[0004] The compound of formula I is a novel, dry powdered inhaled
therapy for the treatment of IPF. Based on results from a first in
human study with single ascending doses it was concluded that the
compound of formula (1) is both safe and well tolerated in man and
favorable PK parameters support once daily dosing for a specific
dose range.
[0005] In a first aspect the present invention relates to a
compound of formula (I)
##STR00001##
for use in a method for treatment of pulmonary fibrosis in a human
comprising administering once-a-day to the narrowest parts of the
lung tissue of the human an amount of the compound of formula (I)
effective to treat said pulmonary fibrosis.
[0006] In a further aspect the present invention relates to a
pharmaceutical composition comprising a compound of formula (I)
##STR00002##
for use in a method for treatment of pulmonary fibrosis in a human
comprising administering once-a-day to the narrowest parts of the
lung tissue of the human, the composition comprising an amount of
the compound of formula (I) effective to treat said pulmonary
fibrosis.
[0007] In a still further aspect the present invention relates to a
method for treatment of pulmonary fibrosis in a human comprising
administering once-a-day to the narrowest parts of the lung tissue
of the human an amount of a compound of formula (I)
##STR00003##
effective to treat said pulmonary fibrosis.
[0008] In a further aspect the present invention relates to a dry
powder inhaler device comprising a compound of formula (I)
##STR00004##
for administration once-a-day to the narrowest parts of lung tissue
of a human of an amount of the compound of formula (I) effective to
treat pulmonary fibrosis.
DETAILED DESCRIPTION
[0009] The compound of formula (I) has the chemical name (IUPAC)
bis (3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl
)-.beta.-D-galtactopyranosyl)-sulfane, and as used herein is
intended to cover the compound of formula (I) in any possible form,
such as solid or liquid, a salt, a solvate, or in free form. The
compound of formula (I) may be prepared as described in
US2014/0121179 or WO2014/067986.
[0010] In one embodiment the compound of formula (I) is bis
(3-deoxy-3-(3-fluorophenyl-1H-1,2,3-triazol-1-yl)-.beta.-D-galactopyranos-
yl)-sulfane as the free form.
[0011] In a further embodiment the pulmonary fibrosis is Idiopathic
pulmonary fibrosis (IPF).
[0012] In a further embodiment the administration is carried out by
a dry powder inhaler. Typically, a single or multiple dose DPI
inhaler is used. In one particular embodiment the dry powder
inhaler is RS01 Monodose Dry Powder Inhaler (Plastiape).
[0013] When the compound of formula (I) is formulated as a dry
powder it may be present in a suitable particle size selected from
a mean mass aerodynamic diameter (MMAD) between 0.1 and 20 .mu.m,
such as a MMAD between 0.5 and 10 .mu.m, such as between 1 and 5
.mu.m, typically between 2 and 3 .mu.m. In the study described in
the Experimental section below the MMAD was measured to 2.5 .mu.m.
The selected ranges does not exclude the presence of particles
sizes outside these ranges, but the selected ranges are those that
provide the desired effect as described herein.
[0014] In a still further embodiment the narrowest parts of the
lung tissue are the bronchioles and the alveoli.
[0015] In a further embodiment the once daily amount is from 0.15
mg to 50 mg, such as 0.15 mg to 1.5 mg, 1.5 mg to 3 mg, 3 mg to 5
mg, 5 mg to 7 mg, 7 mg to 8 mg, 8 mg to 10 mg, 10 mg to 20 mg and
20 mg to 50 mg. In particular the once daily amount form 1.5 mg to
20 mg result in a concentration of the active compound of formula
(I) in BAL fluids or macrophages or both of from 1 nM to 100 .mu.M.
More preferred concentrations of from 10 nM to 10 .mu.M or more
preferred 100 nM to 1 .mu.M can be provided with once daily amount
form 3 mg to 10 mg. Based on the results and studies herein it is
predicted that a once daily amount of from 1.5 mg to 10 mg, such as
2 mg to 7 mg, will provide local concentrations of the compound of
formula I in the lung in a human that will be sufficient to
suppress Galectin-3 and provide safe and effective treatment of
pulmonary fibrosis.
[0016] In a still further embodiment the treatment is chronic
treatment.
[0017] The term "treatment" and "treating" as used herein means the
management and care of a patient for the purpose of combating a
condition, such as a disease or a disorder. The term is intended to
include the full spectrum of treatments for a given condition from
which the patient is suffering, such as administration of the
active compound to alleviate the symptoms or complications, to
delay the progression of the disease, disorder or condition, to
alleviate or relief the symptoms and complications, and/or to cure
or eliminate the disease, disorder or condition as well as to
prevent the condition, wherein prevention is to be understood as
the management and care of a patient for the purpose of combating
the disease, condition, or disorder and includes the administration
of the active compounds to prevent the onset of the symptoms or
complications. The treatment is performed in a chronic way. The
patient to be treated is a human subject diagnosed with pulmonary
fibrosis or other types of lung fibrosis.
[0018] The term "an amount effective to treat pulmonary fibrosis"
of a compound of formula (I) of the present invention as used
herein means an amount sufficient to cure, alleviate or partially
arrest the clinical manifestations of pulmonary fibrosis and its
complications. Effective amounts for each purpose will depend on
the severity of the disease or injury as well as the weight and
general state of the subject. It will be understood that
determining an appropriate dosage may be achieved using routine
experimentation, by constructing a matrix of values and testing
different points in the matrix, which is all within the ordinary
skills of a trained physician or veterinary.
[0019] In a still further aspect the present invention relates to a
pharmaceutical composition comprising the compound of formula (I)
and optionally a pharmaceutically acceptable additive, such as a
carrier or an excipient.
[0020] As used herein "pharmaceutically acceptable additive" is
intended without limitation to include carriers, excipients,
diluents, adjuvant, colorings, aroma, preservatives etc. that the
skilled person would consider using when formulating a compound of
the present invention in order to make a pharmaceutical
composition.
[0021] The adjuvants, diluents, excipients and/or carriers that may
be used in the composition of the invention must be
pharmaceutically acceptable in the sense of being compatible with
the compound of formula (I) and the other ingredients of the
pharmaceutical composition, and not deleterious to the recipient
thereof. It is preferred that the compositions shall not contain
any material that may cause an adverse reaction, such as an
allergic reaction. The adjuvants, diluents, excipients and carriers
that may be used in the pharmaceutical composition of the invention
are well known to a person within the art.
[0022] As mentioned above, the compositions and particularly
pharmaceutical compositions as herein disclosed may, in addition to
the compounds herein disclosed, further comprise at least one
pharmaceutically acceptable adjuvant, diluent, excipient and/or
carrier. In one embodiment the pharmaceutical composition contains
neat compound of formula I. In some embodiments, the pharmaceutical
compositions comprise from 1 to 99 weight % of said at least one
pharmaceutically acceptable adjuvant, diluent, excipient and/or
carrier and from 1 to 99 weight % of a compound of formula I as
herein disclosed. The combined amount of the active ingredient and
of the pharmaceutically acceptable adjuvant, diluent, excipient
and/or carrier may not constitute more than 100% by weight (100%
w/w) of the composition, particularly the pharmaceutical
composition. In accordance with the present invention the
pharmaceutical composition may consist of neat compound of formula
I (that is 100% w/w compound of formula I) or contain a 1-90% w/w,
such as 2-20% w/w, for instance a 3% w/w blend of the compound of
formula I.
[0023] Typically, the 3% w/w blend is a pharmaceutical composition
containing 3% w/w compound of formula I and 97% w/w lactose
carrier. For the clinical trials a 10% w/w blend is used and
consist of a pharmaceutical composition containing 10% w/w compound
of formula I and 90% w/w lactose carrier.
[0024] To the person skilled in the art it is well known that
particles with a mean mass aerodynamic diameter (MMAD) between 0.1
and 20 .mu.m (micro meter) have an increased probability of
depositing in the terminal bronchial and alveolar regions. This
particle size range is ideal for many indications in pulmonary drug
delivery, since a portion of the material will still deposit in the
upper airways as well. (Cf. Controlled Pulmonary Drug Delivery,
Smith and Hickey, Editors, Springer 2011, chapter 13).
[0025] In accordance with Controlled Pulmonary Drug Delivery, Smith
and Hickey, Editors, Springer 2011 in particlular chapters 13, 14
and 15 the skilled person will know how to formulate compounds,
such as the compound of formula (I) for pulmonary drug
delivery.
[0026] Dry powder inhalers (DPI), such as metered dose medicament
inhalers are well known for dispensing medicament to the lungs of a
patient. Some previous inhalers have comprised a pressurized
aerosol dispensing container, wherein the aerosols contain gas
propellants in which the powdered medicament is suspended. Upon
actuation, the aerosol contents are expelled, through a metering
valve, and into the lungs of the patient. Preferred DPIs for use in
the present invention is a monodose dry powder inhaler from
Plastiape (HQ, Osnago, Italy), in particular the RS01 Monodose Dry
Powder Inhaler.
[0027] Current designs include pre-metered and device-metered DPIs,
both of which can be driven by patient inspiration alone or with
power-assistance of some type. Pre-metered DPIs contain previously
measured doses or dose fractions in some type of units (e.g,,
single or multiple presentations in blisters, capsules, or other
cavities) that are subsequently inserted into the device during
manufacture or by the patient before use. Thereafter, the dose may
be inhaled directly from the pre-metered unit or it may be
transferred to a chamber before being inhaled by the patient.
Device-metered DPIs have an internal reservoir containing
sufficient formulation for multiple doses that are metered by the
device itself during actuation by the patient. The wide array of
DPI designs, many with characteristics unique to the design, will
present challenges in developing information in support of an
application. Regardless of the DPI design, the most crucial
attributes are the reproducibility of the dose and particle size
distribution. Maintaining these qualities through the expiration
dating period and ensuring the functionality of the device through
its lifetime under patient-use conditions will probably present the
most formidable challenge.
[0028] Pressurized Metered-Dose Inhalers (pMDI) may also be
suitable delivery devices for the present compound of formula (I)
and are described in Controlled Pulmonary Drug Delivery, Smith and
Hickey, Editors, Springer 2011, chapter 8.
[0029] Several types of non-aerosol, breath actuated dry powder
inhalers have therefore been provided. For example, U.S. Pat. No.
5,503,144 to Bacon, shows a breath-actuated dry-powder inhaler. The
device includes a dry powder reservoir for containing a dry
powdered medicament, a metering chamber for removal of the powdered
medicament from the reservoir in discrete amounts, and an air inlet
for entraining the removed powdered medicament through a mouthpiece
upon patient inhalation.
[0030] U.S. Pat. No. 5,458,135 discloses a method and apparatus for
producing an aerosolized dose of a medicament for subsequent
inhalation by a patient. The method comprises first dispersing a
preselected amount of the medicament in a predetermined volume of
gas, usually air. The dispersion may be formed from a liquid or a
dry powder. The method relies on flowing substantially the entire
aerosolized dose into a chamber that is initially filled with air
and open through a mouthpiece to the ambient. After the aerosolized
medicament has been transferred to the chamber, the patient will
inhale the entire dose in a single breath.
[0031] U.S. Pat. No. 6,065,472 discloses a powder inhalation device
comprising a housing containing a pharmacologically active
compound, a conduit with an outlet extending into the housing
through which a user can inhale to create an airflow through the
conduit, a dosing unit for delivering a dose of the compound to the
conduit and baffles arranged within the said conduit to aid
disintegration of powder agglomerates entrained in said
airflow.
[0032] Regardless of whether an aerosol or non-aerosol inhaler is
used, it is of utmost importance that particles of the dispensed
dry powder medicament be small enough to ensure the adequate
penetration of the medicament into the bronchial region of a
patient's lungs during inhalation. However, because the dry powder
medicament is composed of very small particles, and often provided
in a composition including a carrier such as lactose, non-defined
agglomerates or aggregates of the medicament form at random prior
to being dispensed. It has therefore been found preferably to
provide breath-actuated dry powder inhalers with means for breaking
down the agglomerates of medicament or medicament and carrier
before inhalation of the medicament.
[0033] Further embodiments of the process are described in the
experimental section herein, and each individual process as well as
each starting material constitutes embodiments that may form part
of embodiments.
[0034] The above embodiments should be seen as referring to any one
of the aspects (such as `method for treatment`, `pharmaceutical
composition`, `compound for use as a medicament`, or `compound for
use in a method`) described herein as well as any one of the
embodiments described herein unless it is specified that an
embodiment relates to a certain aspect or aspects of the present
invention.
[0035] All references, including publications, patent applications
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference was individually and
specifically indicated to be incorporated by reference and was set
forth in its entirety herein.
[0036] All headings and sub-headings are used herein fix
convenience only and should not be construed as limiting the
invention in any way.
[0037] Any combination of the above-described elements in all
possible variations thereof is encompassed by the invention unless
otherwise indicated herein or otherwise clearly contradicted by
context.
[0038] The terms "a" and "an" and "the" and similar referents as
used in the context of describing the invention are to be construed
to cover both the singular and the plural, unless otherwise
indicated herein or clearly contradicted by context.
[0039] Recitation of ranges of values herein are merely intended to
serve as a shorthand method of referring individually to each
separate value falling within the range, unless other-wise
indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. Unless
otherwise stated, all exact values provided herein are
representative of corresponding approximate values (e.g., all exact
exemplary values provided with respect to a particular factor or
measurement can be considered to also pro-vide a corresponding
approximate measurement, modified by "about," where
appropriate).
[0040] All methods described herein can be performed in any
suitable order unless otherwise indicated herein or otherwise
clearly contradicted by context.
[0041] The use of any and all examples, or exemplary language
(e.g., "such as") provided herein, is intended merely to better
illuminate the invention and does not pose a limitation on the
scope of the invention unless otherwise indicated. No language in
the specification should be construed as indicating any element is
essential to the practice of the invention unless as much is
explicitly stated.
[0042] The citation and incorporation of patent documents herein is
done for convenience only and does not reflect any view of the
validity, patentability and/or enforceability of such patent
documents.
[0043] The description herein of any aspect or embodiment of the
invention using terms such as "comprising", "having", "including"
or "containing" with reference to an element or elements is
intended to provide support for a similar aspect or embodiment of
the invention that "consists of", "consists essentially of", or
"substantially comprises" that particular element or elements,
unless otherwise stated or clearly contradicted by context (e.g., a
composition described herein as comprising, a particular element
should be understood as also describing a composition consisting of
that element, unless otherwise stated or clearly contradicted by
context).
[0044] This invention includes all modifications and equivalents of
the subject matter recited in the aspects or claims presented
herein to the maximum extent permitted by applicable law.
[0045] The present invention is further illustrated by the
following examples that, however, are not to be construed as
limiting the scope of protection. The features disclosed in the
foregoing description and in the following examples may, both
separately and in any combination thereof, be material for
realizing the invention in diverse forms thereof.
EXPERIMENTAL
[0046] The compound of formula I is a novel, inhaled, dry powdered,
anti-Galectin 3 small molecule drug therapy being developed for the
treatment of IPF. Here we describe results from the First in Human
(FIH) study in healthy male volunteers.
METHODS
[0047] This study was a randomized, double-blind, single center,
placebo-controlled, single ascending dose (SAD), phase I study to
assess the safety, tolerability, PK (pharmacokinetics) and PD
(pharmacodynamics) of the compound of formula I in 36 healthy male
volunteers (HV's). 6 dose cohorts 6 subjects were evaluated using a
4:2 ratio (active:placebo). The compound of formula I was delivered
to the lungs of HV's using the RS01 Monodose Dry Powder inhaler
(Plastiape) at the following 6 doses: 0.15 mg, 1.5 mg, 3 mg, 10 mg,
20 mg and 50 mg. The 0.15 mg, 1.5 mg and 3 mg dose was a 3% w/w
lactose blend, whereas the 10 mg, 20 me and 50 mg dose was
formulated as neat material. The specific capsule filling weights
were 5 mg for the 0.15 mg dose, 50 mg for the 1.5 mg dose, 5 mg for
the 10 mg dose and 50 mg for the 50 mg dose. HV's were housed
overnight and vital signs, EKG, physical exam, urinalysis and
laboratory bloods followed for 14 days. PK blood sampling was taken
prior to dosing and then at intervals up to 48 hrs post-dose.
Plasma samples for drug concentration measurements were analyzed by
the Bioanalytical Unit at Simbec (UK). PK variables were determined
using the non-compartmental analysis option in the software
WinNONLIN 6.3 from Certara based in Princeton, N.J. 08540
(www.eertara.com).
RESULTS
[0048] Administration of the compound of formula I was extremely
well tolerated at all 6 doses. Adverse events were only mild in
nature and included headache, cough and dose-related parageusia
(neat blend only) all of which were self-limiting. There were no
significant changes from baseline in any of the following
parameters; EKG, vital signs, bloods and urinalysis up to 2 weeks
post-dose, The compound of formula I was rapidly absorbed, with
mean tmax values ranging, from 0.8 to 3 hrs, independent of dose.
Drug concentrations increased with increasing dose, based on Cmax
and AUC and exhibited dose proportionality. t 1/2 is 12 hrs.
Clearance (CL/F) is high (.about.50,000 mL/hr or 900 mL/min) i.e.
several fold higher than renal filtration. Given these findings and
those consistent with GLP toxieokinetic studies (.about.90% of the
compound of formula I following murine intravenous dosing is found
in the feces), it is probable that the liver (via bile excretion)
is the major route of elimination in man. Based on radioisotope
studies of lung deposition of the compound of formula I in mice,
whereby concentrations of the compound of formula I are fifty times
greater in the lung than in the circulation, combined with Cmax
data from the 3 mg dose at inhaled concentrations used in man,
local concentrations of the compound of formula I in the lung in
man will be 2 fold in excess of those required to suppress
Galectin-3 in lung target cells based on ex-vivo data of
suppression of Galectin-3 in human derived macrophages.
CONCLUSION
[0049] The compound of formula I is a novel, dry powdered inhaled
therapy for the treatment of IPF. Results from this FIH-SAT) study
indicate that the compound of formula (I) is both safe and well
tolerated in man and favorable PK parameters support once daily
dosing. Part II of this study is ongoing wherein 24 patients with
IPF is continually dosed with ascending doses (0.15 mg, 1.5 mg, 3
mg, 10 mg, 20 mg and 50 mg) of once-daily for 2 weeks with inhaled
compound of formula I. Based on these data the compound of formula
I could provide a valuable, safe treatment option for patients with
IPF in the future.
* * * * *