Roche presents positive phase II results for the first-ever eye implant demonstrating sustained delivery of a biologic medicine to treat people with neovascular age-related macular degeneration

• Roche's investigational Port Delivery System with ranibizumab (PDS) is intended to reduce the burden of frequent eye injections for people with neovascular age-related macular degeneration (nAMD) and address under-treatment that could lead to vision loss
• The majority of PDS patients went six months or longer between the implant of the device and first required refill, and patients in the high dose PDS group achieved similar vision outcomes as monthly ranibizumab eye injections^[1]
• Roche's phase III ophthalmology programme is expected to begin later in 2018 to evaluate both the PDS in nAMD and RG7716 in diabetic macular edema (DME)

Basel, 26 July 2018 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced positive, top-line results from the LADDER study, the first successful phase II study of a long-acting delivery device for the treatment of neovascular ("wet") age-related macular degeneration (nAMD), a leading cause of blindness globally in people aged 60 and over.^[2] LADDER evaluated the efficacy and safety of the investigational Port Delivery System with ranibizumab (PDS) in people with nAMD who had previously responded to treatment with anti-vascular endothelial growth factor (VEGF) therapy. The majority of PDS patients enrolled in the LADDER trial went six months or longer between implant of the device and the first required refill. Vision outcomes in the high dose PDS group were similar to monthly ranibizumab eye injections and were maintained throughout the study period. These late-breaking data were presented at the 36th Annual Meeting of the American Society of Retina Specialists (ASRS) in Vancouver, British Columbia, Canada.^[1]

"The LADDER data clearly highlight the potential of the PDS - our first implantable, drug delivery device - to alleviate the frequent treatment burden for people with nAMD, which could also lead to better vision outcomes in clinical practice," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "With our focus on improving patient outcomes through cutting-edge science in ophthalmology, we are initiating a robust phase III programme that includes the PDS for nAMD and injections of the bispecific antibody RG7716 for diabetic macular edema. We hope to bring these first-of-their kind, innovative solutions to patients as quickly as possible."

Three pivotal studies in Roche's clinical development programme in ophthalmology are expected to begin later in 2018, including: a phase III study of the PDS in nAMD, based on these LADDER data; and two phase III studies of RG7716, a VEGF/Ang-2 (angiopoietin-2) bispecific antibody, based on the phase II BOULEVARD study. BOULEVARD data, which were also presented at ASRS, further confirmed that treatment with RG7716 resulted in clinically meaningful and statistically significant improvements in visual acuity gains compared with ranibizumab alone in people with vision loss from diabetic macular edema (DME).^[3]

About LADDER and the investigational PDS
LADDER study patients implanted with the PDS received one of three concentrations of ranibizumab: 10 mg/mL, 40 mg/mL or 100 mg/mL.^[4] For PDS patients receiving the 100 mg/mL dose (n=59), approximately 80% were able to go six months or longer until their first refill. Of the PDS patients receiving 40 mg/mL (n=62) or 10 mg/mL (n=58), 71.3% and 63.5% respectively were able to go six months or longer before their first refill.^[1]

Secondary endpoints of the study included assessments of vision and anatomic outcomes when compared to monthly intravitreal ranibizumab 0.5 mg injections.^[4] Patients in the PDS 100 mg/mL arm achieved similar gains in Best Corrected Visual Acuity (BCVA) and similar reductions in central retina thickness compared to patients receiving ranibizumab 0.5 mg injections.^[1]

Neovascular AMD can cause rapid and severe vision loss, and affects 17 million people worldwide.^[5,6] People with nAMD may need as often as monthly eye injections with the current standard of care, anti-VEGF therapy, a burden that can lead to under-treatment of nAMD and, potentially, less than optimal vision outcomes.^[7,8] The investigational PDS is a small, refillable device, slightly longer than a grain of rice, surgically implanted in the eye during a procedure that typically lasts approximately 30 minutes. The PDS is uniquely designed to continuously deliver a specialised formulation of ranibizumab over time.

Results from LADDER will help determine the most appropriate dose and fixed treatment interval to study in the phase III programme to sustain optimal vision outcomes in clinical practice for patients with nAMD.^[1] Additional data analyses of the LADDER study are ongoing and will be presented at future medical meetings.

About BOULEVARD and RG7716
ME is a leading cause of vision loss in working-age adults, affecting 21 million people globally.^[9] There is a significant unmet need for more efficacious and longer-lasting therapies for people with this condition.^[10] RG7716 is the first bispecific antibody designed specifically for intravitreal use to simultaneously bind to and neutralise both angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A) with high potency and specificity.^[11] In DME, Ang-2 works synergistically with VEGF to drive biological pathways that cause vessel permeability and inflammation. Both of these contribute to vascular instability and retinal injury, which results in vision loss.^[11,12,13] Therefore, simultaneous inhibition of both Ang-2 and VEGF may lead to improved outcomes, reduced treatment burden, or both.^[14,11,12]

BOULEVARD assessed two doses of RG7716 (1.5 mg and 6 mg) versus ranibizumab standard of care (0.3 mg) given as monthly intravitreal injections. The study met its primary endpoint, demonstrating a significant improvement in adjusted BCVA at week 24 for RG7716 versus ranibizumab in treatment-naïve patients: 6 mg RG7716 resulted in an adjusted mean improvement of 13.9 chart letters from baseline, compared to 11.7 letters in patients treated with 1.5 mg RG7716, and 10.3 letters in patients treated with 0.3 mg ranibizumab. The difference between 6 mg RG7716 and 0.3 mg ranibizumab was statistically significant with an adjusted mean difference of +3.6 letters (p=0.03, 80% CI 1.53-5.61, pre-specified significance level: p<0.2).^[3] In anti-VEGF previously-treated patients, RG7716 treatment resulted in improvements in vision from baseline, directionally supporting the primary BCVA outcome.^[3] Key secondary and exploratory anatomical outcomes - reduction of central retina thickness and improvements in diabetic retinopathy severity scores - were supportive of the primary outcome.^[3,15]

About Roche in ophthalmology
Roche is committed to developing pioneering, transformative therapies for people living with a range of eye diseases that cause significant visual impairment and blindness, including nAMD, DME, diabetic retinopathy (DR), geographic atrophy (GA) and other retinal diseases. Roche is also investigating innovative platforms for sustained ocular drug delivery, including the PDS.

Lucentis® (ranibizumab injection) was developed by Genentech, a member of the Roche Group. Genentech retains commercial rights in the United States and Novartis has exclusive commercial rights for the rest of the world. 

About Roche
Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people's lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare - a strategy that aims to fit the right treatment to each patient in the best way possible.

Roche is the world's largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.
Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. Thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Roche has been recognised as the Group Leader in sustainability within the Pharmaceuticals, Biotechnology & Life Sciences Industry nine years in a row by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2017 employed about 94,000 people worldwide. In 2017, Roche invested CHF 10.4 billion in R&D and posted sales of CHF 53.3 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com.

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References
^[1] Awh C, et al. LADDER trial of the Port Delivery System for ranibizumab: Initial study results. Presented at the 36th Annual Meeting of the American Society of Retina Specialists (ASRS); 2018 Jul 20-25; Vancouver, British Columbia, Canada.
^[2] National Institutes of Health Medline Plus. Leading causes of blindness. [Internet; cited 2018 July]. Available from: https://medlineplus.gov/magazine/issues/summer08/articles/summer08pg14-15.html.
^[3] Singh, R. Anti-VEGF/anti-angiopoietin-2 bispecific antibody RG7716 in diabetic macular edema: 36-week results from the phase 2 BOULEVARD clinical trial. Presented at the 36th Annual Meeting of the American Society of Retina Specialists (ASRS); 2018 July 20-25; Vancouver, British Columbia, Canada.
^[4] ClinicalTrials.gov. Study of the efficacy and safety of the ranibizumab Port Delivery System (RPDS) for sustained delivery of ranibizumab in participants with subfoveal neovascular age-related macular degeneration (AMD) (LADDER). [Internet; cited 2018 July]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02510794.
^[5] Pennington KL, DeAngelis MM. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye and Vision. 2016; 3:34.
^[6] Bright Focus Foundation. Age-related macular degeneration: facts & figures. [Internet; cited 2018 July]. Available from: https://www.brightfocus.org/macular/article/age-related-macular-facts-figures.
^[7] Holz FG, Tadayoni R, Beatty S, et al. Multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration. British Journal of Ophthalmology. 2015; 99:220-226.
^[8] Rao P, Lum F, et al. Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS registry. Ophthalmology. 2018; 125: 522-528.
^[9] Yau JWY, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012; 35: 556-564.
^[10] Massin P, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010; 33(11):2399-405.
^[11] Chakravarthy U BC, Brown D, Campochiaro P, et al. Phase 1 trial of anti-vascular endothelial growth factor/antiangiopoietin 2 bispecific antibody RG7716 for neovascular age-related macular degeneration. Ophthalmology Retina. 2017; 1: 474-485.
^[12] Rangasamy S, Srinivasan R, Maestas J, et al. A potential role for angiopoietin 2 in the regulation of the blood-retinal barrier in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011; 52:3784-3791.
^[13] Regula JT, Lundh von Leithner P, Foxton R, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Molecular Medicine. 2016; 8:1265-1288.
^[14] Boyer DS, Hopkins JJ, Sorof J, Ehrlich JS. Anti-vascular endothelial growth factor therapy for diabetic macular edema. Therapeutic advances in endocrinology and metabolism. 2013; 4:151-169.
^[15] ClinicalTrials.gov. A study of RO6867461 in participants with center-involving diabetic macular edema (BOULEVARD). [Internet; cited 2018 July]. Available from: https://clinicaltrials.gov/ct2/show/NCT02699450.