A clinical overview of the different types of age-related macular degeneration and potential treatments
Age-related macular degeneration (ARMD) causes a gradual loss of central vision. It does not affect peripheral vision. Central vision is needed for detailed work and for everyday activities, like reading and driving. Vision loss from ARMD can vary from months to years and ARMD accounts for 25 per cent of all blind registrations in Ireland (57.1 per 100,000 adults).
‘Wet’ ARMD is the rarer and more severe form but responds to treatment better than ‘dry’ ARMD. New drugs which have come on the market in recent years for wet ARMD can slow down or even halt the progression of visual loss. ARMD is the most common cause of irreversible sight loss in the Western world.
There is no specific treatment yet for ARMD. An optician will advise on maximising sight through using glasses and lenses. Supplements with antioxidant action like Lutein can help, but I will concentrate on the treatment of wet ARMD in this article.
TREATMENT OPTIONSFOR WET ARMD
Treatment may halt or delay the progression of visual loss. Newer treatments may even be able to reverse some of the visual loss. Options include anti-vascular endothelial growth factor (anti-VEGF) drugs, photodynamic therapy, and laser photocoagulation. The aim is to preserve central vision, but despite treatment, most still have some difficulty in reading small print and other visually demanding tasks. The distortion of straight lines (straight lines appear wavy or crooked) can persist in some people.
Anti-VEGF drugs were developed in the last 20 years for wet ARMD. Vascular endothelial growth factor is a chemical that is involved in the formation of new blood vessels in the macula, a cause of wet ARMD. Blocking the action of this chemical prevents the formation of the abnormal blood vessels. Following on trends of other countries, anti-VEGFs are being used more in Ireland in recent years for diabetic macular oedema (DME); I will not be discussing DME in this article.
Anti-VEGFs include ranibizumab (Lucentis), pegaptanib (Macugen), bevacizumab (Avastin), and brolucizumab (Beovu, launched in 2019). In large-scale clinical trials, anti-VEGF treatment maintained visual acuity in over 90 per cent of patients.
Anti-VEGF treatment requires the specialised expertise of retina specialists and is labour-intensive and costly. Anti- VEGF drugs are injected using a fine needle directly into the vitreous humour of the eye. The procedure takes only about five minutes; the injection itself is over in less than 20 seconds. Local anaesthetic drops are applied to numb the eye and minimise discomfort. Results in clinical practice do not give the same level of positive end results than those obtained in rigorous phase 3 trials. Under- treatment and the burden on patients and caregivers from frequent anti-VEGF injections are reasons for suboptimal visual acuity results in clinical practice.
NICE guidance (UK) indicates “no clinically significant differences in effectiveness and safety between the different anti-VEGF treatments have been seen in the trials”. Because of the expense of anti-VEGF drugs, specific criteria
have been set out by NICE to determine eligibility for treatment. Due to a discount agreement, NICE recommends ranibizumab as first choice over the other anti-VEGF drugs (NICE technology appraisal guidance 155).
Of the four anti-VEGF drugs, brolucizumab potentially has the benefit of greater penetrability and concentration in the retina compared to ranibizumab in phase 3 and 4 clinical trials, thus increasing the possibility of extending dosage intervals, which could be up to 12-week intervals instead of four, reducing cost, inconvenience, and discomfort for the patient.
RISKS AND SIDE-EFFECTS
- Red eye: A bleed on the sub-conjunctival space (white of the eye) occurs at the point of injection, which clears within a week. uSore and gritty eye (generally eases after a day).
- ‘Blobs’ or ‘small specks’ in vision (‘floaters’) might be seen for a few days after the injection. The patient may experience transient flashing lights or swirls of light immediately after the injection.
- Significant loss of vision due to this treatment (very uncommon).
- Serious eye infection (one in 1,000 cases).
- Detached retina.
- Increased intraocular pressure.
- Blood clots and bleeding in the eye.
- Inflammation inside the eye.
NICE (UK) evaluated anti-VEGF therapies in August 2008 and gave approval to ranibizumab. Ranibizumab improves vision in about one-in-three people treated. In most, it maintains vision and prevents deterioration in vision. Anti-VEGF drugs do not work at all in about one-in-10.
CONTROVERSY OVER COST OF LUCENTIS VERSUS OFF-PATENT AVASTIN
Off-label intravitreal use of the cancer drug, the anti-VEGF bevacizumab
(Avastin), has been used for ARMD instead of ranibizumab (Lucentis). Its method of action and effectiveness are similar but has a massively reduced cost compared ranibizumab (Lucentis). The cost of Avastin treatment of ARMD is between 1 per cent and 3 per cent of the cost of Lucentis treatment due to the tiny doses of Avastin needed to treat ARMD. The cost of Avastin for treating colon and other cancers is a lot more, as higher doses are needed compared to ARMD.
Smaller studies suggest that bevacizumab is effective in increasing visual acuity, with low rates of ocular adverse effects. The Comparison of ARMD Treatment Trials (CATT) study indicated Avastin had a 1.3-fold increased risk of serious systemic adverse events when compared with Lucentis. This cost disparity has caused a lot of controversy in the ophthalmology field, with Genentech, a biotech unit of Roche (manufacturer of Avastin) acting to stop off-label use of Avastin in 2007. In 2015, UK regulators advised against the off-label use of Avastin for ARMD in the “best interests of public health”, sparking a lot of controversy in medical journals like the BMJ. The off-label use of bevacizumab (Avastin) for ARMD is more common practice elsewhere in Europe and the US, and has been used by ophthalmologists in Ireland.
NEW ANTI-VEGF TYPE DRUG
The newest drug on the market is for wet ARMD is faricimab (Vabysmo). It works by targeting two pathways in retinal angiogenesis, namely VEGF-A and Ang-2, to give it an advantage over other anti-VEGF drugs. It was licensed by the European Medicines Agency in Europe in 2022. National Institute for Health and Care Excellence (NICE) in the UK approved the use of faricimab on the NHS in 2022.
Its big advantage is that it only needs to be injected once every four months instead of every four weeks and it has been proven to be as effective as anti- VEGF drugs. “Faricimab works well at early stages of wet ARMD, when the blood vessel leakage is small and has not led to scarring or damage to retinal cells,” according to Dr Praveen Patel, a consultant ophthalmologist from Moorfields Eye Hospital in London and who was a lead investigator in the trial that ensured NICE approved faricimab on the NHS.
ANTI-VEGF OPTIONS IN IRELAND
Because of cuts to health budgets in Ireland after the 2008 financial crisis, eye consultants found it difficult to get funding for ranibizumab because of its cost. Dr Noel Horgan, a consultant ophthalmic surgeon at the Royal Victoria Eye and Ear Hospital in Dublin, was quoted by Fiona Gartland in The Irish Times in May 2012 that he could no longer obtain funding for ranibizumab. He said most hospitals in the country no longer stock it because of its cost.
According to the HSE‘s 2017 National Clinical Programme for Ophthalmology report titled Model of Eye Care, no additional funding is provided for anti-VEGF treatment, with the report stating a specific budget for the care of patients with ARMD is required. No additional funding has been allocated since, so access to anti-AVGF treatment through the HSE is limited. Patients need to check their individual private health insurance plan to see if it covers anti-VEGF treatments. Faricimab is licensed in Irelandbut is currently still not funded bythe HSE, so patient accessibility is limited. The National Centre for Pharmacoeconomics (NCPE) which decides on the approval of medicines for State funding in Ireland, did a “rapid review” in faricimab in 2022 and their conclusion in October 2022 was that “a full Health Technology Assessment (HTA) is recommended to assess the clinical effectiveness and cost effectiveness of faricimab compared with the current standard of care”, so there is no certainty of when it will be available in Ireland under State funding.
Anti-VEGF drugs are the most successful treatment option for wet ARMD developed so far. The inconvenience and cost of regular eye injections, as well as fear of injections into the eye, reduces patient adherence, so efforts must be made to focus on developing new therapies to extend the dosing interval, thus reducing ‘injection burden’.
Drugs and techniques under development include individualised optical coherence tomography-guided dosing regimens, which use specialised imaging techniques to accurately determine response to anti-VEGF injections, thus increasing intervals
by reducing the number of burdensome injections, as well as longer-acting new agents with similar or new mechanisms of action and sustained- release delivery devices.
New drugs in development include:
- Abicipar pegol: This novel agent was engineered with designed ankyrin repeat proteins (DARPin) technology. Developed by Allergan, it has the benefits of greater treatment intervals, however the FDA rejected abicipar pegol for treatment of wet ARMD in 2020, citing an unfavourable benefit-risk ratio.
- The ranibizumab port delivery system: Developed by Roche, this is an implant version of ranibizumab which will stop the need for four-weekly injections currently required, thus helping patient adherence. Roche got FDA approval for this drug in the US in 2022 and are seeking approval in Europe soon too.
- Intravitreal bevacizumab formulation: Bevacizumab is used in cancer therapy and as discussed earlier, is used off-label for wet ARMD. Outlook Therapeutics Inc gained FDA approval in the US for this drug in 2022 and European approval for Intravitreal bevacizumab for wet ARMD was initially rejected by the European Medicines Agency in 2022.
- Anti-VEGF biosimilars are being developed with confidence; some of these products will be launched within three years, thus bringing down treatment cost.
Treatments like radiation therapy and surgery to the retina are being looked at. For example, a surgical technique where a part of the peripheral retina is grafted into the diseased macular area is being investigated. Research continues around the world — for example, Moorefields Eye Hospital in conjunction with UCL Institute of Ophthalmology in the
UK launched a research project in April 2020 investigating the potential of stem cell technology to prevent and treat wet ARMD.
The development of anti-VEGF drugs in recent years has lead to a reduction in the potentially less effective and more risky techniques, such as photodynamic therapy and laser photocoagulation. So, I will not discuss these options in this article. l
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Written by Eamonn Brady MPSI (Pharmacist). Whelehans Pharmacies, 38 Pearse St and Clonmore, Mullingar. Tel 04493 34591 (Pearse St) or 04493 10266 (Clonmore). http://www.whelehans.ie Eamonn specialises in the supply of medicines and training needs of nursing homes throughout Ireland. Email info@ whelehans.ie