Cenegermin

A recombinant human nerve growth factor produced in E. coli, FDA approved since 2018 as Oxervate eye drops for neurotrophic keratitis, that acts through TrkA and p75 receptors to restore corneal nerve function and epithelial healing.

Also referenced as: Oxervate, cenegermin-bkbj

Also appears in: Other

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What is Cenegermin?

Cenegermin is a recombinant form of human nerve growth factor (NGF) produced in Escherichia coli. It is a 118-amino-acid protein with a relative molecular mass of 13,266 Da, folded and disulfide-bonded like the native growth factor, so it is a small protein rather than a short peptide: it cannot be made by solid-phase synthesis and is not a fragment or mimetic of NGF. The US product, Oxervate (cenegermin-bkbj; the four-letter suffix is the FDA’s naming convention for biologics), is a preservative-free 0.002% (20 mcg/mL) ophthalmic solution developed by Dompé and approved on August 22, 2018 as the first drug for neurotrophic keratitis, a degenerative corneal disease caused by loss of corneal sensory innervation.

Although it is a neurotrophic factor, its clinical action is confined to the ocular surface: cenegermin is applied as eye drops to restore the corneal nerves and the epithelium they maintain, and the approved product does not reach the brain or the systemic circulation in measurable amounts. Cenegermin is not a research-market product; recombinant human NGF sold as a cell-culture reagent is neither the approved formulation nor an ophthalmic product.

How it works

The cornea is one of the most densely innervated tissues in the body, and its sensory nerves release trophic factors that keep the epithelium intact. When those nerves are lost (after herpetic infection, trigeminal injury, diabetes, surgery or long-term topical drug use) the epithelium breaks down into persistent defects and ulcers that do not heal. Cenegermin supplies the growth factor those nerves and epithelial cells depend on.

• Neurotrophin receptor signaling. NGF, the first growth factor identified, supports the differentiation and survival of sensory and sympathetic neurons through the high-affinity tyrosine kinase receptor TrkA and the low-affinity receptor p75NTR; the approved label describes cenegermin’s action through these same receptors in the anterior segment of the eye to support corneal innervation and integrity (Levi-Montalcini, Science, 1987, 237(4819):1154–1162).
• Epithelial healing and recovery of sensation in human corneas. The first clinical demonstration used murine NGF drops in 12 patients (14 eyes) with severe neurotrophic ulcers unresponsive to other treatment: all ulcers healed within 10 days to 6 weeks, and corneal sensitivity improved in 13 of 14 eyes (Lambiase et al., New England Journal of Medicine, 1998, 338(17):1174–1180).
• Measurable regrowth of sub-basal nerves. In 18 patients with neurotrophic keratopathy treated with recombinant human NGF, in vivo confocal microscopy showed a significant increase in sub-basal nerve density, branch number and fiber diameter by week 8, alongside complete epithelial healing in every patient and improved corneal sensation (Mastropasqua et al., American Journal of Ophthalmology, 2020, 217:278–286).
• Local action without systemic exposure. In a double-masked dose-escalation study in 74 healthy volunteers the drops were well tolerated, did not raise circulating NGF and did not induce anti-drug antibodies (Ferrari et al., BioDrugs, 2014, 28(3):275–283); the label’s pharmacokinetic section likewise reports that in 20 healthy subjects dosed up to six times daily, serum NGF showed no relationship to treatment and stayed below the 15 pg/mL assay limit in most subjects.

Research status

Cenegermin has a completed pivotal program in neurotrophic keratitis, regulatory approvals in the United States and the European Union, a mixed record in dry eye disease, and two new Phase 3 programs that began in 2026.

Origins. The 1998 NEJM case series was followed by a prospective, noncomparative series of 45 eyes of 43 patients with moderate to severe neurotrophic keratitis treated with murine NGF, again reporting complete resolution of the epithelial defect in every eye within 12 days to 6 weeks, with improved corneal sensitivity and visual acuity (Bonini et al., Ophthalmology, 2000, 107(7):1347–1351). A recombinant human form was then developed for a regulatory program; a Phase 1 safety and pharmacokinetic study in 74 healthy volunteers (NCT01744704) and a small open-label Phase 1 in patients with neurotrophic keratitis (Bonini et al., Ophthalmology, 2018, 125(9):1468–1471) preceded the controlled trials.

REPARO, Study NGF0212 (NCT01756456). The European Phase 2 trial randomized 156 patients with unilateral stage 2 or 3 (persistent epithelial defect or corneal ulcer) neurotrophic keratitis 1:1:1 to rhNGF 10 µg/mL, 20 µg/mL or vehicle six times daily for 8 weeks, with 48 or 56 weeks of follow-up. At week 4, the primary endpoint, corneal healing (less than 0.5 mm of fluorescein staining in the lesion) occurred in 58.0% of the 20 µg/mL group versus 19.6% of the vehicle group (P < 0.001), and at week 8 in 74.0% versus 43.1%; by the more conservative definition the FDA label uses (no staining of the lesion and no other persistent staining), week 8 healing was 72.0% (36 of 50) versus 33.3% (17 of 51). More than 96% of patients healed on rhNGF remained recurrence-free during follow-up (Bonini et al., Ophthalmology, 2018, 125(9):1332–1343). The 20 µg/mL concentration was carried forward and became Oxervate.

Study NGF0214 (NCT02227147). The US confirmatory trial randomized 48 patients at 11 sites to cenegermin 20 µg/mL or vehicle for 8 weeks, with 24 weeks of follow-up, and treated bilateral disease in both eyes. By the conservative definition of complete healing, 65.2% (15 of 23) of cenegermin patients versus 16.7% (4 of 24) of vehicle patients healed at week 8 (P < 0.001); by the conventional definition, 69.6% versus 29.2% (P = 0.006) (Pflugfelder et al., Ophthalmology, 2020, 127(1):14–26). Across the two trials, recurrence among healed patients during follow-up was about 20% (NGF0212) and 14% (NGF0214), and the label reports that the mean change in corneal sensitivity inside the lesion was not clinically significant in either trial.

Regulatory record. The European Commission authorized Oxervate on July 6, 2017 for moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults. The FDA approved BLA 761094 on August 22, 2018 under orphan designation with a broader indication, treatment of neurotrophic keratitis, that names no stage and no age floor; the current label states that safety and effectiveness have been established in pediatric patients, on the basis of the adult trials plus safety data in children from 2 years of age. The 2019 and 2023 supplements were labeling changes, and the most recent revision is dated October 2026. No new indication was approved in 2025 or 2026, and no complete response letter is on record for the molecule.

Stage 1 disease and later follow-up. DEFENDO (NCT04485546) was a Phase 4, open-label, uncontrolled study of 37 adults with stage 1 neurotrophic keratopathy (epithelial irregularity without a frank defect): 84.8% showed corneal epithelial healing at week 8 and 95.2% of those remained healed at week 32, with eye pain the most common treatment-related adverse event (37.8%) (Hamrah et al., Ophthalmology and Therapy, 2024, 13(2):553–570). Because there was no vehicle arm, these data do not carry the same weight as the pivotal trials; stage 1 use is not part of the EU indication. A prospective, open-label Phase 4 study of 28 Chinese patients with moderate or severe disease reported healing in 84.6% at week 8 (Li et al., Ophthalmology and Therapy, 2025, 14(12):3021–3033), and a 2026 systematic review and meta-analysis of the two randomized trials (148 adults) concluded that cenegermin is effective and well tolerated in moderate to severe disease, with a number needed to treat of 3 (Faroog et al., Therapeutic Advances in Ophthalmology, 2026, 18). Pediatric use rests on case reports and series (26 eyes of 22 children in a 2025 systematic review) rather than a controlled trial (Bakr et al., Cornea, 2025, 44(12):1554–1563).

Dry eye disease. An open-label Phase 2a study of 40 patients with dry eye reported improvements in signs and symptoms (Sacchetti et al., British Journal of Ophthalmology, 2020, 104(1):127–135). The vehicle-controlled Phase 2 dose-ranging trial NGF0120 (NCT03982368, 261 patients) did not meet its primary endpoint: the change in Schirmer I score at week 4 was not significantly different from vehicle for either regimen (P = 0.078 and 0.066), although the Schirmer responder rate and patient-reported symptoms favored cenegermin in secondary analyses (Wirta et al., BMC Ophthalmology, 2024, 24(1):290). Two Phase 3 trials in severe Sjögren’s dry eye followed. PROTEGO-1 (NCT05133180, 104 patients) and PROTEGO-2 (NCT05136170, 85 patients) each had two primary endpoints: the Schirmer I responder rate at week 4 was met in both (19 versus 2 patients, P < 0.001; 19 versus 4 patients, P = 0.002), but the change in SANDE symptom score at week 12 was not (P = 0.322 and P = 0.890). A further Phase 2 trial of lower concentrations (NCT06244316, 317 patients) reported a borderline symptom benefit at 10 µg/mL (P = 0.034) and none at 5 µg/mL, with no difference from vehicle in Schirmer responders. As of November 2026, no dry eye indication has been approved.

Other ophthalmic indications. Dompé ran a Phase 1/2 dose-ranging study of 60 and 180 µg/mL drops in retinitis pigmentosa (NCT02110225, 50 patients) after an academic pilot of murine NGF drops in eight patients with that disease (Falsini et al., Journal of Translational Medicine, 2016, 14:8), a Phase 1 safety study of a 180 µg/mL concentration in primary open-angle glaucoma (NCT02855450, 60 patients), and Phase 2 studies in ocular discomfort after cataract or refractive surgery (NCT03035864, 180 patients) and dry eye (NCT03019627, 150 patients). None progressed to Phase 3. Two new Phase 3 programs were registered in 2026: a 272-participant vehicle-controlled trial of intranasal cenegermin in non-arteritic anterior ischemic optic neuropathy (NCT07453888, started July 1, 2026, primary endpoint a 15-letter gain in best-corrected visual acuity at week 24) and a 150-participant trial of the eye drops in persistent corneal epithelial defect refractory to conventional nonsurgical treatment (NCT07519902, started June 2, 2026). Both are recruiting; neither has reported.

Post-marketing safety. Two analyses of the FDA Adverse Event Reporting System describe a profile confined to the eye. An analysis of 3,288 ocular reports from 2018 to 2022 found 56 disproportionally reported ocular events, among them corneal deposits, eye inflammation, eye ulcer and corneal perforation, with a median onset of 6 days (Li et al., Expert Opinion on Drug Safety, 2024, 23(3):385–391); a second analysis of reports from 2019 to 2023 found eye pain (46.9%), irritation (14.5%) and ocular hyperemia (9.8%) the most common events and no excess reporting in any non-ocular organ class (Choudhry et al., Journal of Ocular Pharmacology and Therapeutics, 2025, 41(6):339–346).

Common dosage forms

• Oxervate multiple-dose vial. A 0.002% (20 mcg/mL) preservative-free ophthalmic solution, supplied as a weekly carton of seven vials dispensed by pharmacy.
• Investigational formulations. A 180 µg/mL concentration was tested in the retinitis pigmentosa and glaucoma studies, lower-concentration (5 and 10 µg/mL) eye drops were tested in a 2024 dry eye trial, and an intranasal spray entered Phase 3 in 2026.

Key considerations

• Regulatory status. The FDA Approved status reflects the August 22, 2018 approval of Oxervate (BLA 761094) for the treatment of neurotrophic keratitis. The EU authorization is narrower (moderate or severe disease, adults only), and no other indication has been approved anywhere.
• A protein, not a peptide. Cenegermin is the full 118-residue mature NGF chain expressed in bacteria and refolded into its native structure. Descriptions calling it an “NGF peptide” or grouping it with short synthetic neurotrophic peptides are inaccurate, and nothing about its ophthalmic data transfers to injected or systemic use.
• Strong but narrow evidence. The approval rests on 151 randomized patients across two 8-week trials with corneal healing as the endpoint. Corneal sensitivity did not change meaningfully in either trial, about 14% to 20% of healed patients relapsed, the stage 1 and pediatric data are uncontrolled, and the dry eye program has repeatedly met tear-production endpoints while not meeting symptom endpoints.
• Local safety signals. Eye pain was the most common adverse reaction in the trials (about 16%), with other local reactions in 1% to 10% of patients. Post-marketing reports show the same ocular profile and no systemic signal, consistent with the lack of measurable systemic exposure.
• Naming. Cenegermin, cenegermin-bkbj, Oxervate and the development-era label rhNGF all refer to the same molecule. It should not be confused with reagent-grade recombinant NGF, with mouse-derived NGF (the material used in the 1998 and 2000 studies), with other neurotrophins such as BDNF or NT-3, or with small-molecule and peptide “NGF mimetics” that have no shared clinical record.