Highlights:
- IHL-42X reduced primary endpoint apnoea hypopnea index relative
to baseline at all three doses that were assessed
- Low dose IHL-42X exhibited superior safety and efficacy metrics
to mid and high doses
- Low dose IHL-42X reduced AHI by an average of 50.7% compared to
baseline with 25% of participants experiencing a reduction in the
apnoea hypopnea index of greater that 80%
- Oxygen desaturation index was reduced by 59.7% relative to
baseline while taking low dose IHL-42X, improving sleep quality and
reducing cardiovascular stress
- In low dose IHL-42X samples, THC concentrations in blood were
well below the limits for impaired driving the morning after dose
administration
- IHL-42X was well tolerated – low dose IHL-42X was observed to
have a lower number of total treatment emergent adverse events than
placebo
- Low dose IHL-42X reduced AHI substantially more effectively
than is reported for the component active pharmaceutical
ingredients, dronabinol and acetazolamide, as unregistered
monotherapies.
MELBOURNE, Australia, June 3, 2022
/PRNewswire/ -- Incannex Healthcare Limited (NASDAQ: IXHL) (ASX:
IHL), ('Incannex' or the 'Company') a clinical-stage
pharmaceutical company developing unique medicinal cannabinoid
pharmaceutical products and psychedelic medicine therapies for
unmet medical needs, is pleased to announce that it has completed
analysis of data from the phase 2 proof-of-concept clinical trial
investigating IHL-42X for treatment of obstructive sleep apnoea
('OSA'). IHL-42X reduced apnoea hypopnoea index ('AHI'), improved
patient reported sleep quality and was well tolerated.
The clinical trial assessed three doses of IHL-42X at reducing
the AHI in patients who suffered from OSA. Data was also collected
for other aspects of sleep quality, THC clearance and safety. Trial
participants received each of the three doses of IHL-42X and
placebo across four seven-day treatment periods, separated by one
week washout periods. At the end of each treatment period, they
attended the clinic for an overnight sleep study where AHI was
determined, along with other measures of sleep quality, quality of
life and drug safety.
The study was conducted at the University of Western Australia
Centre for Sleep Science and The Alfred Hospital. A total of eleven
participants were recruited to the study and ten participants
completed treatment periods. The crossover design of the study
permitted Incannex to generate high quality data with a reduced
participant number compared to a conventional parallel arm study.
Each participant serves as their own internal control and
inter-participant variation is eliminated. Data analysis was
completed by Novotech, the contract research organisation
responsible for management of the study, as well as the Incannex
scientific research team, led by Chief Scientific Officer Dr
Mark Bleackley. The findings of the
clinical trial are presented below.
Effect of IHL-42X on apnoea hypopnoea index (AHI)
AHI is a measure of the number of times per hour a subject's
airway is blocked (apnoea) or partially blocked (hypopnoea). It is
the main criteria used to diagnose and monitor OSA. AHI data was
collected during overnight polysomnography on night seven of the
treatment periods.
- All doses of IHL-42X reduced AHI in patients with sleep apnoea
compared to baseline (Table 1). This reduction was substantially
greater than observed for placebo.
- At the group level the difference relative to baseline with low
dose and medium dose was statistically significant (p<0.05)
- When comparing directly to baseline within subjects the
difference in AHI compared to baseline between all three doses and
placebo was statistically significant (p<0.001) (Table 2)
- Low dose IHL-42X reduced AHI by >50% relative to baseline in
62.5% of subjects and by >80% in 25% of subjects (Table 2).
- Low dose IHL-42X reduced AHI to the greatest extent at both the
group level and when comparing the within subject reduction
relative to baseline
- Low dose IHL-42X reduced AHI to a greater extent than predicted
based on published data for dronabinol and acetazolamide alone
(Table 3).
The reduction in AHI observed during IHL-42X treatment periods
means that when treated with Incannex's proprietary drug, subject's
breathing was interrupted less frequently during sleep. This
supports Incannex's hypothesis that IHL-42X is an effective
treatment for OSA. The observation that low dose IHL-42X was the
most effective at reducing AHI is encouraging for the development
of IHL-42X as a pharmaceutical as a lower dose will reduce risk of
side effects and the cost of goods.
Furthermore, greater reduction in AHI with low dose IHL-42X
compared to dronabinol and acetazolamide at equivalent doses
supports Incannex's hypothesis that the two drugs are acting
synergistically to reduce AHI and provides confidence that IHL-42X
will meet the FDA's combination rule where both APIs must
contribute to the therapeutic effect of a fixed dose combination
product.
Table 1. Average AHI data for baseline and each treatment
period
|
Baseline
|
Placebo
|
Low
|
Medium
|
High
|
Average
AHI
|
42.84
|
40.08
|
21.13
|
22.22
|
27.78
|
Standard
deviation
|
20.33
|
18.16
|
15.92
|
15.52
|
17.61
|
% Reduction relative
to baseline
|
N/A
|
6.44
|
50.69
|
48.13
|
35.16
|
p value compared to
baseline
|
N/A
|
0.76
|
0.029
|
0.031
|
0.12
|
Table 2. Change in AHI from baseline within subject (least
square mean)
|
Average change
in AHI from
baseline
|
p-value relative
to placebo
(Bonferroni
adjusted)
|
Proportion of
subjects
with AHI reduction
>50% relative to
baseline (%)
|
Proportion of
subjects
with AHI reduction
>80% relative to
baseline (%)
|
Placebo
|
1.95
|
N/A
|
10
|
0
|
Low
|
17.51
|
<0.001
|
62.5
|
25
|
Medium
|
14.86
|
<0.001
|
33.3
|
11.1
|
High
|
16.18
|
<0.001
|
22.2
|
11.1
|
|
|
|
|
|
|
Table 3. Comparison of reduction in AHI relative to baseline
with low dose IHL-42X and the predicted reduction with component
drugs as monotherapies at equivalent doses based on reported
data.
|
Reduction in AHI
compared to baseline (%)
|
2.5 mg dronabinol
(1)
|
23.4
|
125 mg acetazolamide
(2)
|
23.4
|
Low dose
IHL-42X
|
50.7
|
Effect of IHL-42X on oxygen desaturation index (ODI)
Oxygen desaturation index ('ODI') is the number of episodes of
oxygen desaturation per hour of sleep, with oxygen desaturation
defined as a decrease in blood oxygen saturation (SpO2)
to lower than 3% below baseline. Reduced oxygen uptake is a key
component of the pathology of OSA and contributes to daytime
sleepiness and the long-term health consequences associated with
OSA. ODI data was collected during overnight polysomnography on
night seven of the treatment periods.
- All three doses of IHL-42X reduced ODI compared to baseline to
a greater extent than placebo.
- For low and medium dose IHL-42X the difference in reduction in
ODI relative to baseline compared to placebo was statistically
significant (p<0.05)
The greater reduction in ODI during IHL-42X treatment periods
compared to placebo means that there is more oxygen in the
subject's blood during sleep while taking IHL-42X. This improves
sleep quality and reduces risks of oxidative stress, bursts of the
stress hormone cortisol, insulin resistance, altered metabolism and
cardiovascular disease.
Table 4. Reduction in ODI compared to baseline during each
treatment period.
|
Reduction in ODI
relative to
baseline (least squares mean)
|
Reduction in ODI
relative to baseline
(%)
|
p value compared
to
placebo (Bonferroni
adjusted)
|
Placebo
|
1.8
|
18.3
|
N/A
|
Low
|
11.7
|
59.7
|
0.021
|
Medium
|
12
|
59.0
|
0.012
|
High
|
8.32
|
28.5
|
0.162
|
Plasma THC levels the morning after IHL-42X dosing
Countries that have set limits for THC above which driving is
illegal have set those limits at 1-2 ng/mL (3-6). It is important
to understand the clearance of THC after dosing with IHL-42X to
determine where there will be an impact on ability to drive in
countries where THC limits are in place. Plasma samples were
collected 2 hours post dose 1 and the morning after dose 7 for each
treatment period. Samples were analysed for concentration of THC
using liquid chromatography with tandem mass spectrometry
(LC-MS-MS).
The morning after dose 7, THC levels in the low dose IHL-42X
samples had an average of 0.20 ng/mL and a maximum of 0.45 ng/mL.
Both of which are below the thresholds for impaired driving. With
medium and high dose IHL-42X the average THC concentrations the
morning after dose 7 were 0.86 and 0.52 respectively.
Effect of IHL-42X on patient reported sleep quality
Each morning of the clinical trial, subjects recorded their
sleep quality for the previous night as very poor, poor, fair,
good, or very good. To compare patient reported sleep quality, the
proportion of subjects who reported good or very good sleep each
night was averaged across each treatment period. During the IHL-42X
treatment periods subjects more frequently reported that their
sleep quality was good or very good than placebo. The highest level
of patient reported sleep quality was observed with low and high
dose IHL-42X (Table 5).
Table 5. Patient reported sleep quality during each treatment
period
|
Proportion of
subjects reporting good or very good sleep quality
|
Placebo
|
26.50%
|
Low
|
49.49%
|
Medium
|
38.47%
|
High
|
50.13%
|
Sleep metrics captured by actigraphy
For the duration of the clinical trial, subjects wore an
Actiwatch, a watch-like device that uses actigraphy to capture data
on activity and sleep. IHL-42X at all doses improved sleep
efficiency (what percentage of time in bed a subject is asleep),
the number of awakenings per night, and the total minutes the
subject was awake during the night (WASO) compared to placebo
(Table 6). These improvements were greatest for low and high dose
IHL-42X. This means that while taking IHL-42X subjects were asleep
for a greater proportion of time they were in bed and woke up less
often.
Table 6. Sleep metrics captured by actigraphy
|
|
Placebo
|
Low
|
Medium
|
High
|
Sleep
efficiency
|
average
|
76.83
|
84.81
|
81.34
|
84.17
|
p value compared to
placebo
|
N/A
|
0.0048
|
0.058
|
0.0078
|
Awakenings per
night
|
average
|
49.31
|
35.8
|
41.44
|
37.33
|
p value compared to
placebo
|
N/A
|
0.0053
|
0.055
|
0.012
|
WASO
(min)
|
average
|
62.59
|
37.55
|
47.22
|
38.55
|
p value compared to
placebo
|
NA
|
0.00011
|
0.0031
|
0.0010
|
Safety considerations
Adverse events were recorded from the time the subjects enrolled
in the trial until their end of study visit. After recording of
treatment emergent adverse events (TEAE) the study team, including
investigators and medical monitors, reviewed the TEAEs to determine
whether they were likely related to the investigational product.
The TEAEs were consistent with what has been reported for
dronabinol and acetazolamide alone. For each treatment period the
proportion of subjects reporting one or more TEAEs (Table 7) as
well as the total number of TEAEs (Table 8) were extracted from the
clinical study report. Low dose IHL-42X had a similar proportion of
subjects reporting TEAEs and a lower number of total TEAEs than
placebo. This indicated that low dose IHL-42X is well
tolerated.
Table 7. Proportion subjects of TEAEs reported for each
treatment period
|
Placebo
|
Low
|
Medium
|
High
|
Total TEAE
(%)
|
81.8
|
33.3
|
55.6
|
66.7
|
Related TEAE
(%)
|
27.3
|
22.2
|
44.4
|
55.6
|
Table 8. Total number of TEAEs reported during each treatment
period
|
Placebo
|
Low
|
Medium
|
High
|
Total
TEAE
|
15
|
6
|
22
|
16
|
Related
TEAE
|
7
|
4
|
16
|
12
|
References:
- Carley DW, Prasad B, Reid KJ, Malkani R, Attarian H, Abbott SM,
Vern B, Xie H, Yuan C, Zee PC. 2018. Pharmacotherapy of apnea by
cannabimimetic enhancement, the PACE clinical trial: Effects of
dronabinol in obstructive sleep apnea. Sleep 41.
- Schmickl CN, Landry SA, Orr JE, Chin K, Murase K, Verbraecken
J, Javaheri S, Edwards BA, Owens RL, Malhotra A. 2020.
Acetazolamide for OSA and central sleep apnea: a comprehensive
systematic review and meta-analysis. Chest 158:2632–2645.
-
https://www.justice.gc.ca/eng/cj-jp/sidl-rlcfa/qa2-qr2.html
- Vindenes, V., et al., (2012) Impairment based legislative
limits for driving under the influence of non-alcohol drugs in
Norway, Forensic Science
International 219(1-3,)1-11
- Wolff, K, et al., Driving Under the Influence of Drugs: Report
from the Expert Panel on Drug Driving, Department of Transport,
London, 2013.
-
https://www.vifm.org/wp-content/uploads/VIFM-Annual-Report-2019-2020.pdf
This announcement has been approved for
release to ASX by the Incannex board of directors.
About Incannex Healthcare Limited
Incannex is a clinical stage pharmaceutical development company
that is developing unique medicinal cannabis pharmaceutical
products and psychedelic medicine therapies for the treatment of
anxiety disorders, obstructive sleep apnoea (OSA), traumatic brain
injury (TBI)/concussion, lung inflammation (ARDS, COPD, asthma,
bronchitis), rheumatoid arthritis and inflammatory bowel disease.
U.S. FDA approval and registration, subject to ongoing clinical
success, is being pursued for each drug and therapy under
development. Each indication represents major global markets and
currently have no, or limited, existing registered pharmacotherapy
(drug) treatments available to the public.
Incannex has a strong patent filing strategy in place as it
develops its products and therapies in conjunction with its medical
and scientific advisory board and partners. Incannex is listed on
the Australian Stock Exchange (ASX) with stock code "IHL" and also
has American Depository Shares listed on NASDAQ under code
"IXHL".
Website: www.incannex.com.au
Investors:
investors@incannex.com.au
Forward-looking statements
This press release contains "forward-looking statements" within
the meaning of the "safe harbor" provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These forward-looking
statements are made as of the date they were first issued and were
based on current expectations and estimates, as well as the beliefs
and assumptions of management. The forward-looking statements
included in this press release represent Incannex's views as of the
date of this press release. Incannex anticipates that subsequent
events and developments may cause its views to change. Incannex
undertakes no intention or obligation to update or revise any
forward-looking statements, whether as of a result of new
information, future events or otherwise. These forward-looking
statements should not be relied upon as representing Incannex's
views as of any date after the date of this press release.
Contact Information
Incannex Healthcare Limited
Mr Joel Latham
Managing Director and Chief Executive Officer
+61 409 840 786
joel@incannex.com.au
US IR Contact
Rx Communications Group
Michael Miller
+1-917-633-6086
mmiller@rxir.com
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SOURCE Incannex Healthcare Limited