Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05733572 |
| Other study ID # |
CHF6467-OPG |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
June 12, 2023 |
| Est. completion date |
April 30, 2026 |
Study information
| Verified date |
February 2024 |
| Source |
Catholic University of the Sacred Heart |
| Contact |
Benedetto Falsini, MD |
| Phone |
0039-06-30156344 |
| Email |
benedetto.falsini[@]unicatt.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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
