Treatment of Exudative Age-Related Macular
Degeneration with a Designed Ankyrin Repeat Protein that
Binds Vascular Endothelial Growth Factor:
a Phase I/II Study
ERIC H. SOUIED, FRANC¸ OIS DEVIN, MARTINE MAUGET-FAY¨SSE, PETR KOLA´ R, UTE WOLF-SCHNURRBUSCH,
CARSTEN FRAMME, DAVID GAUCHER, GIUSEPPE QUERQUES, MICHAEL T. STUMPP, AND SEBASTIAN WOLF,
FOR THE MP0112 STUDY GROUP
 PURPOSE: To evaluate the safety, tolerability and bioactivity
of ascending doses of MP0112, a designed ankyrin
repeat protein (DARPin) that binds with high affinity to
vascular endothelial growth factor-A (VEGF-A), in
treatment-naive patients with exudative age-related macular
degeneration (AMD).
 DESIGN: Phase I/II, open-label, multicenter, doseescalation
study.
 METHODS: Patients were to receive a single intravitreal
injection of MP0112 at doses ranging from 0.04 to 3.6 mg
and be monitored for 16 weeks for safety, efficacy, pharmacokinetics,
and dose response.
 RESULTS: Altogether, 32 patients received a single injection
of MP0112. The maximum tolerated dose was
1.0 mg because of a case of endophthalmitis in the
2.0 mg cohort. Drug-related adverse events were reported
by 13 (41%) of 32 patients; they included ocular inflammation
in 11 patients (7 mild, 4 moderate in severity). Visual
acuity scores were stable or improved compared with
baseline for ‡4 weeks following injection; both retinal
thickness and fluorescein angiography leakage decreased
in a dose-dependent manner. Rescue therapy was administered
to 20 (91%) of 22 patients who received 0.04–
0.4 mg MP0112 compared with 4 of 10 (40%) patients
who received 1.0 or 2.0 mg. Of patients in the higherdose
cohorts who did not require rescue treatment, 83%
(5/6) maintained reductions in central retinal thickness
through week 16.
 CONCLUSIONS: A single injection of 1.0 or 2.0 mg
MP0112 resulted in mean decreases in retinal thickness and
leakage area despite ocular inflammation. Larger-scale studies
are warranted to confirm these observations. (Am J
Ophthalmol 2014;158:724–732. Ó 2014 The Authors.
Published by Elsevier Inc. All rights reserved. This is an
open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).)
A
GE-RELATED MACULAR DEGENERATION (AMD) IS A
leading cause of irreversible central vision loss in
people 65 years of age or older.1–4
The disease can
be subdivided into 2 categories: nonexudative and
exudative.5
Nonexudative AMD is caused by the loss of
photoreceptors through the atrophy of retinal pigment
epithelium in advanced stages of the disease. Exudative
AMD, also termed neovascular AMD, is caused by proliferation
of choroidal neovascularization (CNV), leading to
bleeding and loss of photoreceptors through fibrovascular
scarring. CNV and related manifestations (subretinal hemorrhage,
detachment of the retinal pigment epithelium,
and fibrovascular disciform scarring) are the most common
causes of severe vision loss resulting from AMD.5
Untreated,
exudative AMD can lead to progressive and substantial
loss of central vision and a reduction in quality
of life.
The relationship between vascular endothelial growth
factor-A (VEGF-A) and AMD pathogenesis has led to
the development of anti-VEGF therapies that inhibit
CNV leakage and reduce vessel permeability.6
Several
VEGF antagonists have been developed, including monoclonal
antibodies (ranibizumab and bevacizumab); receptor
fragments (aflibercept); and other molecules (pegaptanib, a
DNA aptamer).7–13
These agents have radically altered the
management of neovascular AMD and have become the
current standard of care. Anti-VEGF agents are injected
directly into the vitreous cavity. Although treatment
has evolved from monthly dosing to individualized regimens,
the best results are achieved with injections every
Accepted for publication May 27, 2014.
From the Department of Ophthalmology, Hoˆpital Intercommunal de
Cre´teil, Cre´teil, France (E.H.S., G.Q.); Centre d’ophtalmologie
Monticelli-Paradis, Marseille, France (F.D.); Centre Ophtalmologique
Rabelais, Lyon, France (M.M.-F.); Eye Clinic of University Hospital
Brno, Masaryk University Brno, Brno, Czech Republic (P.K.); Bern
Photographic Reading Center, Inselspital, Bern University Hospital,
Bern, Switzerland (U.W.-S.); Department of Ophthalmology,
Inselspital, Bern University Hospital, Bern, Switzerland (C.F., S.W.);
Service d’Ophtalmologie des Hoˆpitaux Universitaires de Strasbourg,
Nouvel Hoˆpital Civil, Universite´ Louis-Pasteur, Strasbourg, France
(D.G.); Molecular Partners, Zurich-Schlieren, Switzerland (M.T.S.).
Dr Framme is now at the University Eye Hospital, Medical School
Hannover, Hannover, Germany.
Inquiries to Sebastian Wolf, Department of Ophthalmology, Inselspital,
Bern University Hospital, Bern, Switzerland; e-mail: Sebastian.Wolf@
insel.ch
724 0002-9394
http://dx.doi.org/10.1016/j.ajo.2014.05.037
Ó 2014 THE AUTHORS. PUBLISHED BY ELSEVIER INC. ALL RIGHTS RESERVED.
4–8 weeks in order to maintain improvement in central
vision, placing a considerable burden of treatment on patients,
physicians and healthcare systems.7,14
MP0112 is a recombinant protein of the designed
ankyrin repeat protein (DARPin) family. DARPins are
small, single-domain proteins that can selectively bind to
a target protein with high affinity and specificity.15
These
genetically engineered antibody-mimetic proteins show
greater stability and at least equal affinity with immunoglobulins,
making them effective investigational and therapeutic
tools.16
The in vitro and in vivo effectiveness has
been demonstrated in areas that include preclinical tumor
targeting and diagnostics.17–22
In vitro, MP0112 has been shown to act as a highly potent
antagonist to all VEGF-A isoforms (KD of 1–4 pM; data on
file; Molecular Partners, Zurich-Schlieren, Switzerland).
Animal studies have demonstrated the high efficacy of
MP0112 to inhibit abnormal neovascularization (data on
file, Molecular Partners). In a rabbit model of ocular pharmacokinetics
with vascular leakage inhibition as read-out,
MP0112 was fully active for at least 30 days, whereas
ranibizumab did not show activity after 30 days due to faster
clearance (data on file, Molecular Partners). Good
laboratory-practice toxicology studies were performed and
revealed that inflammation can result from potential
toxicity in patients (data on file, Molecular Partners).
The mechanism of action of MP0112 is similar to that of
ranibizumab, pegaptanib and aflibercept (ie, inhibition of
VEGF-A by binding without receptor interaction via the
Fc region), and MP0112 has shown a number of advantages
compared with the current standard of care: high potency
(ie, IC50 in the low pM range); very long ocular half-life
(about 2 weeks)17
; and very low systemic exposure (data
on file, Molecular Partners). Compared with ranibizumab,
MP0112 has greater binding affinity to VEGF-A and is
retained in the vitreous for a substantially longer time.23
The evidence suggests, therefore, that MP0112 has the potential
to reduce the frequency of intravitreal injections. A
recent study has demonstrated the potential of DARPins
compared with currently available agents in DME.23
The
current study was designed to assess the safety, tolerability
and preliminary efficacy of intravitreal injections of
MP0112 for the treatment of exudative AMD and was
performed in parallel with the DME study.
METHODS
THIS PHASE I/II, OPEN-LABEL, NONCONTROLLED, DOSEescalation
trial was conducted in 8 ophthalmologic centers
in France, Switzerland and the Czech Republic. The study
and data accumulation were carried out with approval from
the following ethics committees: CPP Ile de France III,
Kantonale Ethikkommission Bern, Ethics Committee of
Central Military Hospital, Ethics Committee of Faculty
Hospital Brno, and Ethics Committee of Faculty Hospital
Olomouc. The study adhered to the guidelines of the
Declaration of Helsinki, and the protocol and consent
forms were approved by a local investigational review
board. Each subject provided written consent to participate
in this research study. The study is registered at
ClinicalTrials.gov under the identifier: NCT01086761.
 STUDY POPULATION: Male and female patients 50 years
of age or older who had clinical signs and angiographic
evidence of active primary progressive subfoveal CNV,
including juxtafoveal lesions that affected the fovea on fluorescein
angiography (FA) in the study eye and that were
at least 50% of the total lesion area, were eligible for
enrollment. Patients were also required to meet the Early
Treatment Diabetic Retinopathy Study (ETDRS) bestcorrected
visual acuity (BCVA) of 70 to 25 letters (Snellen
equivalent of 20/40 to 20/320) in the study eye at 4 meters.
Patients with any of the following were excluded from
the study: any prior treatment for neovascular AMD in
the study eye; a total lesion size of >20 mm2
; subretinal
hemorrhage either >_50% of the total lesion area or with
>_2.54 mm2
blood under the fovea; scar or fibrosis >_50%
of the total lesion in the study eye; or scar, fibrosis or atrophy
involving the center of the fovea. Patients with
other causes of CNV or ocular surgery (including cataract
extraction) in the study eye within 3 months of enrollment
were also not eligible to participate.
 STUDY DESIGN: The primary study objective was to
assess the safety and tolerability of intravitreal doses of
MP0112. Secondary objectives were to assess the preliminary
efficacy of MP0112 based on changes in BCVA, central
retinal thickness (CRT) as measured by optical
coherence tomography (OCT), and CNV leakage as
measured by FA. Additionally, the systemic pharmacokinetic
profile and immunogenicity of intravitreally administered
MP0112 were assessed.
The study was designed in 2 stages. Part A consisted of a
dose-escalation design in which 6 cohorts received a single
MP0112 dose of 0.04 mg, 0.15 mg, 0.4 mg, 1.0 mg, 2.0 mg,
or 3.6 mg. Patients were enrolled into the study sequentially.
The first patient in each dose cohort received a single intravitreal
injection of MP0112 in 1 eye. If no severe or serious
ocular adverse event (AE) that was considered to be drug
related occurred within 2 weeks of administration, the
remaining 5 patients in the dose cohort were recruited and
dosed. Dose escalation proceeded only (1) after all patients
in a dose cohort had received the specified dose; (2) if moderate
ocular toxicity, as defined by the protocol, affected no
more than 2 of 6 patients within the dosing cohort after a
minimum follow-up of 1 week; and (3) if the Medical
Review Committee had approved the dose escalation.
 STUDY TREATMENTS AND PROCEDURES: MP0112 was
administered as a single intravitreal injection (0.05 mL)
VOL. 158, NO. 4 725PHASE I/II STUDY OF THE DARPIN MP0112 IN EXUDATIVE AMD
using a 30-gauge needle and standard techniques, including
the use of a lid speculum, topical anesthesia and 5%
povidone-iodine. All patients remained under observation
in the clinic for up to 5 hours after dosing. Patients were
examined before and after injection and received a safety
follow-up call the day after dosing, with referral to an
ophthalmologist if required. Follow-up visits were made
3 days, and 1, 2, 4, 8, 12, and 16 weeks after treatment.
At day 3, patients underwent a complete eye exam
(including slit-lamp biomicroscopy and indirect ophthalmoscopy)
and pharmacokinetic assessment. At each study
visit, patients were assessed for AEs, concomitant medications,
pharmacokinetics (until week 12), complete eye
exams, BCVA and OCT. FA was assessed at baseline and
week 4 (Figure 1).
At the investigators’ discretion, patients could be given
rescue therapy with standard-of-care treatments from
2 weeks after administration of MP0112. The criteria for
initiation of rescue therapy differed slightly by region: in
the Czech Republic and France, patients were eligible for
rescue therapy if they experienced at least 1 of the
following: visual acuity (VA) deterioration of >_6 letters
from baseline; an increase in lesion size or leakage; the formation
of new lesions; or an increase in subretinal fluid. In
Switzerland, rescue therapy applied to patients who experienced
VA deterioration of >_6 letters from baseline or a
decrease in CRT of <50 mm from baseline. All patients,
including those who received rescue therapy, were followed
for 16 weeks.
Optical coherence tomography. OCT was performed at
each study site using Stratus OCT 3 (Carl Zeiss Meditec,
Jena, Germany) and Spectralis OCT (Heidelberg Engineering,
Heidelberg, Germany), if available. The same
OCT unit was used for all visits for a given patient so as
to allow for comparison among visits. Stratus OCT data
FIGURE 1. Schema of the phase I/II multicenter dose-escalation trial of MP0112 in patients with exudative age-related macular
degeneration (AMD) from recruitment to follow-up.
726 OCTOBER 2014AMERICAN JOURNAL OF OPHTHALMOLOGY
were used for comparison across all sites because Spectralis
OCT data were not available for all patients. The central
subfield thickness, which is the average thickness within
the central 1 mm of the fovea, was used as a measure of
CRT for all OCT devices. Scans were acquired using the
fast macular scan protocol on Stratus (Carl Zeiss Meditec),
which consists of 6-line B-scans (each consisting of 128 Ascans
per line), each 6 mm long, centered on the fixation
point and spaced 30 degrees apart around a circle. Scans
were acquired using the high-speed spectral-domain OCT
volume mode on the Heidelberg Spectralis, which
consists of 25 horizontal-line B-scans (each consisting of
512 A-scans per line; the line scans were saved for
analysis after 9 frames and averaged) covering a total area
of 20 3 20 degrees of the macula with a distance of
240 mm between the horizontal lines. OCT images were
analyzed and graded by the Central Reading Center
(Bern Photographic Reading Center, Bern, Switzerland).
Fluorescein angiography. Digital images at the 30- to 40degree
setting (depending on the device) were taken using
the Heidelberg HRA System (Heidelberg Engineering);
MRP OphthaVision (MRP Group, Waltham, Massachusetts,
USA); Ophthalmic Imaging Systems (OIS)
WinStation (Sacramento, California, USA); Topcon
IMAGEnet (Capelle a/d Ijssel, Netherlands); or Zeiss
Visupac digital systems (Carl Zeiss Meditec). The
fluorescein angiogram contained stereoscopic views of 2
fields at specified times (up to 10 minutes) after
fluorescein injection. These fields included the macula
(ETDRS Field 2) of both eyes and the disc field
(ETDRS Field 1M) of the study eye. Stereoscopic redfree
photographs were taken of ETDRS Field 2 in each
eye prior to the injection of the fluorescein dye. FA
images were analyzed and graded by the Central
Reading Center (Bern Photographic Reading Center).
Statistical analysis. No formal significance or analytic
testing was performed due to the small sample size. Continuous
variables were summarized using descriptive statistics,
and categoric variables were described using counts and
percentages.
RESULTS
 BASELINE PATIENT CHARACTERISTICS: Of the 45
patients screened, 32 met the inclusion/exclusion criteria
and received a single intravitreal injection of MP0112 in
the study eye (0.04 mg, 9 patients; 0.15 mg, 7 patients;
0.4 mg, 6 patients; 1.0 mg, 6 patients; 2.0 mg, 4 patients).
All 32 patients completed the study. The baseline characteristics
of the study population are summarized in Table 1.
 SAFETY: AEs that were considered to be drug related
were reported in13 of 32 (41%) patients and included anterior
chamber inflammation (5/13 patients); vitritis (4/13
patients); anterior chamber cell flare (3/13 patients); and
endophthalmitis (1/13) (Table 2). Ocular inflammation
resolved without consequence in all eyes; in 36% (4/11),
this occurred without treatment, and all others received
local anti-inflammatory medication (betamethasone, dexamethasone,
tropicamide, or dexamethasone-tobramycin).
One serious AE (3%) was reported during the study: a
patient who received 2.0 mg MP0112 developed severe
ocular inflammation with hypopyon, initially classified as
endophthalmitis. The patient received a 2-day course of
intravenous vancomycin and ceftriaxone, oral prednisolone,
TABLE 1. Baseline Characteristics for 32 Patients with AgeRelated
Macular Degeneration Who Received a Single
Intraocular Injection of MP0112 Across 5 Dose Cohorts in the
Phase I/II Dose-Escalation Study
MP0112 (n ¼ 32)
Age (years)
Mean 6 SD 78.3 6 5.3
Range 65, 87
Gender, n (%)
Male 11 (34%)
Female 21 (66%)
Ethnicity, n (%)
Caucasian/white 31 (97%)
Ocular measures
Classic CNV, n (%)a
8 (25%)
Occult CNV, n (%)a
29 (91%)
VA score, mean 6 SD (range) 58.7 6 11.6 letters (32–72)
CRT, mean 6 SD (range) 351.5 6 107.8 mm (191–790)
CNV ¼ choroidal neovascularization; CRT ¼ central retinal
thickness; SD ¼ standard deviation; VA ¼ visual acuity.
a
One patient could not be graded, and another patient could
not be graded for classic CNV.
TABLE 2. Treatment-Related Ocular Adverse Events in the
Study Eye Reported for at Least 2 Patients with Age-Related
Macular Degeneration in a Single-Dose Cohort*
MP0112 Dose Cohort
0.04 mg
n ¼ 9
0.15 g
n ¼ 7
0.4 mg
n ¼ 6
1.0 mg
n ¼ 6
2.0 mg
n ¼ 4
Vitritis 0 1 (14%) 0 2 (33%) 1 (25%)
Anterior chamber
inflammation
0 1 (14%) 1 (17%) 2 (33%) 1 (25%)
Anterior chamber
cell flare
0 0 1 (17%) 0 2 (50%)
*Patients received a single intraocular injection of MP0112.
VOL. 158, NO. 4 727PHASE I/II STUDY OF THE DARPIN MP0112 IN EXUDATIVE AMD
and Kefzol eye drops. The hypopyon was completely
resolved within 3 days from onset. No Gram staining or cultures
were performed, but the mild course and response to
steroids suggest that sterile endophthalmitis had occurred.
Based on this severe ocular inflammation, the maximum
tolerated dose was determined to be 1.0 mg. A second stage
of the study that was planned to evaluate repeat doses of
MP0112 was not initiated because ocular inflammation
was observed and was attributed to impurities in the investigative
product.
AEs noted by the investigator to be related to the procedure
were reported in 3 of 32 (9%) patients (conjunctival
hemorrhage, vitreous detachment and hypertension, each
occurring in 1 patient).
Antidrug antibodies were detected in the serum of 8 patients.
No further characterization of these was performed.
 EFFICACY: Optical coherence tomography. The mean and
median CRTs at baseline were 352 mm and 334 mm, respectively
(standard deviation, 107.8 mm; range, 191–790)
(Table 1). Generally, the higher-dose cohorts experienced
a greater decrease in CRT during the 4-week study period
(Figure 2). Patients who received 1.0 and 2.0 mg of
MP0112 showed the greatest median reductions at week 4
of À95 mm and À111 mm, respectively, compared with
7 mm, À12 mm, and À62 mm in patients who received
0.04 mg, 0.15 mg, and 0.4 mg, respectively. The overall
change in CRT across the dosing cohorts is shown in
Figure 2.
The initial reduction in CRT observed at week 1 was
maintained and further reduced at week 4 in the higherdose
cohorts. Patients receiving 1.0 mg showed median
reductions in CRT of À51 mm and À95 mm at weeks 1
and 4, respectively. The median reduction at week 1 in
patients receiving 2.0 mg was À6.5 mm. This compared
with a median reduction of À111 mm at week 4. In
contrast, the CRT of lower-dose cohorts increased or stabilized
after an initial decline (Figure 2, center). Patients who
received 0.04 mg or 0.15 mg MP0112 had median changes
of À33 mm and 7 mm (week 1) or À11 mm and À12 mm
(week 4), respectively.
FIGURE 2. Overall change in central retinal thickness (CRT)
from baseline to week 4, as measured by optical coherence
tomography, after a single injection of MP0112 in 5 study
cohorts with age-related macular degeneration (AMD). (Top)
Median baseline CRT measured at screening or on day 0, if
available, prior to a single intraocular injection of MP0112 in
patients with AMD: 0.04 mg (n [ 9); 0.15 mg (n [ 7);
0.4 mg (n [ 6); 1.0 mg (n [ 6); or 2.0 mg (n [ 4). The
mean baseline CRT of the study eye was 351.5 mm (SD ±
107.8 mm), and all patients had definite macular thickening.
(Center) Median CRT measured 4 weeks after injection of
MP0112 in patients with AMD across 5 dose cohorts. CRT
decreased as early as week 1 and was maintained in patients in
the higher-dose cohorts. (Bottom) Median change in CRT
from baseline to week 4 for all patients by dose cohort. Patients
who received 1.0 or 2.0 mg of MP0112 showed the greatest
mean reductions at week 4 (95 mm and 99 mm, respectively),
compared with patients from the lower-dose cohorts.
728 OCTOBER 2014AMERICAN JOURNAL OF OPHTHALMOLOGY
Visual acuity. The VA remained stable (defined as loss of
<15 letters compared with baseline) and did not vary from
baseline in all dosing cohorts across the study period. Up to
100% of patients experienced either no loss in VA or a gain
from baseline in letters on the ETDRS charts at each time
point (94%, 97%, 94%, 91%, 91%, and 100% of patients at
weeks 1, 2, 4, 8, 12, and 16, respectively). Of 32 patients, 4
(12.5%) experienced reversible loss of >_15 letters secondary
to inflammation at various time points.
Fluorescein angiography. At initial screening, FA showed
that patients had both mean and median leakage areas
of 11.5 mm2
(65.1; range, 1.6–20.8) across dose cohorts.
At week 4, the mean and median leakage areas had
decreased to 2.4 mm2
and 0 mm2
, respectively (63.8;
range, 0–14.3) (Figure 3). FA also demonstrated a mean
decrease in lesion size from 11.1 mm2
(median,
10.9 mm2
) at baseline to 7.6 mm2
(median, 7.3 mm2
) at
week 4. Dose dependency was observed (Figure 3, bottom).
Rescue therapy. Ranibizumab 0.5 mg (Lucentis; Genentech,
San Francisco, California, USA) was administered
as rescue therapy between weeks 4 and 16 to 20 of 22
patients (91%) who received 0.04, 0.15, or 0.4 mg of
MP0112 and to 4 of 10 patients (40%) who received 1.0
or 2.0 mg MP0112 (Table 3) (Figure 4). The median
time to rescue therapy was longer in higher-dose than in
lower-dose cohorts (9.6–10.1 vs 5.1–6.9 weeks,
respectively) (Table 3) (Figure 4). The majority of
patients who were stable on MP0112 treatment
maintained reductions in CRT to week 16. OCT did
not demonstrate any improved benefit of rescue therapy
on CRT in patients from the 1.0 and 2.0 mg MP0112
cohorts.
Pharmacokinetics. Patients who received single intravitreal
doses of 0.04, 0.15 or 0.4 mg had no quantifiable serum
concentrations of MP0112. All samples in these cohorts
were below the lower limit of quantification (LLOQ) of
0.3 nM. Of the patients, 50% (3/6) in the 1.0 mg
MP0112 cohort had systemic MP0112 levels above the
LLOQ, with maximum levels being reached 3 days post
dose (0.3–0.5 nM). After week 1, all patients in this cohort
had serum levels below the LLOQ. All patients who
received 2.0 mg MP0112 had systemic levels of MP0112
above the LLOQ (0.5–1.0 nM) during days 3–7. Serum
levels remained above the LLOQ in half of these patients
at week 2. From week 4 onward, all patients in this cohort
had serum levels below the LLOQ.
DISCUSSION
THE ASSOCIATION OF VEGF-A WITH AMD PATHOGENESIS
has led to the development of anti-VEGF therapy via intraocular
injection. Many studies have demonstrated the
efficacy of VEGF antagonists in inhibiting CNV leakage,
and such therapies have become the current standard
of care.9–13
Best results are obtained with injections every
4–8 weeks, although the frequency of intraocular
injection varies among patients according to individual
needs. Therapies providing a longer duration of VEGF
FIGURE 3. Overall change in leakage area from baseline to
week 4, as measured by fluorescein angiography, after a single
injection of MP0112 in 5 study cohorts with age-related macular
degeneration (AMD). (Top) Median baseline leakage area
measured 10 minutes after fluorescein injection at screening
prior to a single intraocular dose of MP0112 in patients with
AMD: 0.04 mg (n [ 9); 0.15 mg (n [ 7); 0.4 mg (n [ 6);
1.0 mg (n [ 6); or 2.0 mg (n [ 4). Mean baseline leakage
area of the study eye was 11.5 mm2
(SD ± 5.1 mm2
); range,
8.4–15.0 mm2
across treatment groups. (Bottom) Median
leakage area decreased 4 weeks after administration of
MP0112 across all dose cohorts to 0 mm2
(range, 0–14.3).
Mean area was 2.4 mm (SD ± 3.8). One patient in the 2.0 mg
cohort had images that could not be assessed due to poor quality.
VOL. 158, NO. 4 729PHASE I/II STUDY OF THE DARPIN MP0112 IN EXUDATIVE AMD
suppression would reduce the burden of treatment on
patients, physicians, and healthcare systems. MP0112 was
developed to achieve longer duration of VEGF suppression
in the eyes of patients. The results of a single-dose, doseescalation
study of MP0112 in patients with exudative
AMD are reported here, showing that promising efficacy
and long duration were achieved at the highest doses tested.
The primary objective of this study was to assess the
safety and bioactivity of intravitreal injection of MP0112
in patients with exudative AMD. No systemic safety concerns
were identified. Ocular inflammation was expected
to be the dose-limiting AE, based on observations in rabbits.
Similar ocular inflammation was observed in an
MP0112 study in patients with DME.23
An improved purification
process has subsequently been developed; it
removes proinflammatory impurities, as confirmed by rabbit
studies (data on file, Molecular Partners), and the new
investigational product (now called AGN-150998) is
currently being evaluated in a phase II trial in patients
with neovascular AMD.
The small patient numbers (n ¼ 32 in 5 dose cohorts)
involved in this study, as well as the single-dose, openlabel
design, prevent any definitive conclusions from being
drawn. Future repeat-dose studies with appropriate comparators
will be needed to confirm the efficacy and duration of
action of MP0112. Initial observations, however, suggest a
potential benefit to patients, as demonstrated by the stabilization
and improvement of VA and the dose-dependent
reductions seen in CRT and leakage. Patients in the
higher-dose cohorts (1.0 and 2.0 mg) showed tendencies
to experience greater mean reductions in CRT, which
were maintained beyond week 4, as well as reduced needs
for rescue therapy compared with patients in the lowerdose
cohorts (0.04, 0.15 and 0.4 mg). Indeed, OCT did
not demonstrate any improved benefit of rescue therapy
for CRT in patients in the higher-dose cohorts. This is in
line with the pharmacokinetic data of the DME trial, in
which patients achieved very high ocular MP0112 levels
with very low systemic exposure to MP0112.23
With the
exception of 1 subject, all patients who received 1.0 and
TABLE 3. Summary of Rescue Therapy Administered to Patients with Age-Related Macular Degeneration Who Received
a Single Dose of MP0112*
MP0112 Dose Cohort
0.04 mg (n ¼ 9) 0.15 mg (n ¼ 7) 0.4 mg (n ¼ 6) 1.0 mg (n ¼ 6) 2.0 mg (n ¼ 4) All (N ¼ 32)
Patients receiving rescue therapy, n (%) 8 (89%) 7 (100%) 5 (83%) 2 (33%) 2 (50%) 24 (75%)
Time to first rescue therapy (weeks)
Mean (SD) 5.4 (1.3) 8.1 (3.0) 6.8 (2.4) 9.6 (8.3) 10.1 (8.5) 7.2 (3.6)
Median 5.1 6.9 5.9 9.6 10.1 5.9
Range 4, 8 4, 12 5, 10 4, 15 4, 16 4, 16
SD ¼ standard deviation.
*Patients were eligible for rescue therapy from 4 weeks after injection of MP0112 at the study investigator’s discretion.
FIGURE 4. Administration of standard-of-care rescue therapy
in patients with age-related macular degeneration (AMD) between
weeks 4 and 16 after a single intraocular injection of
MP0112. (Top) Percentage of patients with AMD who required
rescue therapy per protocol differed among dose cohorts.
Patients were eligible for rescue therapy 4 weeks after administration
of the study drug at the discretion of the investigator.
Overall, 75% of patients received rescue therapy between weeks
4 and 16. Between 83% and 100% of patients who received
0.04, 0.15 or 0.4 mg MP0112 were given rescue therapy
compared with 33% and 50% of patients who received 1.0
and 2.0 mg MP0112, respectively. (Bottom) Time to rescue
therapy in patients with AMD who received 0.04–0.4 mg
MP0112 (lower-dose cohorts) compared with those who
received 1.0 or 2.0 mg MP0112. The time to rescue therapy
was higher in patients who received 1.0 or 2.0 mg MP0112
compared with those in the lower-dose cohorts: 9.6–10.1 vs
5.1–6.9 weeks, respectively.
730 OCTOBER 2014AMERICAN JOURNAL OF OPHTHALMOLOGY
2.0 mg MP0112 and did not require rescue therapy maintained
reduction in CRT through week 16. This is in clear
contrast to the vast majority (91%) of patients in the lowerdose
cohorts who received rescue therapy from week 4
onward. This points to a potential dose response and underlines
the potential of MP0112 for less frequent dosing. It is
notable that spectral-domain OCT was not performed in
all patients in this study. Further studies using spectraldomain
OCT would likely provide more detailed results.
Another limit of the study is the lack of antidrug antibody
analysis.
DARPins are a novel class of therapeutic molecules that
exhibit significant advantages over monoclonal antibodies.
They bind with high affinity and specificity to their targets,
like monoclonal antibodies, but in addition show increased
potency and longer ocular pharmacokinetics. MP0112 has
significant potential to positively impact the treatment of
ocular disease.15
The pharmacokinetic characteristics of MP0112 have
been reported previously.23
The prolonged duration of
action observed using OCT (3–4 months at >_1.0 mg) in
this trial indicate the possibility of extending the duration
of effect by prolonging suppression of VEGF. Larger clinical
trials, with the new purified investigational product, are
needed to confirm these findings and quantify the effects
of the drug.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST,
and the following were reported. Dr Souied receives consulting fees or honoraria from Allergan, Bayer and Novartis and fees for participation in review
activities from Allergan, Bayer and Novartis and holds board membership with Allergan, Bausch & Lomb, Bayer, and Novartis. Travel/accommodation/
meeting expenses unrelated to activities listed – Allergan, Bayer, Novartis. Dr Devin holds board membership with Alcon, Allergan, Bayer, and Novartis;
consults with Alcon, Allergan, Bayer, Novartis, Ophthotech, and Thea; receives payment for lectures, including service on speakers’ bureaus, from Alcon,
Allergan, Bayer, and Novartis; and receives payment for development of educational presentations from Alcon, Allergan, Bayer, and Novartis. Dr MaugetFay¨sse
receives consulting fees or honoraria, with fees going to the institution, from Molecular Partners and support for travel to meetings for the study of
other purposes from Molecular Partners. Relevant financial activities outside the submitted work include board membership in Bayer and Novartis; payment
for lectures, including service on speakers’ bureaus, with fees going to the institution; from Bayer, Heidelberg, Novartis, and Thea; travel/accommodation/meeting
expenses unrelated to activities listed, with fees going to the institution from Bayer, Heidelberg, Novartis, and Thea. Dr Kola´r receives
consulting honoraria from Molecular Partners. Relevant financial activities outside the submitted work include consultancy with Alcon, Bayer, and Novartis
and payment for lectures, including service on speakers’ bureaus, from Alcon, Bayer and Novartis. Dr Wolf-Schnurrbusch work under consideration for
publication: payment for gradings to institution. Dr Framme holds board membership with Allergan, Bayer and Novartis, is a consultant for Bayer, and
receives payment for lectures, including service on speakers’ bureaus, from Bayer, Heidelberg and Novartis. Dr Gaucher holds board membership in Allergan,
Bayer and Novartis and receives payment for development of educational presentations, with fees going to the institution, from Novartis; and receives
travel/accommodation/meeting expenses unrelated to activities listed from Alcon, Bausch & Lomb, Bayer, and Novartis. Dr Querques receives consulting
fees or honoraria from Molecular Partners; holds board membership in Alimera, Allergan and Bayer; and is a consultant to Alcon, Alimera, Allergan,
Bayer, Bausch & Lomb, Molecular Partners, Novartis, and Ophthotech. Dr Stumpp holds employment, patents and stock/stock options in Molecular Partners.
Dr Wolf has received a grant, with fee to the institution, from Molecular Partners; consulting fees or honoraria, with fees to the institution, from
Molecular Partners; support for travel to meetings for the study of other purposes from Molecular Partners; is a board member of EURETINA; receives
consultancy fees that go to the institution from Allergan, Bayer, Heidelberg Engineering, Novartis, and Optos; and receives fees for expert testimony,
with fees going to the institution, from Bayer. Molecular Partners AG, Zurich, Switzerland, provided support for the study and participated in study design;
conducted the study; and provided data collection, management and interpretation. The study is registered at ClinicalTrials.gov under the identifier:
NCT01086761. Conception and design of study (E.S., M.S., S.W.); Analysis and interpretation of data (E.S., U.W., C.F., G.Q., M.S., S.W.); Preparation
of manuscript (E.S., M.S., S.W.); Critical revision of manuscript (E.S., C.F., G.Q., M.S., S.W.); Final approval of manuscript (E.S., F.D., M.M., P.K., U.W.,
C.F., D.G., G.Q., M.S., S.W.); Data collection (U.W., C.F., S.W.); Provision of materials, patients, or resources (E.S., F.D., M.M., P.K., U.W., C.F., D.G.,
G.Q.). The authors thank Fiona Powell, Facilitate Ltd, Brighton, UK, for editorial assistance in the production of this manuscript.
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Biosketch
Professor Eric H. Souied is head of the Department of Ophthalmology at the Hoˆpital Intercommunal de Cre´teil, France. He
earned his MD and PhD degrees between 1990 and 2006 at Universite´ Paris Est Cre´teil. He also completed a post-doctoral
fellowship at the Jules Stein Eye Institute, UCLA, Los Angeles. Professor Souied has contributed to more than 210 peerreviewed
articles in the field of medical retina (AMD, inherited macular and retinal dystrophies).
VOL. 158, NO. 4 732.e1PHASE I/II STUDY OF THE DARPIN MP0112 IN EXUDATIVE AMD
Biosketch
Sebastian Wolf MD, PhD is director of the Department of Ophthalmology at the Inselspital, University of Bern,
Switzerland. His main areas of scientific interest are age-related macular degeneration, retinal vascular disease, imaging,
and vitreo-retinal surgery. Dr Wolf has authored over 150 publications in peer-reviewed journals and serves on the
editorial board of several journals. He has been appointed as ARVO Gold Fellow and has been elected as General
Secretary of the EURETINA.
732.e2 OCTOBER 2014AMERICAN JOURNAL OF OPHTHALMOLOGY