Dompé S.p.A. CONFIDENTIAL TthNGF in NK
Request for Orphan Drug Designation April 2014 - Page 18 of 46

pg/mg. RT-PCR and in situ hybridization for NGF mRNA and NGF immunohistochemistry
indicated that NGF was produced by epithelium, keratocytes, and endothelium in humans and
rats. Rat corneal epithelium, keratocytes, and endothelium all expressed immunopositivity for
TrkA.

In the same publication, these authors report that, in corneal organ culture, cells of the
epithelium, keratocytes, and endothelium of normal human corneas bind radiolabeled NGF.
Monitoring the rate of healing after creation of a 3-mm-diameter epithelial lesion revealed the
healing process of the wounded area (7.1 mm?) and a marked NGF presence within 24 hours.

As a third element of their work, the same authors used an animal model of epithelial
debridement in which healing was initiated after 4 hours and completed within 24 hours.
Time-course studies showed that the corneal lesion induced a progressive increase of NGF
levels, reaching the highest value at 48 hours (3010 + 284 pg/mg; p <0.01). Thereafter, NGF
. concentrations progressively decreased, arriving at baseline values (706 + 123 pg/mg; p
>0.05) 7 days after induction of the lesion.

‘Fourthly, this team investigated the effects of exogenous NGF and of NGF antibodies in the
debrided eyes of the in vivo model. NGF treatment accelerated healing of the epithelium when
compared with saline-treated eyes. This significant difference was confirmed by ANOVA
(repeated measures per treatment: p=0.0001) and post-hoc comparisons (p<0.05). Four hours
after creation of the lesion, the NGF-treated cornea showed a reduction of wound area, with
59% of the cornea de-epithelialized, while the control eyes showed no sign of healing. The
time to complete healing was 10 +1 hours in NGF-treated eyes versus 16 +2 hours in the
control eyes. In contrast, topical treatment with anti-NGF antibody immediately after
epithelial debridement caused a significant delay in healing.

The specific role of NGF-mediated effects on corneal nerves was further elucidated by Joo et
al (2004) who conducted a prospective double-masked study comparing the effect of topical
NGF with balanced salt solution on corneal sensitivity after laser in situ keratomileusis
(LASIK) in rabbits. Preoperative and postoperative comeal sensitivities were assessed using a
Cochet-Bonnet esthesiometer. Eyes that were treated with topical NGF demonstrated an
earlier and faster recovery of corneal sensitivity after LASIK (p=0.007). A statistically
significant difference in corneal sensitivity was found between the topical NGF and control
group postoperatively at 2 (p=0.01), 3 (p=0.03), and 4 (p=0.03) weeks. The authors conclude
that topical NGF had beneficial effects in the early recovery of corneal sensitivity.


Dompé S.p.A. CONFIDENTIAL TthNGF in NK
Request for Orphan Drug Designation April 2014 - Page 39 of 46

6 DEVELOPMENT FOR A SUBSET OF PERSONS WITH
DISEASE OR CONDITION

Not applicable.


Dompé S.p.A. CONFIDENTIAL thNGF in NK.
Request for Orphan Drug Designation April 2014 - Page 35 of 46

- 20 pg/mL (0.7 pg of rhNGF, total daily dose 2.1 yg).

- 60 pg/mL (2.1 pg of rhNGF, total daily dose 6.31).

- 180 pg/mL (6.3 pg of rhNGF, total daily dose 18.9 1g).
© Part B (multiple ascending dose portion):

A total of 40 subjects were treated with rhNGF administered TID for 5 days at one of 3
concentrations. In Group 0M twelve (12) subjects were treated with rhNGF and four
with placebo. In Groups 1M, 2M & 3M, nine (9) subjects were treated with each of 3
concentrations of rhNGF in a randomly selected eye and the fellow eye was treated with
placebo. In addition, 3 subjects per dose group were treated with placebo in both eyes.

- Group 0M: 20 pg/mL (0.7 pg of rhNGF, total daily dose 2.1 yg per day for 5 days).
- Group 1M: 20 pg/mL (0.7 pg of rhNGF, total daily dose 2.1 yg per day for 5 days).
- Group 2M: 60 pg/mL (2.1 pg of rhNGF, total daily dose 6.3 yg per day for 5 days).
- Group 3M: 180 g/mL (6.3 yg of rhNGF, total daily dose 18.9 yg for 5 days).

Plasma samples were obtained over a 3-day period for Part A and over an 8-day period for
Part B. Samples were taken before dosing, after the first dose and after last administration of
the investigational drug for determination of rhNGF pharmacokinetics.

Samples for the evaluation of rhNGF immunogenicity were obtained before treatment and
approximately 30 days after the end of dosing both in Part A and Part B.

Safety evaluation at each study visit (in all 3 parts of the study) consisted of a complete
ophthalmic examination (slit lamp and fundus examination, plus BCDVA), ECG, vital signs,
urinalysis, clinical chemistry and hematology laboratory testing.

There were no serious adverse events or adverse events of special interest (sight threatening
events) reported during the Study NGF0112. Multiple doses of rhNGF eye drops were safe
and well tolerated when given as a single 35 L drop into eye at a concentration of up to the
maximum 180pg/ml. There were no clinically significant findings in the physical
examinations performed and no clinically significant changes in ECG, vital signs, or clinical
laboratory findings were observed in all study cohorts. Also there was no evidence of
systemic absorption or immunogenicity in both Part A and Part B cohorts.


Dompeé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 44 of 46

9 SPONSOR STATEMENT

The Sponsor, Dompé, is the real party in interest of the development of rhNGF and of the
intended or actual production and sales of the product.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 12 of 46

4 DESCRIPTION OF THE DRUG AND SCIENTIFIC
RATIONALE

4.1 Characterization and Description of Drug

Drug Substance

The biological product under development is a recombinant human form of nerve growth

factor (rhNGF) produced in Escherichia coli. Oe



designation #14-4362 -4-

NGF exerts its effect on neuron survival through modulation of expression of the Bcl-2
gene family. The sponsor provides two publications that describe the efficacy of topical
murine NGF in the treatment of patients with neurotrophic keratitis in two clinical studies
34” Both studies showed that topical NGF could heal the corneas, improve cornea
integrity and sensitivity, and improve vision in patients with neurotrophic keratitis. The
use of rhNGF is currently under clinical evaluation. The initial PK study in healthy
volunteers was completed in 2013. The sponsor is currently conducting a Phase 1/2
placebo-controlled clinical study to assess the safety and efficacy of two dose regimens
(10ug/ml or 20,1g/ml) of rhNGF six times daily versus placebo for inducing complete
healing of stage 2 or 3 neurotrophic keratitis refractory to non-surgical therapy (REPARO
study). The Phase 1 segment was recently completed in 18 patients, and although still
blinded, the corneal lesions completely healed in 73% of patients. The Phase 2 portion of
the study is now enrolling.

Recommendation: It is recommended the recombinant human nerve growth factor be
designated as an orphan drug for use in the treatment of neurotrophic keratitis. The
prevalence of patients with neurotrophic keratitis in the US is currently less than 200,000,

and is approximately 159,100.

Erica K. McNeilly, R.Ph.
Health Science Administrator

Concur: Mh N. Sécah an Date: él) baw

Henry H)Startzman III, M.D.
Directo! Orphan Drug Designation Program
Office of Orphan Products Development



designation #14-4362 -2-

irregularity, stromal scarring, and superficial neovascularization; Stage 2 is characterized
by a persistent epithelial defect with smooth and rolled edges, and Descemet’s membrane
folds and stromal swelling; and Stage 3 is typified by corneal ulcer, stromal melting and
perforation!?,

Treatment of neurotrophic keratitis begins immediately after diagnosis in order to prevent
progression and to promote epithelial healing. Stage 1 and 2 neurotrophic keratitis is
treated by administration of artificial tears in order to improve the corneal surface. All
other topical eye medications should be discontinued. Stage 2 disease may also require
the use of corneal or scleral therapeutic contact lenses in order to prevent the
development of corneal ulcers. Surgical procedures such as tarsorrhaphy or amniotic
membrane transplantation can be used for unresponsive cases. Stage 3 neurotrophic
keratitis is treated by surgical procedures including tarsorrhaphy and conjunctival flap to
improve corneal healing. Small perforations can be treated by application of
cyanoacrylate glue followed by a soft bandage contact lens while larger perforations
could require corneal transplant surgery’.

Hypothesis for Clinical Superiority: Not applicable.
Medically Plausible Subset Analysis: Not applicable.

Population Estimate: The prevalence of neurotrophic keratitis caused by the most
frequent causes, herpetic keratitis and as a complication of surgical procedures for
trigeminal neuralgia, has been estimated to be 1.6 per 10,000. The prevalence of
neurotrophic keratitis from other ocular and systemic conditions cannot be estimated as
no data is available in the literature. Therefore, the overall prevalence of neurotrophic
keratitis as a result of all conditions is estimated to be < 5 per 10,000',

Rationale for Use: The sponsor states that NGF is a cytokine essential for the survival
and growth of sympathetic and sensory neurons that are found in innervated tissues such
as the cornea. NGF exerts its effect on neuron survival through modulation of
expression of the Bcl-2 gene family.

The sponsor provides two publications that describe the efficacy of topical murine NGF
in the treatment of patients with neurotrophic keratitis in two clinical studies **. The first
was an uncontrolled study in which 12 patients (14 eyes) with severe neurotrophic
corneal ulcers associated with corneal anesthesia (i.e. stage 3 neurotrophic keratitis) were
treated with the murine NGF 10 times daily for two days and then 6 times daily until the
ulcers healed. Treatment continued for 2 weeks after the ulcers healed, and the patients
were then followed for up to 12 months. The evolution of the corneal disease during
treatment and follow-up was evaluated by slit-lamp examination, photography,
fluorescein-dye testing, and tests of corneal sensitivity and best corrected visual acuity.
Corneal healing began 2 to 14 days after the initiation of treatment with NGF, and all
patients had complete healing of their corneal ulcers after 10 days to 6 weeks of
treatment. Corneal sensitivity improved in 13 eyes, and returned to normal in 2 of the 13
eyes. Corneal integrity and sensitivity were maintained during the follow-up period
(range, 3 to 12 months). Best corrected visual acuity increased progressively during
treatment and follow-up in all patients. There were no systemic or local side effects of


Dompé s.p.a.

cc:

OOPD/File # 14-4362
OOPD/CHRON

History:

J. Fritsch 6/20/14
E. McNeilly

G. Rao

DESIGNATION GRANTED


Dompé S.p.A 2

Congratulations on obtaining orphan-drug exclusivity. Should you have any questions
regarding this exclusivity, please contact Norris Asare at 301-796-7329 or alternatively at
301-796-8660.

Sincerely,
a)

Debra Y. Lewis, OD, MBA
Acting Director
Office of Orphan Products Development


Dompé s.p.a. 2

All communications concerning the request should be identified with the above
reference number. If you have any questions, please call me at 301-796-8685 or
altematively at 301-796-8660.

Sincerely yours,
Digitally signed by Mary L. Grice -S

Mary L. GriCe vets. 0-Us.covemment outs,

‘ou=FDA, ou=People, cn=Mary L. Grice -

Ss,
S 89232 zsszac0. 130019770
Date arama aes 0s

Designation Coordinator


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 22 of 46

A summary of completed in vivo pharmacology studies is presented in the table below:

Table 4.3.1-2: Summary of Applicant’s completed in vivo pharmacology studies

., No. of a
Study Type cite animals Doses rome peertind Results Reference
per sex
thNGF had no
s Male effect on Study
jafety (n=83) and 5 pl of 0.2, 0.8 or appearance, Harlan
pharmacology 1.2 mg/mL rhNGF P behaviour, .
" | Rat female 2 3 x daily D39098
(modified Irwin _ by topical ocular reflexes,
(n=83) age Al1129BPL/E
test) Wistar rats route respiration,
locomotor activity | GLP study
or grip strength.
Both rhNGF and
mNGF increased
SCG weight dose-
Male dependently.
Superior Sprague- | 1, 10 & 20 pg A direct Study
cervical ganglia | Rat Dawley rhNGF or mNGF by | 1 x daily _| correlation M1109
hypertrophy test rats SC route between increase |Non-GLP |
n=18 in SCG weight and :
extent of neuronal
tissue was
observed.
5 wg rhNGF by Single
—_ Male and __| intravitreal injection | injection | p;NGF protected
Retinitis Ra female 5 wg mNGF by Single against Study M1212
oe t RCS rats _| intravitreal injection | injection | photoreceptor GLP study
n=95 6 ug rhNGF by 3xdaily | degeneration.
topical route for 20 days

Activity in vivo of rhNGF was assessed by comparing it with murine native NGF in the
superior cervical ganglion growth assay [Study Report M1109]. This study was designed to
determine the biological activity of different forms of NGF (mNGF, Genentech-developed
thNGF and company-developed rhNGF, indicated as “thNGF-Anabasis”) using the superior
cervical ganglia (SCG) assay, a sensitive and well-established assay of NGF activity. The
SCG is a tissue composed of about 30,000 neurons and it is one of the tissues most sensitive
to NGF action, in particular during pre- and post-natal development.

The study was conducted in newborn female rats. Each litter was culled to 7 female pups and
each pup was treated with a different sample to avoid unspecific variability. Animals at post-


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 40 of 46

7 REGULATORY STATUS AND MARKETING HISTORY

7.1 Investigational or Marketing Experience or Withdrawal in Other
Countries

thNGF is not marketed in any country and has never previously been marketed and/or
withdrawn. In addition, no application to market rhNGF has ever been filed in any country.

At (4) rhNGF is under development for the treatment of neurotrophic keratitis

No application to conduct a clinical trial with rhNGF has ever been
refused in any country.

No adverse regulatory action has been taken against rhNGF in any country.

7.2 Other Relevant INDs

None.


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 3 of 46

LIST OF FIGURES

Figure 4.1-1: Process flow diagram
Figure 4.1-2: Representation of the non-covalent dimer of rhNGF


Dompé S.p.A. CONFIDENTIAL thNGF in NK

Request for Orphan Drug Designation April 2014 - Page 33 of 46
Multiple
administrations
per day as
follows:
¢ 5x within 20
minutes on
30 pl of 1.2 Day 1. No apparent
oe ‘eatment- Iris
5-day preliminary | New mg/ml rhNGF and | * 2 x on Day 2
ocular tolerance | Zealand |9 males or | 0.25 or 1 mg/ml (8 hours (either effects | p23107013
study with White females methionine by apart). systemic of Non-GLP
methionine rabbits topical ocular ¢ 4x on Day 3 Deal to the
route (right eye) (2.5 hours
apart). eyes).
° 6xon Day4
(1.5 hours
apart),
8 xon Day 5
(every hour).
No apparent _| Iris
New nehnt SANGRE and treatment- _ |D23107113
14-day ocular Zealand |9 males or | 0.25 or | mg/ml | 3 x per day, 3 related effects | 41314 BPLIE
tolerance study . se (either
naar White females methionine by hours apart. + GLP study
with methionine " : systemic of
rabbits topical ocular Draft rt
route (right eye) local to the ralt repot
y eyes).

In all completed studies the assigned NOAEL was the highest administered dose:
- 2.4 mg/kg (IV and subcutaneous routes) in both rats and rabbits.
- 1.2 mg/mL (topical ocular route) in both rats and rabbits.
These ocular doses comprised:
- 6g rhNGF/administration/eye in the rat.
- 36 yg rhNGF/administration/eye in the rabbit.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 19 of 46

Two publications report encouraging results when using murine NGF in patients with NK.

Lambiase et al (1998) studied 12 patients (14 eyes) with severe corneal neurotrophic ulcers
associated with corneal anesthesia who were treated with topical nerve growth factor 10 times
daily for two days and then 6 times daily until the ulcers healed. Treatment continued for 2
weeks after the ulcers healed, and the patients were then followed for up to 15 months. The
evolution of the corneal disease during treatment and follow-up was evaluated by slit-lamp
examination, photography, fluorescein-dye testing, and tests of corneal sensitivity and best
corrected visual acuity. Corneal healing began 2 to 14 days after the initiation of treatment
with nerve growth factor, and all patients had complete healing of their corneal ulcers after 10
days to 6 weeks of treatment. Corneal sensitivity improved in 13 eyes, and returned to normal
in 2 of the 13 eyes. Corneal integrity and sensitivity were maintained during the follow-up
period (range, 3 to 15 months). Best corrected visual acuity increased progressively during
treatment and follow-up in all patients. There were no systemic or local side effects of
treatment.

Bonini et al (2000) also evaluated the efficacy of NGF in a prospective, non-comparative,
interventional case series involving 45 eyes of 43 consecutive patients with moderate (stage
2, n=17) to severe (stage 3, n=28) neurotrophic keratitis unresponsive to other nonsurgical
therapies. After a 10-day washout with preservative-free artificial tears, the eyes were treated
with murine NGF (200 mg/ml) every 2 hours for 2 days followed by one drop six times daily
until the ulcer healed. A maintenance dose of one drop NGF (100 mg/ml) was administered
four times daily for the 2 weeks subsequent to ulcer healing. All patients had complete
resolution of the persistent epithelial defect (with or without an ulcer) after 12 days to 6
weeks of treatment with NGF. Patients affected by both stages of the disease had both
improved corneal sensitivity and visual acuity (p<0.001). No significant differences were
observed in the time to complete corneal healing between stage 2 and stage 3 patients.
Hyperemia and mild and transient ocular and periocular pain were side effects reported
during the first days of treatment. No relapse of the disease was observed during the follow-
up period, with the exception of three patients with trigeminal nerve resection, who required a
single retreatment.

The use of rhNGF in humans is currently under evaluation. In a masked efficacy analysis of
the Phase 1 segment of an ongoing Phase 1/2 study, in which 14 patients are receiving rhNGF
and 4 patients are receiving vehicle, corneal lesions were completely healed in 73% of


oo

Dompé S.p.A.

CONFIDENTIAL

Request for Orphan Drug Designation

ThNGF in NK

April 2014 - Page 25 of 46

Table 4.3.2-2: Summary of completed 4-week ocular pharmacokinetic studies
Typ Species ! Dose / Route / Frequency Comments Reference
thNGF exposure increased more than
dose-proportionally in male rats. For
female rats, exposure approached dose- Stud
Male (n=83) and | Spl of 0.6, 0.8 or 1.2 mg/mL _| proportionality. Harken D39098
female (n=83) thNGF by topical ocular route | After 4 weeks repeated dosing riNGF -A1129BPL/E
Wistar rats (both eyes) 3 x per day. exposure was decreased or stable as GLP stud
compared with Day 1 (AUC y
Week4/Day] ratio 0.3-0.98; therefore no
observed accumulation).
Data were highly variable and with
_ exposure levels frequently below the
Male (n=16) and 30p! of 0.6, 0.8 or 1.2 mg/mL | lower limit of quantitation (indicating Study
female (n=16) . 1 Harlan D39065
N thNGF by topical ocular route | very low exposure).
lew Zealand th oe, . -A1138BPL/E
White rabbits (both eyes) 3 x per day. No toxicokinetic conclusions could be | Gp grug
drawn regarding the gender and time y
dependency
New Zealand 30ul of 0.6, or 1.2 mg/ml Very low or levels below the limit of Study
White rabbit Male | rhNGF by topical ocular route | (antification of rhNGF were found in | frisD23127212
(n=13) Female _| (right eye) 3 x per day for 58_| almost all animals. A1302BPL/E
(13) days GLP study
30yL 3 x per day, 3 hours
apart for 14 days
topical ocular route (right
P Gight eye) Study Iris
-Doses: D23107113
At day | and 14: plasma levels very low | (Harlan Study
New Zealand 1.2 (or 1.36 ) mg/mL thNGF* | 9; below the limit of quantification of Phase D79565)
White rabbits 0.25 (or 0.125) mg/mL L- thNGF,
Males (n= 15) methionine Dompé Study:
A1314BPL/E

1.2 (or 1.36 ) mg/mL rhNGF+
1 (or 0.5) mg/mL L-
methionine

1.2 mg/mL rhNGF+ 1 mg/mL
L-methionine



Dompé S.p.A.

Request for Orphan Drug Designation

CONFIDENTIAL

April 2014 -

thNGF in NK
Page 21 of 46

4.3 Nonclinical data

4.341 Pharmacology
A summary of completed in vitro pharmacology studies is presented in the table below:

Table 4.3.1-1:

Summary of Applicant’s completed in vitro pharmacology studies

No. of

Species . Dose, route, Dosing
Study Type cell type animals concentration regimen Results Reference
per sex
thNGF was more
Human 0.3 pM- active than mNGF | Study
TF-1 n/a 6.76 nM n/a regarding A1130
Cell cells thNGF and mNGF proliferation of Non-GLP
proliferation human TF-1 cells.
assays Rabbit 0.3 pM Rabbit SIRC cells. | suuay
SIRC |n/a - 13.52 nM Wa a GE bar votio A1131
cells thNGF and mNGF ThNGF. Non-GLP
— 10 different thNGF has greater
Binding and concentrations of affinity for human | Study
competition HEK29 | a thNGF and mNGF. | n/a TrkA receptor than | A1226/E
assay on human | 3 cells bene
TrkA receptor Reference standard mNGF (Ki=3.7 | Non-GLP
at 13nM nM vs 6.2 nM.

The biological activity of rhNGF produced in £. coli has been assessed in vitro by
proliferation of human TF1 cells. TF1 is a human erythroleukemic cell line expressing NGF
receptors. NGF induces dose-dependent proliferation of TF1 cells. The results of this study
(study A1130) show that rhNGF was more active (approximately 10 fold) than murine NGF
in the human TF1 cell proliferation assay.



Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 34 of 46

4.4 Clinical trials

Completed study: Protocol NGF0112

The initial clinical trial in humans of Dompé’s topical ophthalmic formulation of rhNGF
(Protocol NGFO112; Ferrari et al, Biodrugs 2013;) was completed in March 2013. This trial
was designed to evaluate the safety profile, pharmacokinetics and immunogenicity of rhNGF
topical ophthalmic solution after single and multiple fractioned doses in healthy volunteers.

A total of 73 healthy male and female volunteers were enrolled. Eligible subjects were
between 18 and 60 years of age with good systemic health, an unremarkable systemic and
ocular past medical history, a BCDVA of 20/20 or better (©83 ETDRS letters), normal
anterior segment on external and slit lamp examination and normal posterior segment on
fundus examination in both eyes. The study subjects were also required to be on no
concomitant ocular or systemic treatment.

Study subjects were screened within 20 days of enrolment (Day -20 to Day -1) and eligible
subjects who provided written informed consent were assigned to one of three phases of the
study.

« Part 0:

A total of 9 subjects (3 subjects per dose) were treated in a randomly selected eye with
one drop of placebo (the rhNGF vehicle) administered once and the fellow eye was
treated with one drop of rhNGF administered once at one of 3 concentrations:

- 0.5 pg/mL (0.0175 yg of rhNGF).
- 5 pg/mL (0.175 pg of rhNGF).
- 20 pg/mL (0.7 pg of rhNGF).
e Part A (single ascending dose portion):

A total of 24 subjects were treated with rhNGF administered TID for 1 day at one of 3
concentrations. Six (6) subjects were treated with each of 3 concentrations of rhNGF ina
randomly selected eye and the fellow eye was treated with placebo. Two (2) subjects per
dose group were treated with placebo in both eyes. The concentrations of rhNGF tested
were:


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 16 of 46

Table 4.1-3: Composition of drug product

Constituent Function oy I
thNGF 0.002
Trehalose dihydrate
Mannitol
NazHPO, anhydrous
NaH2PO, dihydrate
Hydroxypropylmethyl
cellulose
PEG 6000
L-methionine
WFI up to

The drug product will be manufactured in accordance with GMP under environmental and
process aseptic conditions to obtain a final sterile drug product.


Is the approval within

Yes KX No)

scope of designation?
Approval of cenegermin-bkbj for the treatment of neurotrophic keratitis is within
Comments: the scope of orphan drug designation #14-4362 for treatment of neurotrophic
keratitis.
Is the drug or
biologic a New
Has the same drug or .
biologic been YesO) No & (NME) on wai ty Yes X NoO
previously approved? Biological Entity
(NBE)?

Comments:

Per DARRTS, this is a new molecular (biological) entity and Drugs@FDA
confirms this is the first approval for cenegermin-bkbj. Therefore, cenegermin-
bkbj is a new biological entity.

Has the same drug or
biologic already been
approved for the same
disease or condition?

YesO No

Comments:

The FDA News Release dated August 22, 2018 notes that this is the first
approval of a drug indicated for the treatment of neurotrophic keratitis.
Furthermore, pages 3 and 4 of the Deputy Office Director, Deputy Division
Director, and Cross-Discipline Team Leader (CDTL) Review dated 8/22/18
indicates that prior to approval of BLA 761094, there was no FDA approved
pharmacologic therapy for the treatment of neurotrophic keratitis.

Superiority:

Yes NoL Not applicable

Comments:

There is no need to demonstrate superiority since there is no other same biologic
approved for the indication that is the subject of this exclusivity.

Recommendation:

Approval is within scope of orphan drug designation. The same biologic has not
been previously approved for the same disease or condition. Therefore, the
sponsor is eligible for orphan exclusivity for OXERVATETM (cenegermin-bkbj)
indicated for the treatment of neurotrophic keratitis.

Page | 2-9/11/2018 8:34 AM



o~

Dompé S.p.A.
Request for Orphan Drug Designation

CONFIDENTIAL

thNGF in NK

April 2014 - Page 8 of 46

Table 3-1: Etiopathogenesis of neurotrophic keratitis (Semeraro et al, 2013)

Herpes simplex

Infections Herpes zoster
Leprosy
Chemical burns
Contact lens wear
Surgeries
Laser-assisted in situ keratomileusis
Corneal pathologies Corneal incision

Lamellar and penetrating keratoplasty

Dystrophies
Lattice
Granular

Topical medications

Anesthetics
Timolol
Betaxolol
Trifluridine
Sulfacetamide

Cranial nerve V palsy

Trigeminal! neuralgia surgery
Neoplasm
Aneurysm
Facial trauma
Congenital
iley-Day syndrome
Mobius corneal hypoesthesia

Systemic diseases

Diabetes
Vitamin A deficiency
Multiple sclerosis

Miscellaneous

Increasing age
Adie’s syndrome

The most common causes of loss of corneal sensitivity are herpes keratitis, chemical burns,

long-term use of contact lenses, corneal surgery, ablative procedures for trigeminal neuralgia,
and surgical procedures for reduction of jaw fractures. Other less frequent causes are space-
occupying intracranial masses (e.g., schwannoma, meningioma and aneurysms) that can lead
to compression of the nerve and reduce corneal sensitivity. Systemic diseases that may
compromise trigeminal function are diabetes, multiple sclerosis and leprosy. NK may also be
a complication of radiation therapy. Congenital causes, such as the Ridley-Day syndrome,
anhidrotic ectodermal dysplasia, Moebius syndrome, Goldenhar syndrome, and congenital

comeal anaesthesia, are very rare.


o-~

Dompé S.p.A.

Request for Orphan Drug Designation

CONFIDENTIAL

April 2014 -

ThNGF in NK
Page 31 of 46

Table 4.3.3-1: Summary of completed systemic toxicology studies
Single dose
Single dose
with 3 day
0.3, 0.6, 1.2&2.4
. ‘. Male Leb washout NOAEL (IV) | Study Harlan
Single ascending Wistar (n=12) | meKBby IV between each |=2.4mg/kg |D39076 -
. 4 rat Female . administrations | NOAEL (SC) | A!121BPL/E
Single SC dose (n=12) 24 make bySC av) =2.4 mg/kg | GLP study
~ Single dose
(Sc)
Single dose
ith 3 da
0.3, 0.6, 1.2 & 2.4 | WH 3 day Study
. . Male Loh washout NOAEL (IV)
single ascending MeN nd (n=1) mark g by IV betweeneach | =2.4 mg/kg Heed A
. 7 administrations
Single SC dose [Rabbit {Female |, 4 mg/kg by SC | qv NOAEL (SC) | 41120BPL/E
a=) route. vy) =2.4 me/kg GLP stud:
7 Single dose y
(SC)
Repeated dose
Combined 8/26 | Han Male 50 and 100 Daily for8 or |NOAELof | Harlan
weeks Wistar (n= 151); | #g/animal by SC_ | 26 weeks with a | 100 D68304
subcutaneous Tat Female route 2/4-Week pe/animal in | \41306BPL
toxicity study (n= 151) Recovery both males GLP stud:
Period and females. y
90-day New Male 100 and 200 Once perday | NOAEL: 200 | Harlan
subcutaneous Zealand |(n=18); | Hg/animal by the | for 90 days g/day both | D68326
toxicity study white Female (n SC route males and M1305BPL
rabbits | =18) males. GLP study



Dompé S.p.A.

Request for Orphan Drug Designation

CONFIDENTIAL

April 2014 -

rhNGF in NK
Page 28 of 46

Type of Study /
Species

Dose / Route /
Frequency

Comments

Reference

Wistar rats

Male (n= 15)
Female (n = 15r)

Subcutaneous

50 and 100
pg/animal/day for
8/26 weeks

Day 1: 50 pg/animal/day

Cmax (ng/mL): 94.24 (M); 123.65 (F)

Trax (h): 4 (M); 2 (F)

AUC, (ng.h/ml): 580.90(M); 766.48 (F)
Day 29: 50 pg/animal/day

Cymax (ng/mL): 38.28 (M); 74.73 (F)

Tinax (hh): 2 (M); 2 (F)

AUCo, (ng.h/ml): 190.05 (M); 302.82 (F)
Day 61: 50 ng/animaV/day

Crnax (ng/mL): 161.67 (M); 271.45 (F)

Trax (h): 2 (M); 2 (F)

AUCo, (ng.h/ml): 893.27 (M); 1110.36 (F)
Day 89: 50 pg/animal/day

Cmax (ng/mL): 176.46 (M); 190.20 (F)

Trax (h): 4 (M); 4 (F)

AUC, (ng.h/ml): 671.25 (M); 885.73 (F)
Day 176: 50 pg/animal/day

Crax (ng/mL): 100.04 (M); 109.83 (F)

Trnax (h): 2 (M); 2 (F)

AUC, (ng.h/ml): 441.79 (M); 513.05 (F)
Day 1: 100 pg/animal/day

Crrax (ng/mL): 191.41 (M); 283.84 (F)

Trax (h): 4 (M); 4 (F)

AUCo, (ng.h/ml): 1010.59 (M); 1358.61 (F)
Day 29: 100 pg/animal/day

Cmax (ng/mL): 150.09 (M); 280.70 (F)

Trax (h): 2 (M); 6 (F)

AUC5, (ng.h/ml): 764.11 (M); 1952.63 (F)
Day 61: 100 pg/animal/day

Conax (ng/mL): 204.67 (M); 311.20 (F)

Trax (h): 2 (M); 4 (F)

AUCo. (ng-h/ml): 967.61 (M); 1783.26 (F)
Day 89: 100 pg/animal/day

Cymax (ng/mL): 279.58 (M); 688.24 (F)

Trax (h): 6 (M); 4 (F)

AUCo, (ng.h/ml): 1563.16 (M); 3507.90 (F)
Day 176: 100 pg/animal/day

Cmax (ng/mL): 247.17 (M); 284.71 (F)

Trax (h): 2 (M); 2 (F)

AUCo. (ng.h/ml): 926.89 (M); 1642.42 (F)
Exposure in females slightly higher than in males at
both doses. These differences on the exposure
decreased or disappeared when dose is normalized to
body weight.

Accumulation ranged between 0.3 to 1.5.

Study D68304
GLP study



Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 5 of 46

1 ORPHAN DESIGNATION REQUEST

Dompé S.p.A. (Dompé) requests orphan drug designation for recombinant human nerve
growth factor (rhNGF) for the treatment of neurotrophic keratitis (NK).


Dompé S.p.A.

CONFIDENTIAL

Request for Orphan Drug Designation

ThNGF in NK
April 2014 - Page 4 of 46

LIST OF ABBREVIATIONS
Ach Acetylcholine
DNA Deoxyribose nucleic acid

ELISA Enzyme-linked immunosorbent assay

HCP Host cell protein

IEX-HPLC | Ion exchange- high performance liquid chromatography
IV Intravenous

LAL Limulus amebocyte lysate

LASIK Laser in situ keratomileusis

LC-MS Liquid chromatography-mass spectrometry

LNGFR Low-affinity nerve growth factor receptor

mNGF Murine nerve growth factor

NAION Non-arteritic anterior ischemic optic neuropathy

NGF Nerve growth factor

NK Neurotrophic keratitis

NOAEL No observed adverse effect level

PED Persistent epithelial defect

thNGF Recombinant human nerve growth factor

RP Retinitis pigmentosa

rpHPLC Reverse phase high performance liquid chromatography
RT-PCR Real time polymerase chain reaction

sc Subcutaneous

SCG Superior cervical ganglia

SDS-PAGE | Sodium dodecyl sulphate polyacrylamide gel electrophoresis
SE-HPLC Size exclusion high performance liquid chromatography

SP

Substance P



Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 17 of 46

4.2 Rationale for use of rhNGF in NK

NGF is a polypeptide discovered in the early 1950s by Rita Levi-Montalcini, who received
the 1986 Nobel Prize in Physiology or Medicine for the discovery, along with her colleague
Stanley Cohen. It is essential for the survival and growth of sympathetic and sensory neurons
and for differentiation of neurons in the central nervous system.

NGF binds with at least two classes of receptors:
«  TrkA, a transmembrane tyrosine kinase.

+ p75 LNGFR (low-affinity nerve growth factor receptor), often abbreviated as
p75NTR.

Binding of NGF to the high-affinity tyrosine kinase receptor TrkA results in phosphorylation
of the enzyme, which leads to the activation of the PI 3 Kinase, ras, and PLC signalling
pathways.

As opposed to TrkA, p7SNTR plays a somewhat less clear role in NGF biology. Some
researchers have shown this receptor serves as a "sink" for neurotrophins. Cells that express
both p75NTR and Trk receptors might, therefore, have a greater activity, since they have a
higher "microconcentration" of NGF (Reichardt, 2006).

NGF exerts its effects on neuron survival through modulation of expression of the well-
established Bcl-2 gene family, a rise in Bcl-2:Bax ratio being accompanied by enhanced cell
survival while a fall in this ratio signals apoptosis.

Rationale for the use of rhahNGF

The human cornea is the most densely innervated surface tissue in the body. Marfurt et al
(2010) showed that around 70 nerve bundles enter the cornea at the corneoscleral limbus and
then give rise through repetitive branching to a moderately dense midstromal plexus and a
dense subepithelial plexus. It is therefore not surprising that NGF is an important cytokine in
corneal tissue.

Lambiase et al (2000) found that under normal physiological conditions, human and rat
corneas produced and stored NGF. ELISA showed that NGF was present in normal human
corneas at a concentration of 1154 + 376 pg/mg and in the rat at a concentration of 388 + 121


Dompé S.p.A. CONFIDENTIAL ThNGF in NK
Request for Orphan Drug Designation : April 2014 - Page 7 of 46

3 DESCRIPTION OF RARE DISEASE OR CONDITION

Neurotrophic keratitis (NK) is a degenerative corneal disease that follows a partial or total
impairment of trigeminal innervation, leading to a reduction (hypoesthesia) in or loss
(anesthesia) of corneal sensitivity (Semeraro et al, 2013).

Etiopathogenesis

The trigeminal ophthalmic branch has two reflex arcs: one motor arc, regulating the opening
and closing of the eyelids, and one autonomic arc, regulating the lacrimal gland, Meibomian
gland and goblet cell secretion. The integration of these two reflex arcs ensures the stability
of the tear film and, together with related neurotrophic factors (neurotrophins), the vitality of
the epithelium and stroma. The impairment of sensory innervation causes a reduction in the
lacrimation reflex and the vitality, metabolism and mitosis of epithelial cells, with subsequent
deficiency in epithelial repair, stromal and intracellular edema, loss of microvilli, and
abnormal development of the basal lamina.

The study of NK has directed the attention of researchers to the role of neurotransmitters such
as substance P (SP), calcitonin gene-related peptide, neuropeptide Y, vasoactive intestinal
peptide, galanin, methionine-enkephalin, catecholamine, and acetylcholine (Ach). Studies
have shown a decrease in SP and Ach resulting from injury to the corneal nerves, the ability
of SP alone to stimulate the synthesis and growth of corneal epithelial cells, and epithelial
proliferation in vitro by SP, cholecystokinin gene-related peptide and Ach.

NK can be the expression of systemic or ocular congenital or iatrogenic diseases resulting
from damage to the fifth cranial nerve (Table 3-1).


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 23 of 46

natal age 7 days received daily subcutaneous injections of 10 ug/g body weight in 50 pl of
solution (10 mM KP + 150 mM NaCl, pH 7.2) for 5 consecutive days. They were then
sacrificed in order to assess effects on SCG.

The effects of mNGF, rhNGF-Anabasis and Genentech-developed rhaNGF on SGC were all
comparable, while vehicle had no effect (see Table 4.3.1-3). Untreated controls also showed
no effect. A direct correlation between increase in SCG weight and extent of neuronal tissue
was observed. As a result, it was concluded that the effects on retinal protein and mRNA
levels shown by Lenzi are transferable from mNGF to rhNGF (Lenzi et al, 2005).

The data collected are summarized in the table below:

Table 4.3.1-3: | Results of comparison of biological activity of different NGF
preparations

Effect on superior Body weight (g)

cervical ganglia*

Treatment

Before treatment | End of treatment

. Mouse NGF

. th-proNGF-Anabasis

. ThNGF-Genentech/Roche
. thNGF-Anabasis

. th-Propeptide

. non-injected

* +++ comparable to mouse NGF;
++ low effect;

-no effect


(4-43BUR
FAFILE copy

Creative Regulatory Solutions, LLC

RECEIVED
April 23, 2014 APR 25 2014
Director Office of Orphan
Office of Orphan Products Development Products Development

Food and Drug Administration
10903 New Hampshire Avenue
WO32-5271

Silver Spring, Maryland 20993-0002

RE: Request for Orphan Drug Designation for Recombinant Human Nerve
Growth Factor for the Treatment of Neurotrophic Keratitis

Dear Director:

In accordance with 21 CFR 316.20, we are hereby submitting, in duplicate, on behalf of
Dompe s.p.a., an Orphan Drug Designation Request for recombinant human nerve
growth factor ocular drops for the treatment of neurotrophic keratitis. As required, copies
of all references cited in the document have been enclosed. References have been
provided in alphabetical order using numbered tabs. A bibliography follows the Orphan
Drug Designation Request showing the tab number with the associated reference. The
submission contains a single volume containing the formal orphan drug designation
request, followed by the bibliography and copies of the references. An original and a
photocopy of the Orphan Drug Designation Request have been enclosed.

Should you have any questions, please feel free to contact the undersigned by telephone
at (862) 397-4534 or by e mail at bmccormack@creativeregulatory.com.

Sincerely,

[Af

Robert McCormack, PhD.
Regulatory Affairs Consultant

Enclosure: References Removed
/
ona /ia
Creative Regulatory Solutions, LLC Tel: 862-397-4534

14 Edinburgh Drive Fax: 862-397-4535
Randolph, NJ 07869 USA



Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 46 of 46

Lambiase A, Sacchetti M in Benitez-del-Castillo JM, Lemp MA (Eds) Ocular Surface
Disorders JP Medical, London, 2013.

Lenzi L, Coassin M, Lambiase A et al (2005). Effect of exogenous administration of nerve
growth factor in the retina of rats with inherited retinitis pigmentosa. Vision Research 45:
1491-1500.

Liesegang TJ. Corneal complications from herpes zoster ophthalmicus. Ophthalmology1985;
92(3):316-24.

Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation.
Experimental Eye Research 2010;90:478-492.

Reichardt L.F. Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. B (2006)
361, 1545-1564.

Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis. Clinical
Ophthalmology 2014; 8: 571-579.

Semeraro F, Forbice E, Romano V et al. Neurotrophic Keratitis. Ophthalmologica 2013; DOI:
10.1159/000354380.

Sinigaglia F. Phase I/II Dose-Ranging, Randomized Clinical Trial of Recombinant Human
Nerve Growth Factor in the Treatment of Neurotrophic Keratitis: Preliminary Results. ARVO
2014, Presentation Number 4690 - A0315.

Young RC, Hodge DO, Liesegang TJ, Baratz KH. The incidence, recurrence and outcomes of
herpes simplex virus eye disease in Olmsted County, Minnesota, 1976 through 2007: The
impact of oral antiviral prophylaxis. Arch Ophthalmol. 2010; 128(9): 1178-1183.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 10 of 46

This marked difference between Stage 1 and Stages 2-3 might suggest that clinical
manifestations might be induced by different mechanisms.

Diagnosis and symptoms

Diagnosis is based on a detailed medical history to investigate all possible risk factors,
followed by a careful examination of the ocular and periocular area, including the globe and

ocular adnexa.

Previous episodes of redness and eye pain or the presence of cutaneous blistering or scarring
suggest previous herpetic infections. A history of corneal surgery, trauma, abuse of topical
anesthetics, long-term use of topical medications, chemical burns, or contact lens abuse may
be contributory. Long-term use of eye drops such as timolol, betaxolol, sulfacetamide
sodium, or diclofenac can cause a loss of corneal sensitivity, as can the abuse of topical
anaesthetics. Corneal hypoesthesia can sometimes occur in advanced stromal dystrophies
such as latex or granular dystrophies. Any neurological signs or symptoms or expression of
fifth cranial nerve disease such as brain tumors, vascular accidents and thromboangiitis
obliterans should be explored. A history of previous surgical resection of an acoustic neuroma
may suggest an iatrogenic trigeminal nerve injury. The presence of hearing problems may
indicate intracranial tumors such as neuromas of the eighth cranial nerve, especially when the
fifth and seventh cranial nerves are involved. A history of long-term therapy with
neuroleptics, antipsychotics and antihistamines should be investigated, as should a history of
diabetes mellitus, because reduction in corneal sensitivity in diabetes increases with the
duration of the disease.

The symptoms reported by the patient vary depending on the degree of corneal anesthesia, but
usually, the patient complains of a red eye and a slight reduction in visual acuity. The corneal
sensitivity test is the basic examination and can be performed by touching the central and
peripheral cornea with a Cochet-Bonnet aesthesiometer, which locates and quantifies the loss
of corneal sensitivity by recording the patient’s response to the touch of a nylon thread (less
than 5 mm in thread length is regarded as clinically significant corneal hyposensitivity); a less
sensitive test is the response to a touch with the tip of a cotton swab. In general, the severity
of NK is related to the severity of corneal sensory impairment. The disease is usually
unilateral, but if it is bilateral, there will also be a reduction in blinking as well as reduced tear
production due to lack of the afferent arm of the lacrimation reflex. Fluorescein, rose bengal


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 9 of 46

Classification
NK can be classified into 3 stages according to the Mackie classification (Table 3-2).

Table 3-2: Classification of neurotrophic keratitis (from Semeraro et al, 2013)

Punctate epithelial keratopathy

Decreased tear film break-up time

Stage 1 Rose bengal staining of inferior palpebral conjunctiva
Dellen

Gaule spots

Stromal scarring

Epithelial defect
Stromal swelling

Stage 2 Surrounding rim of loose epithelium
Anterior chamber reaction (rare)
Corneal ulcer

Stage 3 Stromal lysis
Perforation

The first stage is characterized by punctate keratitis, epithelial hyperplasia, stromal scarring,
and corneal neovascularization.

The second stage is characterized by a persistent epithelial defect, usually in the paracentral
area, of oval shape with the horizontal axis surrounded by an irregular, oedematous, opaque
epithelium capable of spontaneous detachment. A reaction in the anterior chamber or sterile
hypopyon is rarely seen. At this stage, the mechanism of loss of the corneal epithelium is
similar to that of recurrent erosions, promoted by reduced lubrication of the corneal surface
and by the abnormal corneal epithelium.

In the third stage, there is stromal involvement that appears as a stromal corneal ulcer and
stromal oedema and infiltrates; this may result in perforation and/or corneal thinning due to
stromal melting.

While Stage 1 is a mild condition that in most cases can be managed by continuous
lubrification or therapeutic contact lenses, in Stages 2 and 3 the corneal epithelial defect or
ulcer is persistent, with significant risk of corneal perforation and vision loss. Stages 2 and 3
are usually refractory to any treatment, and often surgery is the only option for the patient.


FDA

U.S. FOOD & DRUG

ADMINISTRATION

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Office of Orphan Products Development

Exclusivity Memorandum

Date: 9/5/2018
From: Norris Asare, Designation Program Coordinator
Th h: Roberta Szydlo, Health Science Administrator SX2( 9 Norge
rough: Henry Startzman III, MD, Director, Orphan Drug Designation Program N57
To File #: 14-4362

Name of drug or
biologic:

OXERVATETM (cenegermin-bkbj)

Orphan designation:

Treatment of neurotrophic keratitis

Designation date: 6/23/2014
Sponsor name: Dompé S.p.A.
BLA#: 761094
Approval date: 8/22/2018

Approved indication:

TM

OXERVATETM (cenegermin-bkbj) ophthalmic solution 0.002% is indicated for
the treatment of neurotrophic keratitis.

3/2018

Page | 1-9/11/2018 8:34

AM


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 42 of 46

The prevalence of NK caused by other conditions, such as diabetes, multiple sclerosis,
acoustic neuroma, and congenital disorders, cannot be estimated because no data are
available in the literature. Therefore, the final prevalence of NK within the population of
Europe can be estimated at <1.6/10,000.”

It may be noted that the prevalence values estimated for herpetic keratitis, HZO and surgical
procedures sum to 1.42/10,000 while the text cites an overall NK prevalence of
“<1.6/10,000”. It may be assumed that the difference of 0.18/10,000 represents an allowance
for the cases secondary to conditions such as diabetes, multiple sclerosis, acoustic neuroma
and congenital disorders, no data being available for even indirect estimates of these.

The sponsor has sought, as far as possible, to confirm the calculations reported by Lambiase
& Sacchetti and to set them in a US context.

Herpetic keratitis

Young et al (2010) retrospectively reviewed the records of all 394 Olmsted County,
Minnesota residents diagnosed with ocular HSV from 1976 through 2007. These authors
comment in their paper that: :

“We estimated an age and sex-adjusted annual incidence rate of 9.2 per 100,000
population new cases of keratitis and 11.8 per 100,000 of any ocular HSV. Labetoulle
and co-investigators prospectively surveyed eye care providers in France and found an
incidence of 13.2 per 100,000 person-years for new cases of herpes keratitis.”

This suggests that the prevalence of herpetic keratitis in the US is very similar to that
recorded for France by Labetoulle et al (2005) and used by Lambiase & Sacchetti as the basis
for their calculations. No case of NK appears on the list of diagnoses in the Young et al paper,
which is consistent with the rarity of the condition.

Herpes zoster ophthalmicus

Borkar et al (2013) from the University of California, San Francisco reviewed the electronic
medical records of Kaiser Permanente Hawaii for 2006 and 2007 and identified 134 cases of
HZO in this population of 217 061 people. The overall incidence of 30.9 per 100 000 person-
years (95% confidence interval [CI], 25.9-36.6) is compatible with the prevalence of
26/100,000 reported by Dworkin et al, 2007 and used by Lambiase & Sacchetti in their
calculations.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 30 of 46

The studies showed that there is a minor systemic absorption dose proportional or
hyperproportional in rat following eye drop administration, and very minimal or absent
systemic absorption in rabbits following eye drop administration.

Following eye drop treatment with rhNGF in rats with abraded cornea, low levels of rhNGF
could be found in serum.

The pharmacokinetic profile, after IV administration, showed a biphasic profile, with rather
parallel terminal phases: the terminal half-life (tz), ranged between 3.0 and 6.3 hours. The
first descending phase was very rapid, leading to eventual uncertainty in the determination of
Cmax and AUCo..

As the serum concentrations following IV administration are again several orders of
magnitude greater than those following ocular administration, this exposure provides a very
high safety margin for the clinical use of the rhNGF.

Subcutaneous administration for 26 weeks in the rat did not result in accumulation but one
out of 6 animals treated with 50 g/animal/day and 3 out of 6 animals treated with 100
ug/animal/day. developed binding antibodies, indicating that there is an immunogenic
potential of rhNGF in the rat when administered daily subcutaneously.

After repeated subcutaneous administration in the rabbit high variability in rhNGF
concentrations was observed in half of the treated animals, possibly due to the fact that
the animals showed anti-drug antibodies. Five out of 8 animals treated with 100
ug/animal and 12 out of 14 animals treated with 200 pg/animal developed binding
antibodies when treated with rhNGF, further suggesting that there is an immunogenic
potential of rhNGF in the rabbit when administered daily by the subcutaneous route.

4.3.3 Toxicology
The completed toxicology studies are summarised in Tables 4.3.3.1 and 4.3.3.2 below:


Orphan Drug Designation Request for rhNGF in the Treatment
of Neurotropic Keratitis
Bibliograph

Tab #1 - Bhatti MT, Patel R. Neuro-ophthalmic considerations in trigeminal neuralgia and its
surgical treatment. Curr Opin Ophthalmol. 2005;16(6):334-40.

Tab #2 - Bonini S, Lambiase A, Rama P et al. Topical treatment with nerve growth factor for
neurotrophic keratitis. Ophthalmology 2000;107:1347-1352.

Tab #3 - Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye 2003; 17: 989-995.

Tab #4 - Borkar DS, Tham VM, Esterberg E et al. Incidence of herpes zoster ophthalmicus:
results from the Pacific Ocular Inflammation Study. Ophthalmology. 2013;120(3):451-6

Tab #5 - Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the management of
herpes zoster. Clin Infect Dis. 2007;44 Suppl 1:S1-26.

Tab #6 - Ferrari M, Mantelli F, Sacchetti M et al Safety and Pharmacokinetics of Escalating
Doses of Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked,
Randomized Clinical Trial. BioDrugs DOI 10.1007/s40259-013-0079-5

Tab #7 - Joo, M-J, Yuhan, KR, Hyon JY et al. The effect of nerve growth factor on corneal
sensitivity after laser in situ keratomileusis. Arch Ophthalmol. 2004;122:1338-1341.

Tab #8 - Katusic S, Beard CM, Bergstralh E, Kurland LT. Incidence and clinical features of
trigeminal neuralgia, Rochester, Minnesota, 1945-1984. Ann Neurol. 1990; 27(1):89-95.

Tab #9 - Labetoulle M, Auquier P, Conrad H et al. Incidence of herpes simplex virus keratitis in
France. Ophthalmology 2005;112(5):888-95.

Tab #10 - Lambiase A, Rama P, Bonini S et al. Topical treatment with nerve growth factor for
corneal neurotrophic ulcers. N Engl J Med 1998;338:1174-80.

Tab #11 - Lambiase A, Manni L, Bonini S et al. Nerve growth factor promotes corneal healing:
structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis
Sci. 2000;41:1063-1069.

Tab #12 - Lambiase A, Sacchetti M in Benitez-del-Castillo JM, Lemp MA (Eds) Ocular Surface
Disorders JP Medical, London, 2013.

Tab #13 - Lenzi L, Coassin M, Lambiase A et al (2005). Effect of exogenous administration of
nerve growth factor in the retina of rats with inherited retinitis pigmentosa. Vision Research 45:
1491-1500.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 29 of 46
Type of Study / Dose / Route / Comments Reference
Species Frequency
Day 1: 100 pg/animal/day
Cmax (ng/mL): 2.34 (M); 2.97 (F)
Trax (h): 2 (M); 4 (F)
AUC. (ng.h/ml): 17.49 (M); 18.60 (F)
Day 87: 100 pg/animal/day
Cmax (ng/mL): 4.18 (M); 10.26 (F)
Tynax (h): 2 (M); 4 (F)
AUC. (ng.h/ml): 23.65 (M); 47.64 (F)
90-days Harl
subcutaneous Subcutaneous Day 1: 260 pg/animal/day 68326
toxicity study 100 and 200 Cc L): 4.69 (M); 4.84 (F)
New Zealand —_| ug/animal max (ng/mL): 4.69 (M); 4. MI30SBPL
White rabbits once per day for Trax (h): 4 (M); 2 (F) GLP study
Male (n= 12); 13 weeks AUC, (ng.h/ml): 38.71 (M); 31.86 (F)
Female (n =12) Day 87: 200 pg/animal/day
Cmax (ng/mL): 7.85 (M); 8.53 (F)
Trax (h): 2 (M); 4 (F)
AUC, (ng.h/ml): 20.49 (M); 81.94 (F)
° Significant inter-animal variability in plasma levels.
Accumulation ranged between 0.5-1.4 in males and 2.6
in females.

Pharmacokinetics have been assessed by IV and SC routes in rats and rabbits at single

ascending doses up to 2.4 mg/kg and with repeated doses up to 200 pg/animal. The topical
ocular route has also been studied at concentrations of up to 1.2 mg/mL administered 3 times
per day for (a) 1 day only in rats and rabbits in an ascending dose regimen, and (b) 4 weeks in
rats and rabbits. Pharmacokinetics has also been evaluated in rats with intact and abraded
corneas following topical ocular administration of 0.8 mg/mL twice a day with a 3-hour
interval. An ELISA specific and validated analytical method was used to determine the
concentrations of rhNGF in serum in the conducted toxicokinetic studies.

After 4-week repeated administration, raNGF exposure tended to be decreased or to be stable
compared with day 1: the AUCo, Week 4 / Day 1 ratios ranged between 0.30 and 0.98. No
accumulation of the test item was therefore observed.



Dompé S.p.A. CONFIDENTIAL ThNGF in NK
Request for Orphan Drug Designation April 2014 - Page 6 of 46

2 SPONSOR AND PRODUCT INFORMATION

SPONSOR INFORMATION
Sponsor Name and Address: Dompé s.p.a.
Via S. Martino 12-12/A, 20122 Milan, Italy
Phone: +39 02 583831; Fax: +39 02 58383324
US Resident Agent:
Sponsor Contact/Regulatory Lamberto Dionigi, M.Sc.
Affairs: Regulatory Affairs & Drug Safety Director
Dompé s.p.a.
Via S. Martino 12-12/A, 20122 Milan, Italy
Phone: +39 366 901 8586; Fax: +39 02 5844 9644
E-mail lamberto.dionigi@dompe.it
Sponsor Representative: Robert J McCormack, PhD
: Regulatory Affairs Consultant
Dompé US Agent
14 Edinburgh Drive

Randolph, NJ 07869
Phone: 862 397 4534; Fax: 862-397-4535

E-mail: bmccormack@creativeregulatory.com

DRUG PRODUCT INFORMATION
Product Name: Recombinant human nerve growth factor (rhNGF)

Manufacturer: Current rhNGF (drug substance and drug product) is
manufactured by the sponsor at its production facilities
in L’ Aquila, Italy.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 20 of 46

patients, while lesion size increased in only one patient who received placebo (open label
treatment of this patient with rhNGF resulted in complete healing of the corneal lesion).


Dompé s.p.a. 2

You must submit to the Office of Orphan Products Development a brief progress report of
drug development within 14 months after this date and annually thereafter until marketing
approval. 21 CFR 316.30.

Please notify this Office within 30 days of submitting a marketing application for the drug’s
designated use. Once your marketing application is approved, please contact Stephanie
Donahoe, RPh, MPH, at 301-796-8681 or alternatively at 301-796-8660 to assess eligibility
for orphan-drug exclusivity.

If you have questions regarding the development of your designated product, please feel
free to contact Erica McNeilly, RPh at 301-796-8679 or alternatively at 301-796-8660.
Congratulations on obtaining your orphan-drug designation.

Sincerely,

N. = «fr Cogebec XK. kao

Gayatri R. Rao,'MD, JD
Director
Office of Orphan Products Development


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 37 of 46

The first patient to be enrolled in the study was included on 29" January 2013 and 18 patients
have now been enrolled into the Phase 1, thus completing the Phase 1 segment of the study.
Recruitment into the Phase 2 segment is continuing.

Results of the recently completed Phase 1 segment: 18 patients (7 males, 11 females, mean
age of 62) with NK caused by diabetes (4), previous ocular surgeries (4), ocular herpes zoster
(2) or simplex (3) infection, neurosurgery (3), others (2) were included in the study. No
significant changes of vital signs and blood values were observed during treatment. Thirty-
seven adverse events (AEs) were recorded and 3 required discontinuation of study drug (2 in
group A and | in group B). Thirteen AEs were possibly related to the study drug. Among the
5 serious AEs observed, only 1 (enlargement of PED) was possibly related to the study drug.
According to the protocol, this patient was unmasked and found to be in the placebo group.
Visual acuity was decreased in 2 patients, and ameliorated in 11 at the end of treatment.

Masked efficacy analysis of the Phase 1 segment showed that NGF was well tolerated
according to VAS scores. Corneal lesions completely healed in 73% (71% in group A and
75% in group B), corneal sensitivity increased in 33% in both groups and Schirmer values
increased in 39% of the patients (33% in group A and 44% in group B).

These initial results show that rhaNGF eye drops are safe and well-tolerated. No significant
systemic or ophthalmic complications were observed.


Dompé S.p.A. CONFIDENTIAL ThNGF in NK
Request for Orphan Drug Designation April 2014 - Page 38 of 46

5 REQUEST FOR DESIGNATION FOR SAME DRUG FOR
SAME RARE DISEASE OR CONDITION

Not applicable - there is no rhNGF authorised for the treatment of NK in the US.


designation #14-4362 -3-

treatment’. The second study prospective controlled study to evaluate the efficacy of
topical murine NGF in 45 eyes (43 patients) with stage 2 (17 eyes) to stage 3 (28 eyes)
neurotrophic keratitis unresponsive to other nonsurgical therapies. After a 10-day
washout with artificial tears, patients received murine NGF (200 microg/ml) every 2
hours for 2 days followed by one drop six times daily until the ulcer healed. A
maintenance dose of one drop NGF (100 microg/ml) was administered four times daily
for the 2 weeks subsequent to ulcer healing. All patients had a complete resolution of the
persistent epithelial defect (with or without an ulcer) after 12 days to 6 weeks of
treatment with NGF. Patients affected by both stages of the disease demonstrated both
improved corneal sensitivity and visual acuity (P<0.001). No significant differences were
observed in the time to complete corneal healing between stage 2 and stage 3 patients.
Hyperemia and ocular and periocular pain were side effects reported during the first days
of treatment. No relapse of the disease was observed during the follow-up period, with
the exception of three patients with trigeminal nerve resection, who required a single
retreatment’.

The sponsor notes that the use of rhNGF is currently under evaluation. The sponsor’s
initial study, completed in 2013, was designed to evaluate the safety profile,
pharmacokinetics (PK), and immunogenicity of single and multiple does of rhNGF in 73
healthy volunteers. The sponsor is currently conducting a Phase 1/2 placeb0-controlled
clinical study to assess the safety and efficacy of two dose regimens (10ug/ml or
20pg/ml) of rhNGF six times daily versus placebo for inducing complete healing of stage
2 or 3 neurotrophic keratitis refractory to non-surgical therapy (REPARO study). The
Phase 1 segment was recently completed in 18 patients (7 men and 11 women) with
neurotrophic keratitis resulting from diabetes (4), previous ocular surgeries (4), ocular
herpes (2), herpes simplex infection (3), neurosurgery complication (3) and other (2) who
received either one of the two doses of rhNGF or placebo. The sponsor notes that a
masked efficacy analysis showed that NGF was well tolerated and that corneal lesions
completely healed in 73% of patients. The Phase 2 portion of the study is now enrolling.

Discussions and Conclusions: The sponsor has provided adequate prevalence
information to show that the prevalence of neurotrophic keratitis is less than 200,000 in
the US. Neurotrophic keratitis is a degenerative corneal disease caused by damage to the
trigeminal nerve that results in corneal epithelial breakdown, impairment of healing, and
development of corneal ulceration, melting, and perforation. The prevalence of
neurotrophic keratitis caused by the most frequent causes of trigeminal nerve damage,
herpetic keratitis and a complication of surgery for trigeminal neuralgia, has been
estimated to be 1.6 per 10,000. The prevalence of neurotrophic keratitis from other
ocular and systemic conditions cannot be estimated as no data is available in the
literature; however, the overall prevalence of neurotrophic keratitis as a result of all
conditions is estimated to be < 5 per 10,000'”. Therefore, the overall prevalence would
currently be 159,100, assuming that the prevalence is no more than 5 per 10,000 anda
current US population estimate of 318.2 million’.

The sponsor has provided adequate scientific rationale to support orphan drug
designation. The proposed product rhNGF is an eye drop consisting of the recombinant
form of human NGF. NGF is a cytokine essential for the survival and growth of
sympathetic and sensory neurons that are found in innervated tissues such as the cornea.


=~

Dompé S.p.A.

Request for Orphan Drug Designation

CONFIDENTIAL

thNGF in NK
April 2014 - Page 26 of 46

Table 4.3.2-3:

Summary of completed IV and SC pharmacokinetic studies

Type of Study ‘ Dose / Route / Comments Reference
Species Frequency
IV studies
Study
Male (n=12) and |°3 81.2 MBKE | ty = 3-4 hours. Harlan
female (n=12) | tout betwee | CE= 5:25—7.51 mL/kg, 39076 -
Wistar rats administrations, _| Vss = 9.362 - 0.538 Likg AlI21BPLIE
GLP study
0.3, 0.6, 1.2 & 2.4 | = 4.3 - 6.3 hours. Study
Male (n=1) and =| mg/kg rhNGF Cl = 1.33 —2.34 mL/min/kg (male) Harlan
female (n=1) New | with 3-day and 1.87 — 5.13 mL/min/kg (female). D39054 -
Zealand Rabbits | washout between | y,,, = 0.0303 - 0.148 L/kg (male) AI120BPL/E
administrations. | and 0.0657 - 0.164 L/kg (female). GLP study



oor,

f oS
Nd

DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

Office of Orphan Products Development
Food and Drug Administration

10903 New Hampshire Avenue

WO32- 5271

Silver Spring, MD 20993

JUN 2 3 2014

Robert J. McCormick, PhD
Regulatory Affairs Consultant
14 Edinburgh Drive
Randolph, NJ 07869

Re: Designation request # 14-4362
Dated: April 23, 2014
Received: April 25, 2014

Dear Dr. McCormick:

This letter responds to your request submitted on behalf of Dompé s.p.a. for orphan-drug
designation of recombinant human nerve growth factor (rhNGF) for “treatment of
neurotrophic keratitis.”

Pursuant to section 526 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bb),
your orphan-drug designation request of recombinant human nerve growth factor (rhNGF)
is granted for treatment of neurotrophic keratitis. Please be advised that it is the active
moiety or principal molecular structural features of the drug! and not the formulation of the
drug that is designated.

If your drug receives marketing approval for an indication broader than what is designated,
it may not be entitled to exclusive marketing rights under section 527 (21 U.S.C. 360cc).
Therefore, prior to submission of your marketing application, we request that you compare
the drug’s orphan designation with the proposed marketing indication and submit additional
information to amend the orphan-drug designation if warranted. 21 CFR 316.26.

If the same drug is approved for the same orphan indication before you obtain marketing
approval of your drug, you will have to demonstrate that your drug is clinically superior to
the already approved same drug in order to obtain orphan-drug exclusivity. Failure to
demonstrate clinical superiority over the already approved same drug will result in your
drug not receiving orphan-drug exclusivity. 21 CFR 316.34(c).

' The term “drug” in this letter includes drug and biological products.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 2 of 46

’ LIST OF TABLES

Table 3-1: Etiopathogenesis of neurotrophic keratitis

Table 3-2: Classification of neurotrophic keratitis

Table 4.1-1: | Assays for protein characterization

Table 4.1-2:  Excipients in the formulation

Table 4.1-3: | Composition of drug product

Table 4.3.1-1: Summary of Applicant’s completed in vitro pharmacology studies
Table 4.3.1-2: Summary of Applicant’s completed in vivo pharmacology studies
Table 4.3.1-3: Results of comparison of biological activity of different NGF preparations
Table 4.3.2-1: Summary of completed short-term ocular pharmacokinetic studies
Table 4.3.2-2: Summary of completed 4-week ocular pharmacokinetic studies
Table 4.3.2-3: Summary of completed IV and SC pharmacokinetic studies

Table 4.3.3-1: Summary of completed systemic toxicology studies

Table 4.3.3-2: Summary of completed ocular toxicology studies


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 45 of 46

10 REFERENCES

Bhatti MT, Patel R. Neuro-ophthalmic considerations in trigeminal neuralgia and its surgical
treatment. Curr Opin Ophthalmol. 2005;16(6):334-40.

Bonini S, Lambiase A, Rama P et al. Topical treatment with nerve growth factor for
neurotrophic keratitis. Ophthalmology 2000;107:1347-1352.

Bonini S, Rama P, Olzi D, Lambiase A. Neurotrophic keratitis. Eye 2003; 17: 989-995.

Borkar DS, Tham VM, Esterberg E et al. Incidence of herpes zoster ophthalmicus: results
from the Pacific Ocular Inflammation Study. Ophthalmology. 2013;120(3):451-6

Dworkin RH, Johnson RW, Breuer J et al. Recommendations for the management of herpes
zoster. Clin Infect Dis. 2007;44 Suppl 1:S1-26.

Ferrari M, Mantelli F, Sacchetti M et al Safety and Pharmacokinetics of Escalating Doses of
Human Recombinant Nerve Growth Factor Eye Drops in a Double-Masked, Randomized
Clinical Trial. BioDrugs DOI 10.1007/s40259-013-0079-5

Joo, M-J, Yuhan, KR, Hyon JY et al. The effect of nerve growth factor on corneal sensitivity
after laser in situ keratomileusis. Arch Ophthalmol. 2004;122:1338-1341.

Katusic S, Beard CM, Bergstralh E, Kurland LT. Incidence and clinical features of trigeminal
neuralgia, Rochester, Minnesota, 1945-1984. Ann Neurol. 1990; 27(1):89-95.

Labetoulle M, Auquier P, Conrad H et al. Incidence of herpes simplex virus keratitis in
France. Ophthalmology 2005;112(5):888-95.

Lambiase A, Rama P, Bonini S et al. Topical treatment with nerve growth factor for corneal
neurotrophic ulcers. N Engl J Med 1998;338:1174-80.

Lambiase A, Manni L, Bonini S et al. Nerve growth factor promotes comeal healing:
structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol
Vis Sci. 2000;41:1063-1069.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 43 of 46

In a series of cases of HZO from the Mayo Clinic (Liesegang, 1985), 15 of 94 patients (16%)
developed NK — a similar proportion to the 12.8% used by Lambiase & Sacchetti.

Surgical procedures for trigeminal neuralgia

Katusic et al (1990) studied the incidence of trigeminal neuralgia in Rochester, Minnesota, for
the period from 1945 through 1984 and calculated an overall crude incidence rate per
100,000 of 4.3 for both sexes combined. The age-adjusted (to total 1980 US population) rate
for women (5.9) was significantly higher than that for men (3.4). As the number of episodes
varied from 1 to 11, and the length of an episode varied from 1 day to 4 years, precise
conversion to a prevalence rate is problematic, but these US statistics are consistent with the
trigeminal neuralgia prevalence of 1.5/10,000 used in the calculations of Lambiase &
Sacchetti.

The paper by Bhatti & Patel (2005) used by Lambiase & Sacchetti as the source for the
frequency with which NK had been reported to be a complication of various surgical
procedures for trigeminal neuralgia originates from the University of Florida and is based on
US data. :

Other causes

Dompé has been unable to identify any published literature reporting the prevalence of NK in
patients with diabetes, multiple sclerosis, acoustic neuroma or congenital diseases. It is
therefore impossible to confirm or refute the assumption made by Lambiase & Sacchetti that
these pathologies contribute to no more than 0.18/10,000 of the overall prevalence of NK.
The paucity even of individual case reports does, however, make this figure plausible.

Total prevalence in the US

If the Lambiase & Sacchetti estimate of the prevalence of NK (<1.6/10,000) is applied to the
US population of 317.5 million (US Census Bureau, February 4, 2014) a total prevalence of
50,800 US residents is obtained. While there is clearly a considerable margin of error in this
estimate, it is reassuring to observe that this total represents only approximately a quarter of
the regulatory ceiling for orphan designation.

On December 31, 2013, the drug Thymosin beta 4 received an Orphan Drug Designation in
US for “Treatment of patients with neurotrophic keratopathy”.


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designatio April 2014 - Page 13 of 46



designation #14-4362 -5-

1. Sacchetti A, Lambiase A. Diagnosis and management of neurotrophic keratitis.
Clinical Ophthalmology 19 March 2014.

2. Lambiase A, Sacchetti A in Benitez-del-Castillo JM, Lemp MA (Eds). Ocular
Surface Disorders. Chapter 26, Neurotrophic Keratitis. JP Medical, London,
2013.

3. Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor
for corneal neurotrophic ulcers. N Eng J Med 1998; 338(17):1174-80.

4, Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor
for neurotrophic keratitis, Ophthalmology 2000; 107(7):1347-51.

5. US Census Bureau. http://www.census.gov


eames,

f 4 7 U.S. FOOD & DRUG

olny

ADMINISTRATION

Office of Orphan Products Development
Food and Drug Administration

10903 New Hampshire Avenue
WO32-5271

SEP 2 4 2018 Silver Spring, MD 20993

Creative Regulatory Solutions, LLC
14 Edinburgh Drive
Randolph, NJ 07869

Attention: Robert J. McCormack, PhD
US Agent for Dompé S.p.A
bmccormack@creativeregulatory.com

Re: Orphan-drug designation #14-4362

Dear Dr. McCormack:

This letter refers to your orphan drug cenegermin-bkbj which was designated pursuant to
section 526 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360bb) on June 23,
2014, for “treatment of neurotrophic keratitis.” We also refer to the letter from the Center
for Drug Evaluation and Research dated August 22, 2018, granting marketing approval of
your Biologics License Application for OXNERVATETM (cenegermin-bkbj) indicated for
the treatment of neurotrophic keratitis.

This letter is to inform you that as the first sponsor of this drug to obtain marketing
approval for this indication, Dompé S.p.A is entitled to seven years of orphan-drug
exclusive approval pursuant to section 527 of the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 360cc). The seven-year exclusive approval began on August 22, 2018, the
date of approval of the Biologics License Application (BLA 761094). The scope of
orphan-drug exclusive approval is described under 21 CFR 316.31.

As the holder of exclusivity, the sponsor is required to assure the availability of sufficient
quantities of this drug to meet the needs of patients. Failure to do so could result in the
withdrawal of the drug’s exclusive approval as stipulated under 21 CFR 316.36(b).


Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 15 of 46

Drug Product

thNGF drug product is a sterile liquid administered topically in the form of eye drops.

Table 4.1-2: Excipients in the formulation

Function Excipient Concentration range

HPMC
L-methionine
PEG 6000

Trehalose dihydrate

Mannitol

The primary packaging being tested consists of a ((3)G) nn

The qualitative and quantitative composition of the drug product intended for commercial use
in NK patients is given in Table 4.1-3.


Dompé S.p.A. CONFIDENTIAL ThNGF in NK
Request for Orphan Drug Designation April 2014 - Page 1 of 46

TABLE OF CONTENTS

LIST OF ABBREVIATIONS
1 ORPHAN DESIGNATION REQUEST.
2 SPONSOR AND PRODUCT INFORMATION ....ssssssssssssssssssossssssssnsvsssssnssesessssnusessessssssssensseees
3 DESCRIPTION OF RARE DISEASE OR CONDITION
4 DESCRIPTION OF THE DRUG AND SCIENTIFIC RATIONALE
41 Characterization and Description of Drug
4.2 Rationale for use of the drug in NK....sssssssssssccssssssssssescsneessenessneseeesanesssnseessnnesessee
4.3 Nonclinical data... :
4.3.1 Pharmacology.
4.3.2 | Pharmacokinetics..
4.3.3 Toxicology...

44 Climical data..eesesssssosssssssesssecsesssssssssssssssnssnsesssssceesesceesssssusnsssnsesseeseeseesseessenssesssesssosnanens OA
5S REQUEST FOR DESIGNATION FOR SAME DRUG FOR SAME RARE

DISEASE OR CONDITION sssssssesccsescssscecesssonsansssesensenseccencersesenerensessnssnsnsssessosesssesessennennanensans 38
6 DEVELOPMENT FOR A SUBSET OF PERSONS WITH DISEASE OR

CONDITION. seeseccccssssccscsrsnsnsssssssssssscoseseneesseereessssnsnssssssssssocsevensesseoveceeseeresnsnnsanososseocessnssenseanensen 39

7 REGULATORY STATUS AND MARKETING HISTORY wesssssssssossssssesssssssesnssssesoessssessesees 40
71 Investigational or Marketing Experience or Withdrawal in

Other Countrie
7.2 Other Relevant IND:
B DISEASE PREVALENCE ..cscsssssssssssssssossssnssnsssssseoeseseesescesenssenssnssssonnussssssovossessentessssnoasssessecseense
9 SPONSOR STATEMENT...
10 REFERENCES



Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 36 of 46

Serum concentrations of rhaNGF were found to be significantly different from basal levels in
only 6 subjects, 2 each at 20, 60, and 180 pg/mL. These changes were sporadic and varied
from positive to negative values, suggesting an individual physiological fluctuation rather
than a treatment-related absorption.

Ongoing study: Protocol NGF0212

The primary objective of this Phase 1/2 clinical study is to assess the safety and the efficacy
of two dose regimens (10 g/ml or 20 pg/ml 6 times a day) of rhNGF eye drops solution
compared to vehicle for inducing complete healing of Stage 2 (PED) and Stage 3 (corneal
ulcer) neurotrophic keratitis (NK) as assessed by the investigator using corneal fluorescein
staining. The study population consists of adult patients diagnosed with stage 2 (persistent
epithelial defect: PED) and stage 3 (corneal ulcer) NK refractory to one or more conventional
non-surgical treatments.

The study had a Phase 1 segment and a Phase 2 segment conducted sequentially as an 8 week,
randomized, double-masked, vehicle controlled, parallel group study each followed by a 48 or
56 week open-label follow-up period. In the Phase 1 segment of the study, two concentrations
of rhNGF (10 and 20 pg/ml) have been evaluated in a sequential fashion in 2 groups of
patients. The duration (48 weeks or 56 weeks) and treatment administered during the open-
label follow-up period is determined for each individual patient based on the initial
randomized treatment received and the healing (completely healed or non-completely healed)
of the PED or corneal ulcer as determined by the study investigator at the conclusion of the
Phase 1 or 2 segment of the study.

At Week 8, all completely healed patients from any of the three treatment arms and not-
completely healed patients following treatment with rhNGF will enter the 48 week open-label
follow-up period. Non-completely healed patients initially randomized to the vehicle control
arm will enter the 56 week open-label follow-up period. During the first 8 weeks of the 56
week open-label follow up period, patients randomized to vehicle control at baseline will
receive open-label rhNGF. At Week 16 all patients completing the open-label treatment phase
will be followed for an additional 48 weeks without any protocol-required study medication
until the end of the open label follow-up period.


Dompé S.p.A.

CONFIDENTIAL

Request for Orphan Drug Designation

April 2014

thNGF in NK

- Page 24 of 46

4.3.2

Pharmacokinetics

Pharmacokinetics following short-term ocular administration, 4-weeks ocular administration
and systemic (IV and SC) administration are shown in Tables 4.3.2-1, 4.3.2-2 and 4.3.2-3

below:

Table 4.3.2-1:

Summary of completed short-term ocular pharmacokinetic studies

Ophthalmoscopy: No treatment-related
abnormalities in any group.

ad pseleiened f Dose / Route / Frequency Comments Reference
Minimal systemic exposure after ocular Study
Male (n=12) and Sul of 0.2, 0.4, 0.6, 0.8 & 1.2 | administration at low dose. Harlan
female (n=12 mg/mL rhNGF by topical . . . D39087 -
female (n=12) ocular route (both eyes) 3 x at Disproportionately greater systemic
Wistar rats 3-hour intervals in 1 day. exposure at the higher doses used in A1122/E
toxicology studies. Non-GLP
Male (n=1) and mea winiGe ‘y topical 12 Systemic exposure following topical ocular | Study D39043
= inistration is margi -AILIS/E
Female (net) New ocular route (both eyes) 3 x at proportional n is marginal and not dose Non-GLP
3-hour intervals in 1 day. . ‘on
Intact corneas: Serum concentrations were
below the limit of detection at both 2 and 4
, Sul of 0.8 mg/mL rhNGF hours after first treatment. Study
Wi ee
Mal le Han Wistar twice in one day (3 hours Abraded comeas: Serum levels were Al215
apart). 0.179-0.266 ng/mL at 2 hours (after one Non-GLP
administration) and 0.188 — 0.676 ng/mL at
4 hours (after 2 administrations).
Intact corneas: No clinical signs.
Abraded corneas: Marginal increases in
rats chlorbutanol) 3 times in one relationship to time. Observations M1202
day (3 hours apart). assigned to chance. Non-GLP



DOMPE S.P.A

Orphan Drug Designation Request

RECOMBINANT HUMAN NERVE GROWTH FACTOR FOR THE
TREATMENT OF NEUROTROPHIC KERATITIS

4/23/2014


Tab #14 - Liesegang TJ. Corneal complications from herpes zoster ophthalmicus.
Ophthalmology1985; 92(3):316-24.

Tab #15 - Marfurt CF, Cox J, Deek S, Dvorscak L. Anatomy of the human corneal innervation.
Experimental Eye Research 2010;90:478-492.

Tab #16 - Reichardt L.F. Neurotrophin-regulated signalling pathways. Phil. Trans. R. Soc. B
(2006) 361, 1545-1564.

Tab #17 - Sacchetti M, Lambiase A. Diagnosis and management of neurotrophic keratitis.
Clinical Ophthalmology 2014; 8: 571-579.

Tab #18 - Semeraro F, Forbice E, Romano V et al. Neurotrophic Keratitis. Ophthalmologica
2013; DOI: 10.1159/000354380.

Tab #19 - Sinigaglia F. Phase I/II Dose-Ranging, Randomized Clinical Trial of Recombinant
Human Nerve Growth Factor in the Treatment of Neurotrophic Keratitis: Preliminary Results.
ARVO 2014, Presentation Number 4690 - A0315.

Tab #20 - Young RC, Hodge DO, Liesegang TJ, Baratz KH. The incidence, recurrence and
. outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976 through
2007: The impact of oral antiviral prophylaxis. Arch Ophthalmol. 2010; 128(9): 1178-1183.


~~

Dompé S.p.A.

Request for Orphan Drug Designation

CONFIDENTIAL

April 2014 -

TthNGF in NK
Page 32 of 46

Table 4.3.3-2: Summary of completed ocular toxicology studies
Mal 5 pl of 0.2, 0.4, NOAEL = 1.2 | Study
Short-term (1 Wistar (re " 2) 0.6, 0.8 & 1.2 3 x at 3-hour mg/mL Harlan
day) topical rat mg/mL rhNGF by | intervals in 1 6 D39087 -
ocular dosing Female topical ocular day. (6 ng per Al122/E
(n=12) route (both eyes). eye). Non-GLP
30 nl of 0.2, 0.4, NOAEL = 1.2 | Stud
Short-term (1 | New ten) ang {05,08&12 | |3xat3-hour |oimt, 1 p39043-
day) topical Zealand Female mg/mL rhNGF by | intervals in 1 ALLI9/E
ocular dosing Rabbit (n=1) topical ocular day. (36 pg per
route (both eyes). eye). Non-GLP
Male > pl oF 0.6, 0.8 or NOAEL = 1.2] Suv.
4-week ocular | Wistar | (n=83) and |/2me/mL mg/mL ;
ici thNGF by topical | 3 x per day. D39098
toxicity study rat fees) ocular route (both (6 pg pereye | 41 129BPL/E
n= i
eyes). 3 x daily). GLP study
New {Male 30 wh oF 06,0 8 NOEL = 1.2 py
4-week ocular Zealand | (n=16) and or 1.2 mg/m . mg/mL D: .
ae . thNGF by topical | 3 x per day. 39065
toxicity study wae (ie) ocular route (both (18 yg per A1138BPL/E
Ht n= i!
eyes). eye 3 x daily). GLP study
30 pl of 0.6 soy
pT of 0.0, or D23127212
2-month Devand fo) 1.2 mg/mL NOEL=1.2 | 41302 BPLE
tolerance/toxicity White thNGF by topical | 3 x per day. mg/ml (18 pg, GLP stud
study bits eee | ocular route (right 3 x daily). study
rabbits {| (n=12) eye). Draft Audited
Report
NOEL = 5 pl | Study
Male 5 pl of 0, 0.6, 0.8 of 1.2 mg/mL rete ;
Han = or 1.2 mg/mL thNGF per .
" 114)
ixidyoety Wistar @ ) ThNGF by topical px er dey, 3 eye3times | Al129BPL/E
¥ rat (iy ocular route (both Part. daily (36 pg | GLP study
eyes). per animal Draft Audited
per day). Report



Dompé S.p.A. CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 41 of 46

8 DISEASE PREVALENCE

Estimation of the prevalence of NK is particularly challenging and resulted in the paucity of
published epidemiological data.

Searches of the PubMed database with the following search strings failed to return any
relevant papers:

= (neurotrophic keratitis[Title/Abstract]) AND prevalence[Title/Abstract]

= (neurotrophic keratitis[Title/Abstract]) AND incidence[Title/Abstract]

= (neurotrophic keratopathy[Title/Abstract]) AND prevalence[Title/Abstract]
= (neurotrophic keratopathy[Title/Abstract]) AND incidence[Title/Abstract]

This has been confirmed by Semeraro and co-workers whose comprehensive 2013 review of
the condition states explicitly that “Epidemiological data on NK have not been reported in the
literature”.

The only option available is to examine the frequency with which NK arises as a
complication of its underlying causes. This approach was pioneered by Alessandro Lambiase
and Marta Sacchetti in an international ocular surface disease book chapter written in 2013
(Lambiase & Sacchetti, 2013), the relevant paragraphs of which are reproduced below:

“NK is a rare disease with an estimated prevalence of <5 per 10,000 individuals. No data
are available in the literature on the epidemiology of NK. However, the prevalence and
incidence of NK may be extrapolated from its causes. Specifically, NK complicated
herpetic keratitis in 4.4-8.0% of cases (Labetoulle et al, 2005). Based on an average NK
prevalence of 6% of all cases of herpetic keratitis (the prevalence of herpetic keratitis is
149/100,000), the NK prevalence can be estimated as 0.89/10,000. Similarly, the
prevalence of NK from herpes zoster keratitis (HZO) may be calculated as 0.33/10,000
by applying an average NK prevalence of 12.8% to the estimated prevalence of HZO
(26/100,000) (Dworkin et al, 2007). NK had been reported to be a complication of
various surgical procedures for trigeminal neuralgia, at a percentage ranging from 0.6 to
5% (mean value 2.8%), depending on the procedure (Bhatti & Patel, 2005). As the
prevalence of trigeminal neuralgia has been reported at 1.5/10,000, the NK prevalence
can be estimated as 0.2/10,000.


Dompé S.p.A. CONFIDENTIAL rhNGF in NK
Request for Orphan Drug Designation April 2014 - Page 27 of 46
Type of Study ! Dose / Route / Comments Reference

Species Frequency
Day | (eye drop)
Sublingual
Cmax: 9.2 ng/mL; Tmax: 4 h; AUCt: 56.4 ng/h/mL
Tail vein
Cmax: 0.10 ng/mL; Tmax: 8 h; AUCt: 0.26 ng/h/mL
Day 3 (eye drop)
Sublingual
Cmax: 4.2 ng/mL; Tmax: 8h; AUCt : 47.4 ng/h/mL
Tail vein
eye drop: Cmax : 0.07 ng/mL; Tmax: 4 h; AUCt: 0.37 ng/h/mL
0.8 mg/mL, three
ti day for 3
days a cay Tor Day | (subcutaneous)
Sublingual
Study Harl:
Wistar rats subcutaneous: Cmax: 69.5 ng/mL; Tmax: 8 h; AUCt: 838 ng/h/mL D6786. an
Male (n= 17) I mgkg once a _| Tail vein : M1301 BPL
day for 3 days Cmax: 174 ng/mL; Tmax: 2 h; AUCt: 1597 ng/h/mL =| GLP study

blood collected
from sublingual
and tail vein

Day 3 (subcutaneous)

Sublingual

Cmax: 73.5 ng/mL; Tmax; 2 h; AUCt : 277 ng/h/mL
Tail vein

Cmax: 173 ng/mL; Tmax: 2 h: AUCt: 555 ng/h/mL

Eye drop dosing: PK profile similar on days 1 and 3

Subcutaneous dosing: concentrations on day 3
decreased faster than on day 1

Eye drop administration: concentrations after tail vein
sampling lower than after sublingual sampling.
Subcutaneous administration: concentrations after tail
vein sampling higher than after sublingual sampling.

SC studies



Dompé S.p.A. CONFIDENTIAL ThNGF in NK
Request for Orphan Drug Designation April 2014 - Page 11 of 46

and lissamine green stains show a reduction in tear break-up time and formation of
geographic dry spots and corneal and/or conjunctival epithelial defects. It is useful to perform
a careful examination of the eyelids, including eyelid edges, positions and motility, to rule out
exposure keratitis and diagnose blepharitis, which is often associated with NK.

Microbiological examination of large, persistent epithelial defects must be performed to
exclude bacterial, fungal or viral infections. The combination of an afferent pupillary defect
and hypoesthesia must be studied to rule out intraconal orbital nerve injury. A reduction in
accommodation can indicate damage to the motor ciliary nerve of the ciliary ganglion. Iris
atrophy is often an expression of a previous herpetic keratouveitis or a lepromatous lesion.
NK should be suspected in all patients who have a discrepancy between reported symptoms
and ocular signs or in patients who have a decreased frequency of eyelid closure.

Current therapy

While NK is frequently asymptomatic, especially at Stage 1, intervention is indicated to
prevent deterioration which may ultimately lead to corneal ulcer (Stage 3) and perforation, an
ocular emergency associated with loss of integrity of the eye and potentially catastrophic
visual sequelae.

In stage 1 disease, treatment can be restricted to simple measures. All topical medications and
systemic therapies such as neuroleptics, antipsychotics and antihistamines that can cause NK.
should be discontinued. The ocular surface can be preserved through the use of artificial tears
without preservatives every 2-4 h and a lubricant ointment at bedtime. The goal at this stage
is to improve the quality of the corneal epithelium, prevent an epithelial breakdown and
preserve corneal transparency. Comorbidities such as exposure keratitis or limbal deficiency
worsen the prognosis and should be treated before beginning [treatment of] NK symptoms
(Semeraro et al, 2013).

In stage 2 and 3 disease, however, more aggressive treatment is warranted. In stage 2 the aim
is to avoid the development of a corneal ulcer and promote healing of the epithelial defect,
while in stage 3 it is to prevent corneal thinning and perforation (Semeraro et al, 2013). It is
in these stage 2 and 3 cases that a role for rhNGF is foreseen.


on
S oe

Nd DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service

ore,

Office of Orphan Products Development
Food and Drug Administration

10903 New Hampshire Avenue
W032-5271

Silver Spring. MD 20993

April 29, 2014

Robert J. McCormack, PhD
Regulatory Affairs Consultant
Creative Regulatory Solutions, LLC
14 Edinburgh Drive

Randolph, NJ 07869

Dear Dr. McCormack:

This letter acknowledges receipt of your orphan drug designation request submitted on
behalf of Dompé s.p.a., pursuant to section 526 of the Federal, Food, Drug, and Cosmetic
Act (21 U.S.C. 360bb) for the following:

Name: Recombinant Human Nerve Growth Factor Ocular Drops

Disease or Condition: Treatment of neurotrophic keratitis.

Date of request: April 23, 2014

Date of receipt: April 25, 2014

Designation reference number: 14-4362

We will correspond with you after we have completed our review of the

request. Please note that your drug or biologic product will not be eligible for
designation if you submitted a new drug application (NDA) or biologics

license application (BLA) for this drug, for this indication before submitting this
designation request.


FH FLECOPY

Review of a Request for Orphan Drug Designation

Designation Number: 2014-4362
Date Received by FDA: April 25, 2014
Date Received by Reviewer: June 4, 2014
Date Review Completed: June 11, 2014
Product: Generic name: recombinant human nerve growth factor (rhNGF)

ocular drops
Trade name: not available

Sponsor: Dompe SPA
Via S. Martino 12-12/A
Milan, 20122
Italy

US Resident Agent: Robert J McCormack, PhD
Regulatory Affairs Consultant
14 Edinburgh Drive
Randolph, NJ 07869

Manufacturer: L’ Aquila, Italy is the current manufacturer of the drug product and
substance.

Proposed Designation: Treatment of neurotrophic keratitis.

Regulatory Status: The sponsor states that rhNGF is being studied for use in the
treatment of neurotrophic keratitis and other ocular diseases, and is not approved or had
any marketing applications filed in any country.

RegeneRx Biopharmaceuticals received orphan drug designation for thymosin beta 4 for
use in the treatment of patients with neurotrophic keratopathy (application# 13-4166) in
December 2013.

Disease Background: Neurotrophic keratitis (keratopathy) is a degenerative corneal
disease caused by damage to the trigeminal nerve that results in corneal epithelial
breakdown, impairment of healing, and development of corneal ulceration, melting, and
perforation. Patients experience a reduction or total loss of corneal sensation. The most
frequent cause of neurotrophic keratitis is from herpetic keratitis and from lesions or
surgeries that compress the trigeminal nerve or ganglion. Other diseases or conditions
that can cause neurotrophic keratitis include chemical burns, physical injuries, corneal
dystrophy, diabetes, multiple sclerosis, congenital syndromes and leprosy!”.

Diagnosis is based on patient history, clinical findings and a corneal sensitivity
evaluation. Staging of neurotrophic keratitis is by the Mackie classification: Stage 1
disease consists of superficial punctate keratopathy, epithelial hyperplasia and


Dompé S.p.A CONFIDENTIAL thNGF in NK
Request for Orphan Drug Designation April 2014 - Page 14 of 46

Figure 4.1-2: | Representation of the non-covalent dimer of rhNGF

The molecular formula has been derived by translating the experimentally determined
nucleotide acid sequence to the predicted amino acid sequence of rhNGF and is
Csg3HoosN 166017383.

The calculated molecular weight of rhNGF is 13,266 Daltons.
Assays to be used for protein characterization are summarised in the table below:

Table 4.1-1: Assays for protein characte