Trial Title:
Safety and Efficacy of the PAINLESS Nerve Growth Factor CHF6467 in Optic Pathway Glioma (OPG)
NCT ID:
NCT05733572
Condition:
Optic Pathway Glioma
Conditions: Official terms:
Glioma
Optic Nerve Glioma
Conditions: Keywords:
Optic pathway glioma, nerve growth factor
optic atrophy
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
This is a phase 2a study intended to demonstrate the superiority over placebo of 10 days'
treatment with CHF6467 in significantly improving the field of vision of children and
young adults with optical pathway glioma, 12 weeks after the start of treatment.
Primary purpose:
Treatment
Masking:
Double (Investigator, Outcomes Assessor)
Masking description:
double masking (patients and outcome assessors)
Intervention:
Intervention type:
Drug
Intervention name:
CHF6467
Description:
drug eyedrops
Arm group label:
active treatment group
Other name:
painless NGF
Intervention type:
Drug
Intervention name:
Placebo
Description:
placebo eyedrops
Arm group label:
placebo group
Summary:
Infantile optic pathway glioma (OPG) is generally benign and slow-growing, but due to
infiltration and compression of sensitive neuronal structures in the optical pathways,
progressive visual loss is a frequent and highly debilitating complication of the
condition. Recently, therapeutic strategies aimed at neuroprotection in the visual
pathway rather than reducing the size of the tumor have been studied.
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.
Recently, two studies have shown that murine NGF can prevent progression of visual damage
in OPG patients. These successful exploratory studies (the last of which was a
randomized, double-blind, placebo-controlled study) represent a significant reference
point in the field of vision loss in OPG patients and provide the basis and rationale for
this study using a recombinant form of mutated NGF, painless NGF (CHF6467), which is
anticipated to prove devoid of adverse effects related to pain at therapeutic doses.
The purpose of this randomised study is to assess the safety and efficacy of multiple
doses of painless NGF CHF6467 eye drops on the visual function of children or young
adults with optic pathway gliomas, whether or not associated with type 1
neurofibromatosis. This study will include serial assessments of both optical pathway
functionality and morphology, using electrophysiological and magnetic resonance imaging
(MRI) techniques of the brain. The comparator will be a placebo preparation based on a
physiologically balanced salt solution. This comparator has no effect on retinal function
and optic nerve, is painless and perfectly tolerated, as reported by numerous clinical
studies including that of our group.
Detailed description:
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.
Pathology of optic pathway glioma in paediatric age Infantile optical pathway glioma
(OPG) is generally benign and slow-growing, but due to infiltration and compression of
sensitive neuronal structures in the optical pathways, progressive visual loss is a
frequent and highly debilitating complication of the condition. Retinal ganglion cells
(RGC) are known to be significantly involved in this process, and the retinal nerve fiber
layer (RNFL), the most distal region of the afferent visual pathway composed of RGC axon,
is considered a structural marker of visual integrity. RNFL thinning has been associated
with clinically noticeable vision loss in children with OPG.
Neurofibromatosis type 1 (NF1) is one of the most common hereditary dominant autosomic
syndromes that occur in young children, with an incidence of approximately 1:3000. NF1
OPGs commonly occur in young children, most before the age of 7. Patients are at
increased risk of developing tumors of the nervous system, and about 10-20% of children
with NF1 will develop low-grade OPG that eventually leads to visual impairment and
blindness. NF1-OPG can occur anywhere along the optical pathways, but most frequently
occurs in the optic nerves and/or chiasma.
To reduce the progression of visual impairment in OPG patients, standard clinical
treatments include surgery, radiotherapy, and chemotherapy, aimed at controlling tumor
expansion. All these treatments have high risks and low effectiveness. More recently,
therapeutic strategies aimed at neuroprotection in the visual pathway rather than
reducing the size of the tumor have been studied.
Rational for the use of CHF6467 in optic pathway glioma Unmodified human NGF has
previously been proposed and studied as a treatment for neuropathy associated with
diabetes and HIV infection, but the discovery that parenteral administration produced
frequent adverse effects of local and generalized pain, which limited dose increase, put
an end to this line of investigation.
Experimental animal studies have shown that NGF applied to the conjunctiva reaches the
retina and optic pathway and the cerebral cortex, demonstrating biological activity in
these regions.
Research into the therapeutic potential of NGF continued, using the well-tolerated murine
NGF, and clinical studies demonstrated the safety and efficacy of NGF eye drops in
patients with corneal ulcers and severe glaucoma . Finally, an ocular preparation of
unmodified recombinant human NGF, cenegermin (Oxervate®) was approved in the EU in 2017
for the treatment of neurotrophic keratitis (EMA, 2017).
Recently, two studies have shown that murine NGF can prevent progression of visual damage
in OPG patients (Falsini, 2016). These successful exploratory studies (the last of which
was a randomized, double-blind, placebo-controlled study) represent a significant
reference point in the field of vision loss in OPG patients and provide the basis and
rationale for this study using CHF6467, which is anticipated to prove devoid of adverse
effects related to pain at therapeutic doses.
Type and design of the study This is a phase 2a study intended to demonstrate the
superiority over placebo of 10 days' treatment with CHF6467 in significantly improving
the field of vision of children and young adults with optical pathway glioma, 12 weeks
after the start of treatment. The study will be conducted under double blind conditions,
using a "staggered" design of parallel groups in order to protect the safety of study
participants. The "staggered" design consists of the serial enrolment of several cohorts
of subjects in which ascending doses of the drug are administered. In our study there
will be 4 cohorts of subjects In each of the first 3 cohorts (A, B and C), 4 children
will be randomised to receive either CHF6467 (3) or matching placebo (1) eye drops 10
days. The planned dosing levels will be 1 drop of study medication to each affected eye
once daily (Cohort A), twice daily (Cohort B) and three times daily (Cohort C). In cohort
D, 24 children will be randomised to receive either CHF6467 (18) or matching placebo (6)
eye drops three times a day for 10 days. In the end, a total of 27 subjects will have
received CHF6467 and 9 subjects placebo (ratio 3:1).
At the end of the 12-week double-blind and placebo-controlled phase, each subject will be
offered the opportunity to join an "open label extension phase" of a further 12 weeks
where each subject will receive CHF6467 at the dose corresponding to their blind-phase
cohort. (1 drop of CHF6467 1 time a day for 10 days for the 4 subjects of Cohort A, 1
drop of CHF6467 twice a day for 10 days for the 4 subjects of Cohort B, 1 drop of CHF6467
three times a day for 10 days for the 28 subjects of Cohort C and D).
Study goals (primary and secondary endpoints) Objectives of the study The purpose of this
randomised study is to assess the safety and efficacy of multiple doses of painless NGF
CHF6467 eye drops on the visual function of children or young adults with optic pathway
gliomas, whether or not associated with type 1 neurofibromatosis This study will include
serial assessments of both optical pathway functionality and morphology, using
electrophysiological and magnetic resonance imaging (MRI) techniques of the brain.
The comparator will be a placebo preparation based on a physiologically balanced salt
solution. This comparator has no effect on retinal function and optic nerve, is painless
and perfectly tolerated, as reported by numerous clinical studies including that of our
group
Criteria for eligibility:
Criteria:
Inclusion Criteria:
-
1. Paediatric or adult subjects between the ages of 3 and 40 (including extremes).
2. Diagnosis of OPG-induced visual damage, with or without type 1 neurofibromatosis
(NF-1) 3. Stable disease with two brain MRI checks, performed at least 6 months
before screening.
Exclusion Criteria:
-
1. concomitant ophthalmological disorder that may affect electrophysiological
evaluation.
2. radiotherapy or chemotherapy or any other specific antineoplastic treatment within 9
months before entry.
Gender:
All
Minimum age:
3 Years
Maximum age:
40 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Catholic University, Policlinico A. Gemelli (Hospital)
Address:
City:
Rome
Zip:
00168
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Benedetto Falsini, M.D.
Phone:
01139-06-3015
Phone ext:
6344
Email:
benedetto.falsini@unicatt.it
Investigator:
Last name:
Benedetto Falsini, M.D.
Email:
Principal Investigator
Start date:
June 12, 2023
Completion date:
April 30, 2026
Lead sponsor:
Agency:
Benedetto Falsini
Agency class:
Other
Source:
Catholic University of the Sacred Heart
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05733572
