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Physicians |
NeuroSystec is committed to
supporting professionals working in the
field of tinnitus, neuroprotection, Meniere’s disease, sudden
sensorineural hearing loss (SSNHL) and other hearing diseases. It
is
our mission to provide new therapeutic modalities to enable the
physician to offer better options and outcomes for these severe
diseases and syndromes. As discussed elsewhere on this website,
parenteral administration of potent neuroleptics is associated with
severe side effects as the non-specificity of the nervous system does
not currently allow us to target the auditory system. To allow
tissue
specific drug delivery to the cochlea and eventually to the auditory
cortex and other related tissues of the hearing system.
NeuroSystec is
also developing a fully implantable micro pump that will deliver low
doses of potent drugs from a reservoir over long periods of time.
Our
initial drug under development is NST-001. In the sections
below we
provide some additional information about our understanding of tinnitus
and how we decided to proceed with our first product.
Initial studies have shown NST-001 is safe for direct injection into
the cochlea. NeuroSystec Corporation has conducted genotoxicity
and local tolerance safety studies to establish the safety of NST-001
to support the phase 1b clinical trial. In addition, there are numerous
in-vivo and in-vitro pharmacological studies in the literature that
document the safety of our compound. Based on current and historical
data, it can be concluded that NST-001 is safe for use in man at the
proposed intra-cochlear doses.
An NMDA receptor antagonist has been used in large phase 2 clinical
studies for treatment of spinal cord and brain injuries at a much
higher dose than our proposed dose.1 The studies used
this
compound at various doses, and determined the maximum tolerated dose
(MTD). NeuroSystec Corporation is proposing to deliver directly to the
tissue and thereby use NST-001 at a much lower dose. In Hannover,
Germany six severe tinnitus patients were treated with NST-001 as part
of a ‘Heilversuche’ (individual patient therapy).2
Each patient
received a constant perfusion of NST-001 into the round window niche
using a Durect IntraEar® Round Window µCath™. No serious
adverse reactions were observed.
Direct treatment of the cochlea, via a site-specific drug
administration, is expected to minimize general side effects while
maximizing therapeutic effect. The distribution of the drug out of the
cochlea will be slow since NST-001 has significant protein and
hydrophobic binding. For these reasons the peripheral exposure of
the drug is expected to be below measurable limits and within the
microdose guidelines. The highest proposed dose will be below the
threshold of toxicological concern (TTC).3-5
All of the above studies led NeuroSystec to conclude that NST-001 is
safe for human use and is expected to be an appropriate therapeutic for
tinnitus treatment which will require continuous, tissue-specific
delivery of the drug.
The phase Ib clinical trial started this year, injects NST-001 into the
inner ear. This approach was chosen for a number of
reasons. As would be true for any potent neurologically active
substance, it is desirable to restrict administration of any NMDA
receptor antagonist to the site of treatment. Administration of
NMDA receptor antagonists by oral or parenteral routes can result in
cognitive impairment,6 motor ataxia,7
schizophrenia-like behavior,6,8
and other undesirable side effects because all the nerves in the body
would be exposed to a therapeutically effective dose. None
of these effects would be deemed acceptable for chronic drug therapy to
control tinnitus. It is for this reason NeuroSystec Corporation
is studying the possibility of treating peripheral (cochlear) tinnitus
by delivering drug directly to the target site. As such, there is
a need for tissue-specific delivery of any drug (in our case an NMDA
receptor antagonist) to the cochlea.
NeuroSystec’s approach for drug delivery is to selectively deliver
NST-001 directly into the scala tympani region of the cochlea, across
the blood labyrinth barrier (BLB). This method of drug delivery avoids
a series of limitations that are present in middle ear delivery (i.e.
drug wash out to GI tract, insufficient amount of drug at target site
because of unknown diffusion rate through the round window
membrane). With inner ear delivery, the drug will diffuse to the
spiral ganglion in a more controlled manner. Drug delivered to
this tissue would have to be delivered via an implanted pump with
needle or another drug delivery device. Such a device would have
to inject the drug through the round window or through a hole drilled
into the cochlea capsule. Preliminary anecdotal data showed that
tinnitus returned to pretreatment levels following cessation of
treatment, supporting the need for an implantable drug delivery device
for patients that desire chronic treatment. A fully implanted
drug delivery system with a convenient refillable drug reservoir
replenished conveniently over time would overcome the serious issues of
middle ear drug delivery and would provide a reproducible delivery of
an effective dose of the therapeutic.
NeuroSystec is developing a drug delivery system to deliver NST-001 to
the inner ear for 1-5 years without requiring refilling the drug
reservoir. In future trials we hope to demonstrate the utility
and effectiveness of a pump/therapeutic combination product. For
these reasons NeuroSystec believes that inner ear drug delivery will be
the optimum option for treating tinnitus and that other methods may
offer advantages for the short term that this will be the best option
for chronic treatment of severe tinnitus sufferers.
There are two questions that direct round window delivery
raises.
The first is how to seal the needle hole following removal of the
delivery needle at the end of the treatment. Since the device
pierces the round window membrane, there is a risk of developing a hole
or tear in the round window membrane causing leakage of the cochlea
perilymph. As a way to avoid permanent leakage NeuroSystec recommends
that upon removal of the injection needle the surgeon place a drop of
blood, fibrin glue, or a piece of fascia over the hole in the round
window membrane. The second question related to whether the drug
delivery system might clog because of drug precipitation in the device
or within the cochlea. NeuroSystec has addressed this question
too. Although unlikely because of the small volume of the dose
(low nL/dose), NST-001 could conceivably precipitate on leaving the
needle following an injection inside the cochlea. In some
respects a precipitation of the compound in the inner ear could be seen
as beneficial. The precipitated drug is chemically stable.
Any precipitated drug in the area of the round window would slowly
dissolve and then diffuse through the cochlea. The solubility of
NST-001 at physiological pH (pH 7.4) is higher than the required
effective concentration and it would maintain a steady state
concentration within the cochlea basal turn until all the precipitated
drug dissolves or until the next dose is
administered. Fortunately, the effective dose from
animal studies is below the saturation point of the drug and so during
the time of solid drug dissolution there would be an effective dose of
NST-001 in the basal turn of the cochlea near the round window.
There is very little risk of drug precipitating inside the catheter as
the drug will be at pH 4.8-6.5. At this pH the drug is soluble at
a far higher concentration than the dose being delivered. For
this reason it is unlikely that the drug will precipitate within the
catheter or after injection.
There are many potential neuro-therapeutics that one might select for
treating tinnitus. NeuroSystec felt that tinnitus is a disease of
hyperactive nerves and a kind of neuropathic pain. An analysis of
the literature suggested that a NMDA receptor antagonist was the best
option for an
effective chronic therapy that actually treated the biochemical cause
of the tinnitus and not just offer a palliative. NeuroSystec is
working under the assumption that tinnitus can be considered analogous
to neuropathic pain, which is produced by pathological changes or
damage to the peripheral or central nervous systems (CNS). Because the
abnormal neuronal firing is generally the result of too much
excitation, strategies to reduce tinnitus attempt to either decrease
excitation or increase inhibition. Four main receptor categories
have been considered as treatment options. [Additional Information and
References for Physicians - Page 1 - CLICK
HERE]
When considering local application in the middle or inner ear, NMDA
antagonists are the most appealing of the possible mechanisms. The
efficacy of GABA receptor modulators α2δ-acting
drugs may all be
secondary to their known anxiolytic activity and they may not be
effective when applied locally. Sodium channel modulators may be
more effective locally, but it is difficult to adjust the dosage
correctly to prevent blockade of neuronal transmission which would lead
to hearing loss. Similarly, blockage of AMPA receptors (and
probably related to kainate receptors) will interfere with
hearing. In addition to the ability of NMDA antagonists to
selectively block sensitized neurons, they are also neuroprotective,
protecting against excitotoxicity.9-16
Excitotoxicity results
from excessive stimulation primarily of NMDA receptors, which causes
Ca++ overload in cells and subsequent death of neurons and hair
cells.12 Loss of hair cells or other neuronal elements
in the
auditory system is one of the possible causes of tinnitus.17
In
addition to studies that demonstrate prevention of acoustic trauma by
NMDA receptor antagonists,9-16 these drugs can protect
cochlear neurons
from intra-operative traumatic stress.18 Based on this
analysis
NeuroSystec considers that a NMDA antagonist is the best option to
treat the hyperactivity of the spiral ganglion.
The issue with many NMDA receptor antagonists reported in the
literature is that they are not very specific for this receptor and
that they do not have the requisite subtype activity splits. For
this treatment to be useful it would have to be very specific for
tinnitus and not affect hearing or have side activities on unrelated
receptors. As described above, an analysis of the likely
neurobiology of the auditory cortex suggests that NMDA receptors are
probably the optimum therapy for treating tinnitus and lead to long
term desensitization of the spiral ganglion. NST-001 is a highly
potent non-competitive antagonist of NMDA receptors with mixed agonist
and antagonist activity, meaning that it will provide effective
blockage of the receptor, independent of the concentration of
glutamate.19,20 It has no significant affinity at a
variety of
other CNS receptors.20 [Additional Information
and References for Physicians - Page 2 - CLICK HERE] Following
systemic administration
in rodents, NST-001 was nearly devoid of any intrinsic
neurotoxicity. Therefore, NST-001 has a much better efficacy to
safety ratio (therapeutic index) than other NMDA antagonists.
Most importantly in the salicylate-induced tinnitus animal model,
NST-001 was highly effective when directly administered to the inner
ear.21,22 In animal safety studies NST-001 was shown
to be safe
at doses nearly 2.5 times the anticipated maximal human dose (data not
published). The human dose for treating tinnitus locally by
direct delivery into the cochlea is about two-thousand times less than
the established MDT (data not published). In an individual
patient therapy in Hannover, Germany of six severe tinnitus patients
treated with NST-001, five patients reported a significant reduction of
tinnitus. 23 In all five that reported
improvement of their
tinnitus during dosing, the tinnitus returned to pretreatment levels
over time following cessation of treatment. In summary, NST-001
is an ideal drug candidate for the treatment of tinnitus and has the
optimum mechanism of action and therapeutic profile.
Our ultimate product objectives are two fold. First it is to
develop an effective tinnitus treatment for a significant segment of
severe tinnitus sufferers and secondly to develop an implantable
micro-pumping system that would enable convenient and efficient drug
delivery of potent neurobiologicals to the cochlea and other areas of
the brain. The current clinical study is to demonstrate that the
drug is safe, establish an MTD within the cochlea if within the planned
dosing range and secondarily if the drug has any efficacy with in the
selected dosing regimen. Should this objective be met, then
NeuroSystec plans to test the commercial configuration of the drug and
fully implantable delivery device. We believe that to be
effective for chronic tinnitus treatment, NST-001 will have to be
delivered chronically to the inner ear. The ultimate
product objective is to develop a fully implanted drug delivery pump
with an internal drug reservoir that will deliver drug for a year or
more and that could be conveniently refilled through the skin or with a
minor surgical procedure. This product will be very convenient
for the patient and will provide dosing and other information
wirelessly to the attending physician about the patient’s usage of the
drug delivery system and allow for adjustment of the dosing procedure
and frequency.
For more information about the planned drug delivery system please
contact NeuroSystec Corporation. For more information
specifically about the Phase Ib clinical trials visit one or more of
the links below.
CLICK HERE for more information
about the current Phase 1b clinical trial in French
CLICK HERE for more information
about the current Phase 1b clinical trial in English
CLICK
HERE for more information
about the current Phase 1b clinical
trial on ClinicalTrials.gov.
References:
1. Lepeintre JF, D'Arbigny P, Mathé JF,
Vigué B, Loubert G, Delcour J, Kempf C, Tadié M (2004)
Neuroprotective effect of gacyclidine. A multicenter double-blind
pilot trial in patients with acute traumatic brain injury,
Neurochirugie 50:83-95.
2. Wenzel GI, Lim HH, Warnecke A, Stöver T, Lobl
T, Schloss J, Schwab B, Lenarz T Effects of gacyclidine extracochlear
perfusion on tinnitus in humans and intracochlear perfusion on ABR
thresholds in guinea pig. 30th MidWinter Research Meeting of the
Association for Research in Otolaryngology, Denver, CO, 10-15 February
2007.
3. EMEA/CHMP/QWP/251344/2006 and
EMEA/CHMP/SWP/431994/2007
4. Cramer GM, ford RA, Hall RL. Estimation of toxic
hazard – a decision tree approach. Food Cosmet Toxicol. 1978; 16:
255-276
5. Kroes R, Renwick AG, Cheeseman M, Kleiner, J,
Mangelsdorf I, Piersma A, Schilter B, Schlatter J, van Schothorst F,
Vos JG, Würtzen G. Structure-based thresholds of toxicological
concern (TTC): guidance for application to substances present at low
levels in the diet. Food Chem Toxicol 2004; 42: 65-83
6. Rowland LM, Astur RS, Jung RE, Bustillo JR,
Laurienllo J, Yeo RA (2005) Selective cognitive impairments associated
with NMDA receptor blockade in humans, Neuropsychopharmacology
30:633-639.
7. Spangler EL, Bresnahan EL, Garofalo P, Muth NJ,
Heller B, Ingram DK (1991) NMDA receptor channel antagonism by
dizocilpine (MK-801) impairs performance of rats in aversively
motivated complex maze tasks, Pharmacol Biochem Behav 40:949-958.
8. Krystal JH, D'Souza DC, Mathalon D, Perry E,
Belger A, Hoffman R (2003) NMDA receptor antagonist effects, cortical
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medication development, Psychopharmacology (Berl) 169:215-233.
9. Oestreicher E, Ehrenberger K, Felix D (2002)
Different action of memantine and caroverine on glutamatergic
transmission in the mammalian cochlea, Adv Otorhinolaryngol 59:18-25.
10. Chen Z, Ulfendahl M, Ruan R, Tan L, Duan M (2004)
Protection of auditory function against noise trauma with local
caroverine administration in guinea pigs, Hear Res 197:131-136.
11. Chen Z, Ulfendahl M, Ruan R, Tan L, Duan M (2003)
Acute treatment of noise trauma with local caroverine application in
the guinea pig, Acta Otolaryngol 123:905-909.
12. Pujol R, Puel JL (1999) Excitotoxicity, synaptic
repair, and functional recovery in the mammalian cochlea: a review of
findings, Ann N Y Acad Sci 884:249-254.
13. Muly SM, Gross JS, Potashner SJ (2004) Noise
trauma alters D-[3H]aspartate release and AMPA binding in chinchilla
cochlear nucleus, J Neurosci Res 75:585-596.
14. Kopke RD, Coleman JK, Liu J, Campbell KC,
Riffenburgh RH (2002) Candidate's thesis: enhancing intrinsic cochlear
stress defenses to reduce noise-induced hearing loss, Laryngoscope
112:1515-1532.
15. Oestreicher E, Arnold W, Ehrenberger K, Felix D
(1998) Memantine suppresses the glutamatergic neurotransmission of
mammalian inner hair cells, ORL J Otorhinolaryngol Relat Spec 60:18-21.
16. Nordang L, Oestreicher E, Arnold W, Anniko M
(2000) Glutamate is the afferent neurotransmitter in the human cochlea,
Acta Oto-Laryngologica 120:359-362.
17. Nuttall AL, Meikle MB, Trune DR (2004) Peripheral
processes involved in tinnitus, in Tinnitus: theory and management,
Snow JB, editor, BC Decker Inc., Publisher, pp. 52-68.
18. Sekiya T, Shimamura N, Hatayama T, Suzuki S
(2000) Effectiveness of preoperative administration of an
N-methyl-D-aspartate antagonist to enhance cochlear neuron resistance
to intraoperative traumatic stress: an experimental study, J Neurosurg
93:90-98.
19. Hirbec H, Kamenka JM, Privat A, Vignon J (2001)
Characterization of 'non-N-methyl-D-aspartate' binding sites for
gacyclidine enantiomers in the rat cerebellar and telencephalic
structures, J Neurochem 77:190-201.
20. Hirbec H, Gaviria M, Vignon J (2001) Gacyclidine:
a new neuroprotective agent acting at the N-methyl-D-aspartate
receptor, CNS Drug Reviews 7:172-198.
21. Guitton MJ, Wang J, Puel J-L (2004) New
pharmacological strategies to restore hearing and treat tinnitus, Acta
Otolaryngol 124:1-5.
22. Guitton MJ, Caston J, Ruel J, Johnson RM, Pujol
R, Puel J-L (2003) Salicylate induces tinnitus through activation of
cochlear NMDA receptors, J Neurosci 23:3944-3952.
23. Wenzel GI, Lim HH, Warnecke A, Stöver T,
Lobl T, Schloss J, Schwab B, Lenarz T Effects of gacyclidine
extracochlear perfusion on tinnitus in humans and intracochlear
perfusion on ABR thresholds in guinea pig. 30th MidWinter Research
Meeting of the Association for Research in Otolaryngology, Denver, CO,
10-15 February 2007.
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