The severity of COVID-19 and seemingly persistent nature, more than a year in now, has not only been endangering the lives of those who have contracted the disease. In efforts to clamp down the rate of transmission, strict social distancing measures, and even lock-downs have been put in place. Naturally, as resources and manpower were diverted to addressing the giant in the room, many other non-emergent conditions had to take a backseat. Clinic visits were either spaced further apart, consultation durations minimised, or taken online entirely. Not a stranger to testing the waters for extending treatment intervals, is the realm of treatment schedules in VEGF inhibitors in neovascular age-related macular degeneration (nAMD).
The Gravity of Age-Related Macular Degeneration
Age-related macular degeneration, as its name suggests, is the degenerative disease affecting the central portion of the retina (macula), that primarily results in a central loss of vision. Essential to daily living activities, like reading, watching the television, and driving, it is a highly disinhibiting condition when not managed well.
The incidence of age-related macular degeneration is higher in older adults, but seems to be decreasing with each new generation. In fact, forecast data conducted in the United States predicted that cases would double in 2050, from 1.7 million reported cases in 2010. Fortunately, this number can be lowered by preventive measures like vitamin prophylaxis, blood pressure control, quitting smoking, and early treatment.
Within AMD there are two kinds, dry AMD and wet AMD, also known as neovascular AMD. The latter is more common in advanced AMD and is responsible for more than 80% of severe cases with visual loss and legal blindness. Unlike dry AMD which is slow in onset, nAMD’s vision distortion and loss can occur in a matter of days to weeks.
The Current Treatment Scene in nAMD
The pathogenesis of nAMD can be understood on the basis of neovascularization – the formation of choroidal blood vessel networks. It is usually maintained in a dynamic balance by membrane-bound and diffusible substance which either promote or inhibit neovascularization.
The substance that was found to be most strongly associated to angiogenesis was the vascular endothelial growth factor (VEGF). More specifically, since it exists as several isoforms, it was the VEGF-A that has been the target of the current treatments for nAMD.
[insert video here]
Intravitreal injection of VEGF inhibitors or inhibitor-like drugs was found to be effective at limiting disease progression, and even reversing vision loss. However, it is the treatment-schedules which are of question, especially in this trying period. A commonly followed schedule often begins with monthly in-clinic injections (ranibizumab, bevacizumab) for a period of 3-6 months, with subsequent requirements as with the patient’s progress. Treatment with aflibercept is slightly more structured, though equally frequent at monthly intervals for the first 3 months, then every 2 months thereafter.
Outside the initial window of treatment, schedules like the “discontinuous” method is used. This method entails that injections are guided as per needed basis based on results from the optical coherence tomography (OCT). Another option is the “treat-and-extend” regimen. This consists of the initial treatment phase and stabilisation, the subsequent follow-ups are adjusted based on clinical findings, at an approximate adjustment value of 2 weeks.
Recent Findings
In this climate, there were some who conducted a study on looking at the optimal extension period of intravitreal injections for nAMD. One of which was a study published by Eye in November 2020, conducted in 1559eyes from Australia, New Zealand, Switzerland and Singapore. Amongst different dosing frequencies, they found that visual acuity was best maintained at injection intervals between 10-12 weeks, as compared to ≤ 6 weeks, 7-9 weeks or > 12 weeks. This saves at least 1 visit for the patient as compared to if they were prescribed a more rigorous dosing frequency in just one treatment cycle. Not going beyond this 12 week mark also helped reduce the relative risk of losing ≥ 15 letters by threefold.
Another exciting mention goes to a novel drug which is still in the midst of its phase III trials – faricimab. Recently, 4 of its trials (YOSEMITE NCT03622580, RHINE NCT03622593, TENAYA NCT03823287, LUCERNE NCT03823300) have proven non-inferiority at a dosing frequency of 2 months, 3 months and up to 4 months, against aflibercept at 2 months. Apart from this prolonged dosing interval, faricimab is targeting a new pathway in the pathogenesis of nAMD. And if approved, will be the first in 15 years, in the treatment of nAMD, with a new modus operandi.
The new pathway is called the Ang-Tie pathway. Notably, Angiopoietin-1 and 2 are angiogenic growth factors, who are also competing ligands that bind to the membrane-bound Tie2 receptor.
Under normal circumstances, Ang-1 is produced in a larger quantity. And its specific binding to Tie2 activates downstream signalling that promotes vascular stability.
In the diseased state, Ang-2 (and VEGF) production in upregulated, and it competes with Ang-1, resulting in vascular instability. Faricimab has then been shown to block Ang-2 and VEGF-A, resulting in a dual mechanism at limiting disease progression of nAMD, with the same potential to reverse vision loss, similar to its predecessors. But all with the advantage of a labelled, extended treatment interval which has great potential to reduce the treatment burden on patients.
Apparent even in the realm of ophthalmology, if there’s one thing that the pandemic has shown us: medicine and the people behind it, won’t be put out by adversity. Hardships, roadblocks, and obstacles are but fuel to greatness.
References:
- Age-related macular degeneration: Clinical presentation, etiology, and diagnosis. UptoDate. [Online] Accessed 26th April 2021.
-
Age-related macular degeneration: Treatment and prevention. UptoDate. [Online] Accessed 26th April 2021.
- Kawasaki R, Yasuda M, Song SJ, Chen SJ, Jonas JB, Wang JJ, Mitchell P, Wong TY. The prevalence of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology. 2010 May;117(5):921-7. doi: 10.1016/j.ophtha.2009.10.007. Epub 2010 Jan 27. PMID: 20110127.
- Teo, K.Y.C., Nguyen, V., Barthelmes, D. et al. Extended intervals for wet AMD patients with high retreatment needs: informing the risk during COVID-19, data from real-world evidence. Eye (2020). https://doi.org/10.1038/s41433-020-01315-x
