Revakinagene Taroretcel Approval Addresses Unmet Need in MacTel

Following its recent FDA approval, revakinagene taroretcel-lwey (Encelto; Neurotech Pharmaceuticals) is the first and only therapy indicated for the treatment of macular telangiectasia type 2 (MacTel), a neurodegenerative disease of the retina that causes progressive, irreversible vision loss.¹ The allogeneic encapsulated cell-based gene therapy employs a novel strategy for administration that facilitates continual benefits for a patient population that previously had no options.

Clinical investigator Charles C. Wykoff, MD, PhD, Retinal Consultants of Texas, discussed revakinagene taroretcel’s mechanism of action and the findings supporting the therapy's FDA approval.

This transcript has been lightly edited; captions were auto-generated.

Transcript

What is revakinagene taroretcel’s mechanism of action, and how does it slow the progression of MacTel?

Yeah, thanks. Great to be here with you, and great to be able to talk about Encelto. Encelto, previously known as NT-501, or revakinagene, is the first generation of what's called ECT, or encapsulated cell therapy. This is a platform technology that's been under development for about 20 years, actually, and it's fascinating technology. Basically, it's a cylinder about 6 mm long and about 1 to 2 mm in diameter, and this cylinder has a semipermeable membrane that houses about 300,000 genetically modified RPE [retinal pigment epithelium] cells. And these cells are living tissue. They're engineered to overexpress a very specific therapeutic protein called CNTF, or ciliary neurotrophic factor, and this implant is surgically implanted into the eye.

You make a 3-mm-long scleral incision, and then you suture this implant to the inside of the eye wall. You close the incision, and you reapproximate the overlying conjunctiva. It's a one-time surgical procedure, and then this implant rests inside the vitreous cavity and produces the therapeutic protein CNTF, which diffuses into the retina, where it has its biological effect. And then, importantly, these cells receive their oxygen and nutrients from the vitreous cavity while remaining sequestered and away from the immune system.

That's what the implant is, and the way that it treats MacTel type 2, or MacTel for short, is through this therapeutic protein CNTF. The pathophysiology of MacTel is incompletely understood, but one of the leading hypotheses is that Muller cells are dysfunctional. And one of the roles of Muller cells—which span the entire neurosensory retina, from the internal limiting membrane to the external limiting membrane and have many biological roles in managing retinal health—one of their functions is to produce neuroprotective factors. One of them is CNTF. The thought here is that if Muller cells become dysfunctional in MacTel, leading to progression of the disease, that we can restore some of that functional neural cell activity by treating patients with CNTF. And, importantly, this is the very first treatment available for patients with MacTel. Before this, there has been nothing for these patients with a disease that is progressive in many cases and causes significant distortion and dysfunction of central vision.

What were the key findings from the phase 3 trials that supported revakinagene taroretcel’s approval?

[Revakinagene taroretcel] has been in clinical trials for MacTel for a long time. There was a phase 1 trial,² there was a robust phase 2 trial,³ and now we have 2 robust phase 3 trials.^4,5 The phase 3 trial was designed based on learnings from the phase 2 trial, and the design was that these were global trials that enrolled adults with MacTel. They had very specific criteria related to vision and ellipsoid zone area breakdown. Vision had to be 20/80 or better, and the ellipsoid zone area of breakdown, or ellipsoid zone break, as it was called, had to be between 0.16 and 2 mm²—very small, very specific measurements to get into the trial. And then patients were randomized equally to 1 of 2 arms: either active treatment with NT-501 or a sham surgical procedure.

There were between 55 and 59 patients in each of those 4 arms. Again, half the patients got active treatment and half the patients got sham treatment. These were 2-year trials, and the primary end point was the rate of change in ellipsoid zone area loss on OCT [optical coherence tomography] from baseline through month 24, and secondary end points included change in retinal sensitivity by microperimetry and reading speed—again, all measured at month 24.

If you look at the patient population that were enrolled, on average, they were about 60 years of age. Baseline vision was about 20/40, and baseline area of ellipsoid zone area loss was just under 0.5 mm². If you look at the key efficacy outcomes at 2 years, treatment with NT-501 reduced ellipsoid zone area loss by 55% and 31% in the 2 clinical trials, respectively, both of them statistically significant, so both trials met their primary end points. The secondary outcomes of interest were microperimetry, which showed a reduction in sensitivity loss of 41% in one trial and 5% in the other; and then the final one was a reduction in reading speed loss of 49% and 69% in the 2 trials.

If you look at the safety profile of this implant, overall, it was well tolerated. The key safety issues were related to the surgical procedure itself, as well as suture issues, as well as long-term device-associated vitreous hemorrhages. All of those were rare and manageable, and the 2 other adverse events were delayed dark adaptation and meiosis happening in a minority of patients, which potentially is related to the effect of CNTF itself.

References

1. McNulty R. FDA approves revakinagene taroretcel for macular telangiectasia type 2. AJMC^®. March 7, 2025. Accessed March 24, 2025. https://www.ajmc.com/view/fda-approves-revakinagene-taroretcel-for-macular-telangiectasia-type-2

2. Ciliary neurotrophic factor (CNTF) safety trial in patients with macular telangiectasia (MacTel). ClinicalTrials.gov. Updated November 22, 2016. Accessed March 24, 2025. https://clinicaltrials.gov/study/NCT01327911

3. A phase 2 multicenter randomized clinical trial of CNTF for MacTel. ClinicalTrials.gov. Updated September 12, 2018. Accessed March 24, 2025. https://clinicaltrials.gov/study/NCT01949324

4. A study to determine the safety and efficacy of NT-501 in macular telangiectasia type 2 - protocol A. ClinicalTrials.gov. Updated September 24, 2024. Accessed March 24, 2025. https://clinicaltrials.gov/study/NCT03316300

5. A study to determine the safety and efficacy of NT-501 in macular telangiectasia type 2 - protocol B. ClinicalTrials.gov. Updated September 24, 2024. Accessed March 24, 2025. https://clinicaltrials.gov/study/NCT03319849