NLS Pharmaceutics : ASCP Annual Meeting, Miami, May 28-May 31, 2024

T22Neuroprotective effect of mazindol on nocturnal activity in an Orexin-B-Saporin-inducednarcoleptic-like model in Sprague-Dawley rats (Study KO-874)

Eric Konofal1,2, Jean-Charles Bizot 3, Christelle Peyron 4, Fabienne Massé 3, Anne-Laure Morel 4, George Apostol 1

• NLS Pharmaceutics AG, The Circle 6, P.O. Box, CH-8058 Zurich Airport, Switzerland - [e-mail]

• APHP, Hôpital Robert Debré, Centre Pédiatrique des Pathologies du Sommeil, 48 boulevard Sérurier, 75019 Paris, France
  3 Key-Obs SAS, 13 avenue Buffon, 45100 Orléans, France

• Centre de Recherche enNeurosciences de Lyon, INSERM U1028, CNRS UMR5292, Lyon 1 University, CH Le Vinatier,Neurocampus MichelJouvet, 95 boulevard Pinel, 69675Bron Cedex, France

Introduction and Rationale

Main Results

Previous experiments have shown that thebilateral infusion of theneurotoxin orexin-B-saporin(OX-B-SAPorHCRT2-SAP), aconjugate of theorexin-Bpeptide and saporin, in thelateral hypothalamus (LH) induced lesions oforexin neurons,producing narcoleptic-likesleepbehavior in rats(Gerashchenkoet al., 2001, 2003).

OX-B-SAP selectively bindsto theorexin-2receptor (OX2R) and lesionsorexin neurons viamicroinjection into the LH, making it avaluabletoolforstudying sleepdisorders.

Aim of the Study

Thisstudy KO-874 aimedto investigate theneuroprotective effects of mazindol on nocturnal activity in arat model with narcoleptic-likesymptoms, induced byOX-B-SAP lesions in thelateralhypothalamus(LH).

Theobjectives were to implement theOX-B-SAPlesion modelat Key-Obs, determine theextent andduration ofcircadianactivitydisruption-particularlythedecrease in activity during the dark phase-andexamine theneuroprotective impact of mazindol on thisdisruption.

The present study shown the neuroprotective effects of mazindol on nocturnal activity in a rat model induced with narcoleptic-like symptoms through the administration of OX-B-SAP lesions in the LH. The main findings are reported Table 2.

• The bilateral infusion of OX-B-SAP (90 ng) into the LH significantly decreased circadian activity, particularly during the dark phase, which effectively modelled the decreased wakefulness seen in narcolepsy. This reduction in activity became significant from the 12th day post-lesion and persisted until the end of the experiment (Day 21).
• Mazindol was administered at 2 doses previously screened (1 mg/kg and 3 mg/kg) to evaluate its therapeutic potential. At a lower dose (1 mg/kg), mazindol showed no therapeutic effect and even appeared to aggravate the reduction in activity between Days 5 and 8 post-lesion.

Table 2. Summary of key findings of all experinents

Parameter	Description and Results
	Lesions caused by OX-B-SAP(orexin-B-saporin) in the
	lateral hypothalamus led to a significant decrease in
OX-B-SAP Lesion	circadian activity from day 12 to day 21 post-lesion. This
(90 ng)	reduction models the decreased wakefulness seen in
	narcolepsy, indicating effective targeting of orexin-

Experiment 2.Rats were subdivided into 3 groups which received a bilateral infusion into the LH of either vehicle (Sham-Veh group) or OX-B-SAP (90 ng) (OX-B-SAP-Veh and OX-B-SAP-Maz groups). They received a p.o. administration of either vehicle (0.9% NaCl; Sham-Veh and OX-B-SAP-Veh groups) or 3 mg/kg mazindol (OX-B-SAP- Maz group) immediately after infusion of vehicle or OX-B-SAP and at the beginning of the dark period for 21 consecutive days. Circadian locomotor activity was recorded as described previously (see Figure 2). At the end of the experiment, animals were sacrificed, the brain was collected, frozen in dry ice and transferred to the CNRS- UMR5292 laboratory for histological analysis of orexin neurons in the LH.

Data analysis. OX-B-SAP groups were divided into subgroups according to the extent of the lesion in comparison with the OX-B-SAP-Veh group: High Lesion (HL) groups (OX-B-SAP-Veh HL and OX-B-SAP-Maz HL groups), which showed less than 50% remaining Orexin neurons in the LH, and Low Lesion (LL) groups (OX-B-SAP-Veh LL and OX- B-SAP-Maz LL groups), which showed more than 50% remaining Orexin neurons in the LH (Figure 5).

Sham-vehicle(Sham-Veh) rats showed a higher activity during the dark period than during the light period (Figure 4).

The bilateral infusion of OX-B-SAP (90 ng) induced a decrease in the number of orexin neurons in the LH, which was not significantly modified by mazindol treatment (Figure 5).

The OX-B-SAP infusion induced a decrease in activity in OX-B-SAP-Veh rats (see Figure 4). This

effect:

• was mostly observed during the dark phase,
• was observed only in high-lesion rats (< 50% remaining neurons in the LH), but not in low-lesion rats, and
• began to be significant from Day 12 following lesion and was present until the end of the experiment.

Mazindol mitigated the OX-B-SAP-induced decrease in activity during the dark phase in high-lesion rats (Figure 4), which was:

On Days 6-8,12-15, and 19-21,OX-B-SAP lesioned rats treated with mazindol (3 mg/kg) showed significantly higher activity levels during the dark phase compared to vehicle-treatedOX-B-SAP lesioned rats (Figure 4)

By Day 21, mazindol not only restored the activity levels to normal but exceeded those of the Sham group during the dark phase, indicating a robust protective effect against the activity disruptions caused by the destruction of orexin cells in the LH.

Detailed analysis showed that the beneficial effects of mazindol were more pronounced in rats with less severe lesions (>50% of orexin neurons remaining). These rats exhibited significantly higher activity levels during the dark phase compared to rats with severe lesions (<50% of orexin neurons remaining).

The bilateral infusion of OX-B-SAP induced a significant decrease in the number of orexin neurons in the LH, which was not significantly modified by mazindol treatment (Figure 5).

Mazindol mitigated the OX-B-SAP-induced decrease in activity during the dark phase in high-lesion rats:

• The number of orexin neurons was significantly reduced in the OX-B-SAP treated groups compared to the Sham group.
• The correlation between the number of orexin neurons and the distance traveled during the dark phase was significant in both the OX-B-SAP and OX-B-SAP + Mazindol groups, but not in the Sham group, suggesting that efficacy of mazindol is closely linked to the preservation of orexin neurons.

The analysis by the Pearson r test shows that the correlation between the activity during the dark phase and the number of Orexin neurons in the LH (Figure 6, upper):

• In Sham-Veh group: was far from significant.
• In OX-B-SAP-Veh group: was significant.
• In OX-B-SAP-Maz group: was significant.

There was no significant correlation between the activity during the light phase and the number of orexin neurons (Figure 6, lower) in Sham-Veh and OX-B-SAP-Veh groups, but a close to significant correlation in OX-B-SAP-Maz group.

Methods and Timeline

Animals were housed individually in transparent cages placed in actimeters to continuously record locomotor activity (distance traveled). The distance traveled each day, during dark and light periods, and during each 1-hour period, was recorded over 24-hourperiods duringvarious phases of theexperiment.Normal rats exhibit locomotor activity that is 4-5 times higher during the dark phase than during the light phase.

Narcolepsy symptomatology, induced here by OX-B-SAP lesions in the LH, should be detected by a decrease in activity during the dark phase, without changes during the light phase.

Animals, drugs, andmaterials used in theseexperiments, including the doses andpreparation methods for both OX-B-SAPand mazindol isreported in Table 1.

Timelinesfor experiments 1A, 1B(Figures 1) and 2(Figure 2),highlighted thesurgical procedure, drugadministration, and

activityrecording. Surgicalprocedure in rat andOX-B-SAPadministrationmethod is shown on Figure 3.

Table 1. Animals, drugs and material

Category	Details
	Experiments at Key-Obs by authorized personnel;
	Compliance with French Ministry of Agriculture guidelines; Approved by Key-Obs SAS Ethical Committee No. 27;
General Points	Conducted in standard conditions (T°= 22.0 ± 1.5°C);
	Experiments conducted blindly;
	No prior experiments on animals.
	Species: Sprague-Dawley rats, male; Age: 3 weeks at delivery, 5 weeks at surgery, 8 weeks at experiment end; Number: N=75; Origin:
	Janvier Labs, France; Housing: Single in transparent cages (1290D Eurostandard Type III, Tecniplast); Litter: Aspen Small; Enrichment:
Animals	Wood brick;

	producing neurons.
	At this dosage, mazindol showed no therapeutic effect on
	the lesion-induced decrease in activity. Interestingly, there
Mazindol (1 mg/kg)	was an observed potential aggravation of decreased
activity between days 5 and 8 post-lesion, suggesting that
	at lower doses, mazindol might not be effective or could
	interfere negatively when administered orally.
	Higher doses of mazindol significantly increased activity on
	days 5, 12, 14, 20, and 21 post-lesion compared to both
	sham-operated and OX-B-SAP-only groups. This suggests a
	dose-dependent effect of mazindol when administered
Mazindol (3 mg/kg)	orally, potentially enhancing the orexinergic signaling or
compensating for the loss of orexin neurons due to the OX-
	B-SAP lesion. The increase in activity supports the
	hypothesis that mazindol at higher doses could stimulate
	the orexin system, which is crucial for maintaining
	wakefulness and regulating circadian rhythms.
	In trials where the dosage of OX-B-SAP exceeded 90 ng,
	administered intraperitoneally (ip), the resultant brain
OX-B-SAP Lesion	damage in rats was excessive, extending beyond the initial
intended lesion area. This extensive damage rendered the
(>90 ng, i.p.)
results scientifically invalid as the conditions exceeded
	those of a controlled lesion, affecting the overall brain
	function and structure beyond the scope of studying
	targeted orexin neuron disruption.

• not significantly different between OX-B-SAP-Maz HL rats and Sham-Veh rats during D 6-8, D 12-15 and D 19-21 periods, and
• higher in OX-B-SAP-Maz HL rats than OX-B-SAP-Veh LL rats during the D 19-21 period.

Mazindol-induced increase in activity was more pronounced in low-lesion rats than in high-lesion rats (Figure 4).

Figures 4. Circadian locomotor activity: distance travelled in open-fields during 12-h dark and 12-h light periods of days 6-8,12-15 and 19-21 following surgery.

	Sham-Veh (N=10) OX-B-SAP-Veh HL (N=5)	OX-B-SAP-Veh HL (N=2)	OX-B-SAP-Maz HL	OX-B-SAP-Maz LL (N=2)
	100 000				**
+ SEM)							*
80 000	**	***					#
mean			#
60 000
(cm;
				*			**
travelled	40 000			*
Distance	20 000
	0	Dark 0-12 h	Light 12-24h	Dark 0-12 h	Light 12-24h	Dark 0-12 h	Light 12-24h
			D 6-8		D 12-15		D 19-21
	Differences (Student's t-test): vs. Sham-Veh group, * p≤ 0.05; ** p≤ 0.01; *** p≤ 0.001; vs. OX-B-SAP-Veh HL group: # p≤ 0.05.

Figures 5. Number of orexin neurons in the LH.

✱✱✱✱

ns

SEM)±

800

✱✱✱✱

mean

600

(N;

400

LL = Low

neurons

Lesion

200

HL = High

Orexin

Lesion

0

Veh

Veh

z

-Ma

ha

-

-

SAP

S

m

P

S

-

-

A

B

B

-

-

OX

OX

Difference (Student's t-test): ****p≤ 0.0001

Figures 6. Correlation between the number of Orexin neurons in the LH and the distance travelled during the dark phase (upper) and the light phase (lower) by Sham-Veh (left), OX-B-SAP-Veh (center) and OX-B-SAP Maz (right) rats.

	12-h Dark - Sham-Veh - D5-21		12-h Dark OX-B-SAP-Veh D5-21			12-h Dark OX-B-SAP-MazD5-21
	120 000			r = 0.535 - p = ns	120 000		r = 0.786 - p ≤ 0.05		120 000		r = 0.913 - p ≤ 0.001
(cm)	100 000				(cm)	100 000					(cm)	100 000
80 000				80 000					80 000
travelled				travelled					travelled
60 000				60 000					60 000
Distance				Distance					Distance
40 000				40 000					40 000
	20 000					20 000						20 000
	0					0						0
	0	200	400	600	800	0	200	400	600	800		0	200	400	600	800
		Orexin neurons (N)			Orexin neurons (N)				Orexin neurons (N)

	12-h Light - Sham-Veh - D5-21					12-h Light OX-B-SAP-VehD5-21					12-h Light OX-B-SAP-MazD5-21
	40 000							r = -0.355 - p = ns			40 000																					40 000
																							r = 0.097 - p = ns
(cm)	30 000								(cm)	30 000																(cm)	30 000							r = 0.528 - p = ns
travelled	20 000												travelled	20 000																				travelled	20 000
Distance												Distance																				Distance
10 000												10 000																				10 000
	0													0																					0
		0	200	400	600	800			0	200	400	600	800			0	200	400	600	800
				Orexin neurons (N)											Orexin neurons (N)								Orexin neurons (N)

Pearson correlation test: r and p values.

	Conditions: T°= 22.0 ± 1.5°C, Hygrometry= 50 ± 30%, Air renewal= 12-25 vol/h, Lighting= 20-30 Lux, Day/night cycle= 12h/12h, Food:
	Rat-mouse A04 (ad libitum), Drink: Tap water (ad libitum)
	OX-B-SAPSupplier: Advanced Targeting Systems (ATSBIO); Vehicle: Veh; Administration: Bilateral intracerebral infusion in LH; Doses:
	Experiment 1A: 490 ng, Experiment 1B: 90, 180 ng, Experiment 2: 90 ng; Application: 1, Volume: 0.5 µL; Preparation: Dissolved in
Drugs	PBS, stored at -20°C, used within 2 days, on ice during tests;
Mazindol Supplier: GreenPharma, Batch Y7391258; Vehicle: HCl 0.1N + 0.9% NaCl + NaOH 0.1N; Administration: Oral gavage (p.o.),
	some i.p.; Doses: Experiment 1: 0.25, 0.5, 1 mg/kg, Experiment 3: 0.5 mg/kg; Application: 1, Volume: 1 ml/kg; Preparation: Stock
	solution at -80°C for 6 weeks, ambient temperature during test
	Pre-surgery: Buprecare 0.03 mg/kg; Anesthesia: Isoflurane; Stereotaxic surgery in standard frame (David Kopf, USA); Coordinates: 3.3
Surgery	mm posterior to bregma, 1.6 mm lateral to sagittal suture, 8.8 mm beneath brain surface; Injection: Veh (Sham) or OX-B-SAP (490 ng,
180 ng, 90 ng); Post-surgery: Ringer Lactate 1 ml s.c., Metacam 2 mg/kg; Follow-up: Ringer Lactate 1 ml s.c., Metacam 1 mg/kg up to
	5 days if necessary
Recording of	Equipment: Plexiglas open-fields (42 cm L, 42 cm W, 40 cm H) with infrared photobeam detection systems (Acti-track, LSI Leticca,
Circadian	Panlab); Conditions: Floor covered with litter, free access to food and water; Data: Distance traveled recorded every 15 min for 24-h
Activity	period, starting at dark period; Read-outs: Distance during 24-hr,12-hr dark, 12-hr light, each 3-hr, each 1-hr period

Conclusion

Mazindoladministered at 3mg/kg after OX-B-SAP-inducedlesions (90 ng) in the LHsignificantly mitigates thereduction incircadian activitytypically ledby the lesions.By Day 21, mazindol not onlyrestores the activitylevels to normal butexceeds those of the Shamgroup during the dark phase. Thisindicates that mazindol has astrong protective effect against the activitydisruptions ledby thedestruction oforexin cells in the LH,potentially offering atherapeutic approach to counteract

narcolepticsymptoms inducedbyorexin cell loss.

Mazindol per osadministered exhibitspotential interaction with theorexin system, asevidenced by itseffects at different dosages in the rat model withOX-B-SAP-inducedlesions.At a higher dose (3mg/kg), mazindolsignificantly increases circadian activity, suggesting itspotential utility intreating disorders like narcolepsy, where orexin system disruption leadsto decreased activity andwakefulness. The lack ofeffect ornegative impactat lower doses (1mg/kg) underscores theimportance ofdosage in achievingtherapeuticbenefitsthroughpotential"orexinergicmechanisms". Thisrelationshipsuggeststhat mazindolmightworkby eitherdirectly or indirectlymodulatingorexinreceptors or the pathwaysinfluencedby the orexinsystem.

Figure 1. Time schedule of Experiment 1A and Experiment 1B

Figure 2. Time schedule of Experiment 2

Comprehensive Timeline of Orexin Research

Beginning		Surgery
of		OXB-SAP
reversed		lesion
light/dark		or			Non-lesioned rats only (Sham:
cycle		Sham lesion			N=7; non-operated: N=2)
					Effect of Mazindol i.p. (1; 3
	1 i,p. administration / day of vehicle		mg/kg) or p.o. (3; 10 mg/kg)

D-15

D-4

D-3

D-2

D-1

D 0

D 1

D 2

D 3

D 4

D 5

D 6

D 7

D 15 - D 22

2 × 24-hr LMA

2 × 24-hr LMA

8 × 24-hr LMA

Beginning

Surgery

of

OXB-SAP lesion

reversed

or

light/dark

Sham lesion

cycle

1 p.o. administration / day of vehicle

D-15

D-4

D-3

D-2

D-1

D 0

D 1

D 2

D 3

D 4

D 5

D 6

D 7

D 8

D12

D13

D14

D15

D19

D20

D21

2 × 24-hr LMA

4 × 24-hr LMA

4 × 24-hr LMA

3 × 24-hr LMA

Legend: x24-hr LMA" = x consecutive 24-hr locomotor activity recording

Beginning

Surgery

of

OXB-SAP lesion

reversed

or

Brain

light/dark

Sham lesion

collection

cycle

1 p.o. administration / day of mazindol (1; 3 mg/kg) or vehicle

D-15

D-3

D-2

D-1

D 0

D 1

D 2

D 3

D 4

D 5

D 6

D 7

D 8

D12

D13

D14

D15

D19

D20

D21

D22

2 × 24-hr LMA

4 × 24-hr LMA

4 × 24-hr LMA

3 × 24-hr LMA

Figure 3. Surgery in OX-B-SAP lesioned rat

Experiment 1A: OX-B-SAP 490 ng; Experiment 1B: OX-B-SAP 90 ng and

180 ng; Experiment 2: OX-B-SAP 90 ng injection in LH

Sleep-inducing potential of orexin reported in

		the treatment of	Primary
		dipsomania	observations on
Orexin introduced	(Brunton L.)	hypothalamus
	lesions in monkeys
as a pharmacological		highlighting its role
agent enhancing		in behavior and
vigilance and		emotional responses
appetite			(Ranson S.W.)
(Penzoldt F.)
1890	1891	1910	1936	1939	1967
Orexin tannate			Discovery by
efficacy in anemia		William Houlihan:
and cachexia,			a patent filed by
highlights its			Sandoz Inc. for
stimulating effects on	compounds including
appetite (Smith W.)		mazindol, initially
				studied for its anti-

inflammatory and/or anticonvulsant and appetite-regulating properties

First significant reports on
mazindol highlighting its	Discovery of a
effectiveness in treating
narcolepsy with cataplexy and	mutation in the
providing therapeutic benefits	hypocretin
comparable to or greater than	receptor 2 (OX2R)
those of amphetamines, but	gene causing
without serious side effects	narcolepsy with
associated (Parkes, J.D.,	cataplexy in dogs
Schachter, M. & Alvarez B.)	(Lin L., Mignot E.)

1973	1976	1979	1985	1991	1998	1999
Pharmacological		Action of mazindol	Co-discovery by two
action of mazindol		on lateral		independent teams and
via cerebral		hypothalamic		designation of orexin for
norepinephrine		neurons is		hypothalamus-specific peptides
metabolism has		independent of	(hypocretin) with
moderate activity		dopaminergic		neuroexcitatory activity, and
on the CNS and		processes		their receptors, crucial for the
anorexia in animal		(Sikdar S.K.)		regulation of sleep and appetite
models (Griffith, J.				(Peyron C., de Lecea L., &
& Gogerty, J.H.)				Sakurai T., Yanagisawa M.)

Pathophysiological hypothesis

Serum orexin A levels are significantly lower in drug-naive children

Relationship identified

suggesting dysfunction in the

orexin system related to ADHD

with ADHD, particularly in the inattentive subtype (Baykal S.)

Orexin-induced

between hypocretin (orexin)

and affecting areas controlling

neurons and CSF hypocretin

wakefulness and reward

Mazindol

Introduction and clinical

Irregular sleep

hyperlocomotion

(orexin-A) levels in

Introducing Dual

processing (Cortese S., Konofal E.)

and stereotypy in

narcolepsy:

Combination use in

trials of TAK-925 and

patterns and higher

rats are

Neurodegeneration of orexin

Orexin Receptor

First report of Yan7874 as

ADHD treatment

TAK-994 as selective

daytime sleepiness

mediated by the

neurons leading to significant

Antagonists

(either as

OX2R agonists, aiming to

in ADHD patients

dopaminergic

reductions of orexin-A level

(DORA), showing

OX1 and OX2 receptors

monotherapy or in

treat narcolepsy with

found and

system in the

in CSF is correlated with

potential to treat

agonist exhibiting receptor-

combination with

promising results,

correlated with

ventral

increased REM sleep and

insomnia by

independent cytotoxicity,

other compounds)

though some trials were

higher energy drink

tegmental area

impaired orexin release

blocking both

which limits its therapeutic

US8293779 B2;

halted due to hepatic

consumption and

(Nakamura T.)

during wakefulness

orexin receptors

potential

patent granted

signal

serum orexin levels

(Gerashchenko D., Mignot E.)

(Yanagisawa M.)

(Konofal E.)

(Takeda, 2016-2023)

(Sungur M.)

2000

2001

2003

2004

2006

2008

2010

2012

2014

2016

2017

2018

2019

Sleepiness-induced

Effects of hypocretin-2-

Demonstration

First orexin-2

Studied reporting the

NLS Pharmaceutics

NLS Pharmaceutics

receptor agonist

effects of mazindol,

received a patent

announced a mechanism

hyperlactivity in

saporin (OX-B-SAP) on

that orexin

with

amphetamine

approval and began

of action on orexin system

children with

sleep and neuronal loss

peptides prevent

anti-obesity activity

modafinil and

development of

and positive phase 2 data

ADHD: First report

in rats: A primary link

cataplexy and

discovered: Initial in

modafinil analog

mazindol

for mazindol extended-

on objective

between severity of

improve

vitro metabolism

compounds on

IR/SR multilayer tablet

release (ER) in adults with

somnolence

narcolepsy symptoms

wakefulness in an

and pharmacokinetic

impulsive behavior in

for the treatment of

ADHD, demonstrating

measured in ADHD

and orexin neuronal loss

orexin neuron-

studies

juvenile Wistar rats

ADHD

significant improvement

(Lecendreux M.,

(Gerashchenko D.)

ablated model of

with BLX-1026

subjected to the T-

(US11207271B2;

in symptoms (Wigal T.,

Konofal E.)

narcolepsy in mice

(Mukherjee A., Sen

Maze procedure

patent granted, 2021),

Konofal E.)

(Mieda M.)

A., Dey B.)

(Bizot J.C., Konofal E.)

Significant role	Disruption of OX2R in dopamine
neurons is found to increase arousal,
found of orexin in	improve cognitive performance, but
sleep disorders	impair inhibitory control and further
like narcolepsy,	evidence for OX2R modulation by
highlighting	mazindol is also provided (Tafti M.)
common
symptoms with	Introduction by Centessa
ADHD such as
Pharmaceuticals of novel selective
disrupted sleep
OX2R agonists, sulfonamide-
patterns and
derivatives (similar to Alkermes,
impaired cognitive
Sumitomo, Merck and Takeda) aimed
abilities (Barateau
at treating sleep disorders, including
L., Dauvilliers Y.)
narcolepsy
2022	2023	2024
Exploration of	NLS Pharmaceutics
announced a	Introduction by Aexon
orexin action on
significant	Labs of First-in-Class
dopaminergic
improvement in	non-sulfonamide
systems
narcolepsy with	Dual Orexin Receptor
modulating theta
cataplexy in adults	Agonists (DOXA) and
during REM sleep
with mazindol ER (3	their potential use for
and wakefulness,
mg/day) in the	the treatment and/or
affecting
POLARIS phase 2	prevention of
attentional
program versus	neurological
processes and
placebo for both	diseases (e.g. narcolepsy
providing
primary and	with cataplexy)
neurobiological
secondary endpoints	(PCT/EP2023/088020)
insights into
and announces the
ADHD
FDA approval for

pathophysiology	AMAZE phase 3
(Bandarabadi M.)
program