Vol.:(0123456789)

Clinical Drug Investigation

https://doi.org/10.1007/s40261-020-00981-9

ORIGINAL RESEARCH ARTICLE

First‑in‑Man Safety, Tolerability, andPharmacokinetics ofaNovel

andHighly Selective Inhibitor ofMatrix Metalloproteinase‑12, FP‑025:

Results fromTwo Randomized Studies inHealthy Subjects

KhalidAbd‑Elaziz

· ChristineVoors‑Pette

· Kang‑LingWang

2,3

· SandyPan

· YishengLee

· JohnMao

·

YuhuaLi

· BenjaminChien

· DavidLau

· ZuzanaDiamant

1,6,7,8

Accepted: 21 October 2020

Abstract

Background and Objectives Matrix metalloproteinases (MMPs) are proteases with diﬀerent biological and pathological

activities, and many have been linked to several diseases. Targeting individual MMPs may oﬀer a safer therapeutic potential

for several diseases. We assessed the safety, tolerability, and pharmacokinetics of FP-025, a novel, highly selective oral matrix

metalloproteinase-12 inhibitor, in healthy subjects.

Methods Two randomized, double-blind, placebo-controlled studies were conducted. Study I was a ﬁrst-in-man study,

evaluating eight single ascending doses (SADs) (50–800 mg) in two formulations: i.e., neat FP-025 in capsule (API-in-

Capsule) and in an amorphous solid dispersion (ASD-in-Capsule) formulation. In Study II, three multiple ascending doses

(MADs) (100, 200, and 400 mg, twice daily) of FP-025 (ASD-in-Capsule) were administered for 8days, including a food-

eﬀect evaluation.

Results Ninety-six subjects were dosed. Both formulations were well tolerated with one adverse event (AE) reported in the

800 mg API-in-Capsule SAD group and seven AEs throughout the MAD groups. The exposure to FP-025 was low with the

API-in-Capsule formulation; it increased dose-dependently with the ASD-in-Capsule formulation, with which exposure to

FP-025 increased in a greater-than-dose-proportional manner at lower doses (≤100mg) but less proportionally at higher

doses. The elimination half-life (t

1/2

) was between 6 (Study I) and 8h (Study II). Accumulation of FP-025 was approxi-

mately 1.7-fold in the MAD study. Food intake delayed the rate of absorption, but without eﬀect in theextent of absorption

or bioavailability.

Conclusion FP-025 was well tolerated and showed a favorable pharmacokinetic proﬁle following ASD-in-Capsule dosing.

Eﬃcacy studies in target patient populations, including asthma, chronic obstructive pulmonary disease (COPD), and pul-

monary ﬁbrosis, are warranted.

Trial registration number: www.clini caltr ials.gov: NCT02238834 (Study I); NCT03304964 (Study II).

Trial registration date: Study I was registered on 12 September 2014 while study II was registered on 9 October 2017.

* Khalid Abd-Elaziz

[email protected]

Extended author information available on the last page of the article

1 Introduction

Matrix metalloproteinases (MMPs) comprise a family of

over 20 zinc-dependent proteases and exhibit a wide range

of biological activities [1–4]. As a class, MMPs show struc-

tural similarities and share an array of common substrates;

however, individual MMPs have distinct functions depend-

ing on their environment [1, 5]. Delivered as inactive zymo-

gens, the pro-MMPs undergo proteolytic and non-proteolytic

cleavage activation into the respective MMPs [6, 7]. MMPs

play a pivotal role in the degradation and removal of the

extracellular matrix, which is vital for several physiologi-

cal processes, including morphogenesis, tissue repair, and

remodeling [2, 8]. More recent data from both animal and

human studies show that MMPs are also involved in various

other biological processes [9, 10], including cell migration

[11], cell proliferation [12], wound healing [13], immunity,

and inﬂammation [14, 15].

K.Abd-Elaziz et al.

Key Points

Non-selective inhibition of matrix metalloproteinases

(MMPs) has been associated with serious side eﬀects

resulting in discontinuation of development programs.

FP-025, an oral MMP-12 inhibitor, was safe, well toler-

ated and showed a favorable pharmacokinetic proﬁle in

healthy subjects at all single- and multiple-ascending

doses tested in ASD-in-Capsule formulation, warranting

exploration of its activity in target populations.

MMP-12 (half maximal inhibitory concentration (IC

0.04 µM), with 90-fold selectivity over the next closest

family member (MMP-2) and two to three orders of magni-

tude selectivity over the seven other MMP family members

(MMP-1, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and

MMP-14) that were tested (unpublished data).

Currently, FP-025 is under development for the treatment

of chronic respiratory diseases. In unpublished experimental

results, FP-025 demonstrated anti-inﬂammatory activities

and reduced levels of tumor necrosis factor-α (TNF-α) and

interleukin-5 (IL-5) in lungs, resulting in improved lung

function and histology in a mouse model of allergic asthma.

In oﬀ-target receptor panel screen, FP-025 did not show

any important secondary pharmacodynamic interactions

or safety related pharmacodynamic issues. Safety pharma-

cology studies of FP-025 revealed no signiﬁcant eﬀects in

animal models.

Here we present the first-in-man safety and pharma-

cokinetics data of FP-025 derived as primary objectives

from two studies in healthy subjects. Secondary objectives

included evaluation of pharmacokinetics of single and mul-

tiple ascending FP-025-doses. An exploratory objective was

food eﬀect on the pharmacokinetics of FP-025.

2 Subjects andMethods

2.1 Study Designs

Two phase I studies were performed. The ﬁrst study (Study

I) was a double-blind, randomized, placebo-controlled, sin-

gle ascending-dose (SAD) study performed at Taipei Veter-

ans General Hospital, Taipei, Taiwan (Fig.2). Participants

were conﬁned to a phase I unit from day −1 till day 2. The

second study (Study II) was a double-blind, randomized,

placebo-controlled multiple ascending-dose (MAD) study,

which also included an open-label food-eﬀect part, con-

ducted at QPS-Netherlands, Groningen, the Netherlands

(Fig.3). Subjects were admitted to the phase I unit on day

−1 and discharged on day 10. Both studies were sponsored

by Foresee Pharmaceuticals Co., Ltd., Taipei, Taiwan and

were conducted in compliance with the current version of

the Declaration of Helsinki for medical research in human

subjects, the International Council for Harmonisation guide-

lines for Good Clinical Practice including locally applicable

regulations. All subjects provided written informed consent

prior to study enrollment.

Both study protocols, including amendments and asso-

ciated documents, were approved by the local institutional

review boards (Study I was approved by institutional

review board, Taipei Veterans General Hospital, Taipei,

Tawian; Study II was approved by Independent Ethics

Committee, Stichting BeBo, Assen, the Netherlands). Both

As a consequence of their pro-inﬂammatory and tissue-

remodelling activities, several MMPs are involved in the

pathophysiology of chronic inﬂammatory airway diseases

[16, 17], and hence, could serve as therapeutic targets. How-

ever, previous studies have shown that non-speciﬁc target-

ing of MMPs resulted in broad-spectrum inhibition of pro-

teolytic activities, inducing a variety of (serious) adverse

events (AEs) and oﬀ-target eﬀects [18], and, consequently,

the clinical development of non-selective MMP-inhibitors

was preliminarily discontinued [19–25]. Selective targeting

may therefore oﬀer a safer option.

Among the MMP family, MMP-12 is a 54-kDa proen-

zyme, which is processed into a 45-kDa and subsequently

into a 22-kDa active form [26, 27]. Known as macrophage

elastase, MMP-12 is predominantly detected in alveolar

macrophages [27]. In addition, MMP-12 is produced by

bronchial epithelial cells [28] and airway smooth muscle

cells [29]. In both animals and humans, this protease is

involved in type 2 inﬂammation as well as in tissue remod-

eling through its ability to turn over elastin during the whole

life cycle [30–33]. Accumulating evidence has suggested the

involvement of MMP-12 in the pathophysiology of chronic

inﬂammatory airway diseases [16, 31]. In patients with

asthma, chronic obstructive pulmonary disease (COPD),

and/or pulmonary ﬁbrosis, the extent of airway remodeling

and/or disease severity correlates with gene expression,

local airway concentrations, and/or activitities of MMP-12

[33–37]. Recent evidence from a transgenic mouse model of

type 2 inﬂammation showed that eosinophil-derived inter-

leukin (IL)4/13 promoted MMP-12 release from alveolar

macrophages and was associated with alveolar destruction

[38]. Similarly, in patients with chronic inﬂammatory airway

disease, sputum eosinophilia was associated with increased

MMP-12 levels, which negatively correlated with lung func-

tion [38]. These data underscore the association between

type 2 eosinophilic inflammation and MMP-12 and its

potentially important role in the pathophysiology of airway

remodeling (Fig.1).

FP-025 (C

S) is a novel oral, non-hydroxy-

maic small molecule. FP-025 is a high-aﬃnity inhibitor of

Safety, Tolerability, and Pharmacokinetics of FP-025

studies were registered in ClinicalTrial.gov (study identiﬁers

NCT02238834 and NCT03304964, respectively).

2.2 Study Subjects

Eligible participants were healthy male subjects (Study I)

or male and female subjects of non-child-bearing poten-

tial (Study II), aged between 18 and 65 years, and were

in overall good physical and mental health condition as

determined by medical history and physical, vital signs,

laboratory and electrocardiographic (ECG) examinations.

Other inclusion criteria consisted of a body mass index

between 18 and 30 kg/m

, a resting pulse rate between 50

and 100 beats per minute and resting blood pressure with

a systolic blood pressure of ≤ 140 mmHg and a diastolic

blood pressure of ≤ 90 mmHg. Male subjects had to use

adequate contraception during and until 3 months after

completion of the study. Main exclusion criteria consisted

of: A history of alcohol or drug abuse, or current smoker

or using other nicotine products. Use of any prescription

or non-prescription medications, herbal remedies, vita-

mins, or minerals within 2 weeks prior to the ﬁrst dose (or

within ﬁve half-lives prior to inclusion for any medica-

tions ingested, whichever was longer). A positive test for

hepatitis virus B or C, or human immunodeﬁciency virus,

or a QT interval (according to ECG examinations after

Bazett’s correction) of more than 450 ms.

2.3 Study Medication andRegimens

Based on the No Observed Adverse Eﬀect Levels (NOAELs)

for the 28-day toxicity studies, the human equivalent dose

for the rat yields a more conservative value of 161 mg/kg/

day. To be conservative, a safety margin of 50-fold is chosen

for the starting dose of the ﬁrst-in-human study, resulting in

a starting dose of 200 mg in humans (161 (mg/kg)/50=3.22

(mg/kg), which is approximately 200 mg using a body

weight of 70 kg). Two diﬀerent oral formulations of FP-025

were tested. The initial formulation was a neat active (spray-

dried API in capsule) pharmaceutical ingredient (API) in

oral capsules of FP-025 (API-in-Capsule), which was tested

at the dose levels of 200 mg, 400 mg, and 800 mg. Due to

the persistence of low exposure to API-in-Capsule formula-

tion in the ﬁrst three cohorts, another formulation was used.

Subsequently, an improved oral formulation was tested,

the amorphous solid dispersion (ASD) of FP-025 (ASD-in-

Capsule) at dose levels of 50 mg, 100 mg, 200 mg, 300 mg,

and 450 mg (Fig.2).

Fig. 1 Role of MMP-12 as a potential mediator of both inﬂammatory processes and structural changes that occur in asthma and chronic obstruc-

tive pulmonary disease (COPD). TGF transforming growth factor, TNF tumor necrosis factor, MMP matrix metalloproteinase

K.Abd-Elaziz et al.

In Study II, the following treatments were administered:

100 mg (treatment A), 200 mg (treatment B), and 400 mg

(treatment C) FP-025 ASD-in-Capsule twice daily (one

dose on Days 1 and 8 , twice-daily doses Days 2–7). In the

food-eﬀect part, eight subjects received 200 mg FP-025

ASD-in-Capsule as a single dose in a randomized manner,

once under fasting conditions (treatment D) and once after

the intake of a high-fat breakfast (treatment E, following

Assessed for eligibility (n=88)

Excluded (n=15)

Not meeting inclusion criteria (n=14)

Declined to participate (n=1)

Approved screening but not included (n=9)

API-in-Capsule (n=18)

ASD-in-Capsule (n=30)

Randomized (n= 64)

Placebo

(n=16)

Cohort 8

450 mg

(n=6)

Cohort 7

350mg

(n=6)

Cohort 6

200mg

(n=6)

Cohort 5

100mg

(n=6)

Cohort 4

50 mg

(n=6)

Cohort 3

800mg

(n=6)

Cohort2

400mg

(n=6)

Cohort 1

200mg

(n=6)

Completed

(n=6)

Completed

(n-6)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Completed

(n-16)

Fig. 2 Subject ﬂow diagram (single ascending dose, Study I). API active pharmaceutical ingredient, ASD amorphous solid dispersion

Fig. 3 Subject ﬂow diagram

(multiple ascending-dose and

food-eﬀect part, Study II)

Assessed for eligibility (n=76)

Excluded (n=25)

Approved screening but not included (n=19)

Multiple ascending dose

Food effect part

Randomized (n= 32)

Sequence ED

(Fed-Fasted)

200 mg

n=4

Sequence DE

(Fasted-Fed)

200 mg

n=4

Placebo

(n=6)

Cohort C

400 mg

(n=6)

Cohort B

200 mg

(n=6)

Cohort A

100 mg

(n=6)

Completed

(n=4)

Completed

(n=4)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Completed

(n=6)

Safety, Tolerability, and Pharmacokinetics of FP-025

the US Food and Drug Administration (FDA) composition),

with a wash-out period of 1 week between successive dos-

ing (Fig.3).

In both studies, matching placebo capsules were used.

The randomization code and randomization list were gener-

ated using SAS program version 9.3.

2.4 Safety andTolerability Assessments

andAnalysis

Safety and tolerability were assessed throughout the studies

by AE reporting, vital sign measurements, physical exami-

nation, laboratory tests, and ECG examinations. All adverse

events were coded according to MedDRA version 20.0.

2.5 Pharmacokinetic Assessments andAnalysis

In Study I, blood samples (6 mL/sample) for plasma concen-

trations of FP-025 were drawn at 0.5, 1, 2, 3, 4, 6, 8, 12, 16,

20, 24, and 36 h after each single dose. In Study II, multiple

blood samples were collected post-dosing on Day 1 (at 0.5,

1, 2, 3, 4, 6, 8, 12, and 16 h) and Day 8 (at 0.5, 1, 2, 3, 4, 6, 8,

10, 12, 16, 20, 24, 30, 36, and 48 h) as well as immediately

pre-morning dose on Days 2–7 and 2 h post-morning dose

on Days 4 and 6.

After collection, blood samples were kept in ice, and

within 15 min of collection were centrifuged at 2000 rpm for

10 min at 4°C, and, subsequently, the plasma was aliquoted,

frozen, and stored at –70°C pending pharmacokinetics

analyses. The samples were subjected to liquid chromatogra-

phy followed by analyses by tandem mass spectrometry (LC-

MS/MS). The analysis method used for the determination of

FP-025 in human plasma is a liquid-liquid extraction (LLE)

and LC-MS/MS. The LC-MS/MS method has two mobile

phases (mobile phase A and mobile phase B). The m/z tran-

sitions from Q1 mass (393.1 amu) to Q3 mass (194.7 amu)

was in 200 ms. The retention time of the component is 1.26

(min). Precision and accuracy of FP-025 plasma concentra-

tions were evaluated intraday, in three separate analysis runs

acquired on three diﬀerent days, and interday, over the same

three analysis runs. This method shows adequate precision

and accuracy over a concentration range of 5.00 to 5000 ng/

mL. The assay is selective for FP-025. Stability of FP-025

in sample extracts was conﬁrmed for 96 h at 2–8°C, and for

a batch size at the length injection of 160 extracts. Recov-

ery of FP-025 and the Internal Standard (IS) was consistent

over the concentration range, and the IS corrected well in

the recovery assessment. No carry-over or matrix eﬀect was

observed for FP-025.

The plasma pharmacokinetics variables were derived by

non-compartmental analyses using Phoenix

WinNonlin

version 6.3 or higher (Pharsight Corporation Inc., Mountain

View, CA, USA).

Fecal excretion (> 97%) was the dominant elimination

route for 14C-FP-025-derived radioactivity after oral admin-

istration in rats, compared to ∼2% urinary recovery (unpub-

lished data), therefore no urine was collected.

No formal dose-proportionality assessments were done

for API-in-Capsule formulation, due to the low exposure.

For the ASD-in-Capsule formulation, the formal dose-pro-

portionality assessment was assessed using a power model

in which log(PK)=α+βXlog(dose). The area under the

plasma concentration-time curve from time zero to 12 h post

dose (AUC

0-12

) was used for the accumulation index. The

observed accumulation ratio calculated as mean AUC

0-12

(Day 8)/AUC

0-12

(Day 1) were 1.68, 1.68, and 1.69 for doses

of 100, 200, and 400 mg, respectively. At all doses, FP-025

accumulation was approximately 1.7-fold after twice-daily

administration.

2.6 Statistical Analysis

Safety and tolerability data were evaluated for the treated

population (all participants who took at least one dose of

study medications). Pharmacokinetic analyses were based

on data from treated participants in whom at least one phar-

macokinetic variable could be calculated and who did not

have any protocol violations that could interfere with these

evaluations. Descriptive statistics were used to evaluate the

safety, tolerability data, plasma concentrations, and pharma-

cokinetic variables of FP-025. Pharmacokinetic variables

were summarized using arithmetic mean, standard devia-

tion, median, minimum, maximum, the percent coeﬃcient of

variation, geometric mean, and a two-sided 95% conﬁdence

limit of the arithmetic mean and the geometric mean. Formal

calculations of sample sizes were not performed. Based on

the nature of the descriptive studies, the number of partici-

pants enrolled in each cohort was considered suﬃcient to

meet the objectives of these phase I studies and to allow for

assessments of pharmacokinetic variables.

For the evaluations of food eﬀect on the pharmacokinetic

proﬁle of FP-025, the analysis of variance (ANOVA) model

included sequence, treatment, and period as ﬁxed eﬀects and

subject nested within sequence as a random eﬀect using the

SAS® mixed model procedure. Each ANOVA included

calculation of least squares means (LSM), the diﬀerence

between LSM under fed condition (Test) over fasted condi-

tion (Reference), and the standard error associated with this

diﬀerence.

At each time-point, mean, median, standard deviation,

minimum, maximum, number of available observations,

and change from baseline were summarized by numeric

parameters.

K.Abd-Elaziz et al.

3 Results

3.1 Subject Disposition andBlinding

In Study I, 88 male subjects were screened and 64 were

randomized (Fig.2). In Study II, 76 male and female sub-

jects were screened, 24 of whom were randomized in the

multiple-dose part, while eight subjects were randomized

in the food-eﬀect part of the study (Fig.3).

All subjects completed the study. Overall, subjects at the

diﬀerent dose levels were similar with regard to age, weight,

height, and body mass index (BMI) distribution (Tables1

and 2).

3.2 Safety andTolerability

All recorded AEs were self-limiting and considered to

be of mild intensity. No moderate, severe, or serious AEs

were reported. No clinically relevant changes from baseline

assessments were observed in weight, vital signs, physical

examination, laboratory, or ECG data after FP-025 at any

time point.

Only one possibly related AE was reported during the

SAD study (Table3). This AE, mild diarrhea, was expe-

rienced by one subject following the API-in-Capsule 800

mg dosing and recovered spontaneously before the follow-

up visit. In the MAD study, a total of seven AEs possibly

related to treatment with FP-025 were reported (Table3).

Two of these events, comprising fatigue and cough, were

reported by two subjects from the 100 mg FP-025 group.

The other ﬁve events were reported by three subjects from

the 200 mg FP-025 group, i.e., one subject with two episodes

of eye irritation, and erythema, one subject with dizziness,

and one subject with skin rash.

In the food-eﬀect part of the study, only two AEs pos-

sibly related to treatment with FP-025 were reported in one

subject. Both events were headache, which occurred under

both fed and fasted conditions.

3.3 Pharmacokinetics: Single Ascending‑Dose

Study (Study I)

In the API-in-Capsule cohorts, median time to reach maxi-

mum plasma concentration (T

max

) was similar for FP-025

200 mg and 400 mg doses, i.e., 5 and 6 h, respectively,

whereas median T

max

appeared shorter (3.5 h) for the 800

mg dose. Mean maximum observed plasma concentration

max

), area under the plasma concentration-time curve

from time zero to time t of the last measured concentration

(AUC

0–t

), and area under the plasma concentration-time

curve from time zero to inﬁnity (AUC

0–inf

) increased in a

more than dose -proportional manner over the dose range of

200–400 mg, but decreased with the further doses (Table4).

In general, with the API-in-Capsule formulation, the expo-

sure to FP-025 was low and inconsistent, with substantial

inter-subject variability, expressed as percent coeﬃcient of

variation of approximately 40%.

In the ASD-in-Capsule cohorts, median T

max

ranged from

1 to 2.5 h over the dose range of 50–450 mg after intake of

single doses. Mean C

max

, AUC

0–t

, and AUC

0–inf

increased in

a more than dose proportional manner over the dose range

between 50 and 100 mg. The drug exposure (mean C

max

AUC

0–t

, and AUC

0–inf

) increased in an approximately dose-

proportional manner from 100 to 450 mg after intake of

single doses of FP-025 (Table4). Dose-proportionality was

found for C

max

, AUC

0–t

, and AUC

0–inf

over the dose range

Table 1 Demographic and baseline characteristics of subjects participating in the single ascending-dose study (Study I)

Data are presented in mean (standard deviation) unless otherwise speciﬁed

API active pharmaceutical ingredient, ASD amorphous solid dispersion, SD standard deviation, n number, cm centimeter, kg kilogram, m meter,

BMI body mass index

Variable Placebo

(SD)

API-in-

capsule 200

mg (SD)

API-in-

capsule 400

mg (SD)

API-in-

capsule 800

mg (SD)

ASD-in-

capsule 50

mg (SD)

ASD-in-

capsule 100

mg (SD)

ASD-in-

capsule 200

mg (SD)

ASD-in-

capsule 300

mg (SD)

ASD-in-

capsule 450

mg (SD)

Subject, n 16 6 6 6 6 6 6 6 6

Age, years 28.8 (6.28) 26.3 (2.66) 28.5 (6.69) 29.5 (8.34) 28.5 (2.51) 28.0 (4.47) 28.3 (5.57) 31.0 (5.44) 25.8 (2.79)

Male, n 16 6 6 6 6 6 6 6 6

Asian race,

16 6 6 6 6 6 6 6 6

Height, cm 173.19

(5.82)

170.95

(6.85)

174.33

(8.98)

173.83

(5.38)

175.77

(8.94)

176.27

(5.79)

177.58

(12.05)

173.5 (5.13) 169.0 (4.34)

Weight, kg 70.7 (9.72) 63.83 (7.89) 64.67 (7.0) 69.17 (7.86) 74.53

(16.22)

71.5 (8.09) 73.2 (14.46) 69.2 (6.56) 62.83 (5.23)

BMI, kg/m

23.50 (2.35) 21.88 (2.96) 21.25 (1.25) 22.95 (2.96) 23.97 (2.29) 23.00 (2.29) 23.17 (3.46) 23.00 (1.94) 21.97 (1.10)

Safety, Tolerability, and Pharmacokinetics of FP-025

of 100–450 mg after single doses of FP-025. Mean values

of T

1/2

were independent of the dose administered over the

range of 50–450 mg after single oral doses of FP-025. Mean

apparent total clearance (CL/F) and mean apparent volume

of distribution (V

/F) of FP-025 were independent of the

dose administered over the range of 100–300 mg. The high-

est exposure was observed in the 450 mg group (Table4,

Fig.4). Compared to the API-in-Capsule formulation,

FP-025 administration using the ASD-in-Capule formula-

tion achieved higher and more consistent exposure, as well

as lower inter-subject variability.

3.4 Pharmacokinetics: Multiple Ascending‑Dose

Study andFood‑Eﬀect Part (Study II)

The peak exposure (C

max

) and the systemic exposure

(AUC) to FP-025 increased in a more-than-dose propor-

tional manner from 100 to 200 mg and approximately in

a dose-proportional manner from 200 to 400 mg after

multiple doses for a week. Median T

max

of FP-025 was

similar among the three escalating dose levels on both

Day 1 and Day 8 (Fig.5, Table5). T

1/2

of FP-025 at sin-

gle doses of 100, 200, and 400 mg was 6.9, 6.0, and 6.5

h on Day 1, respectively; the corresponding values after

intake of multiple doses was 8.4, 8.1, and 6.6 h on Day 8,

respectively. CL/F was 28.7, 20.3, and 24.0 L/h after sin-

gle doses of FP-025 at 100, 200, and 400 mg, respectively.

The corresponding values after multiple doses were 23.1,

16.2, and 18.2 L/h, respectively. The mean trough (pre-

dose) plasma concentrations were used to assess the time

to steady state. Steady state was achieved by Day 6 for all

three dose levels. The AUC ratio of FP-025 (Day 8/Day 1)

was approximately 1.7-fold after twice-daily administra-

tion at all three dose levels.

Co-administering FP-025 with food appears to have

no effect on overall exposure (similar AUCs were

Table 2 Demographic and baseline characteristics of subjects participating in the multiple ascending dose study including the food eﬀect part

Data are presented in mean (standard deviation) unless otherwise speciﬁed

API active pharmaceutical ingredient, ASD amorphous solid dispersion, SD standard deviation, n number, cm centimeter, kg kilogram, m

meter,BMI body mass index

Treatment A = oral dose of 100 mg; treatment B = oral dose of 200 mg; treatment C = oral dose of 400 mg. Treatments A, B, and C are ASD-

in-Capsule. Treatment D = single oral dose of 200 mg ASD-in-Capsule in fasted condition and treatment E = single oral dose of 200 mg ASD-

in-Capsule in fed condition after intake of a high-fat, high-calorie breakfast (following the US Food and Drug Administration composition)

Variable Placebo (SD) Treatment A (SD) Treatment B (SD) Treatment C (SD) Treatment D/E (SD)

Subject, n 6 6 6 6 8

Age, years 30.5 (13.02) 32.3 (10.82) 34.0 (11.1) 33.2 (14.52) 44.5 (12.4)

Male, n 6 6 6 5 7

Black race, n 0 2 3 0 0

White race, n 6 4 3 6 8

Height, cm 183.17 (9.96) 181.73 (4.36) 181.05 (7.95) 182.85 (7.78) 183.78 (7.09)

Weight, kg 82.87 (13.52) 81.95 (9.48) 69.4 (12.12) 73.93 (7.9) 85.33 (13.89)

BMI, kg/m

24.6 (2.37) 24.93 (3.70) 21.12 (3.01) 22.18 (1.96) 25.15 (2.95)

Table 3 Adverse events possibly related to drug administration reported during both single ascending-dose (Study I) and multiple ascending-

dose including the food eﬀect (Study II) studies

API active pharmaceutical ingredient, ASD amorphous solid dispersion

Adverse events description Study Dose level (mg) FP-025 formulation Outcome

Diarrhea (n=1) Single ascending dose 800 API Resolved

Fatigue (n=1) Multiple ascending dose 100 ASD Resolved

Cough (n=1) Multiple ascending dose 100 ASD Resolved

Eye irritation (n=1) Multiple ascending dose 200 ASD Resolved

Erythema (n=1) Multiple ascending dose 200 ASD Resolved

Dizziness (n=1) Multiple ascending dose 200 ASD Resolved

Skin rash (n=1) Multiple ascending dose 200 ASD Resolved

Headache (n=1) Food eﬀect fed status 200 ASD Resolved

Headache (n=1) Food eﬀect fasting status 200 ASD Resolved

K.Abd-Elaziz et al.

obtained with or without food), although the peak time

increased from 1 to 2.5 h and a lower peak concentra-

tion was observed (1050 ng/mL vs. 787 ng/mL) (Fig.6).

1/2

was 9.4 and 8.4 h under fasted and fed conditions,

respectively.

4 Discussion

The present paper reports the first-in-man data of a

novel, highly selective, oral MMP-12 inhibitor, FP-025,

from two phase I (SAD, MAD) studies conducted in 96

healthy subjects. FP-025 exposure appears substantially

increased with an ASD-based formulation, which has been

commonly used to improve oral absorption of drugs with

low solubility [39]. We also found that the ASD-in-Cap-

sule formulation resulted in shorter peak time, increased

peak concentrations, and higher overall plasma exposure.

Moreover, inter-subject variability of the pharmacokinet-

ics variables of FP-025 was lower in the ASD-in-Capsule

groups, and an overall dose-proportional increase was

observed in the majority of the dose range tested. For

example, at the 200 mg FP-025 dose, the ASD-in-Capsule

formulation resulted in 30-fold higher C

max

and AUC

0–inf

when compared to the API-in-Capsule formulation. The

percent coeﬃcient of variation of these parameters also

declined from approximately 30–40% to less than 30%.

The decrease in inter-subject variability was more appar-

ent at higher doses. These observations are consistent with

those of many marketed products using this technology to

improve oral bioavailability of drugs with low solubility

[40].

Although the administration of FP-025 with a high-fat,

high-calorie diet appears to result in a shift in the plasma

concentration profile of the drug, the overall exposure

remains relatively unchanged, suggesting a minor delay in

rate of absorption, but without an eﬀect in extent of absorp-

tion or bioavailability.

Because FP-025 is developed for chronic disease treat-

ment, the minor shift in pharmacokinetic proﬁle may not be

signiﬁcant to mandate dosing with or without food.

Across all dose levels and dosing regimens that have been

studied, FP-025 was safe and generally well tolerated. There

were only a few AEs that were mild, short-lasting, and self-

limited. There was no increase in frequency or intensity of

AEs at higher dose levels. Our data extend and complement

the few clinical studies with previously tested, often non-

selective MMP inhibitors.

Table 4 FP-025 pharmacokinetic parameters (mean and SD) after a single oral dose of FP-025 API-in-Capsule formulation at 200, 400, and 800

mg and FP-025 ASD-in-Capsule formulation at 50, 100, 200, 300, and 450 mg in Study I

Data are arithmetic mean (standard deviation) except for T

max

, which is reported as median (range)

The standard deviation was not calculated for some parameters because the total number was less than three

API active pharmaceutical ingredient, ASD amorphous solid dispersion AUC

0–t

area under the plasma concentration-time curve from time zero

to time t of the last measurable concentration, AUC

0–inf

area under the plasma concentration-time curve from time zero to inﬁnity, C

max

maxi-

mum observed plasma concentration, T

1/2

apparent terminal elimination half-life, T

max

time to reach maximum plasma concentration, λz terminal

elimination rate constant, a* median

Parameter FP-025 API-in-Capsule

200 mg 400 mg 800mg

max

(ng/mL) 34.1 (10.7) 90.6 (40.2) 63.6 (93.2)

max

(h) 5 (2–6) 6 (4–12) 3.5 (3–12)

AUC

0–t

(ng·h/mL) 448 (196) 1380 (771) 1040 (630)

AUC

0–inf

(ng·h/mL) 313 1480 (528) 935

λz (1/h) 0.103 0.0748 (0.01) 0.0569

1/2

(h) 6.7 9.4 (1.5) 12.5

FP-025 ASD-in-Capsule

50 mg 100 mg 200 mg 300 mg 450 mg

max

(ng/mL) 193 (25.2) 498 (113) 1000 (269) 1580 (309) 2570(270)

max

(h) 2 (1–3) 1 (1–3) 2.5 (1–3) 1 (1–3) 2 (1–6)

AUC

0–t

(ng·h/mL) 1580 (402) 4520 (1160) 8960 (2540) 12,900 (2260) 25,400 (4980)

AUC

0–inf

(ng·h/mL) 1680 (472) 4720 (1260) 9180 (2630) 13,200 (2390) 26,000 (5370)

λz (1/h) 0.137 (0.06) 0.113 (0.04) 0.107 (0.03) 0.108 (0.02) 0.108 (0.02)

1/2

(h) 6.2 (3.2) 6.7 (2.0) 6.9 (1.9) 6.7 (1.6) 6.7 (1.4)

Safety, Tolerability, and Pharmacokinetics of FP-025

Early MMP-12 inhibitors showed protective and/or

anti-inﬂammatory eﬃcacy in several animal models of

inﬂammatory airway disease underscoring the relevance

of MMP-12 targeting [31, 32, 41–43]. Chung and col-

leagues reported on the anti-inflammatory efficacy of

AZ11557272, an MMP-12 inhibitor, in a guinea-pig model

of COPD completely eradicating inﬂammatory cells and

desmosine in bronchoalveolar lavage (BAL) ﬂuid [44].

Likewise, Le Quément and colleagues showed inhibition

of MMP-12 with AS111793, another selective MMP-12

inhibitor, on cigarette smoke-induced airway inﬂammation

in a mouse model [43].

Based on their antiangiogenic and putative antimeta-

static properties, several non-selective MMP-inhibitors

have been developed and tested in patients with cancer.

BMS-275291 (rebimastat), a non-selective MMP inhibitor

(targeting MMPs 1, 2, 8, 9, and 14) with limited eﬃcacy,

was associated with unexpected toxicity (i.e., severe sys-

temic side eﬀects, including fatigue, allergic reactions, and

arthralgia) resulting in early termination of phase ll and

phase lll clinical trials [19–21]. BAY 12-9566 (tanomastat),

another non-selective MMP inhibitor (targeting MMPs 2, 3

and 9), failed to show consistent clinical eﬃcacy [22, 23].

More recently, BB-2516 (marimastat), a broad-spectrum

MMP inhibitor, had ameliorated liver injuries and had lim-

ited inﬂammation processes but caused liver ﬁbrosis in the

mouse model of repeated carbon tetrachloride administra-

tion [45].

So far, there are only limited human data on selective

MMP inhibitors. AZD1236, an oral dual MMP-9/12 inhibi-

tor, was evaluated in two phase II studies in patients with

moderate to severe COPD. During 6 weeks, AZD1236

showed an overall good safety and tolerability [24, 25].

There was no apparent eﬃcacy on any of the exploratory

clinical outcomes (i.e., Clinical COPD Questionnaire

(CCQ) scores, lung function, 6-min walk test (6MWT),

body mass index, obstruction, dysponea and excercise

(BODE) index) was observed, despite a potential signal of

eﬃcacy reﬂected by a reduction in urinary desmosine excre-

tion [24, 25].

In vitro studies with FP-025 conﬁrmed its high aﬃnity to

inhibit MMP-12 with a 90-fold selectivity over the next clos-

est family member , indicative of a high selectivity, which

Time (h)

010203

Concentration (ng/mL)

100

120

140

API-in-Capsule, 200 mg (N=6)

API-in-Capsule, 400 mg (N=6)

API-in-Capsule, 800 mg (N=6)

Time (h)

010203

Concentration (ng/mL)

500

1000

1500

2000

2500

3000

ASD-in-Capsule, 50 mg (N=6)

ASD-in-Capsule, 100 mg (N=6)

ASD-in-Capsule, 200 mg (N=6)

ASD-in-Capsule, 300 mg (N=6)

ASD-in-Capsule, 450 mg (N=6)

Fig. 4 Mean (±SD) plasma FP-025 concentration versus time plots

after administration of single oral doses of 200 mg, 400 mg, and 800

mg API-in-Capsule and 50 mg, 100 mg, 200 mg, 300 mg, and 450

mg ASD-in-Capsule in fasted condition. API active pharmaceutical

ingredient, ASD amorphous solid dispersion

DAY 1

Time (h)

0510 15 20 25

Concentration (ng/mL)

500

1000

1500

2000

2500

3000

3500

Treatment A (N=6)

Treatment B (N=6)

Treatment C (N=6)

DAY 8

Time (h)

01020304

Concentration (ng/mL)

1000

2000

3000

4000

5000

Treatment A (N=6)

Treatment B (N=6)

Treatment C (N=6)

Fig. 5 Mean (± SD) plasma FP-025 concentration versus time plots

after administration of multiple oral doses of 100 (treatment A, n =

6), 200 (treatment B, n = 6) and 400 (treatment C, n = 6) mg ASD-

in-Capsule on day 1 and on day 8 of Study II. ASD amorphous solid

dispersion

K.Abd-Elaziz et al.

has been shown to translate into a good safety proﬁle. Com-

bined with a favorable pharmacokinetic proﬁle, these prop-

erties will enable FP-025 to ﬁll the gap in selective and safe

MMP inhibitors and warrant further investigation of eﬃcacy

in relevant patient populations including asthma, COPD and,

pulmonary ﬁbrosis.

5 Conclusions

FP-025, an oral MMP-12 inhibitor, was safe, well tolerated,

and showed a favorable pharmacokinetic proﬁle in healthy

subjects at all single and multiple ascending doses tested in

the ASD-in-Capsule formulation. Results from these studies

warrant exploration and further research of its activity and

therapeutic potentials in target populations.

Acknowledgements The authors would like to acknowledge dr. Rene

Lutter (Department of Respiratory Medicine and Experimental Immu-

nology Amsterdam University Medical Center, University of Amster-

dam, Amsterdam, the Netherlands) for his critical review of the manu-

script; Chern-En Chiang and Diahn-Warng Perng (General Clinical

Research Center, Taipei Veterans General Hospital, Taipei, Taiwan and

School of Medicine, National Yang-Ming University, Taipei, Taiwan)

for their assistance in execution of Study I; and Trista Lin and Yu-Fan

Chen (QPS-Qualitix , Taipei, Taiwan) for their assistance in biostatisti-

cal analysis of safety and eﬃcacy data of both studies.

Declarations

Funding Both studies were funded by Foresee Pharmaceuticals Co.,

Ltd. Taipei, Taiwan.

Table 5 Summary statistics of pharmacokinetic parameters of FP-025 after multiple ascending oral doses of treatments A (100 mg ASD-in-

Capsule), B (200 mg ASD-in-Capsule), and C (400 mg ASD-in-Capsule) in healthy male and female subjects in Study II

ASD amorphous solid dispersion AUC

0-t

area under the plasma concentration-time curve from time zero to time t of the last measurable concen-

tration, AUC

0-inf

area under the plasma concentration-time curve from time zero to inﬁnity, C

max

maximum observed plasma concentration, T

1/2

apparent terminal elimination half-life, T

max

time to reach maximum plasma concentration, λz terminal elimination rate constant, Mean arithme-

tic mean, SD standard deviation

Median

Parameter Treatment A Treatment B Treatment C

N Mean (SD) N Mean (SD) N Mean (SD)

Day 1

C

max

(ng/mL) 6 448 (65.9) 6 1200 (338) 6 2730 (671)

T

max

(h)

6 1.00 (0.50-2.00) 6 1.02 (1.00–4.00) 6 1.00 (1.00–3.00)

AUC

0–12

(ng·h/mL) 6 2670 (532) 6 7810 (1870) 6 14,600 (4480)

AUC

0–24

(ng·h/mL) 6 3290 (593) 6 9720 (2320) 6 18,200 (6520)

AUC

0–t

(ng·h/mL) 6 3290 (593) 6 9710 (2320) 6 18,200 (6510)

AUC

0–inf

(ng·h/mL) 6 3550 (547) 6 10,400 (2520) 6 19,900 (7950)

T

1/2

(h) 6 6.9 (1.8) 6 6.0 (1.0) 6 6.5 (1.9)

Day 8

C

max

(ng/mL) 6 624 (141) 6 1920 (366) 6 3710 (932)

T

max

(h)

6 2.00 (1.00-3.00) 6 1.50 (1.00–3.00) 6 1.50 (0.50–2.00)

C

min

(ng/mL) 6 156 (27.4) 6 524 (196) 6 1010 (651)

AUC

0–12

(ng·h/mL) 6 4380 (543) 6 13,100 (3440) 6 24,700 (8350)

AUC

0–inf

(ng·h/mL) 6 6180 (889) 6 19,200 (5970) 6 36,300 (17,900)

T

1/2

(h) 6 8.4 (2.6) 6 8.1 (2.1) 6 6.6 (2.3)

Time (h)

01020304

Concentration (ng/mL)

200

400

600

800

1000

1200

1400

Treatment D (N=8)

Treatment E (N=8)

Fig. 6 Mean (± SD) plasma FP-025 concentration versus time plots

after administration of single oral doses of 200 mg ASD-in-Capsule

in fasted condition (treatment D, n = 8) and 200 mg ASD-in-Cap-

sule after intake of a high-fat, high-calorie breakfast, following the

US Food and Drug Administration composition (treatment E, n = 8).

ASD amorphous solid dispersion