Encelto
revakinagene taroretcel
Sources:FDA pharmacology/toxicology review ↗US prescribing information ↗FDA summary basis for approval ↗
Species
RatDogRabbitPig
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Minipig, pig and rabbit (ocular tox/PK); rcd1 dog for pharmacology; rat and rabbit for rhCNTF DART
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study in 4–8-month-old minipigs, 4–10-year-old pigs”
Why that species
Disease-relevant animal models support CNTF photoreceptor protection; no explicit species rationale for tox species
“Histopathologic studies in naturally occurring and genetically engineered animal models of photoreceptor dysfunction that phenotypically model retinitis pigmentosa support a role for rhCNTF”
Surrogate molecule
No surrogate cell product; representative NT-501 device used; DART used recombinant human CNTF SC in rat/rabbit
“The nonclinical development program evaluated a product representative of ENCELTO”
Species: general tox
Minipigs and pigs (3-part long-term intravitreal implant toxicology study)
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study in 4–8-month-old minipigs, 4–10-year-old pigs”
Species: DART
Rat and rabbit (4 DART studies of SC rhCNTF: fertility and teratogenicity)
“Four Developmental and Reproductive Toxicity (DART) studies were conducted in rats and rabbits to establish the risks to fertility and teratogenicity associated with the subcutaneous (SC) administration of high doses of rhCNTF.”
Species: carcinogenicity
Not conducted (not warranted per toxicological risk assessments)
“Studies to evaluate the carcinogenicity/tumorigenicity of ENCELTO were not conducted. These studies are not warranted based on the safety profile described in the provided toxicological risk assessments (TRAs).”
Surrogate used in
No surrogate; a product representative of ENCELTO (NT-501) was tested
“The nonclinical development program evaluated a product representative of ENCELTO”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“There was no evidence of systemic exposure to rhCNTF after ITV implantation of NT-501 in minipigs for up to 6 months or in rabbits for up to 9 months.”
Pivotal GLP studies
Non-GLP 12-week rabbit ocular tox/PK; 3-part minipig/pig long-term ITV implant study to 6 months; unencapsulated-cell device failure study in minipigs
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study”
Route in tox
Intravitreal (ITV) implantation via pars plana sclerotomy; SC rhCNTF in DART studies
“ENCELTO is intended for surgical implantation by intravitreal (ITV) insertion via a pars plana sclerotomy.”
Skipped studiesopen answer page →
Genotoxicity
Done: ISO-10993 battery (bacterial, mammalian cell, mouse micronucleus on device extracts), negative
“No genotoxicity was observed in these studies.”
Carcinogenicity
Not conducted (waived based on toxicological risk assessments)
“Studies to evaluate the carcinogenicity/tumorigenicity of ENCELTO were not conducted.”
Instead of genotoxicity
No substitute; ISO-10993 device genotoxicity battery on NT-501 instead of cell-specific assessment
“A battery of genotoxicity studies was conducted to support licensure of NT-501 in keeping with ISO-10993, guidance for biological evaluation of medical devices.”
Reproductive & developmental
Four DART studies of SC rhCNTF in rats and rabbits; no teratogenicity; exemption for device via margin of exposure
“There were no rhCNTF-related teratologic changes reported in the fetuses.”
Safety pharmacology
Not stated as separate studies; ERG assessments for intraocular implants in pharmacology
“Electroretinographic (ERG) Assessments for Intra-Ocular Implantation of”
Genotox: Ames
Negative: bacterial reverse mutation assay of device extract (no 2-fold increase in revertants)
“There were no instances of a 2-fold or greater increase in the mean number of revertants of tester strains.”
Genotox: in vitro mammalian
Negative: in vitro mammalian cell clastogenicity assay of device extract, with and without activation
“Under the conditions of this assay, the test article extract was not considered genotoxic to in the presence or absence of metabolic activation.”
Genotox: in vivo
Negative: mouse bone marrow micronucleus study
“mouse bone marrow micronucleus study, and a Kligman maximization test. No genotoxicity was observed in these studies.”
Carcinogenicity model
Not conducted; waived via toxicological risk assessments for rhCNTF and ENDO medium
“The applicant provided TRAs conducted by to support waivers for carcinogenicity/tumorigenicity studies for rhCNTF and the medium used within the device, human Endothelial-SFM medium (ENDO medium).”
Carcinogenicity timing
Not required (waiver rationale accepted by reviewer)
“This reviewer agrees with the rationale provided in the TRAs for not conducting carcinogenicity/tumorigenicity studies.”
hERG / QT
Not conducted (no safety pharmacology studies with NT-501)
“No safety pharmacology studies with NT-501 were conducted.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Encelto don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL set for device; minimal lens, vitreous and ocular inflammation; no systemic findings. rhCNTF DART NOAELs used for margins of exposure (FDA pharmacology/toxicology review, p. 2)
NOAEL / key findings
No NOAEL set for device; minimal lens, vitreous and ocular inflammation; no systemic findings. rhCNTF DART NOAELs used for margins of exposure
“ITV implantation of NT-501 did not cause any effects on systemic clinical signs, gross pathology, or histopathology of non-ocular organs.”
Risksopen answer page →
Immune & cytokine safety
Minipig/pig studies to 6 months showed no immune response to rhCNTF or cells; mild to moderate ocular inflammation
“Two preclinical studies in minipigs or pigs implanted with NT-501-6A.02 device for up to 6 months showed no immune response to rhCNTF or cell producing the protein.”
Biodistribution & persistence
No systemic rhCNTF exposure after ITV implant (minipig to 6 months, rabbit to 9 months); implants delivered about 7-9 ng/day
“In rabbits, NT-501 implants established CNTF levels averaging about 7-9 ng/day for up to 9 months.”
Modality-specific risk
Local ocular toxicity from capsule/rhCNTF dose (cone effects at high output), device failure with cell release, systemic CNTF exposure
“a dose-response to rhCNTF was present, with eyes implanted with empty capsules and capsules with a low CNTF output cell line exhibiting less intense changes than eyes implanted with NT-501.”
Anti-drug antibodies: animals
No immune response to rhCNTF or cells in minipigs/pigs implanted up to 6 months
“Two preclinical studies in minipigs or pigs implanted with NT-501-6A.02 device for up to 6 months showed no immune response to rhCNTF or cell producing the protein.”
Anti-drug antibodies: patients
Anti-rhCNTF antibodies in 1 of 31 patients (3%); anti-DHFR antibodies in 1 patient (3%)
“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.”
Label warnings
- Severe Vision Loss
- Infectious Endophthalmitis
- Retinal Tear and Detachment
- Vitreous Hemorrhage
- Implant Extrusion
- Cataract Formation
- Suture Related Complications
- Delayed Dark Adaptation
Ocular toxicityBleeding
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Encelto don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for cell therapies
FDA expects preclinical proof-of-concept and toxicology studies to identify active dose levels and support the choice of starting dose and escalation. The 2013 guidance gives no numeric formula or scaling rule for the starting dose.
“Selection of potential starting dose level, dose-escalation schedule, and dosing regimen for clinical trials.”
✓ VerifiedFDA 2013: Preclinical Assessment of Investigational Cellular and Gene Therapy…, p. 7Source ↗
This product's starting point
NOAEL / key findings: No NOAEL set for device; minimal lens, vitreous and ocular inflammation; no systemic findings. rhCNTF DART NOAELs used for margins of exposure (FDA pharmacology/toxicology review, p. 2)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study; long-term intravitreal implantation toxicity study in minipigs and pigs
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study in 4–8-month-old minipigs, 4–10-year-old pigs, and catastrophic device failure of NT-501 was evaluated by ITV injection of unencapsulated NTC-201-6A cells into 8-9 month old minipigs.”
Pivotal GLP studies
Non-GLP 12-week rabbit ocular tox/PK; 3-part minipig/pig long-term ITV implant study to 6 months; unencapsulated-cell device failure study in minipigs
“The effect of long-term ITV implantation of NT-501 was evaluated in a 3-part toxicology study”
DART package
Species: DART
Rat and rabbit (4 DART studies of SC rhCNTF: fertility and teratogenicity)
“Four Developmental and Reproductive Toxicity (DART) studies were conducted in rats and rabbits to establish the risks to fertility and teratogenicity associated with the subcutaneous (SC) administration of high doses of rhCNTF.”
Reproductive & developmental
Four DART studies of SC rhCNTF in rats and rabbits; no teratogenicity; exemption for device via margin of exposure
“There were no rhCNTF-related teratologic changes reported in the fetuses.”
PPND / ePPND: when
Rat SC rhCNTF study from pre-mating to postpartum Day 21 with pup postnatal development, completed before the marketing application
“In female rats administered rhCNTF at dose levels of 0, 10, 100, or 300 μg/kg/day SC for 2 weeks prior to mating to postpartum Day 21, mating performance, fertility and gestational parameters were normal. No adverse effects on fetuses or pup postnatal development were reported.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted per toxicological risk assessments)
“Studies to evaluate the carcinogenicity/tumorigenicity of ENCELTO were not conducted. These studies are not warranted based on the safety profile described in the provided toxicological risk assessments (TRAs).”
Carcinogenicity model
Not conducted; waived via toxicological risk assessments for rhCNTF and ENDO medium
“The applicant provided TRAs conducted by to support waivers for carcinogenicity/tumorigenicity studies for rhCNTF and the medium used within the device, human Endothelial-SFM medium (ENDO medium).”
Carcinogenicity timing
Not required (waiver rationale accepted by reviewer)
“This reviewer agrees with the rationale provided in the TRAs for not conducting carcinogenicity/tumorigenicity studies.”
Safety marginopen answer page →
Safety margin at NOAEL
rhCNTF DART NOAEL margins of exposure above 100 vs modelled maximum blood rhCNTF from intraocular implant
“As shown in the above table, MOEs are above 100, indicating adequate protection of human health and a low risk of adverse reproductive and developmental effects.”
NOAEL / key findings
No NOAEL set for device; minimal lens, vitreous and ocular inflammation; no systemic findings. rhCNTF DART NOAELs used for margins of exposure
“ITV implantation of NT-501 did not cause any effects on systemic clinical signs, gross pathology, or histopathology of non-ocular organs.”
Efficacy evidenceopen answer page →
Efficacy evidence
rcd1 dog model of retinitis pigmentosa: NT-501 implant protected outer nuclear layer from photoreceptor loss
“An early pharmacology study showed that the outer nuclear layer (ONL) in dogs with retinitis pigmentosa caused by rod-cone dysplasia type 1 (rcd1) was protected from photoreceptor loss following implantation of NT-501.”
Why that model
Rcd1 dogs are a well-established animal model for retinitis pigmentosa
“Rcd1 dogs are a well-established animal model for retinitis pigmentosa.”
Reviewer's view of the efficacy data
rcd1 dog study preliminary: used early 11 mm prototype vs 6.5 mm clinical device
“The device used in this study is an early prototype that is 11 mm in length (the proposed clinical device is 6.5 mm). Thus, this study is preliminary regarding assessing the overall pharmacology of the product, NT-501.”
Test articleopen answer page →
Test article vs clinical lot
Dog pharmacology study used an early 11 mm prototype device; the clinical device is 6.5 mm. Bridging: None; reviewers judged the prototype study preliminary for the pharmacology of NT-501
“The device used in this study is an early prototype that is 11 mm in length (the proposed clinical device is 6.5 mm). Thus, this study is preliminary regarding assessing the overall pharmacology of the product, NT-501.”
Genetically modified?
Encapsulated allogeneic RPE cell line NTC-201-6A engineered to express rhCNTF
“The ENCELTO dose of rhCNTF derives from an implant containing 200,000-440,000 allogeneic retinal pigment epithelial (RPE) cells expressing rhCNTF (NTC-201-6A cell line).”
First approval
2025 (FDA)
“Summary Basis for Regulatory Action Date: March 5, 2025”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity/tumorigenicity studies; waived on toxicological risk assessments of rhCNTF and residual medium
Why: Toxicological risk assessments of rhCNTF and residual medium support the safety profile · Weight of evidence
“Studies to evaluate the carcinogenicity/tumorigenicity of ENCELTO were not conducted. These studies are not warranted based on the safety profile described in the provided toxicological risk assessments (TRAs).”
“This reviewer agrees with the rationale provided in the TRAs for not conducting carcinogenicity/tumorigenicity studies.”
DARTAcceptedBeyond the letter
No DART studies with the implant; relies on existing rhCNTF DART studies and margins of exposure above 100
Why: Lack of meaningful systemic exposure after intraocular dosing and no health risks in multiple DART studies · Pharmacology or kinetics · Weight of evidence
“As shown in the above table, MOEs are above 100, indicating adequate protection of human health and a low risk of adverse reproductive and developmental effects. Reviewer conclusion: Based on lack of meaningful exposure and the absence of health risks identified by multiple DART studies, additional DART studies are not warranted for rhCNTF.”
GenotoxicityVerdict not stated
Genotoxicity assessed with an ISO-10993 medical-device battery rather than a standard drug battery
Why: ISO-10993 guidance for biological evaluation of medical devices · Within the guideline
“A battery of genotoxicity studies was conducted to support licensure of NT-501 in keeping with ISO-10993, guidance for biological evaluation of medical devices.”
Efficacy modelVerdict not stated
Dog rcd1 efficacy study used an early 11 mm prototype, not the 6.5 mm clinical device
“The device used in this study is an early prototype that is 11 mm in length (the proposed clinical device is 6.5 mm). Thus, this study is preliminary regarding assessing the overall pharmacology of the product, NT-501.”
Similar precedents
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