Phase I NT-501 Ciliary Neurotrophic Factor Implant Trial for Primary Open-Angle Glaucoma: Safety, Neuroprotection, and Neuroenhancement

Abstract

Purpose

To assess the safety and efficacy of a ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma.

Design

Open-label, prospective, phase I clinical trial.

Participants

A total of 11 participants were diagnosed with primary open-angle glaucoma (POAG). One eye of each patient was assigned as the study (implant) eye.

Methods

The study eye was implanted with a high-dose CNTF-secreting NT-501 implant, whereas the other eye served as a control. All patients were followed up for 18 months. Analysis was limited to descriptive statistics.

Main Outcome Measures

Primary outcome was safety through 18 months after implantation assessed by serial eye examinations, structural and functional testing, and adverse events (AEs) recording. Parameters measured included visual acuity (VA), Humphrey visual field (HVF), pattern electroretinogram, scanning laser polarimetry with variable corneal compensation (GDx VCC), and OCT. These parameters were also used for secondary analysis of efficacy outcome.

Results

All NT-501 implants were well tolerated with no serious AEs associated with the implant. The majority of AEs were related to the implant placement procedure and were resolved by 12 weeks after surgery. Foreign-body sensation was the most commonly reported AE and was self-limited to the postoperative period. The most common implant-related AE was pupil miosis; no patients underwent explant. Visual acuity and contrast sensitivity decreased more in fellow eyes than in study eyes (VA, −5.82 vs. −0.82 letters; and contrast sensitivity, −1.82 vs. −0.37 letters, for fellow vs. study eyes, respectively). The median HVF visual field index and mean deviation measurements worsened (decreased) in fellow eyes (−13.0%, −3.9 dB) and improved (increased) in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer thickness measured by OCT and by GDx VCC (OCT, 2.66 μm vs. 10.16 μm; and GDx VCC, 1.58 μm vs. 8.36 μm in fellow vs. study eyes, respectively).

Conclusions

The NT-501 CNTF implant was safe and well tolerated in eyes with POAG. Eyes with the implant demonstrated both structural and functional improvements suggesting biological activity, supporting the premise for a randomized phase II clinical trial of single and dual NT-501 CNTF implants in patients with POAG, which is now underway.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Glaucoma is the most common cause of irreversible blindness worldwide.¹ Glaucoma is associated with and defined by progressive retinal ganglion cell (RGC) and optic nerve degeneration² with stereotypical loss of peripheral vision detectable on standard automated perimetry, and structural damage that includes cupping of the optic nerve, neuroretinal rim thinning, and retinal nerve fiber layer (RNFL) defects.³ All current medical and surgical treatments target reduction of intraocular pressure (IOP), a major risk factor for glaucoma progression.² In many patients, disease continues to progress despite effective IOP lowering. Reported progression rates in settings of routine clinical care, defined as a mean deviation (MD) rate faster than −1 to −2 dB per year, varies widely among studies ranging from as low as 3% to as high as 17%.4, 5, 6, 7, 8, 9, 10 However, no approved therapies specifically target the neurodegenerative process itself. Thus, a major goal of current glaucoma research is to find complementary therapies that will target RGCs, the retina, and the optic nerve directly toward neuroprotection, neuroenhancement, and neuroregeneration.²

Neurotrophic growth factors have been identified as potential therapeutics for neurodegenerative disease.¹¹ Ciliary neurotrophic factor (CNTF) is one such candidate with strong preclinical evidence for retinal neuroprotection in several animal models12, 13, 14, 15, 16, 17, 18 that improves the survival and optic nerve axon regeneration of RGCs.^2,19 Ciliary neurotrophic factor has been shown to increase retinal thickness in a dose-dependent manner in patients with age-related maculopathy and retinitis pigmentosa.^19,20 Based on these strong preclinical data, we hypothesized that CNTF treatment to the eye could prevent loss of vision (neuroprotection or prevention of neuronal death) and improve vision (neuroenhancement or improved function of surviving neurons) in patients with glaucoma.² Here, we evaluate the effect of CNTF on retinal structure and visual function in a phase I trial in patients with glaucoma using a CNTF-secreting encapsulated cell technology (ECT) NT-501 intravitreal implant for sustained delivery.

It is not known whether CNTF delivery using the NT-501 device could show similar neuroprotection in patients with optic neuropathies, such as glaucoma. The purpose of this phase I study was to primarily assess the safety of the CNTF-secreting NT-501 implant in patients with primary open-angle glaucoma and evaluate the effect of CNTF on retinal structure and visual function.

Methods

Study Design

Eleven participants, 22 eyes, with the diagnosis of open-angle glaucoma were enrolled in the study from April 2011 to February 2012. This prospective study, registered at ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT01408472), was completed at a single center. The study was reviewed and approved by the institutional review board at University of Miami Miller School of Medicine and was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with Food and Drug Administration Good Clinical Practice guidelines, and an Investigational New Device application was held by Dr Goldberg as sponsor-investigator. Informed consent was obtained from all study participants before initiation of the study, and the study was Health Insurance Portability and Accountability Act compliant. Study-specific inclusion and exclusion criteria are listed in Table 1.

Table 1.

Complete Study Inclusion and Exclusion Criteria

Inclusion Criteria

•Must understand and sign the informed consent •Must be medically able to undergo ophthalmic surgery for the NT-501 device insertion and possible removal, as well as the testing required •Diagnosis of glaucoma characterized by (a) clinical evidence of progressive RGC dysfunction and degeneration using both visual field and at least 1 structural modality; (b) residual visual field preservation including BCVA better than 20/100; and (c) failure to contain glaucomatous progression with maximally tolerated reduction of IOP, or visual field defect affecting fixation, but not reducing BCVA below 20/100

Exclusion Criteria

•Other corneal, lens, optic nerve, or retinal disease causing vision loss •Blind in 1 eye •Requirement of acyclovir and related products during study •Receiving systemic steroids or other immunosuppressive medications •Pregnant or lactating •Considered immunodeficient or has a known history of HIV •On chemotherapy, or a history of malignancy, unless it was treated successfully 2 years before inclusion in the trial

BCVA = best-corrected visual acuity; HIV = human immunodeficiency virus; IOP = intraocular pressure; RGC = retinal ganglions cell.

ECT

Each participant received a single NT-501-6A.02 (NT-501) CNTF-secreting, encapsulated cell device into 1 eye. The device measures 1 mm in diameter by 6 mm in length. The implant is composed of an inner matrix framework and an outer semipermeable membrane with a medical-grade sealant and a titanium anchor located at 1 end. Each implant contains ∼200 000 encapsulated cells of the NTC-201-6A line derived from human retinal pigment epithelium, genetically modified to secrete human CNTF at a high-dose rate of 20 ng per day.¹⁰

The encapsulated cell device was placed into 1 eye of each patient, selecting the worse baseline best-corrected visual acuity (VA) and worse MD on Humphrey visual field (HVF) testing, by J.L.G. with assistance from T.A.A. The implant was placed through the pars plana via a 2.0-mm sclerotomy at 3.75-mm posterior and parallel to the limbus in the inferotemporal quadrant. The titanium anchor of the implant was secured to the sclera at a 50% to 90% depth with a single 9-0 prolene suture, and the sclera was closed with a 9-0 nylon mattress suture; the conjunctival peritomy was closed with 7-0 vicryl. An indirect peripheral fundoscopic examination with scleral depression was performed to confirm the location and correct placement of the implant and lack of retinal tear or detachment. At the end of the surgery, subconjunctival injections and topical drops of antibiotics and steroids were administered. Postoperatively, topical antibiotic moxifloxacin was used 4 times per day for 1 week, and topical prednisolone acetate 1% was used 4 times per day for the first week and then tapered off over the subsequent 3 weeks. No changes were made to the patient’s concomitant medications throughout the study.

The primary outcome was ocular safety after NT-501 implantation. A comprehensive eye examination included slit lamp and fundus examination, measurement of best-corrected VA by ETDRS chart, and performance of additional structural and functional testing. Humphrey visual field (HFA2, Carl Zeiss Inc), pattern electroretinogram (pERG), scanning laser polarimetry with variable corneal compensation (GDx VCC, Carl Zeiss Meditec, Inc), and OCT (Cirrus, Carl Zeiss Meditec, Inc) were performed at baseline visits 1 and 2. Examinations for safety without additional testing were conducted on postoperative day 1 and week 1, and then full visits with examinations for safety and additional testing were conducted at postoperative months (POMs) 1, 3, 6, 12, and 18 (Table 2). The patient’s fellow eye was used as a control in the study, primarily to guard against learning effects on HVF testing, although direct comparison was limited by nonrandomization and different disease staging between the 2 eyes. All data were entered into Excel (Microsoft) and then screened for accuracy by K.R.S. by crosschecking each value in the source medical record documents. Any discrepancies were then reviewed with J.L.G. and corrected before locking the data. The examiners were not masked to which eye got the implant because device location and proper position were regularly evaluated for safety aspects. However, both the ophthalmic photographers and the visual field technicians were masked.

Table 2.

Tabulated Examination Data for Anticipated, Successfully Completed, and Analyzed Studies

Examination	Anticipated (n)	Completed (n)	Fellow (n)/Study (n)	%	Analyzed (n)	Fellow (n)/Study (n)	%
ETDRS	154	150	75/75	97.4	150	75/75	97.4
VF	154	96	55/41	62.3	88	53/35	57.1
pERG	308	300	150/150	97.4	300	150/150	97.4
OCT	154	125	66/59	81.2	117	60/57	76.0
GDx VCC	154	137	69/68	89.0	137	69/68	89.0

GDx VCC = scanning laser polarimetry with variable corneal compensation; pERG = pattern electroretinogram; VF = visual field.

Data Collection and Analysis

Visual acuity and contrast sensitivity were measured once per study visit per patient per eye, resulting in a calculated total of 154 ETDRS examinations. Four examinations were missing from the analysis because of 1 patient missing POM3 and POM6 appointment dates (Table 2). Per study protocol, if a patient had a 4-m score of < 20 letters, a 1-m ETDRS examination was performed. Two patients met these criteria during the study.

Adverse events (AEs) were tabulated at every visit and verified against source (medical record) documentation. Adverse events were marked for severity, duration, relationship to investigational product, relationship to implant procedure, intervention(s) if any, and resolution.

Visual field sensitivity was measured by prioritizing the 24-2 (54 points) Swedish Interactive Threshold Algorithm standard HVF once per study visit per eye. Of the 154 intended examinations, 96 24-2 examinations were completed; in most other cases, 10-2 testing was used instead of 24-2 because of advanced stage of disease. Because of the advanced stage of disease in this phase I study and the limited number of eyes that met inclusion criteria for visual field analysis, all of the data available were analyzed regardless of false-positive or false-negative testing percentage. An eye qualified for exclusion from analysis if data from POM18 were not available and there were 3 of 7 or fewer visit examinations completed. One patient failed to have 2 baseline visual field studies within the 2 months before initiation of the study, and both fellow and study eye data were excluded from analysis. In the end, 88 examinations across 8 (72%) of fellow eyes and 6 (54%) of study eyes were included in the analysis of the HVF 24-2 data. Of the 8 fellow eyes included in the visual field analysis, 53 of 55 studies were completed successfully. Of the 6 included study eyes, 35 of 41 studies were completed successfully.

Two pERG examinations per eye were performed at each study visit. Out of 308 total planned examinations, 300 examinations were successfully completed. Eight out of 8 missing examinations were because of a single patient missing POM3 and POM6 appointment dates. All successfully completed studies were included in the analysis of the data.

Retinal morphology and thickness were assessed by optic disc scans using OCT. OCT images were extracted by certified technicians. The images underwent quality review by K.R.S., informed by the guidelines created by the University of California San Diego Reading Center, with assistance from Keri Dirkes and Suzanne Vega. A total of 154 visit examinations were planned, and 66 of 77 fellow eye and 59 of 77 study eye examinations were successfully completed. Of those, 8 scans were excluded for a signal strength of 4 or less, segmentation failure of the algorithms, overall poor scan quality, or an incomplete scan, and thus, 60 of 77 fellow eye and 57 of 77 study eye examinations were included in the analysis of the data.

Retinal thickness was also assessed using the temporal superior nasal inferior temporal values of GDx VCC scans. One hundred thirty-seven scans were successfully completed out of 154 planned scans. All completed scans were included in the analysis of the data.

Results

Baseline Study Population Characteristics

A total of 11 patients, 22 eyes, were enrolled in the study from April 2011 to February 2012. One hundred percent of patients completed the study. The mean participant age was 70.7 years (range, 58–85 years). Four out of 11 study eyes were phakic. Two study eyes, 1 phakic and 1 pseudophakic, underwent prior glaucoma procedures, including trabeculectomy and glaucoma drainage device implantation, and 1 eye had prior vitrectomy. Comprehensive patient and eye baseline characteristics were tabulated (Table 3).

Table 3.

Baseline^∗ Patient and Fellow/Study Eye Characteristics

Characteristics	Patients
Sex
Male	6 (55%)
Female	5 (45%)
Race
White	6 (55%)
African American	2 (18%)
Hispanic	3 (27%)
Age
Mean	70.7
Median	71
Range	58–85

	Fellow Eyes			Study Eyes
	Average	Median	Range	Average	Median	Range
BCVA (ETDRS)	78.64	82	61–88	70.18	73	43–84
Contrast sensitivity	11.27	12	6–14	8.55	9	5–14
VF
VFI (%)	73.94	81.0	27-97	48.25	52.3	9-77
MD (dB)	-10.01	-8.6	(-)21.94-(-)1.40	-17.62	-16.8	(-)29.53-(-)7.5
pERG (μV)
Amplitude	0.36	0.31	0.17-0.54	0.32	0.35	0.16-0.45
Variability	0.25	0.29	0.07-0.36	0.27	0.22	0.07-0.50
Standard deviation	−3.52	-4.04	(-)6.38-(-)1.55	−3.91	-3.71	(-)7.74-(-)2.15
OCT (μm)
Avg RNFL thickness	68.39	67.25	48.85–93.17	63.44	59.0	50.0–82.83
GDx VCC (μm)
TSNIT Avg thickness	40.54	38.75	23.70–61.30	40.35	33.3	28.05–66.0

Avg = average; BCVA = best-corrected visual acuity; GDx VCC = scanning laser polarimetry with variable corneal compensation; MD = mean deviation; pERG = pattern electroretinogram; RNFL = retinal nerve fiber layer; TSNIT = temporal superior nasal inferior temporal; VF = visual field; VFI = visual field index.

^∗Baseline measures are the average of 2 baseline visits when available.

Safety Profile

The NT-501 CNTF-secreting device and surgical implant procedure were well tolerated. There were no serious AEs attributable to the device, implant procedure, or active agent. The majority of AEs were mild, related to the implant surgical placement procedure, and resolved by 12 weeks after surgery. Common procedure-related AEs tabulated over the 18-month study period included foreign-body sensation, erythema, and dry eye sensation (Table 4). The most common device-related AE was pupillary miosis, which was well tolerated by the patients. Two patients had temporary IOP elevation in the study eye, which resolved with standard of care. One patient had eye pressure elevated (IOP = 39 mmHg) at postoperative day 1, in settings of stopping glaucoma medications overnight, and the pressure was normalized after anterior chamber paracentesis and restarting regular glaucoma drops. Another patient had steroid-induced ocular hypertension (IOP = 30 mmHg), which resolved after steroid tapering. One other patient required topical medication addition for both eyes during the study period. The IOP was otherwise stable in both the study and fellow eye during the study period. No patient required device explanation.

Table 4.

Adverse Events for Fellow Eye, Study Eye, Both Eyes, or Other

Adverse Event	Study Eye	Fellow Eye	Both Eyes	Other	Total
Foreign-body sensation	9	0	0	0	9
Dry eye	1	0	6	0	7
Pain	6	1	0	0	7
Conjunctival injection	6	0	0	0	6
Redness	5	0	0	0	5
Blurry vision	5	0	0	0	5
Subjconjunctival hemorrhage	4	0	0	0	4
Ocular hypertension	2	0	1	0	3
Miosis	2	0	0	0	2
Discharge	2	0	0	0	2
Anterior chamber cells	2	0	0	0	2
Blepharitis	1	0	1	0	2
Decreased vision	0	2	0	0	2
Blepharoplasty	1	0	0	0	1
Corneal abrasion	1	0	0	0	1
Tearing	1	0	0	0	1
Dimness	1	0	0	0	1
Irritation	1	0	0	0	1
Posterior capsule opacification	0	0	1	0	1
Tube failure/revision	0	1	0	0	1
Baerveldt shunt	0	1	0	0	1
Increased systemic hypertension	0	0	0	1	1
Nausea	0	0	0	1	1
Squamous cell carcinoma	0	0	0	1	1
Bell's palsy	0	0	0	1	1
Dizziness	0	0	0	1	1
Stroke	0	0	0	1	1

VA and Contrast Sensitivity

There was a greater loss in both VA and contrast sensitivity in fellow eyes than in study eyes (Table 5). In eyes with baseline ETDRS scores of 70 or above, 8 of 8 study eyes and 7 of 7 fellow eyes showed no change or modest improvement in final ETDRS scores, suggesting risk of loss was greater among eyes with worse initial acuity. Study eye data showed a trend toward VA stabilization at 18 months. Examining the average VA ETDRS and contrast sensitivity Pelli–Robson scores for fellow and study eyes (Fig 1A, C) and individual eye change from baseline (Fig 1B, D), 4 of 11 study eyes showed contrast sensitivity improvement, whereas no fellow eyes improved. One fellow eye experienced reduction in VA of 56 ETDRS letters during the study period attributed mostly to progression of epiretinal membrane and cystoid macular edema in that eye (Fig 1C). This outlier affected the POM18 mean VA value because of the large deviation and the small sample size (Fig 1A). When excluding that patient form VA analysis, the fellow eyes showed only a mild decrease of VA during the study period (mean ETDRS letters ± standard error of the mean) of −0.80 ± 2.03, compared with −5.82 ± 5.34 when included.

Table 5.

Results Summary for Study Examinations

Study	Fellow Eyes			Study Eyes
	Baseline∗	18 mos	Change	Baseline∗	18 mos	Change
BCVA (ETDRS), mean	78.64	72.82	−5.82	70.18	69.36	−0.82
Contrast sensitivity, mean	11.27	9.45	−1.82	8.55	8.18	−0.37
VF, median
VFI (%)	81.0	68.0	−13.0	52.3	55.0	2.7
MD (dB)	−8.6	−12.5	−3.9	−16.8	−15.6	1.2
pERG (μV), mean
Amplitude	0.36	0.30	−0.06	0.32	0.30	−0.02
Variability	0.25	0.26	0.01	0.27	0.30	0.03
Standard deviation	−3.52	−4.60	−1.08	−3.91	−4.44	−0.53
OCT (μm), mean
Avg RNFL thickness	68.39	71.05	2.66	63.44	73.60	10.16
GDx VCC (μm), mean
TSNIT Avg thickness	40.54	42.12	1.58	40.35	48.71	8.36

Avg = average; BCVA = best-corrected visual acuity; GDx VCC = scanning laser polarimetry with variable corneal compensation; MD = mean deviation; pERG = pattern electroretinogram; RNFL = retinal nerve fiber layer; TSNIT = temporal superior nasal inferior temporal; VF = visual field; VFI = visual field index.

∗Baseline measures are the average of 2 baseline visits when avalible.

Figure 1.

Visual acuity and contrast sensitivity charts. A, B The mean best-corrected visual acuity (BCVA) (ETDRS) and contrast sensitivity (Pelli–Robson) scores on study and fellow eyes across study visits, respectively. C, D Demonstrate individual visual acuity (ETDRS) and contrast sensitivity (Pelli–Robson) change from baseline scores, respectively, plotted against individual baseline values. Linear least squares regression lines depict squared Pearson correlation coefficients for study and fellow eyes with R² values given. BL = baseline; POM = postoperative month; SEM = standard error of the mean.

Visual Field

Visual field changes for study and fellow eyes are summarized in Table 5. Visual field index and MD showed a modest increase in study eyes compared to the fellow eyes when examined by change from baseline to POM18 or last available data (Fig 2). The pattern standard deviation mean values (dB ± standard error of the mean) did not demonstrate significant change between baseline and POM18 in each of the groups (9.45 ± 0.91 vs. 8.85 ± 1.01 and 7.18 ± 1.40 vs. 7.22 ± 1.24 at baseline and POM18 for study eyes and fellow eyes, respectively).

Figure 2.

Humphrey visual field data from study and fellow eyes. A, B The individual average visual field index (VFI) percentage change and average mean deviation (MD) decibels (dB) change over the course of the study (study delta) graphed against baseline values. Filled markers denote study delta calculated using postoperative month (POM) 18, whereas unfilled markers denote POM12, and the dash denotes POM3. Linear least squares regression lines included with R² correlation coefficient values.

pERG

No differences in pERG amplitude, variability, or standard deviation were observed in CNTF-treated study eyes compared with fellow eyes (Table 5).

Retinal Structural Changes

The NT-501 implant resulted in an increase in average RNFL thickness by 10.16 μm in study eyes versus 2.66 μm in fellow eyes by OCT (Table 5, Fig 3A, B). Similarly, by GDx VCC, temporal superior nasal inferior temporal average thickness increased by 8.36 in study eyes versus 1.58 in fellow eyes (Fig 4A, B). Examination of individual OCT scans did not detect any cystoid or other edema in any eyes. Using either measure, increased RNFL thickness was usually detectable by the 1 to 3 month time points and sustained throughout the course of the 18-month study. Our analysis did not reveal structure-function correlations in this small sample size. Of note, 1 patient had preexisting bilateral epiretinal membrane.

Figure 3.

The optic disc average retinal nerve fiber layer (RNFL) was measured by Cirrus OCT for both study and fellow eyes. A, The average optic disc RNFL thickness (μm) graphed by study visit. B, Displays individual eye change from baseline (study delta, in μm) clustered into study eye and fellow eye groups. Square markers denote postoperative month (POM) 18 as the visit date used for study delta calculation, whereas a rhombus marker denotes POM12, a triangle POM9, and a circle POM6, for cases reporting last data carried forward. BL = baseline.

Figure 4.

The temporal superior nasal inferior temporal (TSNIT) thickness was measured by scanning laser polarimetry with variable corneal compensation (GDx) scan. A, The average TSNIT thickness (nanometers, μm) graphed by study visit (baseline [BL], postoperative month [POM]). B, Displays individual eye POM18 change from baseline (study delta, in μm) clustered into study eye and fellow eye groups.

Discussion

This is the first human trial performed to assess the safety and efficacy of the CNTF-secreting NT-501 implant in patients with glaucoma. Several delivery methods have been proposed to deliver CNTF to the retina, including viral transposons, ECT, and intravitreal injection.^2,21, 22, 23 Encapsulated cell technology allows for long-term, continuous delivery of CNTF to the retina; in 1 study of NT-501 devices later explanted from human patients, cell integrity and CNTF secretion were unchanged from baseline at least 2 years later.²³ In this study, no implants met criteria for explant and no implants were extruded during the study.

There were no serious ocular or extraocular AEs. The most common AEs were typical for postoperative ophthalmic procedures, such as foreign-body sensation likely attributable to conjunctival vicryl closure, which occurred in 9 out of 11 implanted eyes; and most AEs resolved within 3 months after the procedure. Similarly to previously reports, there were no serious AEs related to the surgical procedure, intraocular implant, or CNTF secretion.^20,24,25 Mild miosis (anisocoria) occurred in 2 (18%) of 11 implanted eyes. Prior human studies using the same CNTF-secreting implant have reported miosis in 18.8%²⁴ and 71%²⁵ in macular telangiectasia patient trials and 25%²⁰ and 31%²⁰ in retinitis pigmentosa patient trials. Two earlier phase I trials involving macular degeneration and retinitis pigmentosa reported a lower incidence of miosis ranging from none to < 10%.^19,26

In prior phase I human CNTF implant trials in patients with macular telangiectasia and retinitis pigmentosa, a notable AE also included transient decreases in cone flicker electroretinogram (fERG) in 4 of 7 study eyes²⁵ and 1 of 7 study eyes²⁶, respectively. Interestingly, the lone patient in the phase I retinitis pigmentosa study who had diminished cone fERG responses during the implantation period concurrently was reported to have increased VA.²⁶ Other studies did not report any notable differences in electroretinogram measurements for study or untreated eyes.^19,20 The cone fERG was used in both photoreceptor degeneration studies mentioned above, whereas in this study, we used the pERG to assess the function of the macular RGCs in patients with glaucomatous RGC degeneration and detected no change. This may reflect differences in the physiologic effects of CNTF on outer versus inner retinal function or the distinct cells’ electrical activities measured by these different ERG types. Alternatively, it could represent an artifactual relative insensitivity of pERG in advanced glaucoma compared with fERG in outer retinal diseases.

Beyond the primary end point of safety in this trial, a number of secondary measures were examined for functional and structural evidence of biological effect in glaucoma. It should be noted, however, that this was a small, nonrandomized study, and the baseline level of disease was significantly worse in the implanted eyes than in the fellow eyes. This might potentially bias the results toward observing improvements or less worsening of structural and functional measures in the study eyes. Issues may include greater variability of measurements of visual fields of worse disease, regression to the mean, and floor effects in testing. Thus, we limited analysis of these data to descriptive statistics only and included patient-level data where helpful. With these important limitations, functional measures including central VA, contrast sensitivity, and visual field performance suggested a positive biological effect of NT-501 implant in this study. These stabilizations or improvements in function were generally detectable within 1 to 3 months of implant and sustained through the course of the 18-month study. Other human studies have reported VA stabilization and even marked improvement in study eyes, especially in eyes with better baseline vision, consistent with our study.^19,26

Study eyes with CNTF-secreting implants demonstrated structural change as well, with an increase in RNFL thickness measured similarly by OCT or GDx VCC. This is congruent with increases in the thickness of other retinal layers in prior human studies of macular telangiectasia, age-related macular degeneration, and retinitis pigmentosa.^{19,20,25,27,28} Increasing retinal thickness secondary to CNTF has also been demonstrated in animal models.^17,29 Although thinning or atrophy of the RNFL is associated with glaucomatous degeneration,³⁰ it is not yet known whether thickening similar to that observed here is an indicator of neuroprotection or positive functional improvement, although no alternative explanations, such as retinal edema, were detected. Ciliary neurotrophic factor may act on RGC axons, nerve fiber layer astrocytes, Mueller glial endfeet, or some combination of these to increase RNFL thickness.31, 32, 33, 34 Again, the sample size in this study was not powered to demonstrate meaningful clinical or statistical differences; however, these findings suggest that CNTF delivered by ECT may show coordinated structural and functional findings, supporting the premise of biological activity. A statistically significant neuroprotective effect of the same implants in a phase II trial of macular telangiectasia type 2 was recently published,²⁴ and a phase III trial is currently underway in this disease (ClinicalTrials.gov identifiers: NCT 03319849, NCT 03316300).

The study has several limitations, including the use of a small sample size and an open-label design, which, in designing a subsequent trial, would not be appropriate to detect a function neuroprotective affect. The study only included patients with primary open-angle glaucoma, which limits generalizability to other general populations with glaucoma. In addition, 12.6% of studies anticipated were not completed; of 924 overall anticipated studies, only 808 were completed (detailed in Table 2). Specifically, only 6 study eyes and 8 fellow eyes met the inclusion criteria for visual field analysis and contributed data to the results. Of note, there were no systematic differences between the patients who did or did not contribute to the analysis. Lastly, this study used one-at-a-time, spaced, visual field test schedule without clustering at the beginning or end of follow-up, which would also limit the ability to statistically confirm progression.^35,36

In summary, this phase I trial indicated that CNTF-secreting NT-501 implants are safe and well tolerated in a population of patients with open-angle glaucoma. Advantages of intraocular implant include local, continuous therapeutic delivery of stable treatment doses while eliminating ocular surface toxicity. Other benefits to implant delivery include the ability to retrieve the implant should adverse effects occur. Based on these data, a randomized, sham-controlled, masked, phase II clinical trial in glaucoma, with a trial extension examining dual NT-501 implantation, is now underway (ClinicalTrials.gov identifiers: NCT02862938, NCT04577300).

Manuscript no.. XOPS-D-22-00216.