If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
CORRESPONDING AUTHOR/ADDRESS FOR REPRINTS: Jeffrey L Goldberg, 2452 Watson Ct, Palo Alto, CA 94303
Affiliations
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94303, United StatesShiley Eye Center, University of California San Diego, School of Medicine, San Diego, CA 92092, United StatesBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, United States
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94303, United StatesShiley Eye Center, University of California San Diego, School of Medicine, San Diego, CA 92092, United StatesBascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, 33136, United States
To assess the safety and efficacy of ciliary neurotrophic factor (CNTF) intraocular implant on neuroprotection and neuroenhancement in glaucoma.
DESIGN
Open-label, prospective, phase 1 clinical trial.
PARTICIPANTS
A total of 11 participants 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, while the other eye served as a control. All patients were followed for 18 months. Analysis was limited to descriptive statistics.
MAIN OUTCOME MEASURES
Primary outcome was safety through 18 months post-implant 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 optical coherence tomography (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 implant placement procedure and were resolved by 12 weeks post-op. Foreign-body sensation was the most commonly reported AE, and was self-limited to the post-op period. The most common implant-related AE was pupil miosis; no patients underwent explant. VA and contrast sensitivity decreased more in fellow eyes compared to study eyes (VA -5.82 vs. -0.82 letters, and contrast sensitivity -1.28 vs. - 0.37 letters, for fellow vs. study eyes, respectively). HVF visual field index and mean deviation measurements decreased in fellow eyes (-13.0%, -3.9 dB) and increased in study eyes (2.7%, 1.2 dB). Implanted eyes showed an increase in retinal nerve fiber layer (RNFL) thickness measured by OCT (2.66 μm in fellow eyes vs. 10.16 μm in study eyes) and by GDx VCC (1.58 μm in fellow eyes vs. 8.36 μm in study eyes).
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 implant in POAG patients, now underway.
INTRODUCTION
Glaucoma is the most common cause of irreversible blindness worldwide.
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.
Goldberg JL. The optic nerve. In: Levin, LA.; Nilsson, SF.; Ver Hoeve, J., et al., editors. Adler's Physiology of the Eye. 11th ed. New York: Saunders/Elsevier. 2011:550-573.
In many patients disease continues to progress despite effective IOP lowering. Reported progression rates in settings of routine clinical care, defined as mean deviation (MD) rate faster than -1 to -2 dB/year, varies widely among studies ranging from as low as 3% to as high as 17%.
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/or the optic nerve directly, towards neuroprotection, neuroenhancement, and/or neuroregeneration
Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
Based on this strong pre-clinical data, we hypothesized that CNTF treatment to the eye could prevent loss of vision (neuroprotection, or prevention of neuronal death) and/or improve vision (neuroenhancement, or improved function of surviving neurons) in patients with glaucoma.
Here we evaluate the effect of CNTF on retinal structure and visual function in a phase I trial in glaucoma patients 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 1 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.
MATERIALS AND 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 appropriate institutional review board and was conducted in accordance with the principles of the Declaration of Helsinki, and in compliance with FDA Good Clinical Practice (GCP) guidelines; and an Investigational New Device application held by Dr. Goldberg as Sponsor-Investigator. Informed consent was obtained from all study participants prior to initiation of the study and the study was HIPAA compliant. Study-specific inclusion and exclusion criteria are listed in Table 1.
Table 1Complete 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 one structural modality; (b) residual visual field preservation including BCVA better than 20/100; (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 one eye
•
Requirement of acyclovir and/or 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 prior to inclusion in the trial.
BCVA = best-corrected visual acuity, HIV = human immunodeficiency virus, IOP = intraocular pressure, RGC = retinal ganglions cell.
Encapsulated Cell Technology - Each participant received a single NT-501-6A.02 (NT-501) CNTF-secreting, encapsulated cell device into one 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 one end. Each implant contains approximately 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/day.
The encapsulated cell device was placed into one eye of each patient, selecting the worse baseline best-corrected VA (BCVA) and worse mean deviation (MD) on Humphrey visual field (HVF) testing, by JLG with assistance from TAA. The implant was placed through the pars plana via a 2.0 mm sclerotomy at 3.75 millimeters posterior and parallel to the limbus in the inferotemporal quadrant. The titanium anchor of the implant was secured to the sclera at 50-90% depth with a single 9-0 prolene suture, and the sclera closed with a 9-0 nylon mattress suture; the conjunctival peritomy was closed with 7-0 vicryl. An indirect peripheral fundoscopic exam with scleral depression was performed to confirm 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. Post-operatively, topical antibiotic moxifloxacin was used 4 times/day for 1 week, and topical prednisolone acetate 1% was used 4 times/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 including slit lamp and fundus exam, measurement of BCVA by Early Treatment of Diabetic Retinopathy Study (ETDRS) chart and performance of additional structural and functional testing. HVF (HFA2, Carl Zeiss Inc., Dublin, CA), pattern electroretinogram (pERG), scanning laser polarimetry with variable corneal compensation (GDx VCC, Carl Zeiss Meditec, Inc., Dublin, CA) and optical coherence tomography (OCT, Cirrus, Carl Zeiss Meditec, Inc., Dublin, CA) were performed at baseline visits one and two. Examinations for safety without additional testing were conducted at post-operative day 1 and week 1, and then full visits with examinations for safety and additional testing were conducted at post-operative months (POM) 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 non-randomization and different disease staging between the two eyes. All data were entered into Excel (Microsoft) and then screened for accuracy by KRS by crosschecking each value in the source medical record documents. Any discrepancies were then reviewed with JLG and corrected before locking the data. The examiners were not masked to which eye got the implant, as device location and proper position were regularly evaluated for safety aspects. However, both the ophthalmic photographers and the visual field technicians were masked.
Table 2Tabulated exam data for anticipated, successfully completed, and analyzed studies
Exam
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
ETDRS = Early Treatment Diabetic Retinopathy Study, GDx VCC = scanning laser polarimetry with variable corneal compensation, OCT = optical coherence tomography, pERG = pattern electroretinogram.
Data Collection and Analysis - VA and contrast sensitivity were measured once per study visit per patient per eye, resulting in a calculated total of 154 ETDRS exams. Four exams were missing from the analysis due to one patient missing POM3 and POM6 appointment dates (Table 2). Per study protocol, if a patient had a 4 meter score of less than 20 letters, a 1-meter ETDRS exam 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. AEs were marked for severity, duration, relationship to investigational product, relationship to implant procedure, intervention(s) if any, and resolution.
Visual field sensitivity was measured prioritizing the 24-2 (54 point) Swedish Interactive Threshold Algorithm (SITA) standard HVF once per study visit per eye. Of the 154 intended exams, 96 24-2 exams were completed; in most other cases, 10-2 testing was used instead of 24-2 due to advanced stage of disease. Due to the advanced stage of disease in this phase 1 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 was not available and there were 3/7 or fewer visit exams completed. One patient failed to have two baseline visual field studies within the two months prior to initiation of the study, and both fellow and study eye data were excluded from analysis. In the end, 88 exams 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, 53/55 studies were completed successfully. Of the 6 included study eyes, 35/41 studies were completed successfully.
Two pERG exams per eye were performed at each study visit. Out of 308 total planned exams, 300 exams were successfully completed. Eight out of 8 missing exams were due to 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 KRS, informed by the guidelines created by the University of California San Diego (UCSD) Reading Center, with assistance from Keri Dirkes and Suzanne Vega. A total of 154 visit exams were planned and 66/77 fellow eye and 59/77 study eye exams were successfully completed. Of those, 8 scans were excluded for signal strength of 4 or less, segmentation failure of the algorithms, overall poor scan quality, or an incomplete scan, and thus 60/77 fellow eye and 57/77 study eye exams were included in the analysis of the data.
Retinal thickness was also assessed using the Temporal Superior Nasal Inferior Temporal (TSNIT) values of GDx VCC scans. One hundred and 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, one phakic and one pseudophakic, underwent prior glaucoma procedures, including trabeculectomy and glaucoma drainage device implantation, and one eye had prior vitrectomy. Comprehensive patient and eye baseline characteristics were tabulated (Table 3).
Table 3Baseline patient and fellow/study eye characteristics
Characteristics
Patients
Sex Male Female
6 (55%) 5 (45%)
Race Caucasian African American Hispanic
6 (55%) 2 (18%) 3 (27%)
Age Mean Median Range
70.7 71 58 - 85
Fellow Eyes
Study Eyes
Average
Median
Range
Average
Median
Range
BCVA (ETDRS) Contrast Sensitivity
78.64 11.27
82 12
61-88 6 - 14
70.18 8.55
73 9
43-84 5 - 14
VF VFI (%) MD (dB)
81.0 (-) 8.6
73.94 (-) 10.01
27 - 97 (-) 21.94 - (-) 1.43
52.3 (-) 16.8
48.25 (-) 17.62
9 - 72.5 (-) 29.53 - (-) 8.62
pERG (μV) Amplitude Variability Standard Deviation
0.36 0.25 -3.52
0.31 0.29 (-) 4.04
0.17 - 0.54 0.07 - 0.36 (-) 6.38 - (-) 1.55
0.32 0.27 -3.91
0.35 0.22 (-) 3.71
0.16 - 0.45 0.07 - 0.50 (-) 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, ETDRS = Early Treatment Diabetic Retinopathy Study, GDx VCC = scanning laser polarimetry with variable corneal compensation, MD = mean deviation, OCT = optical coherence tomography, pERG = pattern electroretinogram, RNFL = retinal nerve fiber layer, TSNIT = temporal superior nasal inferior temporal, VF = visual field, VFI = Visual field index.
*Baseline measures are average of two baseline visits
Safety Profile - The NT-501 CNTF-secreting device and surgical implant procedure were well tolerated. There were no serious adverse events (SAEs) 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 post-op. 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 post-operative 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 explantation.
Table 4Adverse events for fellow eye, study eye, both eyes or other
Visual Acuity and Contrast Sensitivity- There was a greater loss in both visual acuity and contrast sensitivity in fellow eyes compared to study eyes (Table 5). In eyes with baseline ETDRS scores of 70 or above, 8/8 study eyes and 7/7 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 visual acuity stabilization at 18 months. Examining the average visual acuity ETDRS and contrast sensitivity Pelli-Robson scores for fellow and study eyes (Figure 1A, 1C) and individual eye change from baseline (Figure 1B, 1D), 4/11 study eyes showed contrast sensitivity improvement, while no fellow eyes improved. One fellow eye experienced reduction in visual acuity of 56 ETDRS letters during the study period attributed mostly to progression of epiretinal membrane and cystoid macular edema in that eye (Figure 1C). This outlier affected the POM18 mean visual acuity value due to the large deviation and the small sample size (Figure 1A). When excluding that patient form visual acuity analysis the fellow eyes show only mild decrease of visual acuity during the study period (mean ETDRS letters ± SEM) of -0.80 ± 2.02, compared to -5.82 ± 5.84 when included.
Table 5Results summary for study exams
Study
Fellow Eyes
Study Eyes
Baseline
18 months
Change
Baseline
18 months
Change
BCVA (ETDRS) Contrast Sensitivity
78.64 11.27
72.82 9.45
-5.82 -1.82
70.18 8.55
69.36 8.18
-0.86 -0.37
VF VFI (%) MD (dB)
81.0 -8.6
68.0 -12.5
-13.0 -3.9
52.3 -16.8
55.0 -15.6
2.7 1.2
pERG (μV) Amplitude Variability Standard Deviation
0.36 0.25 -3.52
0.30 0.26 -4.60
0.06 0.01 -1.08
0.32 0.27 -3.91
0.30 0.30 -4.44
-0.02 0.03 -0.05
OCT (μm) Avg RNFL Thickness
68.39
71.05
2.66
63.44
73.60
10.16
GDx VCC (μm) TSNIT Avg Thickness
40.54
42.12
1.58
40.35
48.71
8.36
Avg = average, BCVA = best‐corrected visual acuity, ETDRS = Early Treatment Diabetic Retinopathy Study, GDx VCC = scanning laser polarimetry with variable corneal compensation, MD = mean deviation, OCT = optical coherence tomography, pERG = pattern electroretinogram, RNFL = retinal nerve fiber layer, TSNIT = temporal superior nasal inferior temporal, VF = visual field, VFI = Visual field index.
*Baseline measures are average of two baseline visits
Figure 1Visual acuity and contrast sensitivity charts. Figure 1A, 1B show the mean BCVA (ETDRS) and contrast sensitivity (Pelli-Robson) scores on study and fellow eyes across study visits, respectively. Figures 1C, 1D 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. ETDRS = Early Treatment Diabetic Retinopathy Study, 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 decreased in fellow eyes and showed a modest increase in study eyes when examined by study visit (Figure 2A, 2C) or by change from baseline to POM18 or last available data (Figure 2B, 2D). The pattern standard deviation (PSD) mean values (dB ± SEM) 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 2Humphrey visual field data from study and fellow eyes. Figure 2A and 2B show the individual average VFI percentage change and average MD dB change over the course of the study (study delta) graphed against baseline values. Filled marker denotes study delta calculated using POM18, while unfilled marker denotes POM12, and dash as POM3. Linear least squares regression lines included with R2 correlation coefficient values. dB = decibel, MD = mean deviation, POM = post-operative month, VFI = visual field index
Pattern Electroretinogram - No differences in pERG amplitude, variability, or standard deviation were observed in CNTF-treated study eyes compared to 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, Figure 3A-B). Similarly, by GDxVCC, TSNIT average thickness increased by 8.36 in study eyes versus 1.58 in fellow eyes (Figure 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 1-3 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, one patient had preexisting bilateral epiretinal membrane.
Figure 3The optic disc average RNFL was measured by Cirrus OCT for both study and fellow eyes. 3A, Shows the average optic disc RNFL thickness (μm) graphed by study visit. 3B, Displays individual eye change from baseline (study delta, in μm) clustered into study eye and fellow eye groups. Square markers denote POM18 as the visit date used for study delta calculation while a rhombus marker denotes POM12, a triangle POM9 and a circle POM6, for cases reporting last data carried forward. BL = baseline, OCT = optical coherence tomography, POM = post-operative month, RNFL = retinal nerve fiber layer
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, encapsulated cell technology (ECT) and intravitreal injection.
The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: relation to parameters of the acute-phase response. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group.
Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases.
ECT allows for long-term, continuous delivery of CNTF to the retina; in one study of NT-501 devices later explanted from human patients, cell integrity and CNTF secretion were unchanged from baseline at least 2 years later
Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases.
. In this study, no implants met criteria for explant and no implants extruded during the study.
There were no serious ocular or extra-ocular AEs. The most common adverse events were typical for post-operative ophthalmologic 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, intra-ocular implant or CNTF-secretion.
Mild miosis (anisocoria) occurred in 2/11 (18%) implanted eyes. Prior human studies using the same CNTF-secreting implant have reported miosis in 18.8%
in retinitis pigmentosa patient trials. Two earlier phase 1 trials involving macular degeneration and retinitis pigmentosa reported lower incidence of miosis ranging from none to less than 10%.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
In prior phase I human CNTF implant trials in patients with macular telangiectasia and retinitis pigmentosa, a notable adverse event also included transient decreases in cone flicker electroretinogram (fERG) in 4/7 study eyes
, 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 visual acuity.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
The cone fERG was used in both photoreceptor degeneration studies mentioned above, while in this study we used the pattern ERG to assess the macular RGCs’ function in patients with glaucomatous RGC degeneration, and detected no change in pERG. 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 to flicker ERG in outer retinal diseases.
Beyond the primary endpoint 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, non-randomized study, and the baseline level of disease was significantly worse in the implanted eyes compared to the fellow eyes. This might potentially bias the results towards 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 visual acuity, 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 1-3 months of implant and sustained through the course of the 18-month study. Other human studies have reported visual acuity stabilization and even marked improvement in study eyes, especially in eyes with better baseline vision, consistent with our study.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
Study eyes with CNTF-secreting implants demonstrated structural change as well, with increase in RNFL thickness measured similarly by OCT or GDx-VCC. This is congruent with increases in thickness of other retinal layers in prior human studies of macular telangiectasia, age-related macular degeneration and retinitis pigmentosa.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
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. CNTF may act on RGC axons, nerve fiber layer astrocytes, Mueller glial endfeet, or some combination of these to increase RNFL thickness.
Ciliary neurotrophic factor-mediated signaling regulates neuronal versus glial differentiation of retinal stem cells/progenitors by concentration-dependent recruitment of mitogen-activated protein kinase and Janus kinase-signal transducer and activator of transcription pathways in conjunction with Notch signaling.
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 encapsulated cell technology 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 2 trial of macular telangiectasia type 2 was recently published
, and a phase 3 trial is currently underway in this disease (ClinicalTrials.gov Identifier: 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 glaucoma populations. 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 six study eyes and eight 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.
In summary, this phase 1 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 2 clinical trial in glaucoma, with a trial extension examining dual NT-501 implantation, is now underway (ClinicalTrials.gov Identifiers: NCT02862938, NCT04577300).
REFERENCES
Quigley HA
Broman AT
The number of people with glaucoma worldwide in 2010 and 2020.
Goldberg JL. The optic nerve. In: Levin, LA.; Nilsson, SF.; Ver Hoeve, J., et al., editors. Adler's Physiology of the Eye. 11th ed. New York: Saunders/Elsevier. 2011:550-573.
Intraocular gene transfer of ciliary neurotrophic factor prevents death and increases responsiveness of rod photoreceptors in the retinal degeneration slow mouse.
Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration.
The pharmacokinetics of subcutaneously administered recombinant human ciliary neurotrophic factor (rHCNTF) in patients with amyotrophic lateral sclerosis: relation to parameters of the acute-phase response. The ALS CNTF Treatment Study (ACTS) Phase I-II Study Group.
Two-year intraocular delivery of ciliary neurotrophic factor by encapsulated cell technology implants in patients with chronic retinal degenerative diseases.
Ciliary neurotrophic factor-mediated signaling regulates neuronal versus glial differentiation of retinal stem cells/progenitors by concentration-dependent recruitment of mitogen-activated protein kinase and Janus kinase-signal transducer and activator of transcription pathways in conjunction with Notch signaling.
MEETING PRESENTATION: An earlier version of these data were presented as part of Dr. Goldberg’s Shaffer Lecture at the American Academy of Ophthalmology.
ACKNOWLEDGEMENTS: NT-501 implants and access to FDA filings were provided by Neurotech. The authors gratefully acknowledge support from the NEI (P30-EY026877), the BrightFocus Foundation, and Research to Prevent Blindness, Inc., and technical support from Keri Dirkes, Suzanne Vega, Manny Acera and Dan Auerbach.
CONFLICT OF INTEREST: None.
PRÉCIS: The CNTF-secreting NT-501 implant was well tolerated and did not cause any serious adverse events, and showed both structural and functional improvement in 11 eyes with primary open-angle glaucoma.
00030-1&id=gr1.jpg){kind=link}
00030-1&id=gr2.jpg){kind=link}
00030-1&id=gr3.jpg){kind=link}
00030-1&id=gr4.jpg){kind=link}