Brolucizumab for Wet Age- Related Macular Degeneration

NEW PRODUCT ■

Brolucizumab for wet age- related macular degeneration

STEVE CHAPLIN

Brolucizumab (Beovu) KEY POINTS is a new monoclonal antibody fragment ■ Brolucizumab is a monoclonal antibody fragment targeting VEGF-A targeting VEGF-A for the ■ It is licensed for the treatment of neovascular (wet) age-related macular treatment of neovascular degeneration (AMD) (wet) age-related macular ■ The recommended dose is 6mg by intravitreal injection every four weeks for the first three doses, then every eight weeks if disease activity continues, or every 12 degeneration (AMD). weeks if AMD is stable This article outlines its ■ In two phase 3 trials, brolucizumab was non-inferior to aflibercept in improving mechanism of action, best-corrected visual acuity from a mean baseline of about 61 letters place in therapy, clinical ■ It showed superiority over aflibercept for certain secondary endpoints, eg efficacy and adverse reduction in central subfield thickness, retinal and subretinal fluid control effects. ■ Adverse events associated with brolucizumab were typical of anti-VEGF agents, and similar in frequency and severity to those associated with aflibercept ■ Broluzicumab costs £816 per dose he 2018 NICE guideline on the man- Tagement of age-related macular a legitimate off-label use2 and the Court degeneration (AMD) recommends treat- of Appeal has ruled that this use is law- ment with an intravitreal anti-vascular ful.3 A cost effectiveness analysis con- endothelial growth factor (anti-VEGF) cluded that the three anti-VEGF options agent (the monoclonal antibody fragment (bevacizumab, ranibizumab and afliber- ranibizumab or the recombinant fusion cept) show similar effectiveness, and protein aflibercept) for late AMD (wet that bevacizumab is the most cost effec- active) in patients with vision within a tive for AMD.4 specified visual acuity range and meeting Anti-VEGF treatment is suspended other ophthalmological criteria.1 These when regular monitoring shows the inhibitors bind to VEGF-A and reduce neo- patient is not benefiting from continued vascularisation and other changes such treatment. Switching between anti-VEGF as retinal oedema. agents can offer a more convenient dose NICE could not evaluate the less regimen but the clinical benefit may be expensive anti-VEGF monoclonal anti- limited.1 NICE is now evaluating a new body bevacizumab because it was not anti-VEGF agent, brolucizumab (Beovu), a licensed for this indication, although a monoclonal antibody fragment that binds footnote in the guidance indicated that to VEGF-A. Brolucizumab works by pre- the three anti-VEGF agents aflibercept, venting VEGF-A binding to its receptors bevacizumab and ranibizumab show VEGFR-1 and VEGFR-2, thus suppressing equivalent clinical effectiveness and endothelial cell proliferation and decreas- safety.1 NHS Trusts have long offered ing neovascularisation and vascular per- treatment with products specially pre- meability. Brolucizumab has recently pared from the Avastin formulation of been accepted by the Scottish Medicines bevacizumab, which is licensed for the Consortium for use within NHS Scotland. treatment of certain cancers. The Medicines and Healthcare products Indications and dosage Regulatory Agency (MHRA) recently ruled Brolucizumab is licensed for the treat- that prescribing bevacizumab for AMD is ment of neovascular (wet) AMD in adults. prescriber.co.uk Prescriber September 2020 ❚ 33 ■ NEW PRODUCT l Brolucizumab

The recommended dose is 6mg adminis- tered by intravitreal injection every four a 10 HAWK weeks for the first three doses. AMD activity should be assessed at 16 weeks 9 after the start of treatment. Treatment 8 every eight weeks should be considered 7 if AMD is active, or every 12 weeks in patients without disease activity. As has 6 been the case with other anti-VEGF treat- 5 ments, clinicians may tailor the treatment 4

regimen to individual need. Treatment LS mean (SE) 3 Brolucizumab 3mg (n=358) should be discontinued if the patient is not benefiting from treatment. 2 Brolucizumab 6mg (n=360) Following administration, broluci- 1

BCVA change from baseline, letters change from baseline, BCVA Aflibercept 2mg (n=360) zumab is absorbed systemically before 0 undergoing proteolysis and renal elimina- tion. No dose adjustment is recom- 0 4 8 12 16 20 24 28 32 36 40 44 48 mended for older people or in individuals Time (weeks) with renal or hepatic impairment, b although it has not been studied in peo- 10 HARRIER ple with hepatic impairment or severe 9 renal impairment. 8 Efficacy 7 Evidence for the efficacy and safety of bro- 6 lucizumab comes from two randomised phase 3 trials of similar design, HAWK 5 (n=1082) and HARRIER (n=743).5 Eligible 4 patients were aged ≥50 years (mean age LS mean (SE) 3 77 years) and had untreated, active cho- 2 Brolucizumab 6mg (n=370) roidal neovascularisation lesions secondary to AMD affecting the central subfield 1 Aflibercept 2mg (n=369) BCVA change from baseline, letters change from baseline, BCVA (the circular area within 1mm around the 0 foveal centre) and comprising >50% of the 0 4 8 12 16 20 24 28 32 36 40 44 48 total lesion area; they also met other oph- Time (weeks) thalmological criteria. The mean baseline best-corrected visual acuity (BCVA, Early Figure 1. Best-corrected visual acuity (BCVA) over time with brolucizumab and aflibercept in Treatment Diabetic Retinopathy Study let- (a) HAWK and (b) HARRIER. From: Dugel PU, et al.5 ter score) at baseline was approximately 61 letters overall. Approximately 90–93% of patients regimens) and during follow-up to 96 Patients were randomised to treat- completed the trial. Over half of all weeks. The proportion of patients with ment with brolucizumab 3mg (in HAWK patients treated with brolucizumab improved visual acuity (≥15 letters gain) only, subsequently unlicensed dose not remained on a 12-week dose schedule at 48 weeks was 33.6% with broluci- discussed further) or 6mg every 12 throughout the trial; this proportion zumab vs 25.4% with aflibercept in weeks after the first three loading doses, increased to around 80–85% in the sub- HAWK, and 29.3% vs 29.9% respectively adjusted to every eight weeks if disease group with no disease activity in the first in HARRIER. Loss of visual acuity (≥15 activity was present, or aflibercept 2mg 12 weeks. letters) occurred in 4–6% of patients, every eight weeks. The primary endpoint After 48 weeks, the mean change in with no significant difference between the was change in mean BCVA from baseline BCVA with brolucizumab 6mg was +6.6 treatments. to Week 48 (non-inferiority). Secondary letters vs +6.8 with aflibercept in HAWK Superiority analyses showed a signif- endpoints of AMD activity were analysed and +6.9 vs +7.6 respectively in HARRIER icantly greater effect for brolucizumab for superiority, if non-inferiority (within a (see Figure 1). Brolucizumab was there- over aflibercept for reduction in central margin of four letters difference) was fore non-inferior to aflibercept (p<0.001). subfield thickness, intraretinal and sub- shown for the primary endpoint but there Other analysis showed similar outcomes retinal fluid control, and duration of effect was no superiority test for the primary for the last 12 weeks of the trial (which (presence of disease activity at 16 endpoint. accommodated differences in dose weeks).

34 ❚ Prescriber September 2020 prescriber.co.uk Brolucizumab l NEW PRODUCT ■

Adverse events respectively in HAWK and 9.5% vs 11.7% bevacizumab, ranibizumab and aflibercept for The nature and frequency of adverse in HARRIER. the treatment of age-related macular degener- events were similar for brolucizumab and ation – A cost-effectiveness analysis from a aflibercept, with ocular events reported References societal perspective. PLoS One 2018; by 49.7% vs 47.2% of patients with brolu- 1. National Institute for Health and Care 13(5):e0197670. 5. Dugel PU, et al. HAWK and HARRIER: Phase cizumab vs aflibercept in HAWK and Excellence. Age-related macular degeneration. 3, multicenter, randomized, double-masked 33.0% vs 32.2% in HARRIER. The most NG82. January 2018. Available from: https:// www.nice.org.uk/guidance/ng82 trials of brolucizumab for neovascular age-re- common ocular adverse events with bro- 2. Medicines and Healthcare products lated macular degeneration. Ophthalmology lucizumab were conjunctival haemor- Regulatory Agency. Review of MHRA published 2020;127:72–84. © 2019 by the American rhage, reduced visual acuity, vitreous statements on the supply and use of Avastin Academy of Ophthalmology. This is an open floaters and eye pain. The incidence of (bevacizumab) for intravitreal use. September access article under the CC BY-NC-ND license: serious ocular events was 3.1% vs 0.8% 2019. Available from: https://assets.publish- http://creativecommons.org/licenses/ with brolucizumab vs aflibercept in HAWK ing.service.gov.uk/media/5d- by-nc-nd/4.0/ and 2.4% vs 1.1% in HARRIER. 8371f8ed915d522e416522/ Review_of_MHRA_published_statements_on_ Non-ocular events occurred in 64.4% Declaration of interests the_supply_and_use_of_Avastin.pdf vs 71.7% with brolucizumab vs afliber- 3. Dyer C. Offering Avastin for wet AMD is None to declare. cept in HAWK and 59.2% vs 57.2% in legal, says appeal court. BMJ 2020; HARRIER. Non-ocular serious adverse 368:m1273. Steve Chaplin is a freelance medical events occurred in 13.1% vs 18.9% 4. van Asten F, et al. The cost-effectiveness of writer specialising in therapeutics

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