2.1 Recommended Dose

For intravitreal implantation only

• ENCELTO is administered by a single surgical intravitreal procedure performed by a qualified ophthalmologist.

• The recommended dose is one ENCELTO implant per affected eye. Each ENCELTO implant contains 200,000 to 440,000 allogeneic retinal pigment epithelial cells expressing recombinant human ciliary neurotrophic factor (rhCNTF) (NTC-201-6A cell line), a neurotrophic factor.

2.2 ENCELTO Surgical Placement

The ENCELTO implant insertion is a surgical procedure performed in an operating room under aseptic conditions by a qualified ophthalmologist. 

Refer to ENCELTO Instructions for Use for detailed guidance on implantation procedure.

2.3 ENCELTO Removal Procedure

Removal of ENCELTO is a surgical procedure performed in an operating room under aseptic conditions by a qualified ophthalmologist. Remove ENCELTO implant, if vitrectomy with a complete gas fill or silicone oil fill is required or if infectious endophthalmitis occurs.

Refer to ENCELTO Instructions for Use for detailed guidance on removal procedure.

5.1 Severe Vision Loss

Severe vision loss defined as three or more lines of visual acuity loss [≥15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] has occurred following ENCELTO implantation [see Adverse Reactions (6)]. Monitor patients for signs and symptoms of vision loss and manage as clinically indicated.

5.2 Infectious Endophthalmitis

Infectious endophthalmitis may occur following ENCELTO implantation. Signs and symptoms of infectious endophthalmitis include progressively worsening eye pain, vision loss, or scleral and conjunctival injection. To mitigate the risk of endophthalmitis, use proper aseptic surgical technique for ENCELTO implantation [see Dosage and Administration (2.2)]. Monitor patients for signs or symptoms of infectious endophthalmitis. Remove ENCELTO implant if infectious endophthalmitis occurs and manage symptoms according to clinical practice.

5.3 Retinal Tear and Detachment

Retinal tears and retinal detachment may occur following ENCELTO implantation. Signs and symptoms of retinal tears include acute onset of flashing lights, floaters, and/or loss of visual acuity. Signs and symptoms of retinal detachment may include progressive visual field loss and/or loss of visual acuity. Use standard vitreoretinal surgical techniques during ENCELTO implantation to minimize the risk of retinal tears and retinal detachment. Monitor for any signs or symptoms of retinal tear and/or retinal detachment. Treat rhegmatogenous retinal detachment and retinal tears promptly. Remove ENCELTO implant, if vitrectomy with a complete gas fill or silicone oil fill is required [see Dosage and Administration (2.3)].

5.4 Vitreous Hemorrhage

Vitreous hemorrhage, which may result in temporary vision loss, has occurred following ENCELTO implantation [see Adverse Reactions (6)]. Patients receiving antithrombotic medication (e.g., oral anticoagulants, aspirin, nonsteroidal anti-inflammatory drugs) may be at increased risk of vitreous hemorrhage. To reduce the risk of vitreous hemorrhage, interrupt antithrombotic medications prior to the ENCELTO implantation. Vitrectomy surgery may be necessary to clear severe, recurrent, or non-clearing vitreous hemorrhage. If the patient has a late onset vitreous hemorrhage (greater than one year following ENCELTO implantation surgery), examine the ENCELTO implantation site for possible implant extrusion. If implant extrusion has occurred, surgically reposition ENCELTO [see Implant Extrusion (5.5)].

5.5 Implant Extrusion

Implant extrusion through the initial scleral wound has occurred following ENCELTO implantation [see  Adverse Reactions (6)]. Signs and symptoms of implant extrusion include recurrent uveitis, vitreous hemorrhage, eye pain more than one year after implantation, or visibility of titanium fixation loop under the conjunctiva. To reduce the risk of implant extrusion, carefully follow the specific surgical steps for ENCELTO implantation [see Dosage and Administration (2.2)].

Evaluate patients after 6 months to confirm proper positioning of ENCELTO and then annually. If ENCELTO begins to extrude, surgically reposition ENCELTO to a proper scleral wound depth either in the same site or in the opposing inferior quadrant of the vitreous cavity.

5.6 Cataract Formation

Cataract formation, including cataract cortical, cataract nuclear, cataract subcapsular, cataract traumatic, and lenticular opacities, has occurred following ENCELTO implantation [see Adverse Reactions (6)].  To reduce the risk of ENCELTO-related cataract formation or progression, carefully follow the specific surgical steps for ENCELTO implantation [see Dosage and Administration (2.2)].

5.7 Suture Related Complications

Suture related complications, including conjunctival erosions due to suture tips and suture knots, have occurred following ENCELTO implantation [see Adverse Reactions (6)].   To mitigate the risk of suture related complications, carefully follow the specific surgical steps for ENCELTO implantation [see  Dosage and Administration (2.2)] and manage suture-related complications as clinically indicated. 

5.8 Delayed Dark Adaptation

Delayed Dark Adaptation, a delay in the ability to adjust vision from a bright lighting condition to a dim lighting, has occurred following ENCELTO administration which remained unchanged for the duration of study follow up [see Adverse Reactions (6)]. Advise patients to take caution while driving and navigating in the dark.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 

The safety data described in this section reflects exposure to ENCELTO in two clinical trials, Study 1 (NTMT-03-A) and Study 2 (NTMT-03-B) and are pooled for analysis. A total of 117 patients received ENCELTO, and 111 patients underwent a sham procedure and were followed for a duration of 24 months [see Clinical Studies (14)]. 

Serious adverse reactions occurred in six patients (5%) including suture related complications (n=5) and implant extrusion (n=1).  

Table 1 lists the most common adverse reactions that occurred in >2% patients and with higher frequency in ENCELTO group compared to Sham group in Study 1 and Study 2.

* Pooled data from Study 1 and Study 2; Adverse reaction rates were comparable between the two studies
**Suture related complications include exposed suture, foreign body sensation, conjunctival wound dehiscence, painful sutures, suture irritation, suture granuloma, scleral wound opening, and itchy suture
*** Includes one case of visual loss due to cataract formation which remained unresolved at the end of the study

8.1 Pregnancy

Risk Summary

There are no data on the use of ENCELTO in pregnant women. Endogenous CNTF is naturally found in maternal plasma, placental cells, and umbilical cord blood. It is not known if the use of ENCELTO increases CNTF above naturally occurring levels in these tissues.

In animal reproduction studies, subcutaneous administration of rhCNTF to pregnant rats and rabbits demonstrated no evidence of teratogenic effects on the fetus. However, when administered to rabbits at a dose level of 10ug/kg/day, a decrease in implantations and live fetuses was observed. When administered to rats at a dose level of 100ug/kg/day a decrease in corpora lutea was observed.    

The estimated background risk of major birth defects and miscarriage in the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

See Risk Summary for details on data.

8.2 Lactation

Risk Summary

There is no data on the presence of ENCELTO in human milk, its effects on the breastfed infant, or its impact on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ENCELTO and any potential adverse effects on the breastfed infant from rhCNTF or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of ENCELTO have not been established in pediatric patients.

8.5 Geriatric Use

There were 38 patients (32%) 65 years of age and older and two patients (1%) 75 years of age and older in Study 1 and Study 2 who received ENCELTO [see Clinical Studies (14)]. Clinical studies of ENCELTO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients.

12.1 Mechanism of Action

ENCELTO secretes recombinant human ciliary neurotrophic factor (rhCNTF), which is one of several neurotrophic factors endogenously produced by neurons and supporting glial cells. Exogenous CNTF is thought to initially target Müller glia to trigger a cascade of signaling events that may promote photoreceptor survival; however, the mechanism of action for ENCELTO is not completely understood.

12.3 Pharmacokinetics

Systemic exposure of rhCNTF was measured in 2 distribution studies in rabbits and in 2 toxicology studies in minipigs. Overall, there was no evidence of systemic exposure to rhCNTF after implantation of ENCELTO in rabbits for periods up to 9 months or in minipigs for periods of up to 6 months.

Following intraocular implantation of a single ENCELTO dose in rabbits at 12 weeks, the mean Cmax of rhCNTF in the vitreous and aqueous was 2.0 and 0.3 ng/mL, respectively, and below the level of quantitation (LLOQ) in the serum and contralateral, untreated eye. Similarly in human patients, rhCNTF levels were below the limit for LLOQ in the serum.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ENCELTO or of other products.

In a six-month Study NTMT-02B in which patients received ENCELTO in a single eye, one out of 31 patients (3%) tested positive for serum antibodies against the ENCELTO secreted product protein rhCNTF and one patient (3%) tested positive to serum non-secreted intracellular protein DHFR.

Because of the low occurrence of anti-drug antibodies, the effect of serum anti-rhCNTF and anti-DHFR antibodies on the safety or efficacy of ENCELTO is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis 

No carcinogenicity or mutagenicity studies have been conducted with rhCNTF. 

Impairment of Fertility

In male rats, fertility was unaffected at subcutaneous doses of rhCNTF up to 300 μg/kg/day. 

See Pregnancy (8.1) for data regarding effects on female fertility. 

16.1 How Supplied

ENCELTO is supplied as a sterile, single-dose, implant that contains 200,000 to 440,000 allogeneic retinal pigment epithelial cells expressing rhCNTF (NTC-201-6A cell line).

ENCELTO is packaged in a protective inner container within an Endothelial Serum Free Media (Endo-SFM), which is maintained sterile by a sealed outer container. ENCELTO is provided attached to a gripper that both suspends ENCELTO in the Endo-SFM and facilitates intraocular insertion. ENCELTO contains no preservatives.

NDC: 82958-501-01

See Table 4, (Figure 16) and ENCELTO “Instructions for Use” for additional details.

Figure 16. ENCELTO Corepack Contents

Figure 17. ENCELTO

Figure 18. ENCELTO Inner Container

Figure 19. pH Color Guide

16.2 Storage and Handling

1. Using the handle, remove the corepack from the larger shipping box (Figure 16). 

2. Store ENCELTO in the corepack at 16º to 37ºC (61º to 99ºF) until ready for use. 

3. Do not freeze or refrigerate.  

4. Inspect the disposable temperature recording device. If a check mark is displayed, the ENCELTO has remained within the acceptable temperature range and may be used. If a “X” is displayed, the ENCELTO was exposed to temperatures outside the acceptable range and must not be used.  Contact Neurotech immediately at (833)-963-9275.

   • Protect ENCELTO from light. 

5. Handle inner container (Figure 18) using sterile technique.

6. Do not use beyond the “use by” date identified on the corepack label. 

7. Do not use ENCELTO if the pH is not within the acceptable range (Figure 19). Contact Neurotech immediately at (833)-963-9275.

   • Prior to disposal of an ENCELTO implant per local institutional protocols, call 1-833-963-9275 for assessment of ENCELTO return or replacement.

Orange to pink liquid hold medium referred to as Endothelial Serum Free Media (Endo-SFM) within packaging inner container may contain visible particles. Particle general description fiber, solid, white, or metallic in appearance.