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Brolucizumab .pptx

  1. BROLUCIZUMAB Nil Financial Interest
  2. VEGF: INTRODUCTION • VEGF (Vascular Endothelial Growth Factor,) which is responsible for growth of blood vessels. • It is also responsible for many retinal diseases by causing new vessels growth and by increasing leakage and thus causing retinal swelling
  3. BROLUCIZUMAB • Humanized monoclonal single-chain variable fragment (scFv) that binds and inhibits vascular endothelial growth factor A (VEGF-A) • Single-chain fragment variable is the smallest functional unit of an antibody, the Fv region • Molecular weight - 26 Kd • Half-life of 3.0 days
  4. ADVANTAGES • Being small fragments, they are able to penetrate tissue more rapidly and evenly • Brolucizumab binds VEGF-A in a 2:1 • Higher binding affinity to VEGF-A isoforms than bevacizumab or ranibizumab • Radily penetrate to the choroid and RPE while having minimal serum concentrations • FDA-approved for treatment of wet ARMD • Longer interval between injections
  5. DOSAGE • Recommended dosage is 6 mg (0.05 mL of solution that is 120 mg/mL) • Once per month for the first 3 doses as loading doses • Dosing interval after is recommended 8 to 12 weeks based on clinician assessment of disease • 30-gauge transconjunctival intravitreal injection via the pars plana
  8. LITERATURE HAWK and HARRIER Purpose- To compare Brolucizumab with Aflibercept in treatment neovascular ARMD Study Design: Double-masked, active-controlled, randomized trials Participants: Patients (N = 1817) with untreated, active choroidal neovascularization due to ARMD in the study eye Reference- Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2020 Jan;127(1):72-84.
  9. Materials and Methods: • Patients were randomized 1:1:1 to receive brolucizumab 3 mg or 6 mg or aflibercept 2 mg (HAWK) or 1:1 to receive brolucizumab 6 mg or aflibercept 2 mg (HARRIER) • After loading with 3 monthly injections, brolucizumab-treated eyes received an injection every 12 weeks (q12w) and were interval adjusted to every 8 weeks (q8w) if disease activity was present; aflibercept-treated eyes received q8w dosing Main outcome measures: The primary hypothesis was noninferiority in mean best- corrected visual acuity (BCVA) change from baseline to Week 48. Other key end points included the percentage of patients who maintained q12w dosing through Week 48 and anatomic outcomes.
  10. RESULTS • BCVA-The mean change in BCVA from baseline at week 48 (primary end point) in brolucizumab-treated eyes was noninferior to that in aflibercept- treated eyes, and these visual gains were maintained to week 96 • Central Subfield Thickness- At week 96, greater CST reductions were observed with brolucizumab 3 mg and 6 mg versus aflibercept in and with brolucizumab 6 mg versus aflibercept in HARRIER • IRF/SRF- In both HAWK and HARRIER, significantly fewer eyes treated with brolucizumab showed IRF or SRF at weeks 16 and 48, and this difference was maintained to week 96. The proportion of eyes with IRF or SRF at week 96 in HAWK was 31% for brolucizumab 3mg, 24% for brolucizumab 6 mg and 37% for aflibercept whereas in HARRIER, it was 24% for brolucizumab 6 mg and 39% for aflibercept
  11. RESULTS • Sub RPE fluid-At week 96, the proportions of eyes with sub-RPE fluid in HAWK were 14% and 11% for brolucizumab 3 mg and 6 mg, respectively, compared with 15% for aflibercept. In HARRIER, the proportion of eyes with sub-RPE fluid was 17% for brolucizumab 6 mg compared with 22% for aflibercept
  12. CONCLUSION • Brolucizumab was noninferior to aflibercept in visual function • Anatomic outcomes favoured brolucizumab over aflibercept resulting in fewer eyes with intra-retinal fluid (IRF), sub-retinal fluid (SRF), or sub-RPE fluid and an increased reduction in central subfield thickness (CST) on OCT • Overall safety with brolucizumab was similar to aflibercept • Combined intraocular inflammation (IOI) (iritis and uveitis) was higher in the brolucizumab 6 mg group of HAWK compared with the aflibercept group
  13. KITE AND KESTREL STUDY FOR DME Purpose: To compare the efficacy and safety of brolucizumab with aflibercept in patients with diabetic macular edema (DME) Design: Double-masked, 100-week, multicenter, active-controlled, randomized trials Reference-Brown DM, Emanuelli A, Bandello F, Barranco JJE, Figueira J, Souied E, Wolf S, Gupta V, Ngah NF, Liew G, Tuli R, Tadayoni R, Dhoot D, Wang L, Bouillaud E, Wang Y, Kovacic L, Guerard N, Garweg JG. KESTREL and KITE: 52-Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema. Am J Ophthalmol. 2022 Jun;238:157-172.
  14. Methods: • Subjects were randomized 1:1:1 to brolucizumab 3 mg/6 mg or aflibercept 2 mg in KESTREL (n = 566) or 1:1 to brolucizumab 6 mg or aflibercept 2 mg in KITE (n = 360) • Brolucizumab groups received 5 loading doses every 6 weeks (q6w) followed by 12-week (q12w) dosing, with optional adjustment to every 8 weeks (q8w) if disease activity was identified at predefined assessment visits • aflibercept groups received 5 doses every 4 weeks (q4w) followed by fixed q8w dosing
  15. RESULTS • At Week 52, brolucizumab 6 mg was noninferior to aflibercept in mean change in BCVA from baseline (KESTREL: +9.2 letters vs +10.5 letters; KITE: +10.6 letters vs +9.4 letters; P < .001) • More subjects achieved central subfield thickness (CSFT) <280 µm, and fewer had persisting subretinal and/or intraretinal fluid vs aflibercept, with more than half of brolucizumab 6 mg subjects maintained on q12w dosing after loading • In KITE, brolucizumab 6 mg showed superior improvements in change of CSFT from baseline over Week 40 to Week 52 vs aflibercept • The incidence of ocular serious adverse events was 3.7% (brolucizumab 3 mg), 1.1% (brolucizumab 6 mg), and 2.1% (aflibercept) in KESTREL; and 2.2% (brolucizumab 6 mg) and 1.7% (aflibercept) in KITE.
  16. CONCLUSION • Brolucizumab 6 mg showed robust visual gains and anatomical improvements with an overall favourable benefit/risk profile in patients with DME
  17. BROLICIZUMAB FOR CRVO INDUCED RECALCITRANT MACULAR EDEMA • A series of 2 patients involving treatment of eyes with recalcitrant macular edema due to CRVO treated with brolicizumab • Patient treated with 10 ranibizumab, 2 bevacizumab, 2 aflibercept and 1 dexamethasone implant • Other patient treated with 12 ranibizumab • Improvement in BCVA following brolicizumab Reference- Chakraborty et al, Brolicizumab in Recalcitrant macular edema. Current eye research, 2021
  18. RISK OF INFLAMMATION AND RETINAL OCCLUSION-RELATED EVENTS WITH BROLUCIZUMAB • Fifty brolucizumab-treated eyes were considered to have definite/probable drug-related events within the spectrum of IOI, retinal vasculitis, and/or vascular occlusion. On the basis of these cases, incidence of definite/probable IOI was 4.6% (IOI + vasculitis, 3.3%; IOI + vasculitis + occlusion, 2.1% • There were 8 cases of at least moderate visual acuity loss (≥15 ETDRS letters) in eyes with IOI (7 in eyes with IOI + vasculitis + occlusion) • Of the 8 cases, 5 experienced their first IOI-related event within 3 months of the first brolucizumab injection • Incidence of IOI in aflibercept-treated eyes was 1.1%, with at least moderate visual acuity loss in 0.14%. Reference- Monés J, Srivastava SK, Jaffe GJ, Tadayoni R, Albini TA, Kaiser PK, Holz FG, Korobelnik JF, Kim IK, Pruente C, Murray TG, Heier JS. Risk of Inflammation,
  19. • Retrospective study on 21 PCV eyes. The median pretreatment vision was 0.6 logMAR and improved to 0.3 logMAR whereas the mean macular thickness improved from 443 ± 60 μm at baseline to 289 ± 25 μm at the last follow-up period • None of the eyes experienced any intraocular inflammation across 48 injection sessions. • Brolucizumab is safe and effective in controlling PCV disease in both treatment- resistant and treatment-naïve eyes Reference- chakraborty D, Maiti A, Sengupta S, Mondal S, Nandi K, Chakraborty S. Initial experience in treating polypoidal choroidal vasculopathy with brolucizumab in Indian eyes - A multicenter retrospective study. Indian J Ophthalmol. 2022 Apr;70(4):1295-1299
  20. • Immediate onset of sterile endophthalmitis with hypopyon after intravitreal Brolucizumab • Vitrectomy biopsy with intravitreal ceftazidime and vancomycin • Microbiological testing of the vitreous fluid did not show any organism on smear, and there was no growth on culture • Polymerase chain reaction for Eubacteria was negative Reference- Narayanan, Raja; Tyagi, Mudit; Gupta, Shashank R1; Nayaka, Ashraya2; Jayadev, Chaitra3. Immediate onset of sterile endophthalmitis with hypopyon after intravitreal Brolucizumab in a case of polypoidal choroidal vasculopathy. Indian Journal of Ophthalmology: February 2021 - Volume 69 - Issue 2 - p 469-470
  21. • A female patient diagnosed with PCV with IMC-NS 2 • LE BCVA 6/12 • LE S/P Accentrix 5 injections • Advised LE Brolicuzumab • Post injection decrease in size of polyp and IRF
  22. PCV
  23. • A patient came with BCVA 6/9P • OCT LE- FVPED with SRF. Diagnosis- LE CNVM • S/P injection Accentrix 3, Avastin 1 • Advised LE Brolicuzumab • Post injection decrease in FVPED with resolution of SRF
  24. CNVM