FOV1101 Licensing opportunity - Sanofi

FOV1101
A fixed-dose combination of prednisolone acetate and cyclosporine A for
the treatment of inflammatory diseases of the ocular surface
Therapeutic Area: Ophthalmology - Inflammatory diseases of the ocular surface, including
allergic conjunctivitis (AC)
Mechanism of action: Anti-inflammatory and immuno-modulator
Planned indication: Treatment of signs and symptoms of allergic conjunctivitis
Patent protection: License from Zalicus,
Patents expire in November 2026 (without patent extension)
US: patented
EU: patent pending
Route of administration: Topical (eye drops)
Development phase: Ready to enter Phase 3 development in the US
1. BACKGROUND AND RATIONALE
Licensing opportunity
Allergy is an over-reaction of the body’s immune system to harmless foreign substances or
allergens. Allergic conjunctivitis (AC) affects 16 to 20% of the general population (Pitt et al.,
2004). AC is characterized by ocular itching, redness, chemosis, eyelid swelling, and watery
discharge from the eyes and nasal passages.
The pathophysiology of AC can be divided into an “early phase” and a “late phase”. In the
early phase, exposure to allergen induces an immunoglobulin E (IgE)-mediated reaction
involving mast cells. The mast cells degranulate and release pre-existing inflammatory
mediators (mainly histamine), which are primarily responsible for the early phase symptoms.
The late-phase response begins 4-6 hours after release of the mast cell mediators. The
response is characterized by T-lymphocyte activation and infiltration of the conjunctiva by
inflammatory cells (Bacon et al, 2000). In many patients, repeated acute exposure and
response to allergy-causing agents lead to a persistent late phase inflammatory reaction (Choi
et al, 2008). In its more persistent form, AC constitutes a complex ocular surface disease
involving many mechanisms (Baudouin, 2007).
Mild AC can be treated with anti-histamine (anti-H1)/vasoconstrictor agents or mast cells
stabilizers (MCS). Additional measures include artificial tears, cool compresses, oral
anti-histamine agents (anti-H1), and allergen avoidance (AAO, 2011). However, in some
patients, the symptoms are not adequately controlled by these options, especially where
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epeated acute exposure to allergens –such as dust mites - induces a persistent inflammatory
reaction (Baudouin, 2007). For these patients, topical corticosteroids can be added to their
treatment regimen in accordance with current therapeutic guidelines that recommend the use
of steroids for patients with AC who are not satisfactorily treated with anti-histamine
agents/mast cell stabilizers (anti-H1/MCS). Given the risk of increased ocular pressure (IOP)
and/or cataract formation with steroids, the lowest dosage and frequency of administration is
preferred.
The distinct mechanisms of action of cyclosporine A (CsA) and prednisolone acetate (PA)
provide a relevant rationale for developing a fixed-dose combination (FDC).
- Glucocorticoids, such as PA, are particularly effective in blocking most inflammatory
pathways in allergic reactions, especially those of late-phase mediators that perpetuate the
persistent and chronic forms of ocular allergy (Bielory, 2008).
- Cyclosporine A, a calcineurin inhibitor, is a potent but selective immuno-modulating
agent that has been identified as a potentially effective drug for AC due to its ability to
inhibit the early phase reaction in AC (Sperr et al, 1997; Whitcup et al, 1996) by the
suppression of mast cell degranulation (Shii et al, 2009). Also, CsA was shown to strongly
suppress certain ocular symptoms in late phase and delayed-type reactions in AC models
(Shii et al, 2010). CsA is also effective in controlling ocular allergic inflammation by
blocking Th2-lymphocytes proliferation and IL-2 production (Kari et al, 2010).
Combining CsA with PA is expected to control inflammation associated with AC in an
additive, or even synergistic manner. Therefore, the anticipated efficacy of such a FDC would
be comparable to a high dose concentration of steroid. From a safety perspective, the
combination would allow the cumulative total dose of PA necessary to achieve efficacy in AC
to be limited, therefore potentially reducing the corticosteroid side effects. In addition, the use
of low doses of both CsA and PA would ensure a better local tolerability whilst achieving
sufficient efficacy to control symptoms in AC, and hence achieve a better compliance than
co-administration of separate products.
2. MARKET
The AC market is worth $1.1 billion worldwide (2011) and is dominated by the US. Most of
the value in the US market today is in Rx anti-H1/MCS, with olopatadine (Patanol ® ,
Pataday ® ) as a clear leader followed by more than 10 other products, including the recent
launches (Bepreve ® 2009 , Lastacaft ® 2011).
In the US, the steroids market is largely dominated by loteprednol (Lotemax ® , Alrex ® ), which
represents more than 90% of prescription steroids.
The treatment armamentarium does not fully satisfy the market, with an identified need for
effective treatments for patients who are not satisfactorily treated with anti-H1/MCS, as well
as a need for better-tolerated products than high dose steroids, due to side-effects (e.g.,
increased IOP and/or cataract formation).
The CsA and PA combination would be the first prescription FDC in the treatment of AC.
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3. OCULAR FORMULATION, PHARMACOKINETICS & CLINICAL STUDIES
Formulation
FOV1101 suspension eye drops are a sterile, preserved FDC of PA 0.12% w/v and
CsA 0.02% w/v in a buffered aqueous vehicle. The product is intended for topical ophthalmic
administration, and is supplied in multi-dose dropper bottles. The FOV1101 formulation
employs excipients which are commonly used in currently marketed ophthalmic products,
including the preservative benzalkonium chloride at a concentration of 0.01%.
Preclinical pharmacokinetic (PK) studies
Sanofi-Fovea has conducted a total of four preclinical PK studies, using CsA alone or with
both components, given as FDC (FOV1101) or in co-administration. The studies showed that
PA was rapidly metabolized to prednisolone in vivo, and that both CsA and prednisolone
were found in the target tissues (conjunctiva and cornea) at levels which increased with dose
and over time, whilst plasma exposure was general below limit of quantification. Further, the
PK profiles of PA, prednisolone and CsA were comparable for the FDC and coadministration
in the target tissues, and independent of the individual components.
Clinical studies
Sanofi-Fovea conducted a proof-of-concept trial (08-003-27; NCT00833495) in 2009 using
co-administered CsA and PA. This prospective, multicenter, randomized, double- blind,
placebo-controlled study with 150 patients was conducted in the USA utilizing Ora′s
Enviro-CAC clinical technology. The co-administration of low doses of CsA and PA was
compared to PredForte ® alone or vehicle alone during a 2-week dosing period.
Co-administration of CsA and PA had the same efficacy and a better safety profile (no
increase in IOP) than PredForte ® , a prescription drug with an 8-fold higher dose of PA, in
patients treated for the signs and symptoms (itching and redness) of persistent ocular allergic
inflammation (non responding to 1-week pre-treatment with Pataday ® ).
Sanofi-Fovea also conducted, in 2010, a prospective randomized, double-blind placebocontrolled
Phase 2b trial (10-003-03; NCT01120132). The purpose of this study was to
determine the efficacy and safety of the administration of CsA and PA compared to placebo
in the treatment of allergic conjunctivitis, using diary and office assessments of various ocular
and nasal allergy signs and symptoms. This 28-day study enrolled 716 patients in the US.
This clinical data package provided key information to design the Phase 3 program that will
be conducted with the FDC product.
4. OCULAR SAFETY PROFILE
For each active substance of the FDC, CsA and PA, there is extensive nonclinical and clinical
safety information available in the literature. The toxicity of CsA has been widely studied
during the development of various pharmaceutical forms for the treatment of systemic or
ophthalmic diseases, whilst that of prednisolone (the active metabolite of PA) is described in
published studies. Summaries of the main findings can be found in the prescribing
information, labels and/or NDA pharmacology reviews of Sandimmune ® and Restasis ® for
CsA, and in the prescribing information for Orapred ODT ® and Pred Forte ® for PA.
For both active substances of the FDC that are given by ocular instillation, the systemic levels
of exposure are estimated to be several hundred-fold lower than the levels encountered after
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oral or parenteral administration. Specifically, blood CsA levels are >600-fold higher in organ
transplant patients than for dry eye patients given eye drops of Restasis ® 0.05% emulsion
(which is 2.5 times more concentrated in CsA than FOV1101), and prednisolone plasma
levels have been predicted to be >400-fold higher for patients taking a 30-mg oral dose than
for those to be treated with FOV1101.
Sanofi-Fovea has conducted a series of local tolerance/toxicity studies of the topical
formulation in rabbits, either with the combination of CsA and PA, or with CsA alone. From
these nonclinical studies and in particular a 6-week safety rabbit study performed with topical
ocular administration of CsA and/or PA compared to vehicle, no overt local or systemic
toxicity effects are to be expected in patients treated with FOV1101 eyedrops QID for up to
6 weeks due to the low dose levels of the drug substances given locally and the subsequent
low systemic exposures
5. VALUE PROPOSITION
FOV1101, through its dual mode of action, represents a new potentially safe therapeutic
option for AC patients who cannot be relieved from their persistent inflammation with current
available treatment. In addition, the use of low doses of both CsA and PA would ensure a
better local tolerability while achieving sufficient efficacy to control symptoms in AC, and
hence achieve a better compliance than co-administration of separate products.
6. REFERENCES
American Academy of Ophthalmology (AAO). Cornea/External disease panel. Preferred Practice Pattern
Guidelines. Conjunctivitis. Limited Revision 2011. San Francisco, CA. American Academy of Ophthalmology.
Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK et al. Tear and conjunctival changes
during the allergen-induced early- and late-phase responses. J Allergy Clin Immunol.2000;106(5):948-954.
Baudouin C. Conditions bordering on allergy. J Fr Opthalmol.2007;30(3):306-313.
Bielory L. Ocular allergy treatment. Immunol Allergy Clin North Am. 2008;28(1):189-224, vii.
Choi SH, Bielory L. Late-phase reaction in ocular allergy. Curr Opin Allergy Clin Immunol. 2008;8(5):438-444.
Kari O, Saari KM. Updates in the treatment of ocular allergies. J Asthma Allergy. 2010;24;3:149-158.
Pitt AD, Smith AF, Lindsell L, Voon LW, Rose PW, Bron AJ. Economic and quality-of-life impact of seasonal
allergic conjunctivitis in Oxfordshire. Ophthalmic Epidemiol. 2004;11(1):17-33.
Shii D, Oda T, Shinomiya K, Katsuta O, Nakamura M. Cyclosporine A Eye Drops Inhibit the Early-Phase
Reaction in a Type-I Allergic Conjunctivitis Model in Mice. J Ocul Pharmacol Ther. 2009;25(4):321-328.
Shii D, Nakagawa S, Yoshimi M, Katsuta O, Oda T, Nakamura M. Inhibitory effects of cyclosporine a eye drops
on symptoms in late phase and delayed-type reactions in allergic conjunctivitis models. Biol Pharm Bull.
2010;33(8):1314-1318.
Sperr WR, Agis H, Semper H, Valenta R, Susani M, Sperr M, et al. Inhibition of allergen-induced histamine
release from human basophils by cyclosporine A and FK-506. Int Arch Allergy Immunol. 1997;114(1):68-73.
Whitcup SM, Chan CC, Luyo DA, Bo P, Li Q. Topical cyclosporine inhibits mast cell-mediated conjunctivitis.
Invest Ophthalmol Vis Sci. 1996;37(13):2686-2693.
6. CONTACTS
Guy Claude Anne Marie SIGOT
Vice President Out-Licensing &Special Projects Senior Manager Out-licensing and Special Projects
Strategy & Business Development Strategy & Business Development
Corporate Licenses Corporate Licenses
Guy.claude@sanofi.com Annemarie.sigot@sanofi.com
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