Download Riboflavin 0.1% (VibeX) for the treatment of keratoconus

Drug Evaluation
Riboflavin 0.1% (VibeX) for the
treatment of keratoconus
1.
Introduction
2.
Keratoconus
3.
Parasurgical crosslinking
Expert Opinion on Orphan Drugs Downloaded from informahealthcare.com by Stefano Caragiuli on 05/17/13
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therapy
4.
Riboflavin
5.
Expert opinion
Cosimo Mazzotta†, Stefano Baiocchi, Tomaso Caporossi, Stefano Caragiuli,
Anna Lucia Paradiso & Aldo Caporossi
†
Siena University, Policlinico Santa Maria alle Scotte, Department of Ophthalmology, Siena, Italy
Introduction: Keratoconus is an ectatic disease of the cornea characterized by
biomechanical instability of stromal collagen leading to reduction of corneal
thickness, variation in posterior and anterior corneal curvatures with associated progressive deterioration of visual acuity mainly due to a secondary
irregular astigmatism. Corneal collagen crosslinking (CXL) is a new approach
to increase the mechanical strength and biochemical stability of the corneal
stromal tissue affected from primary or secondary ectasia. A novel pharmacological series of riboflavin formulations from Avedro, Inc. (Waltham,
Massachusetts, MA, USA), were recently granted orphan drug designation
by the Food and Drug Administration for the treatment of keratoconus and
secondary corneal ectasia.
Areas covered: This report reviews the basic concepts concerning the role of
riboflavin in crosslinking treatment in order to understand the potentiality
of the new VibeX and VibeX Rapid solutions for riboflavin UVA-induced
CXL. The treatment should be offered to those patients with documented
progressive keratoconus and secondary corneal ectasia in order to halt or
delay its progression preventing the necessity of donor corneal graft.
Expert opinion: VibeX solution complies well with other standard riboflavin
solutions currently available on the market for epithelium-off CXL therapy.
Compared with VibeX riboflavin 0.1% -- dextran 20% formula, the VibeX
Rapid has been proposed for a faster and homogeneous corneal soaking,
avoiding the intraoperative corneal thinning often occurring with the
standard riboflavin solutions containing high molecular weight dextran
as excipient.
Keywords: accelerated crosslinking, crosslinking, keratoconus, riboflavin, VibeX, VibeX Rapid
Expert Opinion on Orphan Drugs (2013) 1(3):235-240
1.
Introduction
Keratoconus is an ectatic disease of the cornea characterized by biochemical and
biomechanical instability of stromal collagen leading to reduction of corneal
thickness, variation in posterior and anterior corneal curvatures and progressive
deterioration of visual acuity due to irregular astigmatism [1,2]. The recent advent
of corneal collagen crosslinking (CXL) in the ophthalmology panorama of the
last decade [3,4] transformed the conventional therapy of keratoconus based at
best, on a lifetime of rigid contact lens wearing or at worst on corneal transplant,
improving its conservative treatment, thus reducing the necessity of lamellar or
penetrating corneal graft.
In 2011, the VibeX/KXL system promoted by Avedro, Inc. (Waltham,
Massachusetts, MA, USA), was granted orphan designation by the Food and
Drug Administration (FDA) for the treatment of keratoconus and corneal ectasia
following refractive surgeries [5]. Orphan drug designation is granted by the FDA
Office of Orphan Products Development to promote the development of new
10.1517/21678707.2013.765799 © 2013 Informa UK, Ltd. e-ISSN 2167-8707
All rights reserved: reproduction in whole or in part not permitted
235
C. Mazzotta et al.
Box 1. Drug summary.
Drug name
Pharmaceutical company
Indication
Composition
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Mechanism of action
Route of administration
VibeX
Avedro, Inc. (Waltham, Massachusetts, MA, USA)
Keratoconus and secondary corneal ectasia
100 mL of solution contains: riboflavin 0.1 g, dextran 500,
disodium hydrogen phosphate, sodium phosphate monobasic dihydrate,
sodium chloride, water for injectable solution
Ophthalmic medical device used for corneal crosslinking treatment
Topically
Box 2. Drug summary.
Drug name
Pharmaceutical company
Indication
Composition
Mechanism of action
Route of administration
VibeX Rapid
Avedro, Inc. (Waltham, Massachusetts, MA, USA)
Keratoconus and secondary corneal ectasia
100 mL of solution contains: riboflavin 0.1 g, HPMC, disodium hydrogen
phosphate, sodium phosphate monobasic dihydrate, sodium chloride, water for injectable solution
Ophthalmic medical device used for corneal crosslinking treatment
Topically
therapies for rare diseases and disorders. To date, Avedro,
Inc., distributes four riboflavin solutions outside the
United States: VibeX, VibeX Rapid (Box 1 and 2) (for
epithelium-off crosslinking procedure), Paracel (for transepithelial or epithelium-on treatment) and VibeX Xtra
specifically formulated for the use during a Lasik procedure
(Lasik Xtra) and epithelium-on crosslinking. In this
manuscript, we will refer to the Avedro, Inc. VibeX and
VibeX Rapid solutions.
2.
Keratoconus
3.
Krachmer et al. in a 1984 article [1], defined the keratoconus
as ‘an ectatic, asymmetric, non-inflammatory, progressive corneal degeneration characterized by thinning, increasing of corneal curvatures and loss of transparency of the central cornea’.
The prevalence of keratoconus in the population reported in
the literature [2] is 1/2,000 which is within the threshold
used by the European Union to define a disease as rare disease
(also referred to as an orphan disease) [6], and the incidence is
2 -- 3/100,000 [2], although many authors agree that in the
coming years there will be an increase of these values due
to a more widespread use of corneal topography. According
to the experience of Ophthalmology School of Siena, the
prevalence of keratoconus amounted to 1 in 1,000 or even
1 in 500 inhabitants [4]. Studies conducted in the precorneal
tomography era reported a familiarity of 6 -- 8% meaning
that about 6 -- 8% of patients with keratoconus also has one
or more family members suffering from this disease. Still
more striking epidemiological studies carried out in the
post-corneal tomography era showed that 50% of patients
with keratoconus have at least one close relative suffering
from the same disease [7]. Keratoconus ectasia is characterized
by corneal bulging with thinning typically occurring in the
236
inferior-temporal quadrant that represents the physiological
weakest part of the cornea [8,9]. Keratoconus usually starts in
the second decade of life (generally at puberty) progressing
until the fourth decade of life [2] when it generally stabilizes
due to a natural or physiological (age-related) process of crosslinking of stromal collagen [10]. Diabetes seems to be a protective factor against keratoconus onset and progression, due to
increased crosslinking process related with the hyperglycemia
in the so-called Maillard’s reaction [11,12].
Parasurgical crosslinking therapy
Riboflavin ultraviolet type A (UVA) CXL is a relatively new
approach for increasing the biomechanical and biochemical
stability of the corneal stromal tissue against primary and
secondary ectasia. The surgical technique consists in a photopolymerization of stromal collagen fibers by the combined
action of a photosensitizing substance (riboflavin, also known
as vitamin B2) and UVA. Photopolymerization increases the
rigidity of corneal collagen contrasting ectasia progression.
Different methods of enhancing the crosslinking of corneal
collagen have been comparatively evaluated by Spoerl and
Seiler [13] who discovered that the association of riboflavin
and UV-A was effective (by significantly increasing corneal
stiffening and Young modulus) and less toxic in vivo (by preserving corneal transparency, endothelium, lens and retina).
The data reported in literature [14,15] at this time confirm
that crosslinking has a main role in the management of early
stage progressive keratoconus. In fact, if progression can be
reliably documented by means of serial computerized topography, surface aberrometry and differential optical pachymetry, an early intervention is likely to be most beneficial in
preventing a visual impairment or at least the development
of advanced clinical signs. Sp€orl et al. [16] were the first to
Expert Opinion on Orphan Drugs (2013) 1(3)
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VibeX
investigate the use of riboflavin and UVA irradiation in
achieving crosslinking of corneal collagen. Using this method,
Wollensak et al. [17] demonstrated a marked positive effect of
crosslinking on the biomechanical properties of both porcine
and human corneal tissue: crosslinking was shown to increase
the rigidity of human corneal tissue (expressed by Young’s
modulus at 6% strain) by a factor of 1.5 -- 1.7 x [18] (Young’s
modulus, also known as the tensile modulus, is a measure of
the stiffness of an elastic material). Below we cite the early
clinical studies that have documented the effectiveness of the
crosslinking treatment in slowing down or arresting the progression of keratoconus. The first report of a series of
23 eyes treated with crosslinking was published in 2003 by
the eye school of Dresden [3]. Following Dresden studies,
for the first time in Italy in 2006 the researchers of the Siena
eye school in Italy [4] published the second international
results of a case series of 10 patients affected from progressive
keratoconus stabilized through riboflavin UVA-induced CXL.
The in vivo safety and effective penetration of corneal crosslinking induced apoptotic effect correlating with its biomechanical and clinical efficacy; treatment was documented
for the first time in humans by Mazzotta et al. [19-21] by using
the confocal laser scanning microscopy following the previous
Wollensak’s studies on animal model [22]. The presence of
stromal edema, the reduction in keratocyte density via cells
apoptosis and loss of nerve fibers were observed in the anterior
stroma 1 month after crosslinking [20]. In the same studies, the
progressive reduction of corneal edema associated with
increased stromal density and time-depending cells repopulation of the anterior mid-stromal volume by activated
keratocytes between 3 and 6 months after treatment were
demonstrated; the deep stroma beyond 300 µm, endothelial
cells morphology and count appeared unaffected [20]. Moreover, in a later publication, Mazzotta et al. [21] described
numerous needle-shaped reflective striations or bands in the
anterior mid-stroma until 2 years after crosslinking, interpreted as new structured collagen following treatment
and explaining some morphological- and functional-related
aspects of crosslinking itself [19].
4.
Riboflavin
Riboflavin, also known as vitamin B2, belongs to the class of
water-soluble vitamins. The etymology of the word riboflavin,
composed of ribo(se) and flavin, refers to its chemical composition. Riboflavin is composed of a nucleus of dimethyl isoalloxazine (isoalloxazine is the basic structure of all flavin
molecules) and ribitol (the reduced form of the sugar ribose):
7,8-dimethyl-10-(1¢-d-ribityl) isoalloxazine [23-25]. As suggested by its etymology (flavus in Latin means ‘yellow’), riboflavin crystals have a yellow-orange color, whereas neutral
solutions of riboflavin have a typical yellowish-green color.
This is why they are used as a food coloring, known as
E101. Although riboflavin belongs to the group of watersoluble vitamins, it is in fact one of the least soluble in water
TM
and VibeX RapidTM
(12 mg/100 mL at 25 C) and even less soluble in alcohol. It is
more soluble in acidic solutions up to a temperature of
120 C, but unstable in alkaline media and when exposed to
ultraviolet and visible light. The spectrum of riboflavin has
four absorption peaks at wavelengths 223, 266, 373 and
445 nm. Riboflavin exhibits native fluorescence with an
emission peak at 530 nm [23-25]. Vitamin B2 was first discovered in 1879 by the English chemist Alexander Wynter Blyth
who called it ‘lactoflavin’ because he found it in cow’s milk.
Similar substances were called ‘ovoflavin’, ‘hepatoflavin’ and
so forth, because they were discovered in eggs, liver and other
plant and animal tissues. It was not until 1934 that the Swiss
chemist Paul Karrer and the Austrian-born German chemist
Richard Kuhn, both Nobel laureates in chemistry, discovered
that lacto-, ovo- and hepato-flavin were the same substance,
which they called riboflavin [23,24].
Riboflavin plays a fundamental role acting as photosensitizer, favoring the production of free radicals mediating the
crosslinking of stromal collagen [26]. The release of free radicals or reactive oxygen species induce (in the presence and/
or absence of oxygen) the type I and type II photochemical
reactions (oxidative deamination of corneal collagen) leading
to the formation of molecular bridges (crosslinks) between
and within collagen fibrils. The second role of riboflavin is
the UVA absorption, thus allowing the concentration of ultraviolet light A energy delivered by UV source in the anterior
half of the corneal stroma. The so-called riboflavin shielding
effect reduces the risk of UV-related damage of corneal endothelium, lens and retina [27]. Safety studies have shown that
current UVA exposures associated with crosslinking are below
the thresholds for endothelial cell damage. There is a risk of
endothelial cell toxicity when riboflavin diffuses to the endothelium, and UVA exposures are high enough that they are
not adequately attenuated by absorption on transit through
a riboflavin-soaked cornea.
5.
Expert opinion
Standard riboflavin solution (VibeX) contains the same
formulation of the original riboflavin formula used in the first
crosslinking studies and protocols (Dresden and Siena); 0.1%
riboflavin with 20% dextran T 500 solution has been already
used and commonly applied today in the crosslinking therapy
for progressive keratoconus. This solution has been CE
marked and proven in several published clinical studies to
be optimally tolerated in human eyes [20,27-30]. The drops
contain 20% dextran 500.000 Da molecular mass in
order to make the otherwise hyperosmolar 0.1% riboflavin
solution iso-osmolar with the corneal stroma, thus preventing
intraoperative corneal swelling [31].
The classic 0.1% riboflavin with 20% dextran T 500
solution was well tolerated and nontoxic, nonirritating and
nonallergic for ocular surface during and after epitheliumoff crosslinking treatment. Syringe with large cannula provided in the sterile packaging facilitates an easy and
Expert Opinion on Orphan Drugs (2013) 1(3)
237
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C. Mazzotta et al.
Figure 1. Syringe and cannula, blunt metal spatula
for epithelial scraping and forceps for contact lens in
the epithelium-off accelerated crosslinking technique.
Department of Ophthalmology, Siena University, Italy.
Figure 2. Avedro, Inc. KXLTM : Epithelium-off accelerated
crosslinking procedure. Department of Ophthalmology,
Siena University, Italy.
homogeneous distribution of the riboflavin on the corneal
surface, Figure 1. Homogeneous distribution of the solution
on the corneal surface is essential to avoid the presence of
hot spots. Indeed, if hot spots are present, the damage thresholds may be locally exceeded leading to localized endothelial
damage [27].
The so-called ‘rapid’ riboflavin solution consists in the
presence of hydroxylpropyl methylcellulose (HPMC) instead
of dextran as excipient. HPMC has long been established
for ophthalmic safety and optimal tolerability [32-36]. Methylcellulose has a low surface tension and contact angle, which
increases coating ability, having a lack of elasticity, which
makes it more ‘viscoadherent’ than viscoelastic. It has been
shown not to damage the endothelium [34]. Other advantages
238
are its availability, ability to be autoclaved, low cost and
ability to be stored and shipped at room temperature.
HPMC prevents the corneal thinning caused by corneal dehydration reported in literature with dextran solution as demonstrated by Kymionis et al. [37] and also experienced by us in
the clinical practice (submitted unpublished data).
As reported in literature by Spoerl et al. [27] and by Kamaev
et al. [26], riboflavin and fluorescein have similar polarity and
molecular mass (376 g/mol) with similar diffusion coefficients
of 6 10-7 cm2/s at 35 C. Since the HPMC significantly increases the penetration of topical fluorescein as
compared to other commonly used ophthalmic vehicles [38],
it is theoretically reliable that HPMC could be a good vehicle
for riboflavin molecules allowing its faster diffusion into the
corneal stroma and decreasing the soaking time under
10 min as proposed in the new Avedro, Inc. ‘VibeX Rapid
protocol’. The possibility to shorten the riboflavin soaking
time is particularly favorable for patients and surgeons, being
the entire crosslinking procedure less time-consuming with
relative advantages.
Both Avedro, Inc. riboflavin solutions (standard and rapid)
were intraoperatively and postoperatively optimally tolerated,
with no irritation and allergy and nontoxic for ocular surface
having a good distribution and penetration of riboflavin into
the corneal stroma and anterior chamber, Figure 2.
In our experience, after epithelium-off crosslinking by
using the standard 0.1% -- dextran 20% riboflavin solution
and the rapid 0.1 % riboflavin with HPMC solution, the
reepithelialization was complete after 3 days of soft contact
lens bandage and subjectively patients reported a very small
degree of discomfort.
In conclusion the Avedro, Inc.’s standard riboflavin
solution complies well with other solutions currently available
on the market for epithelium-off crosslinking treatment.
The ‘rapid’ solution containing 0.1 % riboflavin plus
HPMC could become the future device for accelerated
(epithelium-off) CXL.
Declaration of interest
The authors state no conflict of interest and have received no
payment in preparation of this manuscript.
Expert Opinion on Orphan Drugs (2013) 1(3)
VibeX
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Affiliation
Cosimo Mazzotta†1 MD PhD,
Stefano Baiocchi1 MD PhD,
Tomaso Caporossi2 MD, Stefano Caragiuli1 MD,
Anna Lucia Paradiso1 MD &
Aldo Caporossi1 MD FRCS
†
Author for correspondence
1
Siena University,
Policlinico Santa Maria alle Scotte,
Department of Ophthalmology,
Viale Mario Bracci, 53100 Siena, Italy
Tel: +0039 349 5550676;
Fax: +0039 349 5550676;
E-mail: [email protected]
2
Rome Catholic University,
Policlinico Gemelli,
Department of Ophthalmology,
Rome, Italy