Safety and Efficacy of Multiple Doses of the PAINLESS Nerve Growth Factor CHF6467 in Paediatric Subjects With Optic Pathway Glioma (OPG). A Randomized Clinical Trial (RCT)

Background and study rationale Nerve growth factor (NGF) is a neurotrophin that acts on peripheral and central neurons by binding with high affinity to the trkANGFR receptor, which has tyrosine kinase activity, and with low affinity to the non-selective pan-neurotrophin receptor p75NTR that regulates signaling through trkANGFR. The effect of NGF on target cells depends on the ratio of these two co-distributed receptors on the cell surface .

Based on its biological effects on neuronal and non-neuronal cells, the therapeutic potential of NGF has been demonstrated for neurodegenerative diseases, such as Alzheimer's disease, and for the healing of corneal and skin tissues damaged by chemical, physical, surgical and autoimmune insults. The development of recombinant forms of NGF that have less pain induction activity, while fully preserving its pleiotrophic properties, can provide a successful strategy to ensure clinical benefit to subjects suffering from a number of relevant conditions.

CHF6467 (hNGF P61S R100E; hNGFp), is a recombinant and "painless" form of human NGF. The mutation at arginine R100 in mature NGF is linked to the rare human genetic disease HSAN V (hereditary sensory sensory neuropathy type V). In HSAN V subjects, a mutation in the NGFB gene (exon 3, nt C661T), turns arginine R100 into tryptophan, producing a syndrome of complete loss of pain perception without affecting most neurological functions.

In addition to the pain-related R100E mutation, CHF6467 has a second "tagging" P61S mutation, which replaces the proline residue at position 61 with a serine residue. This does not produce any known physiological effects, but the "labeled" molecules of hNGFP61S can be detected selectively compared to wild-type hNGF using a specific monoclonal antibody called 4GA, which helps product research and development.

In vitro and in vivo data confirm that CHF6467 (Chiesi) maintains NGF-identical neurotrophic and neuroprotective properties in a variety of cellular tests, while showing significantly reduced pain induction activity in vivo. These data provide the basis for the development of this "painless" form of NGF for the treatment of neurological disorders and other conditions.