Brolucizumab

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Brolucizumab
Monoclonal antibody
Type Single-chain variable fragment
Source Humanized
Target Vascular endothelial growth factor A (VEGFA)
Clinical data
Trade names Beovu
Other namesbrolucizumab-dbll, RTH258, DLX1008
AHFS/Drugs.com Monograph
MedlinePlus a620001
License data
Pregnancy
category
  • AU:D
Routes of
administration 		Intravitreal
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C1164H1768N310O372S7
Molar mass 26281.17 g·mol−1

Brolucizumab sold under trade name Beovu among others, is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD). [6] [5]

Contents

The most common side effects are reduced visual acuity, cataract (clouding of the lens in the eye), conjunctival haemorrhage (bleeding at the front of the eye) and vitreous floaters (spots in the vision). [6] [5] The most serious side effects are blindness, endophthalmitis (an infection inside the eye), retinal artery occlusion (blockage of the artery in the retina) and retinal detachment (separation of the retina from the back of the eye). [6] [5]

Brolucizumab was designed to attach to and block a substance called vascular endothelial growth factor A (VEGF-A). [6] VEGF-A is a protein that makes blood vessels grow and leak fluid and blood, damaging the macula. By blocking VEGF-A, brolucizumab reduces the growth of the blood vessels and controls the leakage and swelling. [6] [5]

History

Brolucizumab is U.S. Food and Drug Administration (FDA) approved in ophthalmology as Beovu. [7] [8]

Brolucizumab successfully completed phase III development in wet age-related macular degeneration (AMD) meeting the primary efficacy endpoint of non-inferiority to aflibercept in mean change in best corrected visual acuity (BCVA) from baseline to week 48. Furthermore, brolucizumab demonstrated superiority to aflibercept in key secondary endpoint measures of disease activity in wet AMD, a leading cause of blindness in two head-to-head pivotal Phase III studies. [9] [10] [11] [12]

On 8 October 2019, Novartis announced that the U.S. Food and Drug Administration (FDA) approved brolucizumab injection for the treatment of wet AMD. [7] Beovu is the first FDA approved anti-VEGF to offer both greater fluid resolution versus aflibercept and the ability to maintain eligible wet AMD patients on a three-month dosing interval immediately after a three-month loading phase [13] [ failed verification ] with uncompromised efficacy.[ medical citation needed ]

The FDA approved Beovu based on evidence from two clinical trials (Trial 1/ NCT02307682 and Trial 2/NCT02434328) of 1459 patients, 50–97 years old, with wet AMD. The trials were conducted at 336 sites in the United States, Canada, Central and South America, European countries, Israel, Turkey, Australia, New Zealand, Japan, South Korea, Singapore, Taiwan, and Vietnam. [14]

Brolucizumab was approved for use in the European Union in February 2020. [6]

Society and culture

Safety concerns

On 23 February 2020, the American Society of Retina Specialists reported side effects of the drug, specifically in 14 cases of retinal vasculitis reported in Beovu patients, 11 of the cases were occlusive retinal vasculitis that can lead to vision loss. [15] [16] Novartis responded with a statement standing behind the efficacy of Beovu. [17] [18]

On 11 June 2020, the FDA approved an updated Beovu label, that included additional safety information specifically including the characterization of adverse events, retinal vasculitis and retinal vascular occlusion, as part of the spectrum of intraocular inflammation observed in HAWK (NCT02307682) [11] and HARRIER (NCT02434328) [12] clinical trials and noted in the original prescribing information. [19]

Names

Brolucizumab is the International Nonproprietary Name (INN) and the United States Adopted Name (USAN) [20] [21]

Research

Non-ophthalmology indications are under investigation, under the name DLX1008. DLX1008 is under preclinical development for Kaposi sarcoma [22] and glioblastoma. [23]

Related Research Articles

The National Eye Institute (NEI) is part of the U.S. National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. The mission of NEI is "to eliminate vision loss and improve quality of life through vision research." NEI consists of two major branches for research: an extramural branch that funds studies outside NIH and an intramural branch that funds research on the NIH campus in Bethesda, Maryland. Most of the NEI budget funds extramural research.

<span class="mw-page-title-main">Macular edema</span> Medical condition

Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view.

<span class="mw-page-title-main">Macular degeneration</span> Medical condition associated with vision loss

Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

<span class="mw-page-title-main">Anecortave acetate</span> Chemical compound

Anecortave (rINN) is a novel angiogenesis inhibitor used in the treatment of the exudative (wet) form of age-related macular degeneration. Although similar in chemical structure to the corticosteroid hydrocortisone acetate, it possesses no glucocorticoid activity. If it is approved, it will be marketed by Alcon as anecortave acetate for depot suspension under the trade name Retaane. No development has been reported since 2010.

<span class="mw-page-title-main">Intravitreal administration</span>

Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.

Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration, diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion.

<span class="mw-page-title-main">Pegaptanib</span> Drug to treat macular degeneration

Pegaptanib sodium injection is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

<span class="mw-page-title-main">Choroidal neovascularization</span> Creation of new blood vessels in the choroid layer of the eye

Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.

<span class="mw-page-title-main">Maculopathy</span> Term for pathological conditions effecting the macula

A maculopathy is any pathological condition of the macula, an area at the centre of the retina that is associated with highly sensitive, accurate vision.

Aflibercept, sold under the brand names Eylea among others, is a medication used to treat wet macular degeneration and metastatic colorectal cancer. It was developed by Regeneron Pharmaceuticals.

<span class="mw-page-title-main">Macular telangiectasia</span> Disease of the retina affecting central vision

Macular telangiectasia is a condition of the retina, the light-sensing tissue at the back of the eye that causes gradual deterioration of central vision, interfering with tasks such as reading and driving.

<span class="mw-page-title-main">Laser coagulation</span> Procedure widely used in eye surgery

Laser coagulation or laser photocoagulation surgery is used to treat a number of eye diseases and has become widely used in recent decades. During the procedure, a laser is used to finely cauterize ocular blood vessels to attempt to bring about various therapeutic benefits.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

Joan Whitten Miller is a Canadian-American ophthalmologist and scientist who has made notable contributions to the treatment and understanding of eye disorders. She is credited for developing photodynamic therapy (PDT) with verteporfin (Visudyne), the first pharmacologic therapy for retinal disease. She also co-discovered the role of vascular endothelial growth factor (VEGF) in eye disease and demonstrated the therapeutic potential of VEGF inhibitors, forming the scientific basis of anti-VEGF therapy for age-related macular degeneration (AMD), diabetic retinopathy, and related conditions.

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.

Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related macular degeneration that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of visual function over time. It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, which is similar to the prevalence of neovascular (wet) AMD, the other advanced form of the disease.

<span class="mw-page-title-main">Faricimab</span> Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

<span class="mw-page-title-main">Intravitreal injection</span> Method of administration of drugs into the eye by injection with a fine needle

Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.

Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.

<span class="mw-page-title-main">Stem cell therapy for macular degeneration</span> Use of stem cells to treat macular degeneration

Stem cell therapy for macular degeneration is the use of stem cells to heal, replace dead or damaged cells of the macula in the retina. Stem cell based therapies using bone marrow stem cells as well as retinal pigment epithelial transplantation are being studied. A number of trials have occurred in humans with encouraging results.

References

  1. ↑ Medicine registrations Australian Government
  2. ↑ "Beovu Product information". Health Canada. 25 April 2012. Retrieved 29 May 2022.
  3. ↑ "Summary Basis of Decision (SBD) for Beovu". Health Canada. 23 October 2014. Retrieved 29 May 2022.
  4. ↑ "Beovu 120 mg/ml solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 9 March 2020. Retrieved 3 May 2020.
  5. 1 2 3 4 5 "Beovu- brolucizumab injection, solution". DailyMed. 13 January 2020. Retrieved 3 May 2020.
  6. 1 2 3 4 5 6 7 "Beovu EPAR". European Medicines Agency (EMA). 10 December 2019. Retrieved 3 May 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  7. 1 2 "Novartis receives FDA approval for Beovu, offering wet AMD patients vision gains and greater fluid reductions vs aflibercept". Novartis.
  8. ↑ "Drug Approval Package: Beovu (brolucizumab-dbll)". U.S. Food and Drug Administration (FDA). 4 November 2019. Archived from the original on 17 November 2019. Retrieved 17 November 2019.
  9. ↑ Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG (April 2019). "HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration". Ophthalmology. 127 (1): 72–84. doi: 10.1016/j.ophtha.2019.04.017 . PMID   30986442.
  10. ↑ Holz FG, Dugel PU, Weissgerber G, Hamilton R, Silva R, Bandello F, Larsen M, Weichselberger A, Wenzel A, Schmidt A, Escher D, Sararols L, Souied E (May 2016). "Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration: A Randomized Controlled Study". Ophthalmology. 123 (5): 1080–9. doi: 10.1016/j.ophtha.2015.12.030 . PMID   26906165.
  11. 1 2 Clinical trial number NCT02307682 for "Efficacy and Safety of RTH258 Versus Aflibercept - Study 1 (HAWK)" at ClinicalTrials.gov
  12. 1 2 Clinical trial number NCT02434328 for "Efficacy and Safety of RTH258 Versus Aflibercept - Study 2 (HARRIER)" at ClinicalTrials.gov
  13. ↑ BEOVU [prescribing information] East Hanover, NJ. Novartis: 2019
  14. ↑ "Drug Trials Snapshots: BEOVU". U.S. Food and Drug Administration . 7 October 2019. Archived from the original on 17 November 2019. Retrieved 17 November 2019.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  15. ↑ "Novartis Responds to ASRS Note Raising Safety Concerns With Wet AMD Drug Beovu". Eyewire News. 25 February 2020. Retrieved 27 April 2020.
  16. ↑ "Novartis' hot new eye drug Beovu tied to potential vision loss: experts". FiercePharma. 24 February 2020. Retrieved 27 April 2020.
  17. ↑ Sagonowsky E (2 March 2020). "Novartis stands behind Beovu's safety, benefits after vision-loss warning". FiercePharma. Retrieved 27 April 2020.
  18. ↑ "Novartis provides update on use and safety of Beovu (brolucizumab)". Novartis. 28 April 2020. Archived from the original on 17 October 2021. Retrieved 27 April 2020.
  19. ↑ "BRIEF-U.S. FDA Approves Novartis' Updated Beovu Label - Statement". Reuters. 11 June 2020. Archived from the original on 11 June 2020. Retrieved 11 June 2020.
  20. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Brolucizumab Archived 15 August 2016 at the Wayback Machine , American Medical Association .
  21. ↑ World Health Organization (2014). "International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 112". WHO Drug Information. 28 (4): 493. hdl: 10665/331100 .
  22. ↑ Eason AB, Sin SH, Szabó E, Phillips DJ, Droste M, Shamshiev A, et al. (2018). "Abstract 4: Antitumor activity of DLX1008, a single chain antibody fragment binding to VEGF-A, in in vivo preclinical models of Kaposi sarcoma and glioblastoma". Cancer Research. 78 (13 Supplement): 4. doi:10.1158/1538-7445.AM2018-4. ISSN   0008-5472. S2CID   81317833.
  23. ↑ Szabó E, Phillips DJ, Droste M, Marti A, Kretzschmar T, Shamshiev A, Weller M (May 2018). "Antitumor Activity of DLX1008, an Anti-VEGFA Antibody Fragment with Low Picomolar Affinity, in Human Glioma Models". The Journal of Pharmacology and Experimental Therapeutics. 365 (2): 422–429. doi: 10.1124/jpet.117.246249 . PMID   29507055.
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