Novel Cannabinoid Combo Shows Promise for OSA Treatment

Incannex Healthcare Limited (‘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 apnea (‘OSA’). IHL-42X reduced apnea-hypopnea 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 for 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 organization responsible for the 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 apnea-hypopnea index (AHI)

AHI is a measure of the number of times per hour a subject’s airway is blocked (apnea) or partially blocked (hypopnea). It is the main criterion 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 apnea 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, the 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 the 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 analyzed 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 the 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) was 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:

  1. 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.
  2. 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.
  3. https://www.justice.gc.ca/eng/cj-jp/sidl-rlcfa/qa2-qr2.html
  4. 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
  5. Wolff, K, et al., Driving Under the Influence of Drugs: Report from the Expert Panel on Drug Driving, Department of Transport, London, 2013.
  6. https://www.vifm.org/wp-content/uploads/VIFM-Annual-Report-2019-2020.pdf

Source: Icannex

Be the first to comment

Leave a Reply

This site uses Akismet to reduce spam. Learn how your comment data is processed.