This article was originally published in a sponsored newsletter.
For this month's Retina Minute, I have the pleasure of interviewing my good friend, Dr. Tom Albini, who is a professor of ophthalmology at the Bascom-Palmer Eye Institute.
Dr. Albini, recently at the Retina World Congress meeting, you presented data from Neurotech Pharmaceuticals on their product (NT-501) for macular telangiectasia (MacTel). Tell us about the product and the data you presented.
First, MacTel is a disease that is characterized by the loss of photoreceptors and other neural elements, including Muller cells and ganglion cells. Neurotech’s encapsulated cell technology product candidate is exciting. It is a novel intraocular delivery platform that, if approved, could bring a therapeutic option to MacTel patients. So, what is NT-501 and encapsulated cell technology? Neurotech has been able to take human retinal pigment epithelial (RPE) cells and genetically engineer them to produce ciliary neurotrophic factor (CNTF). These cells are then encapsulated in a porous polymer capsule that is smaller than a grain of rice. The capsule's pores allow the CNTF to be released into the vitreous cavity. The pores are too small for immune effector cells to enter the capsule, so no inflammatory reaction occurs. The capsule is surgically embedded into the vitreous cavity via a 3 mm pars plana incision and secured to the sclera. Once inside the eye, the RPE cells receive all their nutrients from within the vitreous cavity. As you know, there is no direct blood supply to the cells.
The longevity of these implants has exceeded expectations. Neurotech has received explanted NT-501s that still show productivity of the CNTF protein with no significant histopathologic change for up to 14 years. The data I presented showed the benefit that NT-501 has produced by this encapsulated cell technology for MacTel. Study patients had an early diagnosis of MacTel with vision 20/80 or better and a prespecified range of ellipsoid zone loss. The primary outcome of the 2 phase 3, multicenter, randomized, controlled pivotal trials was a reduction in the rate of ellipsoid zone loss in participants receiving NT-501 as compared to a sham surgical procedure. Across both studies, approximately 230 patients were enrolled and followed for 2 years. There was a statistically significant reduction in the amount of ellipsoid zone loss, and the primary endpoint was met in both studies.
If approved by the FDA, this technology would be the first treatment available for patients with MacTel without choroidal neovascularization. To date, there has been nothing to offer those patients that has been demonstrated to provide clinical benefits, so this could be an exciting therapeutic option for MacTel patients.
You mentioned the surgery requires placement of the implant through a 3 mm pars plana incision. How challenging is the procedure and how steep do you think the learning curve is?
I do not like to say anything in surgery is straightforward, but it is reminiscent of putting in a Retisert implant (Bausch + Lomb). I have been involved in other clinical studies with the Neurotech implant, and I can tell you that the technicalities of the surgery have evolved over the last decade or so. Neurotech has incorporated the suggestions of many surgical teams to improve the implantation procedure.
The procedure requires preparation, but there is nothing about it that is technically difficult compared to normal vitreoretinal surgery. Perhaps the most challenging parts of it are not the surgery itself, but rather the proper care and handling of the implant. These implants are non-stock devices, so they must be ordered specifically for each patient. Because the NT-501 holds living cells and is delivered in a culture media, you have to pay attention to the temperature at which the device is maintained, how it is opened, how long it is opened, and how long it survives outside of the culture media and outside of the eye because it has to be put into the eye within a certain timeframe.
Tell us about safety.
The safety data of NT-501 is unremarkable and as expected, especially in the context of the concerns that we have had with other gene therapy products that are under development as retina therapeutic candidates. The safety concerns have been mostly miosis and dark adaptation, which have been noted in approximately 20% of the patients across the studies. We also saw surgical suture granuloma-type occurrences, subconjunctival hemorrhage, and other issues that you would expect after a surgical implantation procedure.
However, these occurrences were not significant enough that patients elected to have the device removed. So, although I think there may be some issues that are directly related to the ciliary neurotrophic factor that should be monitored, they are anticipated complications that should be shared with potential NT-501 recipients. Notably, there were no cases of clinically significant retinal vasculitis, RPE changes, or other changes in the retina identified. Overall, for a surgical implant, the safety has been unremarkable so far.
As this product heads toward the FDA and assuming it gets FDA clearance, how do you expect to use it on your patient population? Who are the first patients you will treat?
There is a lot to be said for treating early with this device. You want to decrease the amount of ellipsoid zone loss over time as soon as you can. Patients with early MacTel who are motivated, and certainly patients who have lost a significant amount of vision in one eye and want to preserve the other eye, seem to be good candidates. We may start with patients who have more severe disease until we feel comfortable with the real-world safety of the product, but I expect to move on to treating patients with early MacTel not long after approval.
How do you approach your discussions with patients? Do you focus on visual gain or preservation to prevent visual loss?
Preservation. This product decreases the rate of ellipsoid zone loss. It does not eliminate it, and it does not decrease the amount of ellipsoid zone loss. So, I think the goal is to preserve the vision they have and to start that preservation as soon as possible. We have some post hoc analyses coming out that I expect will tell us more about optimal patients for this device, and how early MacTel patients do with the implant.
I am excited to understand the benefits of this treatment better because I believe it would be the first FDA-approved treatment that uses ellipsoid zone loss as a primary outcome variable as opposed to geographic atrophy lesion size, for example, although the two are not dissimilar.
We also need to look more closely at the functional secondary outcomes in these pivotal trials. There was a statistically significant improvement in microperimetry/retinal sensitivity outcomes in one of the trials, though it was not reproducible in the second trial, perhaps because of the lesion types that were enrolled in each study. Though there was a similar distribution of baseline ellipsoid zone lesion sizes between treatment and sham arms within study, there was a slight difference in the distribution of ellipsoid zone lesion size between studies. That needs to be better studied, but I think there may be easier functional correlates with the ellipsoid zone loss than there were with the geographic atrophy area size. Finally, there also seemed to be better preservation in reading speed in both trials.
We are still learning about these functional outcomes, and I am excited for future work that will be done on all this data.
Has the BLA (biologics license application) been submitted?
Yes, the BLA was submitted on April 18 and a priority review was requested in the application. Neurotech is hoping to get an approval toward the end of this year and is excited about the potential of bringing this therapeutic option to patients with MacTel.
Dr. Albini, thank you so much for sharing this data with us. We may have a new tool to give patients hope with a disease that we have observed for many years.
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