Currently on Phase IV of its clinical trials, the Japanese Treat and Extend Study of Aflibercept in Neovascular Age-related Macular Degeneration (ALTAIR) aims to assess both the efficacy and safety of aflibercept administration methods.
The Phase IV ALTAIR study, conducted in Japan, has been evaluating the efficacy and safety of the anti-VEGF treatment aflibercept solution for intravitreal injection, using Treat and Extend (T&E) dosing regimens with patients who have wet age-related macular degeneration (wAMD). The data indicates that up to 60 percent of patients could have their injection interval increased from every four weeks to 12 weeks or beyond by the end of the second year of treatment.
We asked Professor Gemmy Cheung to explain how those findings translate into real world practice and what they mean for clinicians and patients. Dr Gemmy Cheung is currently Professor and Senior Consultant Ophthalmologist at Singapore National Eye Centre (SNEC), Duke-NUS Medical School, National University of Singapore (NUS), where she is also the is the Head of the Medical Retina Department.
1. What is wAMD?
Age-related macular degeneration (AMD) is one of the leading causes of severe vision loss in older adults in the developed world, if left untreated. Macular degeneration is diagnosed as either dry (non-exudative) or wet (exudative or neovascular) age-related macular degeneration. It occurs when the structures in the back of the eye produce excess vascular endothelial growth factor (VEGF), a naturally occurring protein which triggers the formation of new blood vessels. This excess VEGF causes the growth of abnormal new blood vessels under the macula – the part of the eye responsible for central vision – which can leak fluid into the eye and damage central vision, causing vision loss. Although we refer to dry and wet AMD as subtypes, wAMD is actually just a progression of the disease, a more severe form of AMD. About 10 percent of AMD patients go on to develop wAMD. Although it can take many years for a patient to progress from dry AMD to wAMD, once it becomes wAMD the disease progresses much more quickly and can lead to complete and irreversible vision loss in as little as three months.
2. What is the ALTAIR study?
The Phase IV ALTAIR study evaluated the efficacy and safety of the anti-VEGF treatment aflibercept using two different treat and extend (T&E) dosing regimens in Japanese patients with wAMD. Patients taking part in the study received aflibercept treatment for three consecutive monthly doses followed by an injection after two months (week 16 of the study). At week 16, patients were randomized 1:1 into two groups, in which the T&E dosing regimen was applied with either a four-week interval adjustment group or a two-week interval adjustment group. A total of 246 patients, an average of 74 years old participated in the trial.
During the T&E phase, injection interval was defined by treating physicians based on the pre-defined criteria that considered imaging findings and changes in best-corrected visual acuity (BCVA). The interval between intravitreal aflibercept injections after the 16-week randomization could not be shorter than eight weeks or longer than 16 weeks.
The primary endpoint in ALTAIR was change from baseline in BCVA as measured by early treatment diabetic retinopathy study (ETDRS) letter score at week 52. Other efficacy endpoints include the proportion of patients who maintained vision, proportion of patients who gained at least 15 letters of vision compared to baseline, mean change in Central Retinal Thickness (CRT) from baseline, and proportion of patients without fluid on Optical Coherence Tomography (OCT), at weeks 52 and 96 respectively. Treatment exposure-related parameters like number of injections and last injection interval were also investigated.
3. What were the results of the ALTAIR study?
The ALTAIR study demonstrated that aflibercept injections can halt the progression of wAMD and reverse some of the vision loss. What is new about the ALTAIR results is that they also demonstrate that after the wAMD is stabilized with the initial intensive phase of injections, the treatment intervals can be doubled or even tripled in many patients, while still maintaining the vision gains.
For wAMD the standard treatment regimen was monthly injections but ALTAIR has shown that after the first three months it is usually safe, based on the physician’s judgement of visual and anatomic outcomes, to extend the treatment interval to two months; and if after another four or five treatments the wAMD is stable, the physician can try extending the interval even further to 10 or even 12 weeks to find the patient’s optimal treatment window. The most rapid recovery of visual acuity - measured by the number of additional letters the patient can identify on a Snellen or LogMAR chart - occurs during the first three months of treatment but may continue at a slower rate for several more rounds of treatments. Improvement typically plateaus within the first year. The standard treatment protocol was to continue with the monthly treatments, but ALTAIR has shown that once improvements in sharpness have plateaued, we can safely extend the treatment interval without losing any of the gains.
In the ALTAIR study, vision gains achieved at 52 weeks were largely maintained at the end of 96 weeks using the T&E dosing regimens with aflibercept; a mean improvement of 6.1 letters was achieved by patients in the four week adjustment group with a maximum interval of 12 weeks and 7.6 letters for those in the two week adjustment group with a 10 or 12 week interval. These results at 96 weeks were similar to those observed in the pivotal Phase III aflibercept studies VIEW1 and VIEW2 at the same time point.
The mean number of injections from week 52 to week 96 in the four-week group was 3.7 and in the two-week group 3.6, with a mean last injection interval up to week 96 of 12.5 and 12.2 weeks, respectively. The proportion of patients with a last injection interval of 12 weeks or more at week 96 was up to 60 percent across the study, and the mean number of injections received through 96 weeks was less than 11.
4. What do the ALTAIR findings mean for clinicians and patients?
There are several important and practical messages. One of the advantages of a proactive T&E dosing regimen is the opportunity to personalize and adjust the treatment interval to the individual needs of every patient, by gradually extending or shortening the dosing interval, based on the patient’s disease activity at the time of injection rather than following a rigid schedule. There are also great savings in time and money. For the elderly patients affected by wAMD and their caregivers, reducing the number of visits to the hospital for injections from once a month to once a quarter saves time, saves on the cost of medication and can generally improve the quality of life by reducing the travel burden and the time spent waiting in hospitals. For hospitals and healthcare providers, this strategy can lead to more efficient use of healthcare resources and reduce overcrowding and waiting time.
John Battersby, an experienced medical and pharma writer