Santen Announces Additional Data from the Phase III SAKURA Program
at The Association for Research in Vision and Ophthalmology (ARVO)
Integrated Primary Analysis and a Key Secondary Endpoint of Intravitreal (IVT) Sirolimus
in the Treatment of Non-Infectious Uveitis of the Posterior Segment
Emeryville, CA – May 7, 2017 – Santen Inc., the U.S. subsidiary of Santen Pharmaceutical Co., Ltd. (Osaka, Japan), announced today that results from its SAKURA global clinical development program were presented at the Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting in Baltimore, Maryland, May 7-11, 2017. 1,2 These data suggest the efficacy and safety of IVT sirolimus (440 μg) in the treatment of non-infectious uveitis of the posterior segment (NIU-PS).
“Non-infectious uveitis of the posterior segment presents significant management challenges, both in terms of the disease course and the treatment options we currently have available,” said Pauline T. Merrill, MD, Assistant Professor, Department of Ophthalmology at Rush University Medical Center. “These results from the Phase III SAKURA program are encouraging because the bar for clinical success was set high. Many of the patients enrolled had posterior and panuveitis, often the hardest forms to treat, and none were allowed to continue systemic immunomodulator therapy. Not only did intravitreal sirolimus reduce vitreous haze in these patients, particularly those with multiple measures of inflammation, but some patients also achieved zero to trace vitreous haze as they were successfully tapered off systemic corticosteroid therapy. By providing a new mechanism of action in this disease and a favorable safety profile, intravitreal sirolimus could represent an important addition to our treatment armamentarium.”
SAKURA Study Design
The SAKURA (Sirolimus study Assessing double-masKed Uveitis tReAtment) Program is the largest Phase III global clinical program to date evaluating patients with non-infectious uveitis of the posterior segment. The SAKURA program comprises two multinational, randomized, double-masked Phase III trials designed to evaluate the comparative safety and efficacy of an active control dose and two active doses of intravitreal injection (44 μg, 440 μg and 880 μg sirolimus) for intermediate, posterior, or panuveitis. In SAKURA 2, the 880 μg dose was phased out and eligible subjects were randomized in a 1:1 ratio to receive 44 or 440 μg.
The analyses reported at ARVO focused on the integrated Intent-to-Treat (ITT) population comparing the 44 μg and 440 μg treatment arms. All subjects had VH ≥1.5+ in the study eye at baseline, measured on a modified Standardization of Uveitis Nomenclature (SUN) Working Group scale. Non-corticosteroid systemic immunosuppressants (IMTs) and topical corticosteroids (CSTs) were discontinued before baseline. The primary efficacy measures were collected at Month 5 and safety data were collected up to Month 24.
SAKURA Results
In the integrated ITT population, 21.2% and 13.5% of subjects (in 440 μg and 44 μg, p=0.0381) met the primary endpoint of “VH 0 response”, defined as having a VH score of 0 in the study eye at Month 5.
Half of patients (50%) in the 440 μg arm and 40.4% in the 44 μg group (p=0.0488) met the secondary endpoint of “VH 0 or 0.5+ response”, defined as having a VH score of 0 or 0.5+ in the study eye at Month 5. A VH score of 0.5+ is described by clinicians as trace haze.
Within the ITT population, 81% of patients (n=171, 440 μg; n=163, 44 μg) presented with multiple measures of inflammation (MMI) at baseline. This assessment was defined as having VH ≥1.5+ and one or more additional markers of disease, including:
Systemic CSTs at an overall prednisone-equivalent dose greater than 5 mg/day,
Impaired vision: Best-corrected visual acuity of 75 ETDRS letters (Snellen equivalent: 20/32) or less
Macular edema (central retinal thickness ≥300 μm on optical coherence tomography).
In the integrated subpopulation of patients with MMI, 21.1% in the 440 μg dose group achieved VH=0 at Month 5 without the use of rescue therapy, as compared to 8.0% in the 44 μg dose group (p=0.0007). Against the secondary endpoint, 48.0% of patients with MMI in the 440 μg dose group reached VH 0 or 0.5+ at Month 5 without the use of rescue therapy, as compared to 37.4% in the 44 μg dose group (p=0.0519).
CST tapering success was evaluated in 46 patients from the 440 μg group and 32 from the 44 μg group who began the trial on an overall prednisone-equivalent dose of at least 7.5 mg/day. CST tapering success was defined as achieving an overall prednisone-equivalent dose of 5 mg/day or less at Month 5 without the use of any rescue therapy.
Although the difference did not meet statistical significance due to small sample size (p=0.1676), the proportion of patients who achieved CST tapering success with an improvement of VH to 0 or 0.5+ at Month 5 was numerically higher in the 440 μg dose group than in the 44 μg dose group (43.5% vs 28.1%).
Serious adverse event rates were similar among all treatment groups. The results of the SAKURA program support Santen’s U.S. regulatory submission for IVT sirolimus in this indication. The investigational treatment received orphan drug designation from the U.S. Food and Drug Administration and the European Commission in 2011.
About Intravitreal (IVT) Sirolimus
IVT sirolimus (440 μg), an mTOR inhibitor, is a first-in- class targeted, immunoregulator being developed for the treatment of non-infectious uveitis of the posterior segment – a progressive and recurrent inflammatory disease of the eye. IVT sirolimus inhibits the protein kinase, mTOR which plays a key role in inflammation. The result is immunoregulation by interrupting the inflammatory cascade through the inhibition of T-cell activation, differentiation and proliferation, and promoting immune tolerance by increasing regulatory T lymphocytes (Tregs).
About Uveitis
Uveitis is a leading cause of preventable blindness in working-age adults and is estimated to account for 10 to 15 percent of cases of total blindness in the developed world. 2 It is characterized by intraocular inflammation that is often chronic, can recur at any time and can lead to visual impairment and vision loss. Non-infectious uveitis of the posterior segment includes intermediate, posterior and panuveitis.
About Santen
As a specialty company dedicated to the ophthalmic field, Santen carries out research, development, sales, and marketing of pharmaceuticals and devices. Santen is the market leader in Japan for prescription ophthalmic pharmaceuticals and sells products in over 50 countries worldwide. As a leading company in the field of ophthalmology, Santen aims to contribute to society by supplying valuable products and services to satisfy unmet medical needs. For more details, please see Santen’s website (www.santen.com).
1. Nguyn QD, Merrill PT, Clark L. Efficacy and safety results from the SAKURA program: Two phase III studies of intravitreal sirolimus every other month for non-infectious uveitis of the posterior segment. ARVO Abstract # Posterboard Number: 517 - B0072
2. Maturi R. Corticosteroid tapering success with every-other- month intravitreal sirolimus for non-infectious uveitis of the posterior segment: Results of the SAKURA program. ARVO Abstract #Posterboard Number: 520 - B0075