作者: Chang, Sunghee ; Dvorak, Ann M ; Kang, Peter M ; Shen, Mei ; Jaminet, Shou-Ching ; Sitohy, Basel ; Benjamin, Laura E ; Dvorak, Harold F ; Sciuto, Tracey E ; Bhatt, Rupal S ; Nagy, Janice A ; Masse, Elizabeth

Tumors induce their heterogeneous vasculature by secreting vascular endothelial growth factor (VEGF)-A. Anti-VEGF/VEGF receptor (VEGFR) drugs treat cancer, but the underlying mechanisms remain unclear. An adenovirus expressing VEGF-A (Ad-VEGF-A¹⁶⁴) replicates the tumor vasculature in mice without tumor cells. Mother vessels (MV) are the first angiogenic vessel type to form in tumors and after Ad-VEGF-A¹⁶⁴. Multiday treatments with a VEGF trap reverted MV back to normal microvessels. We now show that, within hours, a single dose of several anti-VEGF drugs collapsed MV to form glomeruloid microvascular proliferations (GMP), accompanied by only modest endothelial cell death. GMP, common in many human cancers but of uncertain origin, served as an intermediary step in MV reversion to normal microvessels. The vasodisruptive drug combretastatin CA4 also targeted MV selectively but acted differently, extensively killing MV endothelium. Antivascular changes were quantified with a novel Evans blue dye assay that measured vascular volumes. As in tumors, Ad-VEGF-A¹⁶⁴ strikingly increased endothelial nitric oxide synthase (eNOS) expression. The eNOS inhibitor N(G)-Nitro-l-arginine methyl ester mimicked anti-VEGF/VEGFR drugs, rapidly collapsing MV to GMP. Inhibition of eNOS reduces synthesis of its vasodilatory product, nitric oxide, leading to arterial contraction. Patients and mice receiving anti-VEGF/VEGFR drugs develop hypertension, reflecting systemic arterial contraction. Together, anti-VEGF/VEGFR drugs act in part by inhibiting eNOS, causing vasocontraction, MV collapse to GMP, and subsequent reversion of GMP to normal microvessels, all without extensive vascular killing.

2011-11-01·Zhonghua zhong liu za zhi [Chinese journal of oncology]

[Effect of recombinant adenovirus Ad-DT-A in targeted therapy for malignant cancer cell lines with loss of IGF2 imprinting].

Article

作者: Qu, Li-li ; Xu, Xiong-fei ; Pan, Yu-qin ; He, Bang-shun ; Zhu, Chan ; Wang, Shu-kui

OBJECTIVETo explore the feasibility of IGF2 imprinting system in target gene therapy for tumors.METHODSThe mouse H19 enhancer, DMD and promoter H19 were amplified by PCR from mouse genomic DNA and then cloned into the plasmid pDC312. The EGFP and DT-A fragments were amplified by PCR and cloned into the recombinant plasmid, and then the shuttle plasmid were transfected into HEK293 cells together with the adenoviral vector Ad5, namely, Ad-EGFP and Ad-DT-A. Adenovirus hexon gene expression was applied to confirm the presence of adenovirus infections. The effect of the IGF2 imprinting system was tested by fluorescence microscopy. RT-PCR and Western blotting after transfection of the recombinant adenoviral vectors into cancer cells were used to show loss of IGF2 imprinting (LOI) and maintenance of IGF2 imprinting (MOI), respectively. The anti-tumor effect was assessed by MTT and flow cytometry after the HCT-8 (LOI). Human breast cancer cell line MCF-7 (MOI) and human normal gastric epithelial GES-1 (MOI) cell line were transfected with Ad-DT-A in vitro. The anti-tumor effect was detected by injecting the Ad-DT-A in nude mice carrying HCT-8 tumors.RESULTSThe expression of EGFP protein, DT-A mRNA and DT-A protein were seen to be positive only in the HCT-8 tumor cell line. Infection with Ad-DT-A resulted in obviously growth inhibition in HCT-8 cells (75.4 ± 6.4)% compared with that in the control group, and increased the percentage of apoptosis in the HCT-8 cells (20.8 ± 5.9)%. The anti-tumor effect was further confirmed by injecting the recombinant adenoviruses in HCT-8 tumor-bearing nude mice, and the results showed that the Ad-DT-A inhibited the tumor growth, with on inhibition rate of 36.4%.CONCLUSIONSThe recombinant adenoviruses carrying IGF2 imprinting system and DT-A gene have been successfully constructed, while Ad-DT-A can effectively kill the tumor cells showing loss of IGF2 imprinting. It might play an important role in future target gene therapy against malignant tumors based on loss of IGF2 imprinting.

2011-10-01·Acta Biochimica et Biophysica Sinica2区 · 生物学

BMP2 and VEGF promote angiogenesis but retard terminal differentiation of osteoblasts in bone regeneration by up-regulating <italic>Id1</italic>

2区 · 生物学

Article

作者: Tao Wang ; Xiaobin Song ; Xiaoying Zhang ; Xun Qu ; Fengcai Wei ; Shaohua Liu ; Yingwei Hu

Inadequate vascularization limits the repair of bone defects. In order to improve angiogenesis and accelerate osteogenesis, the synergism of co-cultured cells with genetic modification in bone regeneration was investigated in this study. Endothelial progenitor cells (EPCs) and bone marrow stem cells (BMSCs) were transfected with the genes of vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) by adenovirus, respectively. The co-cultured cells, designated as four groups including BMSC + EPC, Ad-BMP2-BMSC + EPC, BMSC + Ad-VEGF-EPC, and Ad-BMP2-BMSC + Ad-VEGF-EPC groups, were seeded on an alginate gel and then implanted into rat intramuscularly to evaluate the effects on angiogenesis and osteogenesis. Both VEGF and BMP2 could induce the overexpression of inhibitor of DNA-binding 1(Id1) gene which significantly promoted tube formation in vitro and increase the amount of blood vessels in the Ad-BMP2-BMSC + Ad-VEGF-EPC group after implantation. Nevertheless, overexpression of Id1 retarded the terminal differentiation of osteoblasts and the bone formation. Later, osteogenic gene expression at transcriptional level, calcium nodules, and alkaline phosphatase (ALP) activity showed a gradual decrease and the amount of newly formed osteogenesis area exhibited a small increase in the Ad-BMP2-BMSC + Ad-VEGF-EPC group. This finding suggests that a balanced regulation of Id1 expression in VEGF-EPCs and BMP2-BMSCs may be critical to cell-based and gene-based approaches for bone regeneration.

项与 EG-016 相关的新闻（医药）

2023-08-20

·Firstwordpharma

Higher-dose Eylea gets swift US nod following recent CRL

The FDA has approved a higher-dose version of Regeneron Pharmaceuticals' Eylea (aflibercept) for patients with wet age-related macular degeneration (wAMD), diabetic macular oedema (DME) and diabetic retinopathy (DR). The decision marks a swift turnaround from June when the US regulator issued a complete response letter for Eylea 8mg citing an ongoing review of inspection at third-party manufacturer Catalent.The approval also comes on the heels of another FDA nod for a Regeneron drug – the C5 antibody branded Veopoz (pozelimab-bbfg) to treat CHAPLE disease. With Veopoz's approval, Regeneron hinted that a positive decision for Eylea 8mg could be forthcoming as pre-approval inspection issues that had led to the June CRL were now addressed.Regeneron said the latest clearance was based on 48-week results of the pivotal PULSAR and PHOTON trials. Last year, the company and partner Bayer reported that the primary endpoint was met in both Phase III trials – PULSAR in wet AMD and PHOTON in DME – with high-dose Eylea demonstrating non-inferior and clinically equivalent vision gains at 48 weeks with both 12- and 16-week dosing regimens, compared to an eight-week dosing regimen using the drug's original 2mg version.Regeneron noted that the vast majority of patients randomised at baseline to high-dose Eylea were able to maintain the 12- and 16-week dosing intervals through 48 weeks. The recommended dose for Eylea 8mg is monthly injections for the first three months across all indications, followed by every eight to 16 weeks in wAMD and DME, and every eight to 12 weeks for DR.The most common adverse reactions, occurring at a rate of ≥3%, in patients on the high-dose version of Eylea were cataract, conjunctival haemorrhage, higher intraocular pressure, ocular discomfort, blurred vision, vitreous floaters, vitreous detachment, corneal epithelium defect and retinal haemorrhage.Regeneron maintains exclusive rights to Eylea, including the high-dose version, while Bayer has licensed exclusive marketing rights outside of the US, where the companies share equally in profits from sales of the drug. Regulatory filings for Eylea 8mg are under review in Europe and Japan, with submissions also planned in other markets.Analysts have said an approval of the higher-dose version of Eylea could provide Regeneron a defence against rivals such as Roche's Vabysmo (faricimab-svoa), which won US approval early in 2022 to treat both wet AMD and DME. Roche's bispecific antibody, designed to block pathways involving Ang-2 and VEGF-A, allows less frequent dosing than standard therapy with Eylea 2mg.For related analysis, see Regeneron eyes key drug approval in Q3 and Physician Views Results: Ophthalmologist feedback shows Roche’s Vabysmo in rude health.

上市批准临床3期临床结果

2023-08-18

·Firstwordpharma

Regeneron scores US nod for Veopoz to treat ultra-rare CHAPLE disease

The FDA on Friday approved Regeneron Pharmaceuticals' C5 antibody Veopoz (pozelimab-bbfg) for adult and paediatric patients ages one year and older with CHAPLE disease, making it the first therapy indicated specifically for the ultra-rare hereditary syndrome. The company noted that the decision also addresses some pre-approval inspection issues that recently scuttled its high-dose Eylea (aflibercept) application, and paves the way for FDA action on that filing "in the next few weeks."The FDA submission for Veopoz, which was granted a priority review in February, was based on data from an open-label Phase II/III trial involving 10 patients ages three to 19 years old. CHAPLE disease, also referred to as CD55-deficient protein-losing enteropathy, can cause potentially life-threatening gastrointestinal and cardiovascular symptoms.Participants were given a single loading dose of Veopoz intravenously on the first day, followed by subcutaneous weekly weight-based doses. Regeneron said all the patients achieved normalisation of serum albumin and serum IgG concentrations by week 12, and maintained these concentrations through at least 72 weeks of treatment.The company noted that half the study participants had received a total of 60 albumin transfusions in the 48 weeks leading up to treatment, whereas only one patient received a single albumin transfusion in the 48 weeks after starting on Veopoz. Hospitalisations also decreased – with nine of the 10 patients having been hospitalised for a total of 268 days in the 48 weeks prior to treatment, compared with two patients hospitalised for a total of seven days in the 48 weeks post-treatment. The most common adverse reactions associated with Veopoz included upper respiratory tract infection, fracture, urticaria and alopecia."Beyond CHAPLE, we believe Veopoz has promise in a variety of complement-mediated diseases and are driving forward several clinical programmes to explore its broader potential," remarked George Yancopoulos, chief scientific officer at Regeneron. Veopoz is also being evaluated in combination with Alnylam Pharmaceuticals' C5-targeting RNAi therapeutic cemdisiran for paroxysmal nocturnal haemoglobinuria and myasthenia gravis.Meanwhile, in June, the FDA issued a complete response letter (CRL) regarding Regeneron's application seeking approval of a new 8mg version of Eylea for patients with wet age-related macular degeneration (AMD), diabetic macular oedema (DME) and diabetic retinopathy. At the time, Regeneron noted that the CRL was "solely due" to an ongoing review of inspection findings at third-party manufacturer Catalent, and that there were "no issues with clinical efficacy or safety, trial design, labeling or drug substance manufacturing…identified."Analysts have said an approval of the higher-dose version of Eylea could provide Regeneron a defence against rivals such as Roche's Vabysmo (faricimab-svoa), which won US approval early in 2022 to treat both wet AMD and DME. Roche's bispecific antibody, designed to block pathways involving Ang-2 and VEGF-A, allows less frequent dosing than standard therapy with Eylea 2mg.For related analysis, see Regeneron eyes key drug approval in Q3 and Physician Views Results: Ophthalmologist feedback shows Roche’s Vabysmo in rude health.

上市批准临床结果优先审批临床3期

2023-07-20

·GlobeNewswire-Health Care

New clinical and real-world data for Roche’s Vabysmo at ASRS reveal improved outcomes for people with two leading causes of vision loss

Late-breaking post-hoc data indicate Vabysmo leads to less fibrosis, which may negatively impact vision, than aflibercept in people with diabetic macular edema (DME)Real-world data reinforce that first-line Vabysmo use improves outcomes and extends treatment intervals rapidly during the first four months for people with neovascular or ‘wet’ age-related macular degeneration (nAMD) and DMEClinical data reiterate Vabysmo’s positive anatomical outcomes, including reduced blood vessel leakage in the macula and greater and faster retinal fluid control Vabysmo is currently approved in over 70 countries to treat nAMD and DME, with more than one million doses distributed globally Basel, 20 July - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that data from its ophthalmology portfolio will be highlighted in 25 abstracts at the 2023 American Society of Retina Specialists (ASRS) Annual Meeting, which will be held from 28 July to 1 August in Seattle, United States. The data further advance the depth of clinical and real-world evidence supporting the use of Vabysmo® (faricimab), the first and only bispecific antibody for the eye, for the treatment of neovascular or ‘wet’ age-related macular degeneration (nAMD) and diabetic macular edema (DME).1-14 “The clinical and real-world data at ASRS reinforce the improvement in outcomes brought by Vabysmo in two leading causes of vision loss, particularly new analyses suggesting that Vabysmo is associated with less vision-impacting fibrosis than aflibercept,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “By improving disease control while offering a potentially less frequent treatment regimen, Vabysmo may help people spend less time managing their condition.” Vabysmo is currently approved in over 70 countries to treat nAMD and DME, with public reimbursement in over 20 markets and more than one million doses distributed globally.15 Neovascular AMD and DME are two leading causes of vision loss worldwide, affecting more than 40 million people.16-19 The following key data will be presented at ASRS 2023: Late-breaker: Vabysmo’s effect on epiretinal membrane (ERM) formation in DME compared to aflibercept Two-year post-hoc data from the YOSEMITE and RHINE phase III studies will be presented for the first time on ERM formation in DME patients, indicating Vabysmo leads to less retinal fibrosis than aflibercept.3 ERMs are fibrotic tissues on the surface of the retina, which may negatively impact the anatomy of the eye and compromise vision.20 Vabysmo drying and durability data Data will be presented reiterating positive anatomical outcomes previously seen with Vabysmo treatment, including reduced blood vessel leakage in the macula, and greater and faster retinal fluid control.4,6,7 Blood vessel leakage can cause a build-up of fluid and swelling in the back of the eye, contributing to sight loss.21,22 Data will also further support how increased intervals between doses of Vabysmo to treat nAMD and DME, compared to aflibercept, do not compromise outcomes.4,6,7 Vabysmo real-world data Roche’s expanding programme of real-world studies for Vabysmo includes more than 8,500 participants in almost 30 countries.15 Updates will be presented on real-world data from the FARETINA studies of Vabysmo in nAMD and DME looking at extended dosing intervals and impact on vision, including Vabysmo’s use as a first-line treatment.9,10 Preliminary data on early outcomes and treatment patterns in the United Kingdom FARWIDE studies of Vabysmo in nAMD and DME will be shared for the first time.11,12 In addition, independent investigator studies of Vabysmo are expected to be presented. The TRUCKEE study, which focused on real-world outcomes in people with nAMD across 14 sites in the United States is scheduled for presentation on 31 July during the Wet AMD Symposium 3 (1:38 PM to 1:44 PM PDT).23 Further information on select Roche abstracts that will be presented at ASRS 2023 can be found in the table below. TopicAbstract TitlePresentation DetailsVabysmo An Assessment of the Impact of Disease Activity Criteria on Dosing Interval Assignment in Clinical Trial Patients With nAMD Paper PresentationSession: Wet AMD Symposium 1July 29, 20238:49 AM to 8:53 AM PDTElevatum Study Design and Rationale: A Phase 4 Trial of Faricimab (VABYSMO) in Underrepresented Patients With Diabetic Macular Edema Paper PresentationSession: Diabetic Retinopathy Symposium 2July 30, 20232:04 PM to 2:07 PM PDTImpact of Faricimab vs Aflibercept on Epiretinal Membrane Formation Over 2 Years in Eyes with DME in the YOSEMITE/RHINE Phase 3 Trials Paper PresentationSession: Late Breaking AbstractsJuly 30, 20233:58 PM to 4:03 PM PDTFaricimab Reduces Macular Leakage vs Aflibercept in Patients With DME Paper PresentationSession: Diabetic Retinopathy Symposium 3July 31, 202310:53 AM to 10:57 AM PDTFaricimab Causes Rapid and Sustained Intraocular Suppression of Ang-2 and VEGF-A for Up to 16 Weeks in nAMD and DMEPaper PresentationSession: Diabetic Retinopathy Symposium 3July 31, 202310:57 AM to 11:01 AM PDTTime to Retinal Fluid Control With Faricimab vs Aflibercept in Patients With DME in the Phase 3 YOSEMITE/RHINE TrialsPaper PresentationSession: Diabetic Retinopathy Symposium 3July 31, 202311:01 AM to 11:05 AM PDTFaricimab Rapidly Improves Fluid Parameters in Patients With nAMD Paper PresentationSession: Wet AMD Symposium 3July 31, 20231:30 PM to 1:34 PM PDTEfficacy, Durability, and Safety of Faricimab in DME: 1-year Results from China Subpopulation of Phase 3 RHINE Trial Virtual Paper on Demand PresentationVabysmo Real-World Data Early Treatment Patterns and Outcomes in Patients with Diabetic Macular Edema Treated with Faricimab: the FARETINA-DME Study Paper PresentationSession: Diabetic Retinopathy Symposium 3 July 31, 202311:05 AM to 11:09 AM PDTEarly Treatment Patterns and Outcomes in Patients with Neovascular Age-Related Macular Degeneration Initiating Faricimab: the FARETINA-AMD StudyPaper PresentationSession: Wet AMD Symposium 3July 31, 20231:34 PM to 1:38 PM PDTReal-world Use of Faricimab to Treat nAMD Patients in the UK Virtual Paper on Demand PresentationReal-world Use of Faricimab to Treat DME Patients in the UK Poster PresentationSusvimoPort Delivery System With Ranibizumab (PDS) for Continuous Treatment in DME and DR: Additional Results From the Phase 3 Pagoda and Pavilion TrialsPaper Presentation Session:Late Breaking AbstractsAugust 1, 202310:53 AM to 10:59 AM PTAnti-IL-6 (for Uveitic Macular Edema)A Novel Intravitreal Anti-IL-6 Monoclonal Antibody for Uveitic Macular Edema (UME): Preliminary Results From the Phase 1 DOVETAIL StudyPaper PresentationSession: Inflammatory & Infectious Diseases SymposiumJuly 29, 20234:04 PM to 4:10 PM PDT About neovascular age-related macular degenerationAge-related macular degeneration (AMD) is a condition that affects the part of the eye that provides sharp, central vision needed for activities like reading.16 Neovascular or ‘wet’ AMD (nAMD) is an advanced form of the disease that can cause rapid and severe vision loss if left untreated.24,25 It develops when new and abnormal blood vessels grow uncontrolled under the macula, causing swelling, bleeding and/or fibrosis.24 Worldwide, around 20 million people are living with nAMD – the leading cause of vision loss in people over the age of 60 – and the condition will affect even more people around the world as the global population ages.16-18 About diabetic macular edemaAffecting around 21 million people globally, diabetic macular edema (DME) is a vision-threatening retinal condition associated with blindness and decreased quality of life when left untreated.19 DME occurs when damaged blood vessels leak into and cause swelling in the macula – the central area of the retina responsible for the sharp vision needed for reading and driving.21,26 The number of people with DME is expected to grow as the prevalence of diabetes increases.27 About the Vabysmo® (faricimab) clinical development programmeRoche has a robust phase III clinical development programme for Vabysmo® (faricimab). The programme includes AVONELLE-X, an extension study of TENAYA and LUCERNE evaluating the long-term safety and tolerability of Vabysmo in neovascular or ‘wet’ age-related macular degeneration (nAMD), and Rhone-X, an extension study of YOSEMITE and RHINE evaluating the long-term safety and tolerability of Vabysmo in diabetic macular edema (DME).28,29 In addition, Roche is investigating the efficacy and safety of Vabysmo in people with macular edema following retinal vein occlusion in two phase III studies, BALATON and COMINO.30,31 Roche has also initiated several phase IV studies, including the ELEVATUM study of Vabysmo in underrepresented patient populations with DME, the SALWEEN study of Vabysmo in a subpopulation of nAMD highly prevalent in Asia, as well as the VOYAGER study, a global real-world data collection platform.32-34 Roche also supports several other independent studies to further understand retinal conditions with a high unmet need.15 About Vabysmo® (faricimab)Vabysmo® (faricimab) is the first bispecific antibody approved for the eye.13,14 It targets and inhibits two signalling pathways linked to a number of vision-threatening retinal conditions by neutralising angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).35,36 Ang-2 and VEGF-A contribute to vision loss by destabilising blood vessels, causing new leaky blood vessels to form and increasing inflammation.35,36 By blocking pathways involving Ang-2 and VEGF-A, Vabysmo is designed to stabilise blood vessels. Vabysmo is approved in over 70 countries around the world, including the United States, Japan, the United Kingdom and in the European Union for people living with neovascular or ‘wet’ age-related macular degeneration and diabetic macular edema.13-15,37,38 Review by other regulatory authorities is ongoing. About Roche in ophthalmologyRoche is focused on saving people’s eyesight from the leading causes of vision loss through pioneering therapies. Through our innovation in the scientific discovery of new potential drug targets, personalised healthcare, molecular engineering, biomarkers and continuous drug delivery, we strive to design the right therapies for the right patients. We have the broadest retina pipeline in ophthalmology, which is led by science and informed by insights from people with eye diseases. Our pipeline includes gene therapies and treatments for geographic atrophy and other vision-threatening diseases, including rare and inherited conditions. Applying our extensive experience, we have already brought breakthrough ophthalmic treatments to people living with vision loss. Susvimo™ (Port Delivery System with ranibizumab) 100 mg/mL for intravitreal use via ocular implant is the first U.S. Food and Drug Administration-approved refillable eye implant for neovascular or ‘wet’ age-related macular degeneration that continuously delivers a customised formulation of ranibizumab over a period of months.39 Vabysmo® (faricimab) is the first bispecific antibody approved for the eye, which targets and inhibits two signalling pathways linked to a number of vision-threatening retinal conditions by neutralising angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A).13,14,35,36 Lucentis®* (ranibizumab injection) is the first treatment approved to improve vision in people with certain retinal conditions.40 *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 Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. In recognising our endeavour to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the thirteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work. 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. All trademarks used or mentioned in this release are protected by law.References[1] Zarbin M, et al. An assessment of the impact of disease activity criteria on dosing interval assignment in clinical trial patients with nAMD. Paper presentation at: American Society of Retina Specialists (ASRS) Annual Meeting; 28 July – 1 August 2023.[2] Coney JM, et al. Elevatum study design and rationale: a phase IIII trial of faricimab (VABYSMO) in underrepresented patients with diabetic macular edema. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[3] Jaffe GJ, et al. Impact of faricimab vs aflibercept on epiretinal membrane formation over two years in eyes with DME in the YOSEMITE/RHINE phase III trials. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[4] Nudleman E, et al. Faricimab reduces macular leakage vs aflibercept in patients with DME. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[5] Muni RH, et al. Faricimab causes rapid and sustained intraocular suppression of Ang-2 and VEGF-A for up to 16 weeks in nAMD and DME. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[6] Rachitskaya AV, et al. Time to retinal fluid control with faricimab vs aflibercept in patients with DME in the phase III YOSEMITE/RHINE trials. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[7] London NJ, et al. Faricimab rapidly improves fluid parameters in patients with nAMD. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023. [8] Sun X, et al. Efficacy, durability, and safety of faricimab in DME: one-year results from China subpopulation of phase III RHINE trial. Virtual Paper on Demand Presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[9] Borkar D, et al. Early treatment patterns and outcomes in patients with diabetic macular edema treated with faricimab: the FARETINA-DME study. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[10] Leng T, et al. Early treatment patterns and outcomes in patients with neovascular age-related macular degeneration initiating faricimab: the FARETINA-AMD study. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023.[11] Patel PJ, et al. Real-world use of faricimab to treat nAMD patients in the UK. Virtual Paper on Demand Presentation at: ASRS Annual Meeting; 28 July – 1 August 2023. [12] Gale RP, et al. Real-world use of faricimab to treat DME patients in the UK. Poster Presentation at: ASRS Annual Meeting; 28 July – 1 August 2023. [13] United States Food and Drug Administration (U.S. FDA). Highlights of prescribing information, Vabysmo. 2022 [Internet; cited July 2023]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761235s000lbl.pdf. [14] Medicines and Healthcare products Regulatory Agency. MHRA approves faricimab through international work-sharing initiative [Internet; cited July 2023]. Available from: https://www.gov.uk/government/news/mhra-approves-faricimab-through-international-work-sharing-initiative. [15] Roche data on file.[16] Bright Focus Foundation. AMD: Facts and figures [Internet; cited July 2023]. Available from: https://www.brightfocus.org/macular/article/age-related-macular-facts-figures. [17] Connolly E, et al. Prevalence of AMD-associated genetic risk factors and four-year progression data in the Irish population. Br J Ophthalmol. 2018;102:1691–5.[18] Wong WL, et al. Global prevalence of AMD and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:106–16.[19] Yau JWY, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35:556–64.[20] Moorfields Eye Hospital NHS Foundation Trust. Epiretinal membrane [Internet; cited July 2023]. Available from: https://www.moorfields.nhs.uk/condition/epiretinal-membrane#:~:text=An%20epiretinal%20membrane%20is%20a,cause%20problems%20with%20central%20vision. [21] All About Vision. Macula lutea [Internet; cited July 2023]. Available from: https://www.allaboutvision.com/resources/macula.[22] Kaiser PK, et al. Retinal fluid and thickness as measures of disease activity in neovascular age-related macular degeneration. Retina. 2021;41:1579-86.[23] Chang EY, et al. Real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study. Paper presentation at: ASRS Annual Meeting; 28 July – 1 August 2023 Presentation.[24] Pennington KL, DeAngelis MM. Epidemiology of AMD: associations with cardiovascular disease phenotypes and lipid factors. Eye and Vision. 2016;3:34.[25] Little K, et al. Myofibroblasts in macular fibrosis secondary to nAMD - the potential sources and molecular cues for their recruitment and activation. EBioMedicine. 2018;38:283-91.[26] National Eye Institute. Diabetic retinopathy [Internet; cited July 2023]. Available from: https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/diabetic-retinopathy. [27] Liu E, et al. DME: clinical risk factors and emerging genetic influences. Clin Exp Optom. 2017;100:569–76.[28] Clinical Trials.gov. A study to evaluate the long-term safety and tolerability of Vabysmo in participants with nAMD (AVONELLE-X) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT04777201. [29] Clinical Trials.gov. A study to evaluate the long-term safety and tolerability of Vabysmo in participants with DME (Rhone-X) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT04432831.[30] Clinical Trials.gov. A study to evaluate the efficacy and safety of faricimab in participants with macular edema secondary to branch retinal vein occlusion (BALATON) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT04740905.[31] Clinical Trials.gov. A study to evaluate the efficacy and safety of faricimab in participants with macular edema secondary to central retinal or hemiretinal vein occlusion (COMINO) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT04740931. [32] Clinical Trials.gov. A study to investigate faricimab treatment response in treatment-naïve, underrepresented patients with DME (ELEVATUM) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT05224102. [33] APVRS. Design and rationale of the SALWEEN trial: a phase IIIb/IIII study of faricimab, a dual angiopoietin-2 and vascular endothelial growth factor-A inhibitor, in patients with polypoidal choroidal vasculopathy [Internet; cited July 2023]. Available from: https://2022.apvrs.org/abstract/?code=200351. [34] Clinical Trials.gov. A real-world study to gain clinical insights into Roche ophthalmology products (VOYAGER) [Internet; cited July 2023]. Available from: https://clinicaltrials.gov/ct2/show/NCT05476926. [35] Heier JS, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for nAMD (TENAYA and LUCERNE): two randomised, double-masked, phase III, non-inferiority trials. The Lancet. 2022; 399:729-40.[36] Wykoff C, et al. Efficacy, durability and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with DME (YOSEMITE and RHINE): two randomised, double-masked, phase III trials. The Lancet. 2022; 399:741-55.[37] Chugai Pharmaceutical Co. Ltd. Chugai obtains regulatory approval for Vabysmo, the first bispecific antibody in ophthalmology, for nAMD and DME [Internet; cited July 2023]. Available from: https://www.chugai-pharm.co.jp/english/news/detail/20220328160002_909.html. [38] European Medicines Agency. Summary of Product Characteristics, Vabysmo, 2022 [Internet; cited July 2023]. Available from: https://www.ema.europa.eu/en/documents/product-information/vabysmo-epar-product-information_en.pdf. [39] U.S. FDA. Highlights of prescribing information, Susvimo. 2006 [Internet; cited July 2023]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761197s000lbl.pdf. [40] U.S. FDA. Highlights of prescribing information, Lucentis. 2006 [Internet; cited July 2023]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125156s114lbl.pdf. Roche Group Media Relations Phone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58Nathalie AltermattPhone: +41 79 771 05 25Karsten KleinePhone: +41 79 461 86 83Nina MählitzPhone: +41 79 327 54 74 Kirti PandeyPhone: +49 172 6367262Sileia UrechPhone: +41 79 935 81 48 Roche Investor Relations Dr. Bruno Eschli Phone: +41 61 68-75284 e-mail: bruno.eschli@roche.comDr. Sabine BorngräberPhone: +41 61 68-88027 e-mail: sabine.borngraeber@roche.comDr. Birgit MasjostPhone: +41 61 68-84814e-mail: birgit.masjost@roche.comDr. Gerard Tobin Phone: +41 61 68-72942 e-mail: gerard.tobin@roche.com Investor Relations North America Loren KalmPhone: +1 650 225 3217 e-mail: kalm.loren@gene.com Attachment 20072023_MR_ASRS Global Curtain Raiser_en

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