Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study
Marta Sacchetti, Alessandro Lambiase, Doreen Schmidl, Leopold Schmetterer, Mauro Ferrari, Flavio Mantelli, Marcello Allegretti, Gerhard Garhoefer, Marta Sacchetti, Alessandro Lambiase, Doreen Schmidl, Leopold Schmetterer, Mauro Ferrari, Flavio Mantelli, Marcello Allegretti, Gerhard Garhoefer
Abstract
Background: Dry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED.
Methods: Forty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test.
Results: Of 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1.
Conclusions: The data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED.
Trial registration number: NCT02101281.
Keywords: clinical trial; ocular surface; pharmacology; tears.
Conflict of interest statement
Competing interests: MS and AL: Consultant—Dompé Farmaceutici SpA. MA, FM and MF: Employee—Dompé Farmaceutici SpA. MS, AL: report personal fees from Dompé Farmaceutici SpA, Italy, outside the submitted work. MA, MS, MF, GG: report personal fees from Dompe Farmaceutici spa, during the conduct of the study.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6922013/bin/bjophthalmol-2018-312470f01.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6922013/bin/bjophthalmol-2018-312470f02.jpg)
Figure 3
Both high and low doses…
Figure 3
Both high and low doses of rhNGF eye drops treatments showed a significant…
Figure 4
The higher dose of rhNGF…
Figure 4
The higher dose of rhNGF at 20 µg/mL concentration showed improvement of lacrimal…
- Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial.Ferrari MP, Mantelli F, Sacchetti M, Antonangeli MI, Cattani F, D'Anniballe G, Sinigaglia F, Ruffini PA, Lambiase A. Ferrari MP, et al. BioDrugs. 2014 Jun;28(3):275-83. doi: 10.1007/s40259-013-0079-5. BioDrugs. 2014. PMID: 24327173 Free PMC article. Clinical Trial.
- Study design and baseline findings from the progression of ocular findings (PROOF) natural history study of dry eye.McDonnell PJ, Pflugfelder SC, Stern ME, Hardten DR, Conway T, Villanueva L, Hollander DA. McDonnell PJ, et al. BMC Ophthalmol. 2017 Dec 28;17(1):265. doi: 10.1186/s12886-017-0646-5. BMC Ophthalmol. 2017. PMID: 29284427 Free PMC article. Clinical Trial.
- Autologous serum eye drops for dry eye.Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Pan Q, et al. Cochrane Database Syst Rev. 2017 Feb 28;2(2):CD009327. doi: 10.1002/14651858.CD009327.pub3. Cochrane Database Syst Rev. 2017. PMID: 28245347 Free PMC article. Review.
- Evaluation of an enhanced viscosity artificial tear for moderate to severe dry eye disease: A multicenter, double-masked, randomized 30-day study.Lievens C, Berdy G, Douglass D, Montaquila S, Lin H, Simmons P, Carlisle-Wilcox C, Vehige J, Haque S. Lievens C, et al. Cont Lens Anterior Eye. 2019 Aug;42(4):443-449. doi: 10.1016/j.clae.2018.12.003. Epub 2018 Dec 17. Cont Lens Anterior Eye. 2019. PMID: 30573298 Clinical Trial.
- Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease.Daull P, Amrane M, Ismail D, Georgiev G, Cwiklik L, Baudouin C, Leonardi A, Garhofer G, Garrigue JS. Daull P, et al. J Ocul Pharmacol Ther. 2020 Jul/Aug;36(6):355-365. doi: 10.1089/jop.2020.0011. Epub 2020 Jun 3. J Ocul Pharmacol Ther. 2020. PMID: 32493105 Free PMC article. Review.
- Innovation in the Development of Synthetic and Natural Ocular Drug Delivery Systems for Eye Diseases Treatment: Focusing on Drug-Loaded Ocular Inserts, Contacts, and Intraocular Lenses.Pelusi L, Mandatori D, Mastropasqua L, Agnifili L, Allegretti M, Nubile M, Pandolfi A. Pelusi L, et al. Pharmaceutics. 2023 Feb 13;15(2):625. doi: 10.3390/pharmaceutics15020625. Pharmaceutics. 2023. PMID: 36839947 Free PMC article. Review.
- Clinical observation of recombinant human nerve growth factor in the treatment of neurotrophic keratitis.Hao M, Cheng Y, Wu J, Cheng Y, Wang J. Hao M, et al. Int J Ophthalmol. 2023 Jan 18;16(1):60-66. doi: 10.18240/ijo.2023.01.09. eCollection 2023. Int J Ophthalmol. 2023. PMID: 36659958 Free PMC article.
- A, B, C's of Trk Receptors and Their Ligands in Ocular Repair.Gupta A, Galletti JG, Yu Z, Burgess K, de Paiva CS. Gupta A, et al. Int J Mol Sci. 2022 Nov 15;23(22):14069. doi: 10.3390/ijms232214069. Int J Mol Sci. 2022. PMID: 36430547 Free PMC article. Review.
- NGF Prevents Loss of TrkA/VEGFR2 Cells, and VEGF Isoform Dysregulation in the Retina of Adult Diabetic Rats.Fico E, Rosso P, Triaca V, Segatto M, Lambiase A, Tirassa P. Fico E, et al. Cells. 2022 Oct 15;11(20):3246. doi: 10.3390/cells11203246. Cells. 2022. PMID: 36291113 Free PMC article.
- Corneal Neuro-Regenerative Effect of Transcutaneous Electrical Stimulation in Rabbit Lamellar Keratectomy Model.Yoo YS, Park S, Eun P, Park YM, Lim DH, Chung TY. Yoo YS, et al. Transl Vis Sci Technol. 2022 Oct 3;11(10):17. doi: 10.1167/tvst.11.10.17. Transl Vis Sci Technol. 2022. PMID: 36223127 Free PMC article.
-
- Bonini S, Aloe L, Bonini S, et al. . Nerve growth factor (NGF): an important molecule for trophism and healing of the ocular surface. Adv Exp Med Biol 2002;506:531–7. - PubMed
-
- Lambiase A, Manni L, Bonini S, et al. . Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 2000;41:1063–9. - PubMed
- Clinical Trial, Phase II
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Dry Eye Syndromes / drug therapy*
- Dry Eye Syndromes / physiopathology
- Female
- Humans
- Lubricant Eye Drops / administration & dosage*
- Lubricant Eye Drops / adverse effects
- Lubricant Eye Drops / therapeutic use
- Male
- Middle Aged
- Nerve Growth Factors / administration & dosage*
- Nerve Growth Factors / adverse effects
- Nerve Growth Factors / therapeutic use
- Recombinant Proteins / administration & dosage
- Recombinant Proteins / adverse effects
- Recombinant Proteins / therapeutic use
- Severity of Illness Index
- Tears / physiology
- Treatment Outcome
- Lubricant Eye Drops
- Nerve Growth Factors
- Recombinant Proteins
- ClinicalTrials.gov/NCT02101281
- Full Text Sources
- Other Literature Sources
- Medical
NCBI Literature Resources
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![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6922013/bin/bjophthalmol-2018-312470f03.jpg)
Figure 4
The higher dose of rhNGF…
Figure 4
The higher dose of rhNGF at 20 µg/mL concentration showed improvement of lacrimal…
- Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial.Ferrari MP, Mantelli F, Sacchetti M, Antonangeli MI, Cattani F, D'Anniballe G, Sinigaglia F, Ruffini PA, Lambiase A. Ferrari MP, et al. BioDrugs. 2014 Jun;28(3):275-83. doi: 10.1007/s40259-013-0079-5. BioDrugs. 2014. PMID: 24327173 Free PMC article. Clinical Trial.
- Study design and baseline findings from the progression of ocular findings (PROOF) natural history study of dry eye.McDonnell PJ, Pflugfelder SC, Stern ME, Hardten DR, Conway T, Villanueva L, Hollander DA. McDonnell PJ, et al. BMC Ophthalmol. 2017 Dec 28;17(1):265. doi: 10.1186/s12886-017-0646-5. BMC Ophthalmol. 2017. PMID: 29284427 Free PMC article. Clinical Trial.
- Autologous serum eye drops for dry eye.Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Pan Q, et al. Cochrane Database Syst Rev. 2017 Feb 28;2(2):CD009327. doi: 10.1002/14651858.CD009327.pub3. Cochrane Database Syst Rev. 2017. PMID: 28245347 Free PMC article. Review.
- Evaluation of an enhanced viscosity artificial tear for moderate to severe dry eye disease: A multicenter, double-masked, randomized 30-day study.Lievens C, Berdy G, Douglass D, Montaquila S, Lin H, Simmons P, Carlisle-Wilcox C, Vehige J, Haque S. Lievens C, et al. Cont Lens Anterior Eye. 2019 Aug;42(4):443-449. doi: 10.1016/j.clae.2018.12.003. Epub 2018 Dec 17. Cont Lens Anterior Eye. 2019. PMID: 30573298 Clinical Trial.
- Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease.Daull P, Amrane M, Ismail D, Georgiev G, Cwiklik L, Baudouin C, Leonardi A, Garhofer G, Garrigue JS. Daull P, et al. J Ocul Pharmacol Ther. 2020 Jul/Aug;36(6):355-365. doi: 10.1089/jop.2020.0011. Epub 2020 Jun 3. J Ocul Pharmacol Ther. 2020. PMID: 32493105 Free PMC article. Review.
- Innovation in the Development of Synthetic and Natural Ocular Drug Delivery Systems for Eye Diseases Treatment: Focusing on Drug-Loaded Ocular Inserts, Contacts, and Intraocular Lenses.Pelusi L, Mandatori D, Mastropasqua L, Agnifili L, Allegretti M, Nubile M, Pandolfi A. Pelusi L, et al. Pharmaceutics. 2023 Feb 13;15(2):625. doi: 10.3390/pharmaceutics15020625. Pharmaceutics. 2023. PMID: 36839947 Free PMC article. Review.
- Clinical observation of recombinant human nerve growth factor in the treatment of neurotrophic keratitis.Hao M, Cheng Y, Wu J, Cheng Y, Wang J. Hao M, et al. Int J Ophthalmol. 2023 Jan 18;16(1):60-66. doi: 10.18240/ijo.2023.01.09. eCollection 2023. Int J Ophthalmol. 2023. PMID: 36659958 Free PMC article.
- A, B, C's of Trk Receptors and Their Ligands in Ocular Repair.Gupta A, Galletti JG, Yu Z, Burgess K, de Paiva CS. Gupta A, et al. Int J Mol Sci. 2022 Nov 15;23(22):14069. doi: 10.3390/ijms232214069. Int J Mol Sci. 2022. PMID: 36430547 Free PMC article. Review.
- NGF Prevents Loss of TrkA/VEGFR2 Cells, and VEGF Isoform Dysregulation in the Retina of Adult Diabetic Rats.Fico E, Rosso P, Triaca V, Segatto M, Lambiase A, Tirassa P. Fico E, et al. Cells. 2022 Oct 15;11(20):3246. doi: 10.3390/cells11203246. Cells. 2022. PMID: 36291113 Free PMC article.
- Corneal Neuro-Regenerative Effect of Transcutaneous Electrical Stimulation in Rabbit Lamellar Keratectomy Model.Yoo YS, Park S, Eun P, Park YM, Lim DH, Chung TY. Yoo YS, et al. Transl Vis Sci Technol. 2022 Oct 3;11(10):17. doi: 10.1167/tvst.11.10.17. Transl Vis Sci Technol. 2022. PMID: 36223127 Free PMC article.
-
- Bonini S, Aloe L, Bonini S, et al. . Nerve growth factor (NGF): an important molecule for trophism and healing of the ocular surface. Adv Exp Med Biol 2002;506:531–7. - PubMed
-
- Lambiase A, Manni L, Bonini S, et al. . Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 2000;41:1063–9. - PubMed
- Clinical Trial, Phase II
- Research Support, Non-U.S. Gov't
- Adult
- Aged
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Dry Eye Syndromes / drug therapy*
- Dry Eye Syndromes / physiopathology
- Female
- Humans
- Lubricant Eye Drops / administration & dosage*
- Lubricant Eye Drops / adverse effects
- Lubricant Eye Drops / therapeutic use
- Male
- Middle Aged
- Nerve Growth Factors / administration & dosage*
- Nerve Growth Factors / adverse effects
- Nerve Growth Factors / therapeutic use
- Recombinant Proteins / administration & dosage
- Recombinant Proteins / adverse effects
- Recombinant Proteins / therapeutic use
- Severity of Illness Index
- Tears / physiology
- Treatment Outcome
- Lubricant Eye Drops
- Nerve Growth Factors
- Recombinant Proteins
- ClinicalTrials.gov/NCT02101281
- Full Text Sources
- Other Literature Sources
- Medical
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6922013/bin/bjophthalmol-2018-312470f04.jpg)
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Source: PubMed