Brolucizumab

Brolucizumab, sold under the trade name Beovu, is a humanized single-chain antibody fragment for the treatment of neovascular (wet) age-related macular degeneration (AMD).[3][2]

Brolucizumab
Monoclonal antibody
TypeSingle-chain variable fragment
SourceHumanized
TargetVascular endothelial growth factor A (VEGFA)
Clinical data
Trade namesBeovu
Other namesbrolucizumab-dbll, ESBA1008, RTH258, DLX1008
AHFS/Drugs.comMonograph
MedlinePlusa620001
License data
Pregnancy
category
  • AU: D
Routes of
administration		Intravitreal
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only) [1]
  • US: ℞-only [2]
  • EU: Rx-only [3]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC1164H1768N310O372S7
Molar mass26281.17 g·mol−1

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).[3][2] 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).[3][2]

Brolucizumab was designed to attach to and block a substance called vascular endothelial growth factor A (VEGF-A).[3] 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.[3][2]

History

This drug was developed by ESBATech[4][5] (discovery to phase 2a), Alcon Laboratories (phase 2b), and Novartis (phase 3).

Brolucizumab is U.S. Food and Drug Administration (FDA) approved in ophthalmology as Beovu.[6][7]

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.[8][9][10] [11]

On 8 October 2019, Novartis announced that the U.S. Food and Drug Administration (FDA) approved brolucizumab injection for the treatment of wet AMD.[6] 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[12] with uncompromised efficacy.

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.[13]

While brolucizumab was initially developed for ophthalmology, non-ophthalmology indications (to which Cell Medica hold development rights) are also under investigation, under the name DLX1008. DLX1008 is under preclinical development for Kaposi sarcoma[14] and glioblastoma.[15]

Brolucizumab was approved for use in the European Union in February 2020.[3]

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.[16][17]

Novartis responded with a statement standing behind the efficacy of Beovu.[18][19]

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)[20] and HARRIER (NCT02434328)[21] clinical trials and noted in the original prescribing information.[22]

Names

Laboratory development names were RTH258 (Novartis Compound Code) and ESBA1008 (ESBATech AG).

Brolucizumab is the International Nonproprietary Name (INN) and the United States Adopted Name (USAN)[23][24]

References
  1. "Beovu 120 mg/ml solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 9 March 2020. Retrieved 3 May 2020.
  2. "Beovu- brolucizumab injection, solution". DailyMed. 13 January 2020. Retrieved 3 May 2020.
  3. "Beovu EPAR". European Medicines Agency (EMA). 10 December 2019. Retrieved 3 May 2020. This article incorporates text from this source, which is in the public domain.
  4. "ESBATech case story" (PDF). 6 July 2011. Retrieved 17 November 2019.
  5. "RTH258". Biomedtracker. Retrieved 17 November 2019.
  6. "Novartis receives FDA approval for Beovu, offering wet AMD patients vision gains and greater fluid reductions vs aflibercept". Novartis.
  7. "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.
  8. 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.
  9. 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.
  10. "Efficacy and Safety of RTH258 Versus Aflibercept - Study 1 (HAWK)". ClinicalTrials.gov. 4 December 2014. Retrieved 3 May 2020.
  11. "Efficacy and Safety of RTH258 Versus Aflibercept - Study 2 (HARRIER)". ClinicalTrials.gov. 5 May 2015. Retrieved 3 May 2020.
  12. BEOVU [prescribing information] East Hanover, NJ. Novartis: 2019
  13. "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. This article incorporates text from this source, which is in the public domain.
  14. Eason, Anthony B.; Sin, Sang-Hoon; Szabó, Emese; Phillips, Douglas J.; Droste, Miriam; Shamshiev, Abdijapar; Dittmer, Dirk P.; Weller, Michael (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.
  15. 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". J. Pharmacol. Exp. Ther. 365 (2): 422–9. doi:10.1124/jpet.117.246249. ISSN 0022-3565. PMID 29507055.
  16. "Novartis Responds to ASRS Note Raising Safety Concerns With Wet AMD Drug Beovu". Eyewire News. 25 February 2020. Retrieved 27 April 2020.
  17. "Novartis' hot new eye drug Beovu tied to potential vision loss: experts". FiercePharma. Retrieved 27 April 2020.
  18. "Novartis stands behind Beovu's safety, benefits after vision-loss warning". FiercePharma. Retrieved 27 April 2020.
  19. "Novartis provides update on use and safety of Beovu (brolucizumab)". Novartis. 28 April 2020. Retrieved 27 April 2020.
  20. "Efficacy and Safety of RTH258 Versus Aflibercept - Study 1 - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 11 June 2020.
  21. "Efficacy and Safety of RTH258 Versus Aflibercept - Study 2 - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 11 June 2020.
  22. "BRIEF-U.S. FDA Approves Novartis' Updated Beovu Label - Statement". Reuters. 11 June 2020. Retrieved 11 June 2020.
  23. Statement On A Nonproprietary Name Adopted By The USAN Council - Brolucizumab, American Medical Association.
  24. World Health Organization (2014). "International nonproprietary names for pharmaceutical substances (INN): proposed INN: list 112". WHO Drug Information. 28 (4): 493. hdl:10665/331100.
  • "Brolucizumab". Drug Information Portal. U.S. National Library of Medicine.
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