Clinical deep dive 

Disease state overview
MacTel type 2 is a rare neurodegenerative disease that affects the macula, which processes central and color vision. It is a bilateral asymmetric condition; typically, both eyes are impacted, but they may have different clinical presentations. The exact mechanism of the disease pathogenesis is not fully understood. However, evidence suggests the condition is neurodegenerative in nature rather than vascular, with Müller cell dysfunction being characteristic of this theory. Müller cells are involved in a host of different processes in the retina, some of which include neuroprotection, photoreceptor survival, and angiogeneis/antiangiogenesis, and thus, the dysfunction of these cells plays a significant role in the pathophysiology of MacTel type 2.

Disease progression is attributable to changes to the retinal capillaries such as thickening and increased permeability. A reduction in nutrients leads to outer retinal atrophy and degeneration. In turn, this causes photoreceptor damage and pigment migration, leading to vision loss. Typically, patients have a defect of the photoreceptor inner segment – outer segment junction line (IS/OS) or ellipsoid zone (EZ) when evaluated via spectral-domain optical coherence tomography (OCT), and the loss of the EZ has been shown to be associated with focal retinal function loss. Patients with early MacTel type 2 typically do not have any symptoms. As the disease progresses, patients may experience blurred, distorted vision. Loss of central vision may also occur over a period of 10 to 20 years. The typical course of visual acuity loss is about 1 letter per year. MacTel type 2 does not typically impact peripheral vision and normally does not result in total blindness; however, patients with this condition have notably reduced vision compared to a normal age-matched group. Subretinal neovascularization (growth of abnormal blood vessels) occurs in some patients, which can substantially hinder vision. MacTel type 2, therefore, can sometimes be misdiagnosed as age-related macular degeneration if neovascularization is part of the patient’s clinical presentation. 

Epidemiology 
MacTel type 2 prevalence rates vary, and studies have shown rates between 0.0045% and 0.1%. Patients with this condition are often diagnosed in middle age, which is most commonly in the range of 40 to 60 years of age. As previously mentioned, the exact cause of the disease is unknown; however, patients with diabetes and hypertension may be at an increased risk of developing MacTel type 2. Additionally, it is thought that there may be a genetic component involved, but this pattern is not completely understood.

Treatment 
Several different treatments have been evaluated in clinical trials to treat MacTel type 2, which have limited or no efficacy. These treatments include options such as laser therapy, intravitreal steroid injections, and anti-vascular endothelial growth factor (VEGF) injections, with treatment choices differing for nonproliferative forms and for subretinal neovascularization. Patients with MacTel type 2 may also utilize low vision aids to assist with their remaining vision. 

Drug and clinical trial overview 

The safety and efficacy of revakinagene taroretcel was evaluated in two identical multicenter, randomized, sham-controlled Phase 3 trials. NTMT-03-A and NTMT-03-B enrolled 115 and 113 participants, respectively. Patients were eligible for inclusion if they were > 21 to < 80 years of age with at least one study eye with a positive diagnosis of MacTel type 2. Additionally, participants were required to have an EZ loss between 0.16 and 2.00 mm² and a best corrected visual acuity (BCVA) of 54 or better as measured by the Early Treatment Diabetes Retinopathy Study (ETDRS) chart at screening. The trials excluded patients with intraretinal or subretinal neovascularization as well as patients who received intravitreal anti-VEGF therapy in the study eye or within the past 3 months of the fellow eye at randomization. Patients were randomized in a 1:1 fashion to receive either revakinagene taroretcel or sham procedure. The primary efficacy endpoint in both trials was the rate of change in the EZ area loss from baseline to month 24. At the primary endpoint, a 55% (0.075 mm²/24 months for the treatment arm vs. 0.166 mm²/24 months for the sham arm; p<0.0001) and 31% (0.111 mm²/24 months for the treatment arm vs. 0.160 mm²/24 months for the sham arm; p=0.0186) rate of reduction was observed in the EZ area loss for NTMT-03-A and NTMT-03-B, respectively. Treatment with revakinagene taroretcel resulted in preserved retinal sensititvity in NTMT-03-A. The secondary endpoint of mean change in aggregate retinal sensitivity loss from baseline through month 24 between the treatment arm and sham was 25.27 vs. 43.02 decibel (dB) (p=0.0199), respectively, for NTMT-03-A. No statistically significant differences in retinal sensitivity were seen in NTMT-03-B between the treatment arm and sham. Additionally, reading speed at 24 months appeared better preserved with revakinagene taroretcel; the secondary endpoint of mean change from baseline in reading speed between the treatment group and sham, respectively, was -6.18 vs. -12.20 words per minute (wpm) (p=0.3849) for NTMT-03-A and -5.46 vs. -18.88 wpm (p=0.0331) for NTMT-03-B. Treatment-related serious ocular adverse events occurred at a low rate and were observed in ≤ 7% of patients who received revakinagene taroretcel in both trials. The serious ocular adverse events were primarily related to the surgical procedure. In both trials, no adverse events led to explantation.