WO 2006/083645 PCT/US2006/002606
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Formulations and Dosing Regimen for PPAR-alpha Modulators
FIELD OF THE INVENTION
This invention relates to methods for treating diseases or conditions with
PPAR-alpha modulators. In particular, this invention relates to dosing regimens for
PPAR-alpha agonist and compositions thereof. A further embodiment of the present
invention is an oral formulation of Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-
comprising 75 g or less of Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl- per
dosage unit.
BACKGROUND OF THE INVENTION
PPAR-alpha agonists are being studied for use to treat or prevent cardiovascular
conditions and/or dyslipidemia. PPAR-alpha agonist compounds are known in the art.
For example, WO 02/038,553 (herein "the '553 patent") discloses PPAR agonist
compounds, methods for preparing, formulations, and uses therefore. However,
applicants are aware of no publications teaching less than daily oral dosing for selective
PPAR alpha agonist compounds.
The '553 publication teaches that the PPAR modulators described therein can be
administered using a daily dosing regimen. The regimen may include a total daily dose
administered in divided doses during the day; however, the dosing regimen does not
direct the artisan to utilize intentional less than daily periodic dosing.
Drug dosing regimens are typically designed to be convenient for the patient, to
promote compliance, to produce maximal benefit, and to minimize undesired side effects.
For most drugs, this is best achieved through constant drug effect at the lowest level.
Daily drug administration is often required to achieve a constant drug effect. For drugs
given daily, efficacy and side effects are generally separable by total drug dosage, with
side effects occurring at drug dosages that are higher by some multiple than the dosage
producing the desired effect.

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Many patients prefer to take medications only once-weekly, once-monthly, or
every other week for increased convenience, improved dosing compliance, and to
minimize patient drug exposure. The present invention fulfills the patient's desire for a
convenient less-than daily dosing regimen for PPAR alpha agonist. The dosing regimen
provided by the present invention may offer patients a more pharmaceutically desirable
safety profile. Further, the surprisingly high potency of the LY518674 compound may
not enable administration of a lower dosage of the compound for a patient desiring a
lower dose. The less frequent dosing regimen provided herein offers such patients a
desirable dosing option that allows the patient to customize or titrate their dose.
In addition to enhanced patient safety, minimization of drug and health provider
cost is sometimes part of the rationale for less than daily dosing. Additionally, less than
daily oral drug administration can be desirable for patients having difficulty swallowing
pills. The dosing regimen provided herein offers patients a dosing option with minimal
drug exposure, convenience, and the potential for enhanced health economics outcomes.
The present invention further provides a clinically desirable formulation
comprising about 75 g or less of Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl or a
pharmaceutically acceptable salt thereof. The formulation offers a pharmaceutically
acceptable, consistent dose, and effective drug delivery of the Propanoic Acid, 2-[4-[3-
[2,5-dihydro-1 -[(4-methylphenyl)methyl] -5-oxo- IH-1,2,4-triazol-3-yl]propyl]phenoxy] -
2-methyl pharmaceutically active agent.
DESCRIPTION of the DRAWINGS
Figure 1. Figure 1 illustrates the time profile of percentage change from baseline for
LDL-C following the administration of daily oral doses of LY518674 over 14 days and
30 day follow up afterwards, in healthy obese subjects in MDSS of a study conducted
substantially as described by Example 1.
Figure 2. Figure 2 illustrates simulated time profiles of percentage change from baseline
for LDL-C following the administration of LY518674 according to different dosing
regimens and placebo as described by Example 4. The total dose administration is similar

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across regimens. The model used -to generate the simulations was based on the results of
an MDSS clinical study conducted substantially as described in Example 1.
SUMMARY OF THE INVENTION
The present invention provides a once monthly dosing regimen for PPAR alpha
modulators.
The present invention provides a once monthly dosing regimen for

In a further embodiment of the present invention, a twice-monthly dosing regimen for
PPAR alpha modulators is provided. The present invention provides a twice-monthly
dosing regimen for

or a pharmaceutical salt thereof.
Further, the present invention provides a pharmaceutically effective bi-weekly dosing
regimen for PPAR alpha compounds. The present invention provides a bi-weekly dosing
regimen for

WO 2006/083645 PCT/US2006/002606

or a pharmaceutical salt thereof.
Briefly, in one aspect, the present invention provides a method of treating a
disease or condition, for example, hyperlipidemia, with a PPAR-alpha agonist comprising
administration of the PPAR-alpha agonist according to a dosing schedule that comprises
at least one period of less than daily dosing of the agonist, for example alternate day
dosing or once every other week or one time per month. The most preferred PPAR-alpha
agonist is LY518674.
A further embodiment of the present invention is a formulation for daily or less
than daily dosing wherein the active PPAR alpha agonist is formulated to contain about
75 g or less per dosage unit. In a further embodiment it may be preferred that the dosage
unit contains about 50 g or less per dosage unit. A further desired embodiment is a
formulation containing about 25 g or less per dosage unit. The active PPAR alpha
agonist that is preferred for the oral dosage form is Propanoic Acid, 2-[4-[3-[2,5-dihydro-
l-[(4-mefhylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-.
Orally administered Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-
oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl- has now demonstrated surprising
potency in human patients. It may be especially preferred that the oral dosage form is
provided as a solid. It can be especially desirable to provide the patient with the smallest
effective dose to provide maximal therapeutic benefit while minimizing any undesired
side effects that may appear in a given patient taking the drug.
Another feature of the present invention is a solid formulation comprising about
25 (.g or less Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-
lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl- per dosage unit and one or more
pharmaceutically acceptable carriers or excipients. Another feature of the present
invention is a solid oral formulation comprising about 25 g or less Propanoic Acid, 2-[4-

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[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-1H-l,2,4-triazol-3-
yl]propyl]phenoxy]-2-methyl- per dosage unit and one or more pharmaceutically
acceptable carriers or excipients. A further feature of the present invention is an oral
formulation comprising 25 g or less Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-per
dosage unit and one or more pharmaceutically acceptable carriers or excipients. It may
be especially desired that each dosage unit contains from about 5 g to about 25 g of
Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-
triazol-3-yl]propyl]phenoxy]-2-methyl-. It may also be preferred that the dosage unit
contains from about 10 g to about 25 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-. The oral
formulation will generally be provided as a liquid or solid dosage unit.
The doing regimen of mis invention, as compared to previously taught dosing
regimens comprising daily or twice daily administration of PPAR-alpha agonist, may
result in no significant decrease in efficacy, for example control of lipids in the blood, but
with a significant decrease in the risk for undesired effects, such liver, cardiac, or skeletal
muscle toxicity. Or, for example, minimizing patient exposure to a potent PPAR-alpha
agonist can further minimize the potential for any dosage related adverse reactions in the
patient.
The dosing regimen of this invention may be used in conjunction with other
treatments. For example, the PPAR-alpha agonist dosing regimen of this invention can
be used in combination with a statin or drugs that increase insulin sensitization.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, a "PPAR-alpha agonist" includes any compound that
selectively activates human PPAR-alpha as demonstrated by any accepted, validated
assay for PPAR alpha activity, or any compound generally recognized as a PPAR-alpha
agonist. See, for example, the PPAR-alpha assay methods described in the '553 patent.
Such PPAR-alpha agonist may be an agonist of more than one PPAR subtype; however,
the PPAR-alpha agonist will selectively activate PPAR-alpha to a significantly greater
degree than PPAR gamma, PPAR delta, or PPAR gamma/delta dual activity. It is

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generally preferred that the PPAR alpha agonist is at least twice as potent agonist of
PPAR alpha as for any other PPAR subtypes. Preferred PPAR-alpha agonists include,
for example, those disclosed in the '553 patent. Particularly preferred are PPAR-alpha
agonist compounds in clinical development, such as, the Eli Lilly and Company
LY518674, Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylpheayl)mthyl]-5-oxo-lH-
1,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-.
As used herein the term "SDSS" means single-blinded, single- placebo-controlled,
dose-escalation study, and the term "MDSS" means multiple-dose placebo-controlled,
dose-escalation study.
In addition to the typical daily drug dosing regimen, there are examples of drugs
that use dosing regimens in which the interval between drug doses is more than a single
day. While the interval may be two days (i.e. alternate-day dosing), or one week (i.e.
once weekly dosing), or an extended period of no dosing following a period of daily
dosing, the underlying principles are the same. In this discussion, any regimen
intentionally comprising an inter-dose interval greater than one day is referred to as less
than daily dosing.
As used herein, the compound LY518674 and Propanoic Acid, 2-[4-[3-[2,5-
dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-
methyl-, each refer to a compound having the structural formula:.

Less than daily dosing is known to be useful for certain pharmacological agents.
For example, less than daily dosing is discussed in therapeutic areas in which
glucocorticoid therapy is a mainstay. See, for example, Axelrod L., Glucocorticoids,
Textbook of Rheumatology, 4th edition, vol 1, pp 779-ff, (1986); Physicians Desk
Reference, 48th edition, section on DELTASONE, pp 2408-2409, (1994); Holland and
Taylor, Glucocorticoids in clinical practice, J Family Prac 32: 512-519, (1991); and

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Hodson EM, Knight JR, Willis NS, and Craig JC, Corticosteroid therapy for nephrotic
syndrome in children (Cochrane Review), The Cochrane Library, Issue 4, (2001).
Alendronate, used for prevention and treatment of osteoporosis, was originally
developed for daily dosing. Subsequently, for various reasons, including minimization of
esophagitis seen as a side effect, the drug was approved for once-a-week dosing. In this
case, knowledge of pharmacokinetics specifically that the drug distributes only into bone
was used to predict that infrequent dosing would be fully efficacious since bone is the
target tissue for the drug. See, for example, Schnitzer, TJ, Update on Alendronate: Once-
Weeklv dosing. Expert Opin Pharmacother 2: 1461-1472, (2001).
The clinical effect for the less than daily dosing regimen for PPAR alpha agonist
appears to be independent of the drug pharmacokinetics. For example Propanoic Acid, 2-
[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-
yl]propyl]phenoxy]-2-methyl- is believed to be cleared from the body within hours;
however, the beneficial effect of the PPAR alpha agonist continues even after the drug
has effectively cleared from the body.
The PPAR alpha agonist, LY518674, is currently being studied for its
effectiveness to slow progression of coronary artery atherosclerosis (reduction in
atheroma volume percent change from baseline vs. placebo on a background of standard
of care) using intravascular ultrasound, during a 2 year period. Additionally, LY518674
is being studied for its effectiveness to slow progression of atherosclerosis in the carotid
artery using carotid intima-media thickness (CMT), i.e, a statistically significant
reduction in the progression of mean maximum CMT vs. placebo on a background of
standard of care during a 2 year period. The LY518674 compound is being studied for a
statistically significant reduction in cardiovascular morbidity/mortality with a relative
reduction in secondary prevention of major adverse cardiac events (MACE) vs. placebo
on a background of standard of care during a 5 year period. LY518674 is also being
studied for an association with a statistically significant decrease in biomarkers associated
with vascular inflammation (e.g. hsCRP) verses placebo, and for regression of
atherosclerosis as may be shown in vascular imaging trials. The LY518674 compound

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can be beneficial for slowing the progression of atherosclerosis through treatment of
dyslipidemia in patients with low HDL and elevated triglycerides.
Pharmaceutical agents that are PPAR alpha agonists can be beneficial for
improving insulin resistance (reducing homeostasis model assessment and qualitative
insulin sensitivity check index). Additionally, PPAR alpha agonists can reduce serum
free fatty acids, increase adiponectin, and decrease the local inflammatory response (high-
sensitivity C-reactive protein [hsCRP], interleukin-6 [IL-6], and tumor necrosis factor
alpha [TNF-]. Further, PPAR alpha agonists can lower levels of fasting triglycerides, and
enhance atherosclerotic plaque stability that may further decrease the risk of ASCVD.
As used herein "Less than daily dosing" will be used to indicate any intentional
dosing regimen that comprises at least one period in which the frequency of dosing is less
than daily, for example every other day, every other week, or one time per month, or
which comprises at least one gap of at more than 1 day where there is no administration
of the PPAR-alpha agonist. In the case of dosing regimens that comprise a gap or day
without administration, as used herein such gaps or days without administration of the
PPAR-alpha agonist must be preceded and followed by administration of agonist once the
initial dose has been administered. This is meant to include any dosing regimen
comprising gaps in dosing of more than one day. For example, the dosing regimens of
this invention include regimens comprising 1 day with and 2 days without, 1 day with and
5 days without, 1 day with and 7 days without, 1 day with and 6 days without, 1 day with
and 14 days without, 1 day with and 13 days without, 1 day with and 21 days without, 1
day with and 20 days without, 1 day with and 30 days without, 1 day with and 28 days
without, 1 day with and 11 days without, 1 day with and 22 days without, 1 day with and
1 day without, etc. This is true regardless of the average number of doses per day. For
example, twice-daily administration every other day would be less than daily dosing. The
dosing regimen of this invention can include several days or weeks of daily or twice daily
dosing followed by a period of less than daily dosing. As used herein a day with dosing
or a day with administration of agonist includes once, twice, or any number of doses on
that particular day.
The present invention relates to a pharmaceutical composition comprising a
compound or pharmaceutically acceptable salt of the present invention, along with a
pharmaceutically acceptable diluent or carrier, is found to show surprising properties.
The pharmaceutical composition of the present invention, therefore, is synergistic.
Preferred dosing regimens are those that comprise periods of once weekly dosing,
or once every other week or that comprise six or thirteen consecutive days without

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administration. When the PPAR-alpha agonist dosing regimen of this invention is used in
combination with administration of a statin or drug(s) that increase insulin sensitivity, or
other additional drug(s) (collectively "combination treatment"), the combination
treatment can be administered with a dosing regimen that is the same as or different from
the PPAR-alpha agonist regimen. As used herein "dosing" and "administration" are
intended to be identical.
As used herein the term "75 g or less of Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-
[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-"
means that the formulation contains no more than about 75 g of Propanoic Acid, 2-[4-[3-
[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-
2-methyl- per dosage unit. It is generally preferred that each dosage unit will contain at
least 1 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-
l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl- or a pharmaceutically acceptable salt
thereof.
As used herein the term "LY518674" means Propanoic Acid, 2-[4-[3-[2,5-
dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-
methyl- as the free acid or a pharmaceutical salt thereof. One preferred salt of Propanoic
Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-
yl]propyl]phenoxy]-2-methyl- is the sodium salt.
EXAMPLES
EXAMPLE 1
Low doses and/or a less than daily dosing regimen clinical study.
A single-blinded, single- (SDSS) and multiple-dose (MDSS), placebo-controlled,
dose-escalation study is designed to evaluate the safety, pharmacokinetics, and
pharmacodynamics of orally administered study drug in healthy obese men and women.
Three different groups of subjects complete a one-step escalation of the study drug dose
within Periods 1 and 2 (SDSS). The design includes a total of 6 active doses (0.1,1,10,
30, 60, and 100 mg) to be tested. The decision to escalate to higher doses is based on the
safety assessment of preceding doses. The minimum time between dose escalations
within Periods 1 and 2 is one week.

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Each of the 3 groups of subjects consist of approximately 9 subjects in a 2:1 ratio
of active treatment to placebo, where the order of placebo administration is randomized
across both the SDSS and MDSS portions of the study. All 3 groups of subjects shall be
scheduled to participate in both SDSS and MDSS portions. However, the SDSS portion
is completed and analyzed several months prior to beginning the MDSS (Period 3/4). The
45-day MDSS portion of the original study is designed to test 4 active doses (0.025,0.1,1
and 10 mg) administered daily for the first 14 days of the study. The MDSS portion
recruits subjects to form 4 groups of subjects. Approximately 36 subjects (9 per dose
group) are enrolled into the MDSS portion of the study.
Safety is assessed throughout the study by physical examination, adverse event
monitoring, electrocardiograms, clinical laboratory tests, and vital sign measurements.
Pharmacodynamic evaluation includes a postprandial lipid response during the single-
dose safety portion. During the multiple-dose safety study, the pharmacodynamic
evaluation includes an oral glucose tolerance test, a fasting lipid panel and a postprandial
lipid test. The static lipid panel included triglycerides, total cholesterol, low-density
lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C],
Apoliproteins Al, A2, B, and C3 for cholesterol metabolism. C-reactive protein (CRP)
and adiponectin are measured as biomarkers for inflammation and peroxisome
proliferated agonist receptor (PPAR) gamma activity, respectively. The dynamic lipid
tests include post-prandial measurements of glucose and triglycerides.
The clinical study of Example 1 can be useful to demonstrate the effectiveness of low
doses of study drug and/or less than daily dosing as claimed, respectively, herein.
Results:
An SDSS clinical study was conducted substantially as described above by this
Example 1 using LY518674 as the study drug. Gastrointestinal intolerance was assessed
at 30 and 60 mg prohibiting administration of higher doses. Therefore, the 6th dose
(100 mg) was replaced by a 0.01 mg dose.
Patients receiving the 0.01 mg dose displayed an LDL-C reduction consistent with
the reduction observed at the higher doses. ApoB and ApoC decreased in a fashion

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similar to that seen for LDL-C changes. The compound was rapidly absorbed after oral
administration in healthy obese subjects. The median time at maximal concentration
(tmax) was approximately 0.5 to 1 hour. The exposure appeared dose-proportional within
the studied range. No differences were noted in the pharmacokinetics of the compound
following single- and multiple-dose administration. Steady-state exposure of LY518674
was reached within 2 days, achieving minimal accumulation (mean accumulation ratio of
no more than 1.35), consistent with a short half-life (less than 10 hours).
Results of an SDSS study:
A meal tolerance test (MTT) was performed from 24 to 37 hours after each single
dose during the SDSS portion of a clinical trial conducted substantially as described
herein by Example 1 using LY518674 as the study drug. The data are analyzed by
calculating an area under the concentration-time curve"for triglycerides, nonesterified
fatty acids and glucose over the postprandial periods from breakfast to lunch (area under
the effect curve [AUEC{24-28}]), after lunch (AUEC[28-37]), and the entire test period
(AUEC[24-37]).
LY518674 had a rapid and profound reduction of triglyceride (TG) AUEC, as
shown in Table 1 of this report. Furthermore, LY518674 exhibits a clear dose response
that appears to approach a maximum AUEC reduction at approximately 1 mg.
Remarkably, the effect continues throughout the test period as exhibited by the data
obtained between 28 through 37 hours post dose.

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Table 1.
Comparison of Triglyceride AUEC (mmol-hr/L) Between Study drug and Placebo
from Meal Tolerance Test in Single-Dose Portion
SDSS Dynamic Lipid Ratio of geometric means
TG
(mmol-hr/L) Dose
(nig) Geometric mean
(95% CI) Dose in row vs. Placebo
(95% CI) [p-value]
AUEC(24-37) Placebo 44.6(39.7, 50.1)
0.01 37.8(31.2, 45.8) 0.85 (0.70,1.02) [0.083]
0.1 27.6(23.0, 33.2) 0.62 (0.52, 0.74) [<001*]
1 23.9 (20.0, 28.6) 0.54 (0.45,0.64) [<.001*]
10 24.3(20.1, 29.5) 0.55 (0.45,0.67) [<001*]
30 20.0 (16.3, 24.5) 0.45 (0.37,0.54) [<.001*]
60 25.2(20.6, 30.7) 0.56 (0.46, 0.69) [<.001*]
Abbreviations: AUEC = area under the effect curve; CI = confidence interval; SDSS = single-dose safety
study; TG = triglycerides.
* p-values < 0.05.
The results of this single dose study illustrate that LY518674 can provide a
pharmaceutically desirable effect when dosed as low as 100 .g using a less than daily
dosing regimen.

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Results of an MDSS study
The data from treatment period (Days 1 through 14) and recovery period (Days 15
through 44) for LDL-C is depicted in Figure 1. LDL-C was dramatically reduced by
LY518674 with similar responses for total cholesterol and apolipoproteins B and C3. All
doses produced similar magnitudes of change in these parameters. All parameters were
back to baseline within 2 weeks after cessation of dosing. The maintenance of a
pharmacological effect for nearly 14 days after dosing stopped, despite the half life of
about 10 hours for LY518674 further supports that a less than daily dosing regimen may
be desired for LY518674. The results of this study illustrate that LY518674 can provide
a pharmaceutically desirable effect when dosed as low as 25 g, using a less than daily
dosing regimen.
EXAMPLE 2
The effectiveness of the low doses claimed herein can be further demonstrated by
the following example.
This is a single- and multiple-dose, randomized, single-blind, placebo-controlled
study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of orally
Study drug in adult male subjects. This study consists of two portions for single dose and
multiple doses. The doses selected for this study will be 1 (g, 10 |g, 25 |0.g and 100 g.
Subjects will be assigned to one of the 4 dose groups. Subjects will receive both single
and multiple dose of study drug or placebo. Each subject will receive the same Study
drug dose (or placebo) in their single and multiple dose periods. Each subject will have
control day (Baseline day) with safety measures (ECGs, blood pressure and pulse rate)
matched time on Day 1 or Day 19 before Study drug or placebo dose and will be admitted
to the clinical research unit (CRU) on Day -1 (the day before dosing day of single dose
period) and remain in the CRU until Day 22. Subjects will be discharged on Day 22 after
safety evaluation. After discharged, subjects will visit the CRU for the follow-up
evaluation between 5 and 10 days after last dose.

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On Day 1, subjects will receive single doses of study drug (or placebo) and On
Day 6, subjects will start the 1st dosing for multiple dose period. Subjects receive the
study drug (or placebo) every morning on Day 7 - 19. (Table 1).

Dosing Schedule- Table 1
Groupa Number of Subject Single dose period
Dayl Multiple Dose Period
Day 6 -19
1 8
2 Study drug 1 g
Placebo Study drug 1 g
Placebo
2 8
2 Study drug 10 g
Placebo Study drug 10 g
Placebo
3 8
2 Study drug 25 g
Placebo Study drug 25 g
Placebo
4 8
2 Study drug 100 g
Placebo Study drug 100 g
Placebo
a It is intended that 40 subjects will be enrolled.
It is intended that up to 52 subjects may be enrolled into 4 dose groups to complete a
minimum of 32 subjects (8 per group). The multiple doses of study drug should be
started after obtaining safety information from Day 1 to the morning of Day 6 in all
subjects (8 active and 2 placebo) at each group. The single dose administration for the
next dose group should be given after obtaining safety information at final dosing (Day
19) from all subjects for previous group. Safety will be assessed throughout the study.
Blood samples will be collected from all subjects receiving active study drug and placebo.
The Example 2 clinical study can be conducted substantially as described herein
above in Japanese male subjects using LY518674 as the study drug. This study design
can be used to demonstrate the clinical effectiveness of a dosage containing 25 (g, 10 g
and 1 .g respectively of LY518674.

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Example3
Less than daily dosing pre-clinical study
Studies will be performed in human apoA-I transgenic mice to characterize the
ability of Study drug to increase HDL-C and to lower serum triglycerides in a less than
daily dosing paradigm. Animals will be divided into groups of six and dosed with 0.3
mg/kg Study drug either daily, every-other day, every three days or once a week for two
weeks by oral gavage with suspensions of me free acid or with vehicle (1% wt/v CMC,
0.25% Tween 80). Animals will be bled by cardiac puncture following euthanasia with
CO2. Serum will be prepared for determination of HDL-cholesterol by fast protein liquid
chromatography (FPLC) and for determination of total serum cholesterol and
triglycerides by enzymatic analysis from individual animals. Triglyceride and HDL-
cholesterol levels from animals administered less than daily dosing Study drug will be
compared to levels obtained from animals administered the daily dosing paradigm.
Effects of a less than daily dosing paradigm of Study drug on LDL-cholesterol
will be determined using Golden Syrian hamsters fed a high-fat/high-cholesterol diet
(10% coconut oil, 0.12% cholesterol). Animals will be divided into groups of six and
dosed with 3 mg/kg Study drug either daily, every-other day, every three days or once a
week for two weeks by gavage with suspensions of the free acid or with vehicle (1% wt/v
CMC, 0.25% Tween 80). Animals will be bled by cardiac puncture following euthanasia
with CO2. Serum will be prepared for determination of LDL-cholesterol by fast protein
liquid chromatography (FPLC). LDL-cholesterol levels from animals administered less
than daily dosing Study drug will be compared to levels obtained from animals
administered the daily dosing paradigm.
The results of these studies can be useful to demonstrate that triglyceride-
lowering, HDL-raising, and LDL-lowering efficacy mediated by LY518674 may be
achieved with less than daily dose administration.
EXAMPLE 4
Clinical Simulation of less than daily dosing using results from a clinical trial-
MDSS study completed substantially as described in EXAMPLE 1.

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The effectiveness of less than daily dosing claimed herein can be further
demonstrated through mathematical simulations. A model was built based on MDSS data
that related the time course of drug concentration to the time course of LDL reduction.
The relationship is based on a hypothesized stimulation of LDL clearance as the
mechanism of action for LY518674 LDL reducing effect. The model enabled simulations
of many different scenarios of dosing regimens. To illustrate the effectiveness of less than
daily doses, the following 90-day dosing scenarios were simulated and compared to
placebo: Once daily dosing, 6 once-daily dosing periods interrupted by one dose-free day,
2 once-daily dosing periods interrupted by one dose-free day, once every-other-day
dosing, 1 dose every 3 days, 1 dose every week. The total dose administration was kept
the same across the dosing scenarios, where the daily dosing amount during the dosing
periods for the less-than-daily dosing scenarios was increased compared to the once-daily
dosing scenario. The starting baseline LDL-C was 142 mg/dL, which was observed in the
MDSS study. The dose used in the mathematical simulations was 100 ug for the once-
daily dosing scenario. The methods used to create the mathematical simulations reported
herein are consistent with typical methods known to the skilled artisan.
Results.
The model-predicted time-course of LDL is depicted in Figure 2. The area under LDL
time course (AUEC-LDL) represents the total effectiveness, and when compared after 3
weeks from the start of therapy it represents steady-state behavior. The AUEC-LDL from
3 to 13 weeks after the start of therapy was calculated for the aforementioned scenarios
and is presented in Table 3. As seen from Figure 2 and Table3, all dosing regimens
provide clear effectiveness, to varying degrees, compared to placebo.

WO 2006/083645 PCT/US2006/002606
18

Table 3. The area under the LDL-C time curve from 3 weeks to 13 weeks of
administration in comparison to placebo.
Scenario % Change in AUEC-LDL from
placebo
Placebo 0
Once Daily -27
6 Out of 7 Days -26
2 Out of 3 Days -26
1 Out of 2 Days -26
1 Out of 3 Days -24
Once Weekly -15


What is claimed is;
1. Method of treating a disease or condition with Propanoic Acid, 2-[4-f 3-[2,5-
dihydro- l-l(4-methylphenyl)methyl]-5-oxo-lH- l,2,4-triazol-3-
yl)propyl]phenoxy]-2-methyl- or a pharmaceutical salt thereof (LY518674),
comprising administration of LY518674.according to a dosing schedule, which
comprises a period of less than daily dosing.
2. . The method as claimed by Claim 1 wherein the dosing schedule comprises at
least one day in which there is no administration of LY518674.
3. The method as claimed by any one of Claims 1 through 2 wherein the dosing
schedule comprises seven consecutive days in which there is no administration of
LY518674.
4. The method as claimed by any one of Claims 1 through 3 wherein the dosing
schedule comprises administration of LYS18674 no more frequently than a period
selected from the group consisting of once-weekly and bi-weekly.
5. The method as claimed by Claim 4 wherein the dosing schedule is no more
frequently than once-weekly.
6. A method as claimed by any one of Claims 1 mrough 5 wherein the PPAR-alpha
agonist is

7. A method as claimed by any one of Claims 1 through 6 wherein the disease or
condition is selected from the group consisting of hyperglycaemia, dyalipidemia,
Type II diabetes, Type I diabetes, hypertension, obesity, anorexia bulimia,
anorexia nervosa, and cardiovascular disease, including ischemia-reperfusion
injury and atherosclerosis, cancer, and Alzheimer's Disease.
8. A method as claimed by Claim 7 wherein the disease or condition is selected from
the group consisting of dyslipidemia and cardiovascular disease.
9. The method of Claim 8 wherein the disease or condition is hyperlipidemia.

10. The method of Claim S wherein the disease or condition is atherosclerosis.
11. Methods as claimed by any one of Claims 1 through 10 further comprising
administration of insulin or an agent that stimulates insulin sensitization.
12. A method as claimed by any one of Claims 1 through 10 further comprising the
administration of an agent that lowers the blood level of undesired lipids.
13. A method as claimed by any one of Claims 1 through 10 further comprising the
administration of an agent that increases the blood level of HDL or a desired lipid.
14. A method as claimed by any one of Claims 1 through 10 further comprising
administration of an agent is selected from the group consisting of a statin or a
fibrate.
15. A kit comprising at least one pharmaceutically effective dosage unit of Propanoic
Acid,2-[4-L3-L2,5-dihydro-l-[{4-methylphenyl)methyl]-5-oxc-1Hm-l,2,4-triazol-3-
yl]propyl]phenoxyl-2-methyl- or a salt thereof, and further comprising labeling
instructions.for administration according to a continuous schedule having a dosing
interval selected from the group consisting of once-weekly dosing and bi-weekly
dosing.
16. A dosage unit comprising about 75 g or less Propanoic Acid, 2-[4-[3-[2,5-
dihydro-l-[(4-methylphenyl)methylJ-5-oxo-lH-l,2,4-triazol-3-
yl]propyl]phenoxy]-2-methyl- or a salt thereof, and at least one pharmaceutically
acceptable carrier or excipient
17. A dosage unit as claimed by Claim 16 wherein the dosage unit is a formulation
comprising less than about 50 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-or
a salt thereof,
18. A dosage unit as claimed by Claim 17 wherein the dosage unit is a formulation
comprising less than about 25 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)roethyl]-5-oxo-lH-l,2,4-triazol-3-yllpropyl]phenoxy]-2-methyl-or
a salt thereof.
19. A dosage unit as claimed by Claim 18 wherein the dosage unit is a formulation
comprising about 25 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl|-5-oxo- IH- l,2,4-triazol-3-yl]propyl]phenoxy|-2-methyl- or
a salt thereof.

21
20. A dosage unit as claimed by any one of Claims 16 through 19 wherein the dosage
unit is a solid formulation,
21. A dosage unit as claimed by Claim 20 wherein the dosage unit is a formulation
comprising from about 10 g to about 25 g Propanoic Acid, 2-f4-[3-[2,5-
dihydro-1 -[(4-methylphenyl)methyl)-5-oxo- IH-1,2,4-triazol-3-
yl]propyllphenoxyI-2-methyl- or a salt thereof.
22. A dosage unit as claimed by Claim 20 wherein the dosage unit is a formulation
comprising from about 5 g to about 10 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-
l-l(4-methylphenyl)methyl]-5-oxo-lH-l,2,4-triaxoI-3-yl]propyl]phenoxy]-2-
methyl- or a salt thereof.
23. A dosage unit as claimed by Claim 20 wherein the dosage unit is a formulation
comprising less than about 5 g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo- 1H-1,2,4-tiiazol-3-yl]propyl }phenoxy]-2-methyl- or
a salt thereof.
24. A dosage unit as claimed by claim 20 wherein the dosage unit is a formulation
comprising about I g Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methyl]-5-oxo- IH-1,2,4-mazol-3-yl]propyl]phenoxy]-2-rnethyl- or
a salt thereof.
25. A dosage unit as claimed by any one of Claims ) 6 through 24 wherein the dosage
unit is a pharmaceutical formulation.
26. A dosage unit as claimed by any one of Claims 16 through 24 wherein the dosage
unit is a tablet or capsule formulation.
27. A dosage unit as claimed by Claim 26 wherein the dosage unit is a tablet
formulation.
28. A dosage unit as claimed by any one of Claims 16 through 27 wherein the dosage
unit is an oral formulation.
29. A dosage unit as claimed by any one of Claims 16 through 28 wherein the active
Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-methylphenyl)methyl]-5-oxo- 1H-
l,2,4-triazol-3-yI]propyl]phenoxy]-2-methyl- is the free acid.
30. A dosage unit as claimed by any one of Claims 16 through 28 wherein the dosage
unit is a formulation comprising from about 5 g to about 25 g Propanoic Acid,

2-[4-[3-[2,5-dihydro-l"((4-meihylphenyl)methyl]-5-oxo-lH-U,4-triazol-3-
yl]propyl]phenoxy]-2-methyl- or a salt thereof.
31. A pharmaceutical composition comprising 75 g or less
Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[ (4-methylphenyl) methyl] -5-oxo-
lH-l,2,4-triazol-3-yl] propyl] phenoxy] -2- methyl or a salt thereof, and at
least one pharmaceutically acceptable carrier or excipient.
Dated this 23 rd day of August, 2007.
32. A pharmaceutical composition as claimed in Claim 1, wherein
the pharmaceutical composition is a formulation comprising less than about
50 ug Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4- methylphenyl)methyl]-5-
oxo-lH-l,2,4-triazol-3-vllpropvllphenoxvl-2-methvl- or a salt thereof.

The present invention provides dosing regimens for Propanoic Acid, 2-[4-[3-[2,5-
dihydro-1 -[(4-methylphenyl)methyl]-5-oxo- IH-1,2,4-triazol-3-yI[propyI]phenoxy]-2-
methyl- and compositions thereof. A further embodiment of the present invention is a
solid oral formulation of Propanoic Acid, 2-[4-[3-[2,5-dihydro-l-[(4-
methylphenyl)methylJ-5-oxo-lH-l,2,4-triazol-3-yl]propyl]phenoxy]-2-methyl-
comprising 75 µg or less of Propanoic Acid, 2-[4-[3-[2.5-dihydro-l-f(4-
methylphenyl)methyl]-5-oxo-lH-l,2,4-triazol-3-yllpropyl]phenoxy]-2-methyl- per
dosage unit.