Nerve growth factor: From discovery to development for human use

The cornea and endogenous nerve growth factor

Currently, there are 2 phase 3 clinical trials underway investigating the safety and efficacy of cenegermin in severe Sjögren dry eye disease (PROTEGO-1 [NCT05133180] and PROTEGO-2 [NCT05136170]). (Adobe Stock/H_Ko)

The cornea is the most densely innervated tissue of the body with an estimated 7000 nociceptors/mm², making it 400 times more sensitive than skin.¹ Sensory innervation of the cornea is derived from the first branch of the trigeminal nerve. In addition to serving as an afferent arm of the blink and tear reflex, sensory corneal nerves also provide trophic support to the corneal epithelium while facilitating and maintaining ocular surface homeostasis.^2,3 This is achieved in part by secretion of neuropeptides and neurotrophins from sensory corneal nerves and corneal epithelia, respectively,⁴ interplay between which is key in maintaining corneal homeostasis.^1,3

One such pertinent neurotrophin is nerve growth factor (NGF), which plays a role in proliferation, differentiation, and survival of sympathetic and sensory neurons.⁵ In the cornea, sensory nerves help regulate ocular homeostasis.⁶ NGF signaling occurs through its cognate receptors, high-affinity receptor tropomyosin related kinase A (TrkA) and low-affinity pan-neurotrophin 75 receptor (p75NTR).⁷ TrkA is expressed not just on corneal nerves but also on several cell types throughout the eye, including but not limited to the corneal epithelium, stromal keratocytes, endothelium, retinal ganglion cells, retinal bipolar and glial cells, and the optic nerve.^4,8 This pro-survival effect of NGF-TrkA binding is responsible for maintaining integrity of the ocular surface, which is critical for clarity of the corneal optical medium and, hence, vision.⁹

Development for ophthalmic use in humans

Drs Rita Levi-Montalcini and Stanley Cohen discovered and isolated a “neuron-stimulation factor” at the Washington University in St Louis, Missouri, in Dr Viktor Hamburger’s laboratory, that was called NGF and for which Drs Levi-Montalcini and Cohen were awarded the Nobel Prize for Physiology or Medicine in 1986.^5,10 In the late 1990s, the first evidence of the potential clinical application of NGF in ophthalmology was published through a case series of patients with neurotrophic keratitis (NK) treated with topical murine NGF drops.¹¹

In 2010, Dompé Farmaceutici acquired rights to develop NGF for potential medicinal use. Given the highly conserved homology between murine and human NGF,¹² Dompé Farmaceutici sought to engineer a recombinant human protein of NGF (rhNGF), which could be safe and effective for human use. Despite facing numerous challenges in formulation, storage, dosing and administration, scientists at Dompé Farmaceutici successfully engineered and manufactured the first rhNGF biologic (cenegermin) for topical use as an ophthalmic formulation.

rhNGF and NK

In the event of injury to the trigeminal nerve, both by systemic and local disease, sensory innervation to the cornea becomes compromised.^13,14 Impaired sensory corneal innervation dysregulates the supply of neuropeptides and neurotrophins needed for trophic support,² and integrity and renewal of the corneal epithelium,leading to subsequent decompensation of the ocular surface.³ This situation is further worsened by the reduced blink and tear reflex and forms the fundamental basis of NK.⁶ NK can result from myriad etiologies including but not limited to ocular herpetic infections; chronic ocular surface diseases; iatrogenic causes such as vitrectomy, refractive surgery, ocular surgeries, corneal grafting procedures, radiotherapy and neurosurgical procedures; toxicity from ocular medications; systemic diseases involving the central nervous system and diabetes; and rarer conditions such as vitamins B12 and A deficiency, Goldenhar syndrome, multiple sclerosis and leprosy.^1,15-17

NK is a corneal degenerative condition that usually presents as unilateral disease with decreased corneal sensitivity and corneal epitheliopathy with or without stromal involvement.^3,15 Hence, corneal sensitivity testing forms the first and foremost diagnostic test for NK in patients presenting with noninfectious persistent corneal epithelial damage with lack of symptoms.¹⁸ Clinically, NK is classified into 3 stages based on the Mackie classification system¹⁹ and each stage can be identified by a unique set of clinical signs¹⁵: stage 1 with epithelial dystrophy or punctate keratopathy; stage 2 with persistent epithelial defect; and stage 3 with a corneal ulcer.

The scientific breakthrough for the use of cenegermin, marketed as Oxervate (cenegermin-bkbj; Dompé) ophthalmic solution, 0.002% (20 mcg/mL), received approval from both the European Medicines Agency (2017)20 for treatment of moderate (persistent epithelial defect) or severe (corneal ulcer) neurotrophic keratitis in adults, and the FDA (2018)²¹ for the treatment ofneurotrophic keratitis.²² The FDA granted cenegermin a Breakthrough Therapy Designation.

Potential future applications of rhNGF beyond neurotrophic keratitis (NK)

The research and development team at Dompé is exploring potential future applications of rhNGF in ocular diseases beyond NK. Given the canonical expression of TrkA receptors in the eye, coupled with the pleiotropic protective effects of NGF on cells of both the ocular surface^23,24 and retina,^24,25 the potential applications of rhNGF in ocular diseases beyond NK are of great interest.²⁶

Currently, there are 2 phase 3 clinical trials underway investigating the safety and efficacy of cenegermin in severe Sjögren dry eye disease (PROTEGO-1 [NCT05133180] and PROTEGO-2 [NCT05136170]). This patient population is considered to be 1 of the most challenging groups of dry eye patients²⁷ because they are of complex etiology^28,29 and some continue to suffer from suboptimal management and poor quality of life.^27,29 To explore the full potential of the utility of rhNGF, Dompé is also building programs to investigate the potential use of cenegermin in neuropathic corneal pain and diseases of other sensory organs. Dompé is also investigating the safety and tolerability of an intravitreal formulation of rhNGF through a phase 1b randomized controlled trial (EudraCT# 2021-005592-39) in Italy. The next few years will be exciting for continuing to evaluate the ways in which rhNGF may expand the frontiers of therapeutics in ophthalmic and neurodegenerative diseases.

References

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3. Mastropasqua L, Massaro-Giordano G, Nubile M, Sacchetti M. Understanding the pathogenesis of neurotrophic keratitis: the role of corneal nerves. J Cell Physiol. 2017;232(4):717-724. doi:10.1002/jcp.25623

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18. Dana R, Farid M, Gupta PK, et al. Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy. BMC Ophthalmol. 2021;21(1):327. doi:10.1186/s12886-021-02092-1

19. Mackie I. Neuroparalytic keratitis. In: Fraunfelder F, Roy FH, Meyer SM, eds. Current Ocular Therapy. WB Saunders: 1995:452-454.

20. Oxervate. Summary of product characteristics. Dompé; 2018. Accessed November 29, 2022. https://www.ema.europa.eu/en/documents/product-information/oxervate-epar-product-information_en.pdf

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24. Dompé Farmaceutici. Investigator’s Brochure. Recombinant Human Nerve Growth Factor (rhNGF). Ed. no. 12. Non-Clinical Studies p37-64. Published online December 2, 2021.

25. Guo L, Davis BM, Ravindran N, et al. Topical recombinant human nerve growth factor (rh-NGF) is neuroprotective to retinal ganglion cells by targeting secondary degeneration. Sci Rep. 2020;10(1):3375. doi:10.1038/s41598-020-60427-2

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28. Akpek EK, Bunya VY, Saldanha I. Sjögren’s syndrome: more than just dry eye. Cornea. 2019;38(5):658-661.

29. Moerman RV, Arends S, Mossel E, Kroese FGM, Vissink A, Bootsma H. 10-year follow-up of patients with rheumatoid arthritis and secondary Sjögren’s syndrome or sicca symptoms in daily clinical practice. Clin Exp Rheumatol. 2020;38(4)(suppl 126):64-72.