Retinopathy of Prematurity: Transforming Treatment Paradigms

Supplement to May/June 2020 SPONSORED BY NOVARTIS PHARMA AG

Prof. Andreas Stahl University Medical Center Greifswald, Germany Prof. Neil Marlow University College London London, United Kingdom Prof. Maria Ana Martinez-Castellanos Association to Prevent Blindness in Mexico Hospital “Luis Sánchez Bulnes,” I.A.P Mexico City, Mexico

This supplement is intended for non-promotional scientific purposes only and may contain information on products or indications currently under investigation and/or that have not been approved by the regulatory authorities. The opinions and views expressed in this supplement are those of the faculty members and do not necessarily constitute the opinions or recommendations of Novartis. The presentations were accurate at the time of presentation. Any data on competitor product(s) are based on publicly available information at the time of presentation. Prescribing information may vary depending on local health authority approval in each country. Before prescribing any product, always refer to the SmPC or product information approved in your local country. Permissions for all content within have been received from each copyright holder for the presentations. Separate use, adaptation, and/or translation requires application for specific use permissions from each copyright holder. All product names, trademarks and registered trademarks are property of their respective owners. Retinopathy of Prematurity: Transforming Treatment Paradigms

Retinopathy of Prematurity: Transforming Treatment Paradigms This supplement features a summary of a Novartis-sponsored webcast which took place in April 2020 entitled, “Retinopathy of Prematurity: Transforming Treatment Paradigms,” presented by Prof. Andreas Stahl, Prof. Neil Marlow, and Prof. Maria Ana Martinez-Castellanos.

PROF. ANDREAS STAHL PROF. NEIL MARLOW PROF. MARIA ANA MARTINEZ- n University Medical Center, n University College London, CASTELLANOS Greifswald, Germany London, United Kingdom n Association to Prevent Blindness n Financial disclosure: Consultant, n Financial disclosure: Consultant in Mexico, Hospital “Luis Sánchez Honoraria, Travel (Bayer, Novartis); (Novartis) Bulnes,” I.A.P, Mexico City, Mexico Research Funds (Novartis) n Financial disclosure: None acknowledged

Introduction Andreas Stahl Retinopathy of prematurity (ROP) is one of the most common avoidable causes of blindness in children.1 Of the 15 million babies born preterm (i.e., before 37 completed weeks of gestation) every year,2 approximately 15 to 20% are affected with ROP.3 This frequency increases to 30% in babies with a birth weight of 750 to 999 g.3 “Annually, an estimated 32,300 infants worldwide are diag- nosed with irreversible visual impairment from ROP, of whom an estimated 20,000 become blind or severely visually impaired,4” said Prof. Andreas Stahl. The key risk factors for the development of ROP are low gestational age, low birth weight, and postnatal oxygen supply. Other factors contributing to the risk of ROP are hypoxemia, low postnatal weight gain, postnatal hyperglycemia, neonatal infections, and hypercarbia.5-7 These risk factors are often connected with undernutrition and other comorbidities such as neurological dysfunc- tion, poor brain growth, necrotising enterocolitis, intraventricular haemorrhage, and bronchopulmonary dysplasia.5 A Neonatal Perspective on Preterm Morbidity and Retinopathy Neil Marlow The duration of a normal pregnancy is around 38 to 42 weeks of gestation, and full-term infants weigh between 2,500 and 4,000 g at birth.8 The

definition of a preterm baby is one born alive at Most common complications of premature infants1 8 less than 37 weeks, with ‘very preterm’ infants born at less than • Respiratory distress syndrome • Apnea and bradycardia • Immature gastrointestinal and • Transient tachypnea • Infections digestive system 32 weeks of pregnancy and ‘extremely preterm’ infants born at or • Bronchopulmonary dysplasia • Jaundice • Anaemia before 28 weeks.9 Since gestational age is only accurate if based • Pneumonia • Intraventricular haemorrhage • Patent ductus arteriosus (PDA) • Inability to maintain body heat • Retinopathy of prematurity (ROP) on an early first trimester scan, birth weight is also used to classify • Necrotising enterocolitis preterm babies into low birth weight (< 2,500 g; generally equivalent to all preterm babies), very low birth weight (< 1,500 g; generally equivalent to < 31 weeks’ gestation) and extremely low birth Figure 1. Disorders associated with prematurity.

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while the proportion of babies surviving has increased, the rate of disability in the overall population has remained relatively unchanged (Figure 3).16 “We have now gone from trying to save more lives to looking at the quality of those lives that we’re saving,” said Prof. Marlow. “We also have to think about our care with respect to what happens after the neonatal period as the child grows up, because we know that this has a strong relationship to the perinatal period.” A direct relationship has been noted between gestational age at birth and the risk of special educational needs later in childhood.17 Other outcomes of prematurity that can continue to impact individuals through to adulthood include neurocognitive issues (e.g. educational and behavioral problems), Figure 2. Survival to discharge for infants born 22 to 26 weeks of gestation and admitted to respiratory problems (e.g. asthma), and ocular problems (e.g. neonatal intensive care units (NICU) in the United Kingdom from 1995 to 2016. strabismus, low visual acuity, and myopia).5,9 ROP is an important morbidity associated with prematurity, weight (< 1,000 g; generally equivalent to < 27 weeks’ gestation).9 but its prevention is challenging. Strategies include the use of “However, some more mature babies may be of low birth weight antenatal steroids to reduce the rate of respiratory disease and for their gestational age, so these correlations between birth weight the need for oxygen, as well as ensuring that oxygen saturation and gestational age are not always accurate,” said Prof. Marlow. targets are maintained.18 However, these approaches are not The factors that affect the premature baby after birth can be necessarily simple. The Neonatal Oxygenation Prospective Meta- classified into two major groups: injuries (particularly to the brain, analysis (NeOProM) collaboration, which investigated the use of resulting in problems such as cerebral palsy) and developmental different oxygen saturation targets in extremely preterm infants, issues (Figure 1).10 “Being born early means that the baby’s devel- reported that lower oxygen saturation targets were associated opment tends to slow down, with a range of adverse outcomes. with a higher risk of death and necrotizing enterocolitis, but a In the lung, infection and the use of mechanical ventilation may lower risk of ROP.19 “We’ve known since the late 1940s about the lead to a loss of lung function. But being born early also leads to an danger of giving excess amounts of oxygen to premature babies, arrest in the development of the alveoli and a reduced number of but this must be balanced against the risk of giving insufficient alveoli at full term, which exacerbates these injuries. Similar changes oxygen and causing excess mortality. For the neonatologist, man- can be seen in vascular function, sensory function, and in other aging oxygen is a very fine line between reducing untreatable organ systems,” said Prof. Marlow. Premature infants are prone to outcomes and causing ROP,” said Prof. Marlow. a wide range of complications, including pneumonia, infections, It is therefore very important that strong protocols are in place necrotising enterocolitis, ROP, and many others.11 to monitor and minimize the use of oxygen, as well as those for Advances in obstetric practice; newborn thermal and nutritional identifying babies requiring screening. United Kingdom guide- care; management of antibiotics; infections and respiratory lines recommend screening for babies of birthweight ≤ 1,500 g or complications; and improvements in neonatal intensive care over < 32 weeks of gestation at birth, with screening at 2-week intervals the past century have led to a reduction in neonatal mortality from 30 to 31 weeks postmenstrual age or 4 to 5 weeks of age, to rates in the United States, England, and Wales from 40 deaths be increased in frequency based on the presence of signs of ROP.20 per 1,000 live births in 1900 to fewer than 5 in 2010.12 Survival “All of this demands close liaison between the neonatologist and rates for extremely preterm babies have steadily and substantially the ophthalmic team. Although the baby remains in the neonatal increased, even over the past 20 years (Figure 2).13-15 However, unit, the responsibility for screening and carrying out that screening sits with the ophthalmologist,” said Prof. Marlow.

Highlights • Prematurity is a pervasive problem affecting many organ systems, and long-term impairments are common. • Close liaison between the neonatologist and the ophthalmologist is required for the care of preterm babies. • Strong protocols must be put in place to monitor and optimize the use of oxygen. • Developing a screening protocol for retinopathy of prematurity Figure 3. Levels of survival and disability in preterm babies born in the United Kingdom in 1995 (ROP) is crucial to ensure timely diagnosis and treatment. and 2006.

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ROP: Epidemiology and Clinical Perspective Maria Ana Martinez-Castellanos The incidence of ROP has increased in recent years as a result of advances in neonatal care and the subsequent increase in premature births.2,3,21 In 2010, ROP was the cause of severe visual impairment or blindness in 1.1% of children in high-income countries (defined by the World Bank as those with a gross national income per capita of US$12,376 or more in 2018) and 2.5 to 2.8% of children in other regions (including middle- and low- income countries in Eastern Europe, Central Asia, Latin America, and Africa).22 In middle-income countries, due to differences in standards Figure 5. Categorization of ROP by stages. of care in neonatal intensive care units (NICUs) compared with high-income countries, use of the same screening standards imple- Prof. Martinez-Castellanos. According to international classifica- mented in high-income countries may not be appropriate.23 “In tion of ROP terminology, ROP is categorized according to the a study carried out in our hospital, we discovered that 100 of 352 zones of the retina in which disease is visible via dilated fundus newborns with ROP evaluated between January 2011 and March examination and the severity (or stage) of the disease.26 2017—nearly one-third—fell outside the current screening guide- Zone 1 includes the macula and optic nerve; it forms a circle, lines of the American Academy of Ophthalmology, having a birth the radius of which is twice the distance from the optic nerve to weight greater than 1,500 g or a gestational age of more than 30 the macula (Figure 4). ROP in Zone 1 is the most likely to prog- weeks,23” said Prof. Maria Ana Martinez-Castellanos. ress and become severe. Zone 2 surrounds Zone 1 and extends to The pathophysiology of ROP is characterized by abnormal the ora serrata on the nasal side.26 ROP found here may progress neovascularization. The disruption of angiogenesis in preterm quickly, although warning signs such as increasing vascular dila- infants with ROP typically occurs in two postnatal phases.24 In tion and tortuosity usually predate the threshold by a week or 2. phase 1 (from birth up to 30 weeks’ postmenstrual age), hyperoxia Zone 3 is a crescent area of temporal retina, which rarely shows inhibits vascular growth in the retina.5 As the retina becomes more aggressive disease.27 metabolically active (from around 30 weeks’ postmenstrual age), its When categorizing ROP by disease stage, in Stage 1 a demarca- incomplete vascularization causes it to become hypoxic, resulting tion line can be clearly seen between normally vascularized retina in the secretion of various angiogenic factors including VEGF and and the peripheral retina with no blood vessels (Figure 5).27,28 In subsequently to VEGF-driven neovascularization and intraocular Stage 2, the demarcation line is elevated into a ridge, but with no fibrosis.5 Ultimately this can result in retinal detachment and pathological new vessels; in Stage 3 these new vessels are pres- visual disability.5,24 ent.27,28 Stage 4 and 5 represent partial and total retinal detach- A key early advance in the management of ROP was the formal ment, respectively.20,21 “Stage 5 is very sad. This means that we classification of ROP terminology in the international classifica- are too late to save this eye, and the best outcome following tion of ROP in the 1980s.25 “With this classification now used surgery would be only light perception or movement,” said Prof. worldwide, we’re all talking the same language, which means Martinez-Castellanos. Aggressive posterior ROP (AP-ROP) may that we can act appropriately at each stage of the disease,” said also be present. This usually occurs in Zone 1 and can progress very quickly to retinal detachment.27 The zone and stage of ROP can be combined to give the ROP ‘type’ (Figure 6), which differentiates eyes with significant changes of ROP that require treatment (Type 1) from eyes with significant changes that do not require treatment but must be carefully monitored (Type 2).29 Severe ROP leads to long-term visual loss, with blindness in the most severe cases, so timely treatment is vital.5 ROP is also associated with a range of other eye problems later in life, such as retinal detachment, glaucoma, and refractive errors, so lifelong monitoring is required.5 Traditional treatment options for ROP include cryotherapy and surgery, though these are associated with complications.26 Laser therapy is the current standard of Figure 4. Categorization of ROP by zones. care for treating ROP, but it is an invasive, resource-intensive

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injection of bevacizumab reaches the circulation and suppresses VEGF, not only in the eye, but also systemically.32” In order to collect further evidence on the use of anti-VEGF therapy in infants with ROP, the German Retina.net ROP registry was set up in 2012 with the aim of capturing treatment patterns and outcomes.33,34 It now includes data from over 330 treated patients, which corresponds to around 10 to 15% of all treated ROP infants in Germany.34 Analysis of the registry data reveals that treatment patterns have changed over time in Germany, with anti-VEGF treatment given to 10% of treated eyes in 2011 but to 56% and 30% in 2014 and 2015, respectively (Figure 7).34 Almost all eyes with AP-ROP or Zone 1 disease received anti- Figure 6. Categorization of ROP by types. VEGF treatment, while Zone 2 disease was predominantly treated procedure used in patients with advanced disease only.30 More with laser.34 “We’re currently looking at the data from 2016 and recently, anti-VEGF therapy is being used for the treatment of onwards to see how these trends developed further in the follow- ROP, especially in Zone 1.26 ing years,” said Prof. Stahl. More recently, the CARE-ROP study was an interventional Highlights investigator-initiated study performed to investigate the use of ranibizumab in 19 infants with ROP, given at two different doses: • Severe retinopathy of prematurity (ROP) leads to long-term visual 0.12 mg and 0.20 mg, corresponding to 24% and 40% of the adult loss and potential blindness, so timely treatment is vital. dose.35 CARE-ROP was a blinded, randomized, multicenter study • Lifelong monitoring of ROP is required due to a range of associated performed in Germany, with the primary endpoint (the propor- eye problems which may occur later in life. tion of infants who did not require rescue therapy) at 24 weeks • Traditional treatment options for ROP include cryotherapy and and follow-up ongoing to 5 years.35 In the group who completed surgery, though these are associated with complications. the study, 88.9% of infants (94.4% of eyes) in the 0.12-mg group • Laser is the current standard of care for ROP, but it is an invasive, and 85.7% of infants (92.9% of eyes) in the 0.20-mg group did not resource-intensive procedure used in advanced disease only. require rescue therapy at 24 weeks, suggesting that both doses • More recently, anti-VEGF therapy is being used for the treatment of were equally successful in controlling ROP. VEGF plasma levels ROP, especially in Zone 1. were not altered in either group, indicating a limited systemic drug exposure.35 Building on the evidence of CARE-ROP, the RAINBOW study was the first global, phase 3 randomized controlled trial on ranibizumab in ROP. A total of 225 patients from 87 centers were Clinical Research—Studies on enrolled and randomized 1:1:1 to ranibizumab 0.2 mg, ranibizumab Anti-VEGFs 0.1 mg, or laser.36 The primary outcome measure was survival with no active retinopathy, no unfavorable structural outcomes, and no Andreas Stahl need for a different treatment modality at or before 24 weeks.35 In 2011, BEAT-ROP became the first randomized, Treatment success occurred in 80% of infants receiving multicenter trial of anti-VEGF therapy in ROP, ranibizumab 0.2 mg compared with 75% of infants receiving reporting significant treatment effects for bevacizumab over laser therapy for Zone 1 (but not Zone 2) disease in infants with Stage 3+ ROP.28 However, BEAT-ROP left some unresolved questions regarding the appropriate dose for anti-VEGF therapy in infants with ROP.31 BEAT-ROP used half the dose of bevacizumab usually used (off-label) in adults with retinal disorders, but without conducting dose-finding studies. The majority of infants with ROP require bilateral treatment for ROP, so according to the BEAT-ROP protocol, they ultimately received a total dose of bevacizumab therapy equivalent to that which an adult receives (off-label) for unilateral treatment.31 “There’s cer- tainly room for discussion here as to whether this is the right dose,” said Prof. Andreas Stahl. “Another open question is that of systemic safety. We know from studies in infants with ROP that an ocular Figure 7. Treatment patterns in the Retina.net ROP registry.

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Highlights • Retinopathy of prematurity (ROP) registries provide important information on the real-world use of anti-VEGF therapy in ROP. • In the RAINBOW study, a treatment success rate of 80% was achieved with ranibizumab 0.2 mg versus 66% with laser. • Infants treated with ranibizumab 0.2 mg were twice as likely to achieve treatment success versus laser which was considered clinically relevant. • Ranibizumab 0.2 mg was well tolerated in patients with ROP and Figure 8. Results of the RAINBOW study. the safety profile was as expected in a preterm population. ranibizumab 0.1 mg and 66% of infants after laser therapy • In September 2019, ranibizumab was approved in the European (Figure 8). Statistical significance in the comparison of Union for the treatment of ROP in preterm infants with Zone 1 ranibizumab 0.2 mg versus laser therapy was narrowly missed (Stage 1+, 2+, 3 or 3+), Zone 2 (Stage 3+), or aggressive posterior- (odds ratio 2.19 [95% CI 0.99-4.82]; P = .0507). “One might ask ROP disease. why this success rate was lower compared to CARE-ROP? First, the definition of treatment success in RAINBOW was quite strict, including the fact that to qualify, infants had to survive until the primary endpoint. In addition, they obviously could not have any active ROP at the primary endpoint and no treatment except study treatment, but they could also not have any unfavorable Discussion: Current Clinical structural outcomes,” said Prof. Stahl. Unfavorable structural Considerations on ROP outcomes (defined as any one of retrolental membrane obscuring the view of the posterior pole; substantial temporal Neil Marlow, Maria Ana Martinez-Castellanos, retinal vessel dragging causing abnormal structural features or and Andreas Stahl macular ectopia; posterior retinal fold involving the macula; and retinal detachment involving the macula) were found more Andreas Stahl moderates a discussion session in which the panel responds frequently in the laser arm than in the ranibizumab 0.2-mg to questions relating to the clinical management of patients with ROP. arm. In terms of safety, death, serious and non-serious systemic adverse events and ocular adverse events were evenly distributed How should the neonatologist and ophthalmologist ideally interact between groups. Plasma VEGF levels were measured at baseline when it comes to therapy, screening, and treatment? and at around days 14 and 28 in each treatment group, and these Prof. Marlow: This is a key question because ROP involves a showed no evidence of systemic suppression (Figure 9).36 The small number of patients for whom treatment is time critical. It 5-year extension study of RAINBOW is currently ongoing, with can be very difficult to examine the eyes of a baby in a neonatal results expected in 2022.36 unit who’s undergoing critical care, who’s on a ventilator, and Based on the results of RAINBOW, ranibizumab was approved who may have other headgear on for other forms of ventilation. in the European Union in September 2019 for the treatment Of course, these babies are the ones who we really don’t want to of ROP in preterm infants with Zone 1 (Stage 1+, 2+, 3 or 3+), miss. The level of skill required on the part of the ophthalmolo- Zone 2 (Stage 3+), or AP-ROP disease.37 gist to identify those that need to be considered for treatment is very high. For this reason, in the United Kingdom, standards of care for ROP were developed by a group of clinicians that includ- ed both neonatologists and ophthalmologists. Our National Audit program records not whether ROP was screened for suc- cessfully or what the retinal stage was, but rather did the retinal screening occur on time, because that’s the most critical thing.

Prof. Martinez-Castellanos: In Mexico, the situation is complicated. As in any middle-income country, we have both very good and very bad NICUs. We can see the results of this, both good and bad, in the babies that are treated there. In the worst NICUs, oxygen is given at 100% concentration without oximetry, resulting in very Figure 9. Systemic VEGF levels in RAINBOW. severe cases of ROP. What standard of NICU a premature infant

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is treated at depends on the economic background of the family. the expense of traveling to a center frequently over a number of There are fewer cases of ROP in families that are able to pay for months, but if they are not able or willing to bring the child back a better standard of care, but in poorer families many babies go to the clinic for follow-up then it might actually be dangerous to blind because of poor oxygen management in the NICU. use an anti-VEGF agent. If anti-VEGF therapy is to be used, it is the responsibility of the ophthalmologist to educate the family Do you as a neonatologist ask ophthalmologists their opinion when it on the importance of follow-up. comes to setting the right oxygen level? Prof. Marlow: No, because clinical trials have been performed, What are the next steps in ROP that you would like to see following which provide us with this information. However, although the these developments in anti-VEGF therapy? relationship of ROP with oxygen was recognized in the 1940s, it Prof. Martinez-Castellanos: Having access to screening is a key has only been over the last 10 years that these studies have been point, as not every country has a real screening program for ROP performed to refine the relationship further, and there is still more yet. Next, good communication between ophthalmologists and to learn in terms of understanding how we use oxygen. To improve neonatologists is important, so that they can liaise efficiently mortality and reduce the risk of necrotizing enterocolitis, which is a to ensure that all babies at risk of developing ROP receive systemic and quite catastrophic disease, we currently have to toler- screening. Finally, in cases where babies do develop ROP, good ate levels of retinopathy that we would have hoped to reduce. communication with the parents regarding treatment and follow-up is required. Parents need to understand that ROP is What are the factors that influence your decision on the treatment a lifetime disease. Even though we can cure it, it can have long- modality to use? term consequences, following either laser or anti-VEGF therapy. Prof. Martinez-Castellanos: In Mexico, the decision depends on what is available in that area. Laser is available in some, but not Prof. Stahl: Yes, we need a screening program that detects ROP all, NICUs. This means that anti-VEGF therapy is the only treat- before the disease reaches its worst extent. We then need a second ment option available for ROP in some units. lifelong ‘screening phase’ to ensure that we limit the number of amblyopia from strabismus or from refractive errors and that we Prof. Stahl: Where possible, however, the availability of treat- pick up retinal changes that may lead to late retinal detachment. ment shouldn’t affect the treatment decision. Whenever the options of laser therapy versus anti-VEGF injections are pre- Prof. Marlow: Neonatologists should attempt to reduce the sented, we should be able to offer both at an equal quality. This is amount of respiratory disease in our client population. Currently why treatment for ROP should always take place at centers with in the United Kingdom, the majority of women who deliver prior expertise in this area and with both treatment options available to 32 weeks receive antenatal steroids. We are also now begin- at the same quality, because otherwise there is always a tendency ning to use much less oxygen in the delivery room, as it may cause to favor one treatment over another depending on what is avail- hyperoxia, which we know is potentially very dangerous, even over able or what we can do best. These factors should not, however, a relatively short period of time. In addition, we are learning that be guiding our treatment decisions. cutting the umbilical cord immediately after birth promotes respiratory disease, if it is done too quickly, so we are trying to delay this Prof. Marlow: I agree; it is clear that ROP cases should be procedure until the circulation becomes stable. With these devel- managed in specialized centers by doctors with a high level of opments, plus others relating to treating infection and preventing expertise. Another factor to consider is the circumstances of the lung disease, which drives the need for oxygen, we should be able patient’s family. It can be quite challenging for families to go to to reduce the risk of ROP considerably. n

Summary and Closing Comments Andreas Stahl In conclusion, retinopathy of prematurity (ROP) is one of the most common causes of avoidable blindness in children,1 causing irreversible visual impairment in over 32,000 infants worldwide each year.4 “Prevention is at the core of neonatal intensive care,” said Prof. Stahl. “Careful management of supplemental oxygen therapy, screening, and timely referrals are key clinical considerations.5” In the RAINBOW study, a treatment success rate of 80% was achieved with ranibizumab 0.2 mg compared with 66% with laser, and ranibizumab 0.2 mg was well tolerated in patients with ROP.36 RAINBOW is the first study to report pharmacokinetics and systemic VEGF data in ROP. The results of its 5-year extension study are expected by 2022.36 Based on the results of RAINBOW, ranibizumab is now the first anti-VEGF therapy to be approved for the treatment of ROP.

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View the full webcast, including live Q&A session, at this address bit.ly/ROPwebinar1 or by scanning the QR code below

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