Download Assessment of the safety, tolerability and

Poster number: W5279
Assessment of the safety, tolerability and pharmacokinetics of single
doses of oral dexanabinol in healthy subjects, using an adaptive protocol
A Connor1, P Evans1, C Doherty1, P Scholes1, C Flanagan1, S Lavin2, A Saunders2, D. Hynes2, P. McKeown2
1. Quotient Clinical Limited, Nottingham, UK; 2. E-Therapeutics plc, Oxfordshire, UK
BACKGROUND
Dexanabinol
is
a
synthetic
analogue
of
tetrahydrocannabinol (THC) in development as a
potential anti-cancer therapy.
Dexanabinol binds only weakly to cannabinoid receptors
1 and 2 (CB1 and CB2), reducing its psychotropic
potential in comparison to other molecules in the
cannabinoid class. It has been shown to impact
signalling of the protein complex, nuclear factor kappalight-chain-enhancer of activated B cells (NFκB), to block
the action of TNFα at the post-transcriptional level in the
rat closed head injury model and reduce the secretion of
prostaglandin
E2
produced
by
the
enzyme
cyclooxygenase-2 (COX-2). The multivalent nature of
dexanabinol’s inhibitory activity is likely to play a role in
its observed tumouricidal activity, rendering dexanabinol
an effective novel anti-cancer therapy [1-5].
Dexanabinol has previously been investigated in
traumatic brain injury and e-Therapeutics have identified,
through its Network Pharmacology platform, that there
was a potential anti-tumour activity. To date, no clinical
studies have been conducted via the oral route,
however, dexanabinol formulated for intravenous (IV)
infusion is currently undergoing clinical trials in patients
in both the UK and in the US.
PURPOSE
The purpose of this programe was to select a liquid
formulation, and administer in an adaptive first-in-human
(FIH) study to assess the safety, tolerability and
pharmacokinetics (PK) of dexanabinol via the oral route
METHODS
Translational Pharmaceutics
• Translational Pharmaceutics is a platform that
combines “real-time” manufacturing with immediate
clinical dosing, achieved by the co-location of GMP
manufacturing suites and a clinical unit [6].
• Drug product formulation development and analytical
facilities are also housed at the same site.
• Within the clinical program, the use of real-time
manufacturing reduces the shelf life requirements to
support the FIH study and therefore significantly
reduces the timelines to generate the submission data
package.
• This platform supported an adaptive clinical protocol,
enabling the determination of dose and number of
cohorts in real-time, based on emerging data.
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Formulation selection
• A program of solubility screening was performed with
a range of lipophilic solvents to identify a suitable
formulation. Nine lipophilic vehicles were screened.
• Miglyol 812N was identified as the most appropriate
formulation for the clinical study.
• A matched placebo was developed and taste masking
achieved by pre-rinsing with Bitrex.
• Batch release and short-term stability data (4 hrs) on
the formulation strengths bracketing the planned dose
range were filed.
FIH Clinical study design
• Healthy males, aged 18-45 participated in a doubleblind, placebo-controlled single ascending dose study.
• Three cohorts were initially planned (6 active:2
placebo), with the option for a further 3 cohorts.
• Two optional cohorts were invoked, resulting in single
oral doses of dexanabinol administered over 5 dose
levels.
• Subjects were on-site from 08:00 on Day -1 until 48 h
post-dose and returned to the clinic for a follow-up
visit between 5 to 10 days post-dose.
• Safety was evaluated through assessment of clinical
laboratory tests, ECG, and vital signs.
• Blood samples for dexanabinol PK were withdrawn at
regular intervals and standard PK parameters were
estimated.
• Blood samples for future analysis of potential bloodborne PD biomarkers were also withdrawn and
retained.
• Dose escalation was based on safety and PK review.
• GMP manufacture of the selected formulation was
conducted at the clinical site immediately prior to
dosing. This enabled real-time, within-study
adjustments in drug product dose based on emerging
safety, and PK data (Figure 1).
RESULTS
Formulation selection
• Solubility screening, formulation selection and
generation of data for the regulatory submission were
completed in 6 weeks.
• The selected product for dosing was drug in bottle, resuspended with Miglyol 812N.
• Approval from MHRA was provided in 7 days.
Subjects and safety findings
• 40 subjects were enrolled
•
•
Age (mean (SD)): 31 (8) years
BMI (mean (SD)): 26.7 (3.07) kg/m2
• Dexanabinol was well tolerated. There were no
serious adverse events and no clinically significant
abnormalities considered related to the study drug.
Pharmacokinetics
• Quantifiable plasma concentrations sufficient for
parameter estimation were measured at Cohort 2 and
above (Table 1, Figure 2).
Cohort
N
Tmax1 (h)
Cmax (ng/mL)
AUC(0-24)
(ng.h/mL)
3
6
(2-6)
3.69
(62.3)
NC2
6
6
(2-8)
7.99
(48.7)
106
(21.9) [n=3]
3
6
6
(2-8)
13.7
(104.3)
167
(118.2) [n=3]
4
6
6
(1-6)
26.3
(71.3)
252
(46.6) [n=5]
5
6
2
(1-6)
24.5
(67.2)
192
(68.8)
1
2
1) Median (range)
2) Not calculated
Table 1:
GMP
manufacture
Clinical dosing
Data review
Decision step
7 - 14 day cycle time
Figure 1: Translational Pharmaceutics enabled study construct
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Geometric Mean (CV%) Values for Key PK Parameters for
Dexanabinol
• Dose proportional increases in Cmax and AUC with
increasing dose were confirmed up to and including
Cohort 4.
• At Cohort 5, the PK profiles were highly variable and
on average Cmax and AUC reduced in comparison with
Cohort 4.
• Plasma concentration values for dexanabinol were
variable, indicating evidence of low solubility and
absorption-limited PK.
AAPS 2014
[email protected]
Figure 2: Geometric Mean Plasma Concentration Time Profiles for
Dexanabinol
CONCLUSION
A liquid formulation was selected to conduct this
preliminary investigation into the PK of dexanabinol
following single oral doses to healthy volunteers. Clinical
assessment was performed using an adaptive FIH
design. Doses were selected based on emerging safety
and PK data, and formulations only manufactured ‘on
demand’, thereby conserving drug substance. Oral
dexanabinol was safe and well tolerated at the doses
tested, and approximately dose proportional systemic
exposure confirmed up to Cohort 4. Further
investigations
and
optimisation
regarding
the
opportunities for an oral formulation of dexanabinol are
ongoing at e-Therapeutics.
REFERENCES
1. Basseres DS and Baldwin AS. Nuclear factor-кB and inhibitor of кB kinase
pathways in oncogenic initiation and progression. Oncogene. 2006; 25:
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are resistant to skin carcinogenesis. Nature Medicine. 1999; 5: 828–831.
3. Warzocha K, Ribeiro P, Bienvenu J, et al. Genetic polymorphisms in the
tumor necrosis factor locus influence Non-Hodgkin’s lymphoma outcome.
Blood. 1998; 91: 3574-3581.
4. Shohami E, Gallily R, Mechoulam R et al. Cytokine production in the brain
following closed head injury: dexanabinol (HU-211) is a novel TNF-α
inhibitor and an effective neuroprotectant. J Neuroimmunol. 1997; 72: 169–
177.
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regulate inflammation related genes. United States Patent Application 2005;
Appl. No. 10/942,504.
6. Connor A, Scholes P, Stevens L, et al. Flexible Approaches to Incorporate
Formulation Assessments and Selection into First-in-Human (FIH) Safety
and Tolerability Studies. AAPS 2013, Poster R6305.
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