Breaking News
November 14, 2018 - Change Within the Eye May Be Early Warning for Macular Degeneration
November 14, 2018 - Study of 500,000 people clarifies the risks of obesity
November 14, 2018 - Ultrasound releases drug to alter activity in targeted brain areas in rats | News Center
November 14, 2018 - Cancer stem cells depend on amino acid metabolism, and it’s proving to be their Achilles’ heel
November 14, 2018 - Epigenetic link found between prenatal exposure to maternal smoking and offspring’s cardio-metabolic health
November 14, 2018 - Meditation, music may change biomarkers of cellular aging and Alzheimer’s disease in older adults
November 14, 2018 - Multidisciplinaryresearch teams selected to study age-related brain disorders
November 14, 2018 - The Current issue of “The view from here” is concerned with Informatics
November 14, 2018 - Researchers identify tool to help transgender women have a more authentic voice
November 14, 2018 - Four faculty members appointed to endowed professorships | News Center
November 13, 2018 - Research finds strongest evidence yet that obesity causes depression
November 13, 2018 - Researchers compare stools of breastfed and formula-fed infants
November 13, 2018 - Entasis Therapeutics Announces Zoliflodacin Phase 2 Results Published in The New England Journal of Medicine
November 13, 2018 - Gene changes driving myopia reveal new focus for drug development
November 13, 2018 - $6 million grant to support study of preeclampsia, atherosclerosis links | News Center
November 13, 2018 - Beneficial gut microbes metabolize high-fiber diet to improve heart health in mouse model
November 13, 2018 - Excessive use of social media through visual postings linked to increase in narcissistic traits
November 13, 2018 - Study finds why obesity both fuels cancer growth and helps immunotherapy to kill tumors
November 13, 2018 - Women prefer and invest more in daughters, while men favor sons
November 13, 2018 - With hospitalization losing favor, judges order outpatient mental health treatment
November 13, 2018 - Transgenic rat model may provide new insights into cerebral amyloid angiopathy
November 13, 2018 - Study identifies factors tied to greater risk of advanced liver disease in cystic fibrosis patients
November 13, 2018 - Risk of blindness among premature babies with low levels of blood platelets
November 13, 2018 - A new strategy for combatting antibiotic-resistant infections
November 13, 2018 - Study aims to find which outreach method is more effective at improving cancer screening rates
November 13, 2018 - Insufficient sleep duration linked with unhealthy lifestyle profile among children
November 13, 2018 - IIASA researchers introduce new, simple measure for human wellbeing
November 13, 2018 - Magnetic nanosprings used as targeted drug delivery agents for anticancer therapy
November 13, 2018 - Scientists examine FCMs containing silver nanoparticles
November 13, 2018 - Failed DNA repair triggers chromosomal chaos
November 13, 2018 - Study shows new emerging role of osteopontin in HCV-related hepatocellular carcinoma
November 13, 2018 - Food insecurity during pregnancy linked to severity of neonatal abstinence syndrome
November 13, 2018 - Majority of Americans are concerned about health threat posed by antibiotic resistance
November 13, 2018 - Addition of Elotuzumab Ups PFS in Refractory Multiple Myeloma
November 13, 2018 - Study finds women with pregnancy-related nausea, vomiting use marijuana more
November 13, 2018 - Lethal heart rhythm more likely to be found in patients with common heart failure
November 13, 2018 - Study provides new clues to origin and development of multiple sclerosis
November 13, 2018 - Climate change could pose threat to male fertility
November 13, 2018 - Researchers discover how mitochondria deploy a powerful punch against disease-causing bacteria
November 13, 2018 - AHA: Traumatic Childhood Could Increase Heart Disease Risk in Adulthood
November 13, 2018 - Feeling the Burn? | NIH News in Health
November 13, 2018 - Women’s birth canals in Kenya, Korea, Kansas not the same: study
November 13, 2018 - Fecal microbiota transplantation effective against ICI-associated colitis
November 13, 2018 - New physical activity guidelines released that urge people to “move more”
November 13, 2018 - Angiotensin receptor blockers improve sodium excretion in blacks
November 13, 2018 - New project seeks to address alarming injury rate in youth footballers
November 13, 2018 - Fish oil or omega 3 fatty acid supplements can prevent heart attacks finds study
November 13, 2018 - The Human Heart-in-a-Jar That Could One Day Replace Animal Testing
November 13, 2018 - Treat patients’ partners without a doctor visit
November 13, 2018 - Belgian beer landscape mapped using scientific insights
November 13, 2018 - ‘Master key’ gene has links to both ASD and schizophrenia
November 13, 2018 - Gladstone scientists gain new insights into the aging brain
November 13, 2018 - Drug therapy can improve outcomes for acutely ill heart patients
November 13, 2018 - Three landmark studies provide better understanding of sudden cardiac arrest
November 13, 2018 - Cholesterol control revised in the latest AHA/ACC guidelines
November 13, 2018 - Vulnerable young teenagers urgently need better sex education, say researchers
November 13, 2018 - Breakthrough research reveals how deadly pneumococcus avoids immune defenses
November 13, 2018 - Researchers discover possible path forward in preventing cancers tied to two viruses
November 13, 2018 - Wishes can help pediatric patients to get better over time
November 13, 2018 - Janssen Reports Positive Topline Results for FLAIR Phase 3 Study of a Novel, Long Acting Injectable Two-Drug Regimen for the treatment of HIV-1
November 13, 2018 - Experimental compound reduces Gulf War illness-like behavior in mice
November 13, 2018 - Small-stature in rainforest populations may be linked to cardiac adaptations
November 13, 2018 - Study shows how pneumococci challenge the immune system
November 13, 2018 - Simple cysts can be safely ignored, study finds
November 13, 2018 - First fully personalized tissue implant engineered from patient’s own materials and cells
November 13, 2018 - FDA Approves Keytruda (pembrolizumab) in Combination with Carboplatin and Either Paclitaxel or Nab-Paclitaxel for the First-Line Treatment of Patients with Metastatic Squamous Non-Small Cell Lung Cancer (NSCLC)
November 13, 2018 - Scientists take big step toward finding non-addictive painkiller
November 13, 2018 - Diabetes medication reduces risk of heart failure hospitalization
November 13, 2018 - Achieving high follow-up rates for violently injured patient population is feasible
November 13, 2018 - Shortage of specific gene ‘silencing’ molecules linked with pediatric low-grade gliomas
November 13, 2018 - Abx-Resistant Enterobacteriaceae Tied to Clinical Failure in UTI
November 13, 2018 - US approves first new type of flu drug in 2 decades
November 13, 2018 - Is zinc the link to how we think? Some evidence, and a word of warning
November 13, 2018 - Dispelling taboos, Michelle Obama talks IVF and miscarriage
November 13, 2018 - Medical experts discuss future challenges of healthcare at HSMA’s inaugural conference
November 13, 2018 - Growth and spread of deadly eye tumor suppressed in cells, animals
November 12, 2018 - Study finds huge shortfall in use of home-based medical care by frail seniors
November 12, 2018 - Cocaine Cut With Anti-Worming Drug, Levamisole, May Cause Brain Damage
November 12, 2018 - Obese mice lose a third of their fat using a natural protein
November 12, 2018 - Behind many a Parkinson’s case lurks a mutation in a gene called LRRK2 — why?
Two-year data for Novartis brolucizumab reaffirm superiority versus aflibercept in reducing retinal fluid in patients with nAMD

Two-year data for Novartis brolucizumab reaffirm superiority versus aflibercept in reducing retinal fluid in patients with nAMD

image_pdfDownload PDFimage_print

Basel, 27 October, 2018 – Novartis announced additional brolucizumab Phase III results from year two that reaffirmed its positive year one findings. Brolucizumab met its primary endpoint of non-inferiority versus aflibercept in best corrected visual acuity (BCVA) and exhibited superiority in key retinal outcomes at year one (48 weeks)[1],[2]. Secondary endpoints at year two (96 weeks) reaffirmed superiority of brolucizumab 6 mg in reduction of retinal fluid, an important marker of disease activity in patients with neovascular age-related macular degeneration (nAMD)[1],[3]. Approximately 20 to 25 million people are affected by nAMD, also known as wet AMD, a leading cause of blindness worldwide[4],[5].

The year two HAWK and HARRIER findings demonstrated that fewer patients with nAMD had intra-retinal fluid (IRF) and/or sub-retinal fluid (SRF) – key markers used by physicians to determine injection frequency in clinical practice – with brolucizumab 6 mg versus aflibercept at week 96 [24% for brolucizumab 6 mg vs. 37% for aflibercept in HAWK (P=0.0001); 24% vs. 39%, respectively, in HARRIER (P

Additionally, brolucizumab 6 mg patients continued to demonstrate reductions in central subfield thickness (CST) at week 96[1]. An increase in CST in nAMD is an important measure of abnormal fluid accumulation and edema and may result in reduced vision. Absolute reductions in CST from baseline were -175 µm for brolucizumab 6 mg versus -149 µm for aflibercept in HAWK (P=0.0057) and -198 µm versus -155 µm, respectively, in HARRIER (P

Also at week 96, fewer brolucizumab 6 mg patients had sub-retinal pigment epithelium (sub-RPE) fluid (11% for brolucizumab 6 mg vs. 15% for aflibercept in HAWK; 17% vs. 22%, respectively, in HARRIER)[1]. Additionally, of the patients on brolucizumab 6 mg who successfully completed year one on a 12-week dosing interval, 82% in HAWK and 75% in HARRIER were maintained on a 12-week dosing interval in year two[1].

“These findings at year two reaffirm the excellent year one brolucizumab data regarding retinal fluid reduction, a key goal for physicians treating patients with nAMD,” said Dr. Pravin U. Dugel, Managing Partner, Retinal Consultants of Arizona; Clinical Professor, Roski Eye Institute, Keck School of Medicine, University of Southern California; and principal investigator of both trials. “These consistent results continue to support brolucizumab as a potential new treatment for patients with nAMD.”

As previously announced, HAWK and HARRIER met their primary endpoint of non-inferiority in mean change in BCVA at week 48 with brolucizumab versus aflibercept[2]. Brolucizumab maintained robust visual gains in year two, with mean change in BCVA of 5.9 letters for brolucizumab 6 mg versus 5.3 letters for aflibercept in HAWK, and 6.1 letters versus 6.6 letters, respectively, in HARRIER[1].

“Over two years, brolucizumab consistently dried retinal fluid better than aflibercept while keeping many patients on a quarterly dosing schedule. Additionally, the robust visual gains shown in year one with brolucizumab were maintained in year two,” said Shreeram Aradhye, Global Head Medical Affairs and Chief Medical Officer, Novartis Pharmaceuticals. “With sustained improvements in key anatomical outcomes that denote disease activity, brolucizumab is an important scientific advance and underscores our commitment to reimagining medicine.”

No new, previously unreported types of safety events were identified at week 96, and brolucizumab continued to be comparable to aflibercept with the overall incidence of adverse events balanced across all treatment groups in both studies[1]. The most frequent ocular adverse events (>=5% of patients in any treatment arm) were reduced visual acuity, conjunctival hemorrhage, vitreous floaters, eye pain, dry eye, retinal hemorrhage, cataract and vitreous detachment[1]. The most frequent non-ocular adverse events were typical of those reported in a nAMD population; there were no notable differences between arms[1].

These new 96-week data, based on pre-specified secondary endpoints from the HAWK and HARRIER trials, were presented at the American Academy of Ophthalmology (AAO) 2018 Annual Meeting as a follow-up to the year one data presented in November 2017[1],[2].

About brolucizumab (RTH258)

Brolucizumab (RTH258) is a humanized single-chain antibody fragment (scFv) and the most clinically advanced, humanized single-chain antibody fragment to reach this stage of development. Single-chain antibody fragments are highly sought after in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation and drug delivery characteristics[6],[7],[8].

The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms[6],[9]. In preclinical studies, brolucizumab inhibited activation of VEGF receptors through prevention of the ligand-receptor interaction[6],[8],[9]. Increased signaling through the VEGF pathway is associated with pathologic ocular angiogenesis and retinal edema[10]. Inhibition of the VEGF pathway has been shown to inhibit the growth of neovascular lesions, resolve retinal edema and improve vision in patients with chorioretinal vascular diseases[11].

About HAWK and HARRIER study design

With more than 1,800 patients across 400 centers worldwide, HAWK (NCT02307682) and HARRIER (NCT02434328) are the first and only global head-to-head trials in patients with nAMD that prospectively demonstrated efficacy at week 48 using an innovative q12w/q8w regimen, with a majority of patients on q12w immediately following the loading phase[2],[12],[13]. Both studies are 96-week prospective, randomized, double-masked multi-center studies and part of the Phase III clinical development of brolucizumab[12],[13].

The studies were designed to compare the efficacy and safety of intravitreal injections of brolucizumab 6 mg (HAWK and HARRIER) and 3 mg (HAWK only) versus aflibercept 2 mg in patients with nAMD[12],[13]. In both trials, patients were randomized to either brolucizumab or aflibercept. Immediately following the 3-month loading phase, patients in the brolucizumab arms received a q12w dosing interval with an option to adjust to a q8w dosing interval based on masked disease activity assessments at defined visits. Aflibercept was dosed bi-monthly according to its label at the time of study initiation[2],[12],[13].

Brolucizumab met the primary efficacy objective of non-inferiority versus aflibercept in mean change in best-corrected visual acuity (BCVA) from baseline to week 48 with high statistical significance[2]. Additionally, brolucizumab demonstrated superiority in three secondary endpoints considered key parameters of nAMD: central subfield retinal thickness, retinal fluid (intraretinal fluid and/or subretinal fluid) and disease activity[2].

At year two, the most frequent ocular adverse events (>=5% of patients in any treatment arm) for brolucizumab 3 mg, 6 mg and aflibercept, respectively, in HAWK were conjunctival hemorrhage (10.9%, 8.1% and 8.9%), reduced visual acuity (9.5%, 6.1% and 8.1%), vitreous floaters (7.3%, 6.1% and 4.4%), eye pain (7.8%, 5.0% and 5.8%), retinal hemorrhage (3.9%, 5.8% and 5.6%), cataract (5.0%, 5.6% and 3.6%), vitreous detachment (6.7%, 5.3% and 5.3%) and dry eye (5.6%, 5.3% and 7.2%)[1]. The incidences of these events for brolucizumab 6 mg and aflibercept, respectively, in HARRIER were conjunctival hemorrhage (4.6% and 5.1%), reduced visual acuity (8.6% and 7.0%), vitreous floaters (4.1% and 1.4%), eye pain (3.5% and 5.1%), retinal hemorrhage (3.2% and 1.1%), cataract (3.0% and 11.7%), vitreous detachment (2.7% and 2.2%) and dry eye (2.7% and 3.0%)[1].

About neovascular age-related macular degeneration (nAMD or wet AMD)

nAMD is the leading cause of severe vision loss and legal blindness in people over the age of 65 in North America, Europe, Australia and Asia, impacting an estimated 20 to 25 million people worldwide[4],[5]. nAMD occurs when abnormal blood vessels form underneath the macula, the area of the retina responsible for sharp, central vision. These blood vessels are fragile and leak fluid, disrupting the normal retinal architecture and ultimately causing damage to the macula[14],[15],[16].

Early symptoms of nAMD include distorted vision or metamorphopsia and difficulties seeing objects clearly[17]. Prompt diagnosis and intervention are essential. As the disease progresses, cell damage increases, further reducing vision quality. This progression can lead to a complete loss of central vision, leaving the patient unable to read, drive or recognize familiar faces[14]. Without treatment, vision can rapidly deteriorate[18].

About Novartis in ophthalmology

For more than 70 years, patients, caregivers and healthcare providers worldwide have looked to Novartis for state-of-the-art treatments in eye diseases. We continue to invest in science as well as in strategic alliances to help ensure patients have access to screening, diagnosis, and our eye medicines. Our commitment to vision extends globally across ages, from premature infants to seniors, from rare diseases to those affecting millions, from eye drops to gene therapies. Our aspiration: reimagining eye care to help everyone see possibilities.

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political and economic conditions; safety, quality or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 125,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.

References

[1] Dugel P, et al. Phase 3, randomized, double-masked, multi-center trials of brolucizumab versus aflibercept for neovascular AMD: 96-week results from the HAWK and HARRIER studies. Presented at: The American Academy of Ophthalmology on October 27, 2018, Chicago.
[2] Dugel P, et al. HAWK & HARRIER: 48-week results of 2 multi-centered, randomized, double-masked trials of brolucizumab versus aflibercept for neovascular AMD. Presented at: The American Academy of Ophthalmology on November 10, 2017, New Orleans.
[3] Arnold J, et al. The role of sub-retinal fluid in determining treatment outcomes in patients with neovascular age-related macular degeneration–a phase IV randomised clinical trial with ranibizumab: the FLUID study. BMC Ophthalmol. 2016;143(4):679-680.
[4] Chopdar A, et al. Age related macular degeneration. BMJ. 2003;26(7387):485-488.
[5] Schmidt-Erfurth U, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol. 2014;98:1144-1167.
[6] Escher D, et al. Single-chain antibody fragments in ophthalmology. Oral presentation at EURETINA congress. 2015. Abstract.
[7] Nimz EL, et al. Intraocular and systemic pharmacokinetics of brolucizumab (RTH258) in nonhuman primates. The Association for Research in Vision and Ophthalmology (ARVO) annual meeting. 2016. Abstract 4996.
[8] Gaudreault J, et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. ARVO Annual Meeting abstract. Invest Ophthalmol Vis Sci 2012;53:3025. http://iovs.arvojournals.org/article.aspx?articleid=2354604 (link is external). Accessed October 2018.
[9] Tietz J, et al. Affinity and Potency of RTH258 (ESBA1008), a Novel Inhibitor of Vascular Endothelial Growth Factor A for the Treatment of Retinal Disorders. IOVS. 2015; 56(7):1501.
[10] Qazi Y, et al. Mediators of ocular angiogenesis. J. Genet. 2009;88(4):495-515.
[11] Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol. 2007;55(6):413-415.
[12] ClinicalTrials.gov. Identifier NCT02307682. Available at https://clinicaltrials.gov/ct2/show/NCT02307682 (link is external). Accessed October 2018.
[13] ClinicalTrials.gov. Identifier NCT02434328. Available at https://clinicaltrials.gov/ct2/show/NCT02434328 (link is external). Accessed October 2018.
[14] World Health Organization. Priority eye diseases: Age-related macular degeneration. Available at http://www.who.int/blindness/causes/priority/en/index7.html (link is external). Accessed October 2018.
[15] NHS Choices. Macular Degeneration. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Introduction.aspx (link is external). Accessed October 2018.
[16] National Eye Institute. Facts About Age-Related Macular Degeneration. Available at https://nei.nih.gov/health/maculardegen/armd_facts (link is external). Accessed October 2018.
[17] NHS Choices. Macular degeneration – Symptoms. Available at http://www.nhs.uk/Conditions/Macular-degeneration/Pages/Symptoms.aspx (link is external). Accessed October 2018.
[18] van Lookeren Campagne M, et al. Mechanisms of age-related macular degeneration and therapeutic opportunities. J Pathol. 2014; 232(2):151-64. doi: 10.1002/path.4266.

Source: Novartis

Posted: October 2018

Tagged with:

About author

Related Articles