Apr 1, 2015 - CSF and plasma concentration-time profiles of BI 409306 were shaped ... the maximum plasma concentrations
SAFETY AND TOLERABILITY ASSESSMENTS
2
1
Table 2a. PK parameters of BI 409306 in CSF and plasma (PK analysis set*)
pressure, pulse rate, respiratory rate, and body temperature), recording 12-lead electrocardiogram (ECG), and conducting clinical laboratory assessment, physical examination, and visual tests.
STATISTICAL ANALYSES
25 mg (n=4)
ll Exposure of BI 409306 in CSF relative to plasma and the cGMP change
from baseline were explored using mixed models. ll Two-sided 90% confidence intervals (CIs) were calculated for the point
estimates (gMean of Cmax or Emax ratios). calculated.
gMean Cmax (%gCV), nmol/L
RESULTS ll Overall, 20 male subjects were enrolled, treated, and completed the ll All enrolled subjects were white; mean age (range) was 37.9 (21–50)
gMean Cmax (%gCV), nmol/L
functioning of glutamatergic pathways in (pre-) frontal cortical and limbic areas of the brain.3
differences were not considered relevant to the study objectives owing to the small sample size (Table 1).
Figure 1. Study design Screening
Treatment period
End of trial examination
ll Activation of N-methyl-D-aspartate (NMDA) receptors on postsynaptic
neurons activates nitric oxide synthase and stimulates production of cyclic guanosine monophosphate (cGMP), which leads to activation of protein kinases, manifestation of long-term potentiation, and synaptic plasticity.4
BI 409306 25 mg (n=4)
BI 409306 50 mg (n=4)
• Medical examination
BI 409306 100 mg (n=4)
• Color discrimination test and visual acuity test • Blood pressure, pulse rate, and respiratory rate • 12-lead ECG
ll Disruption of glutamatergic NMDA neurotransmission leads to reduced
cGMP levels.3
N=20
ll Inhibition of phosphodiesterase 9A (PDE9A) is expected to increase
cGMP levels in the brain, thereby enhancing glutamatergic signaling and strengthening synaptic plasticity.5
BI 409306 200 mg (n=4)
• Laboratory and urinalysis
ll Herein, evidence for the proof-of-clinical-mechanism of BI 409306, a
PDE9A inhibitor, is reported.
OBJECTIVE
Placebo (n=4) Visit 1 Day –28 to –1
Visit 2 Day 1 to 3
Visit 3 Day 10 to 17
ECG, electrocardiogram
METHODS SUBJECTS ll Healthy male subjects genotyped as homozygous CYP2C19 extensive
metabolizers (this included both extensive and ultra-rapid metabolizers), aged 21–50 years and body mass index (BMI) 18.5–29.9 kg/m2.
STUDY DESIGN ll This was a randomized, double-blind, double-dummy, placebo-
controlled, parallel-group, single-dose, single-center, phase I study. ll 20 subjects were randomized 1:1:1:1:1 to receive 1 oral dose of
BI 409306 25 mg, 50 mg, 100 mg, 200 mg, or placebo (Figure 1). Four subjects were allocated to each of 5 treatment groups.
Mean age (SD), years Mean BMI (SD), kg/m2 Smoking status Never smoked Ex-smoker Currently smokes Drinking status Non-drinker Drinks – no interfence1
BI 409306 Placebo 25 mg 50 mg 100 mg 200 mg Total (n=4) (n=4) (n=4) (n=4) (n=4) (n=20) 29.5 (8.9) 39.5 (7.9) 46.3 (2.9) 38.5 (11.5) 35.8 (9.0) 37.9 (9.4) 24.2 (1.3) 27.0 (2.2) 27.8 (2.1) 24.9 (2.4) 25.5 (3.2) 25.9 (2.5)
1 (25.0) 3 (75.0)
3 (75.0) 1 (25.0) 0 (0.0) 2 (50.0) 2 (50.0)
2 (50.0) 1 (25.0) 1 (25.0) 1 (25.0) 3 (75.0)
3 (75.0) 1 (25.0) 0 (0.0) 0 (0.0) 4 (100.0)
2 (50.0) 12 (60.0) 0 4 (20.0) 2 (50.0) 4 (20.0) 1 (25.0)
5 (25.0)
1.50 (0.77–2.02)
46.9 (84.3)
183 (51.3)
271 (39.7)
902 (36.3)
0.267 (18.4)
EXPLORATORY PRIMARY ENDPOINTS ll Ratio of Cmax of BI 409306 in CSF versus plasma ll Geometric mean (gMean) Emax (maximum change calculated as ratio),
maximum percent change (presented as relative change from baseline), and maximum absolute change in cGMP in CSF from baseline to end of visit (7 to 14 days after the last study procedure)
PHARMACOKINETIC (PK) AND PHARMACODYNAMIC (PD) SECONDARY ENDPOINTS ll BI 409306: maximum concentration (Cmax) and time to reach Cmax (tmax) in
plasma and CSF
ll cGMP: Cmax and tmax in CSF.
0.244 (15.8)
0.294 (42.8)
1000
Drinks – possible 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 interfence Line number from Snellen chart 7 0 (0.0) 1 (25.0) 0 (0.0) 1 (25.0) 0 (0.0) 2 (10.0) 8 0 (0.0) 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0) 1 (5.0) 9 4 (100.0) 3 (75.0) 3 (75.0) 3 (75.0) 4 (100.0) 17 (85.0) All presented color plates read Yes 4 (100.0) 4 (100.0) 4 (100.0) 4 (100.0) 4 (100.0) 20 (100.0) *Treated set included all treated subjects. Data are n (%) unless indicated otherwise. 1’No interference’ and ‘possible interference’ of drinking status during study participation was assessed by the investigator. BMI, body mass index; SD, standard deviation
ll CSF and plasma concentration-time profiles of BI 409306 were shaped
similarly across BI 409306 dose groups (Figure 2 and 4). –– After administering single doses of 25 to 200 mg BI 409306, concentrations in plasma increased rapidly with a median tmax of 0.75 to 1.25 hours (h) across dose groups (Table 2a). ll Maximum CSF concentrations were reached within 0.75 to 1.25 h after
the maximum plasma concentrations in the respective dose group (median tmax of 1.5 to 2.0 h), indicating the ability of BI 409306 to cross the blood-brain barrier (Table 2a). ll After reaching Cmax, BI 409306 concentrations declined in a biphasic
manner in plasma and in a monophasic manner in CSF. In the highest dose group, the last detectable BI 409306 concentration in CSF was measured 14 h after the drug administration.
ll The gMean Cmax of BI 409306 in both plasma and CSF increased with
dose. Dose-adjusted gMean (95% CI) CSF to plasma ratio of the BI 409306 Cmax was 28.31% (25.42% to 31.53%) (Table 2b).
4200
13.0 cGMP changes from baseline cGMP absolute change from baseline (nmol/L) cGMP relative change from baseline
11.0 9.0
BI 409306 concentrations (nmol/L)
7.0
BI 409306 in CSF BI 409306 in plasma
3600 3300 3000 2700 2400 2100
5.0
1800 3.0
1500 1200
1.0
900
–1.0
600 300
–3.0
0 0
0.335 (5.74)
3900
2
4
6
8
10 12 14 Time (hours)
16
18
20
22
24
Table 3. Change in cGMP levels (PD analysis set*) BI 409306 Placebo (n=4)
25 mg (n=4)
50 mg (n=4)
100 mg (n=4)
200 mg (n=4)
cGMP maximum change from baseline (Emax; adjusted by-treatment)
CSF 25 mg (n=4) CSF 50 mg (n=4) CSF 100 mg (n=4) CSF 200 mg (n=4)
100
gMean (%gCV)
1.23 (10.55) 1.75 (62.86) 2.42 (43.33) 2.94 (45.34) 5.84 (66.42)
Adjusted gMean (%gCV)1
1.48 (33.18) 1.83 (32.06) 2.25 (32.18) 3.03 (32.02) 4.86 (33.20)
90% CI
(1.11; 1.96) (1.39; 2.41) (1.71; 2.97) (2.30; 3.99) (3.66; 6.47)
cGMP maximum percent change from baseline (adjusted by-treatment)
10
1
Mean (SD)
0.24 (0.13)
1.01 (1.31)
1.59 (1.19)
2.14 (1.20)
5.65 (3.65)
Adjusted mean (SE)1
0.91 (0.74)
1.17 (0.71)
1.33 (0.72)
2.25 (0.71)
4.97 (0.74)
90% CI
0.1 2
4
6
8
10 12 14 Time (hours)
16
18
20
22
24
CSF, cerebrospinal fluid; PK, pharmacokinetic
(–0.39; 2.21) (–0.09; 2.42) (0.07; 2.59) (0.99; 3.50) (3.67; 6.27)
Table 2b. BI 409306 Cmax ratio of CSF to plasma (PK analysis set*)
Cmax
214.26
756.83
Mean (SD)
1.01 (0.53)
2.36 (2.17)
3.35 (1.36)
5.28 (1.84)
8.83 (1.92)
Adjusted mean (SE)1
0.75 (0.85)
2.30 (0.83)
3.45 (0.83)
5.24 (0.82)
9.09 (0.85)
90% CI
Dose-adjusted Dose-adjusted Ratio of Cmax gMean Cmax in gMean Cmax in in CSF to Cmax CSF, nmol/L plasma, nmol/L in plasma, (n=16) (n=16) %
95% CI for gMean ratio Lower limit, %
Upper limit, %
25.42
31.53
28.31
*PD analysis set included all subjects in the treated set who provided at least 1 evaluable observation for at least 1 PD endpoint. 1 Adjusted for baseline cGMP cGMP, cyclic guanosine monophosphate; CI, confidence interval; gCV, geometric coefficient of variation; gMean, geometric mean; PD, pharmacodynamic; SD, standard deviation; SE, standard error
SAFETY AND TOLERABILITY
ll No deaths, serious AEs, or AEs leading to drug discontinuation.
intensity of the reported AEs; all AEs were of mild to moderate intensity and mostly related to the study procedure (Table 4).
ll No clinically relevant findings with respect to laboratory parameters, ECG
recordings, vital sign measurements, or visual tests.
Treatment group 50 mg
100 mg
200 mg
4.0
Table 4. Summary of AEs (treated set*) BI 409306
3.0
Placebo (n=4)
25 mg (n=4)
50 mg (n=4)
100 mg (n=4)
200 mg (n=4)
Total (n=20)
1.0
Drug-related AEs1
2 (50.0)
2 (50.0)
2 (50.0)
1 (25.0)
2 (50.0)
9 (45.0)
0.0
AEs by preferred term Headache
1 (25.0)
2 (50.0)
3 (75.0)
1 (25.0)
3 (75.0)
10 (50.0)
Back pain
2 (50.0)
0 (0.0)
2 (50.0)
1 (25.0)
2 (50.0)
7 (35.0)
Post-lumbar 2 (50.0) puncture syndrome
1 (25.0)
0 (0.0)
2 (50.0)
2 (50.0)
7 (35.0)
PD ENDPOINTS
Sensation of pressure
1 (25.0)
1 (25.0)
0 (0.0)
1 (25.0)
1 (25.0)
4 (20.0)
ll After single-dose administration of 25 to 200 mg BI 409306, cGMP
Pain in extremity
0 (0.0)
0 (0.0)
1 (25.0)
1 (25.0)
1 (25.0)
3 (15.0)
Paresthesia
0 (0.0)
2 (50.0)
0 (0.0)
0 (0.0)
0 (0.0)
2 (10.0)
Nausea
0 (0.0)
0 (0.0)
0 (0.0)
1 (25.0)
1 (25.0)
2 (10.0)
2.0
-1.0 0
2
4
6
8
10 12 14 Time (hours)
16
18
20
22
24
cGMP, cyclic guanosine monophosphate; PD, pharmacodynamic
concentrations in CSF increased to the maximum concentration within 2 to 5 h (mean Cmax range, 5.96 nmol/L [25 mg group] to 11.2 nmol/L [200 mg group]) and returned to approximately baseline levels 10 to 14 h after administration (Figure 3 and 4). ll Dose-dependent increases in cGMP were noted (Table 3).
Poster number: 114, 15th International Congress on Schizophrenia Research, 28 Mar–1 Apr, 2015, Colorado Springs, CO, USA
uptake of BI 409306 in plasma and CSF was followed by a more gradual and dose dependent increase of cGMP in CSF. –– Delay in response of about 0.5 to 3 h (when comparing median tmax values). ll Overall, BI 409306 showed good safety and tolerability with no clustering
of specific AEs.
DISCLOSURES This study was funded by Boehringer Ingelheim International GmbH. The author(s) meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors received no direct compensation related to the development of the poster. Boehringer Ingelheim Pharmaceuticals Inc. was given the opportunity to review the poster for medical and scientific accuracy as well as intellectual property considerations. SP was employee of BI at the time of abstract submission. LG has received payment from Boehringer Ingelheim for work on this clinical trial.
ACKNOWLEDGEMENTS Writing, editorial support, and formatting assistance for this poster was provided by Saurabh Shinde of Cactus Communications Pvt. Ltd., which was contracted and compensated by Boehringer Ingelheim Pharmaceuticals Inc. for these services.
REFERENCES 1. Holder SD et al. Am Fam Physician. 2014;90:775–82. 3. Lewis DA et al. Arch Neurol. 2006;63:1372–76.
Figure 3. Mean relative change from baseline in cGMP over time by BI 409306 treatment group (PD analysis set) 25 mg
ll Comparison of concentration-time profiles over time showed that rapid
2. Surmeli T et al. Clin EEG Neurosci. 2012;43:133–44.
ll There were no apparent dose-dependent increases in the number or
Placebo
concentrations reached 28.31% of the maximum plasma concentrations, with a delay of approximately 0.75 to 1.25 h compared with plasma, indicating that BI 409306 can cross the blood-brain barrier.
(−0.75; 2.25) (0.85; 3.75) (1.99; 4.91) (3.79; 6.69) (7.59; 10.59)
*PK analysis set included all subjects in the treated set who provided at least 1 evaluable observation for a PK endpoint. CI, confidence interval; CSF, cerebrospinal fluid; Cmax, maximum concentration; gMean, geometric mean; PK, pharmacokinetic
6.0
ll After single-dose oral administration of BI 409306, maximum drug CSF
cGMP, cyclic guanosine monophosphate; PD, pharmacodynamic
cGMP maximum absolute change from baseline (adjusted by-treatment)
3 (75.0) 15 (75.0)
PK ENDPOINTS
STUDY ENDPOINTS
2700 (38.9)
1.75 (1.50–3.00)
plasma 25 mg (n=4) plasma 50 mg (n=4) plasma 100 mg (n=4) plasma 200 mg (n=4)
0
2 (50.0) 1 (25.0) 1 (25.0)
922 (36.5)
2.00 (1.00–2.00)
5.0
ll To assess the exposure of BI 409306 in cerebrospinal fluid (CSF) relative
to plasma and to evaluate the effect of different doses of BI 409306 on cGMP levels in CSF in healthy subjects.
Table 1. Demographics and baseline characteristics (treated set*)
Bl 409306 concentrations (nmol/L)
ll Cognitive dysfunction in schizophrenia is associated with impaired
ll Demographic characteristics were generally similar, and small
treated in cohorts, with each cohort comprising 1 subject from the 5 individual treatment groups.
0.75 (0.48–1.00)
2.00 (2.00–3.00)
10000
Relative change from baseline in cGMP
involves hallucinations, disordered thinking, and deficiencies in cognition, affecting ~1% of the population worldwide,1 and has no cure.2
0.88 (0.75–1.50)
Figure 2. Geometric mean concentration-time profiles of BI 409306 in plasma and CSF (PK analysis set)
years, and mean BMI (range) was 25.9 (22.1–29.8) kg/m .
ll For the treatment groups to be investigated in parallel, subjects were
751 (35.7)
Figure 4. Mean changes in concentrations of cGMP and BI 409306 over time after administration of 200 mg dose (PD analysis set)
200 mg (n=4)
CSF
2
ll Schizophrenia is a chronic, severe, and disabling brain disorder that
100mg (n=4)
*PK analysis set included all subjects in the treated set who provided at least 1 evaluable observation for a PK endpoint. CI, confidence interval; Cmax, maximum concentration; CSF, cerebrospinal fluid; CV, coefficient of variation; gMean, geometric mean; PK, pharmacokinetic; RCmaxCSF/PLA, Ratio of Cmax in CSF compared with plasma; %gCV, geometric coefficient of variation; tmax, time to reach Cmax
study.
METHODS
0.75 (0.50–0.75)
176 (92.6)
RCmaxCSF/PLA
1
INTRODUCTION
1.25 (0.75–1.50)
Median tmax (range), h
ll Descriptive statistics for safety and additional PK and PD endpoints were
50 mg (n=4)
Plasma Median tmax (range), h
1
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 2Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 3SGS Life Science Services – Clinical Research, Antwerpen, Belgium; 4Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
BI 409306
ll Assessed by monitoring adverse events (AEs) and vital signs (blood
KATJA BOLAND , VIKTORIA MOSCHETTI , CHANTARATSAMON DANSIRIKUL , SOLEN PICHEREAU , 3 4 LIEN GHEYLE , MICHAEL SAND 1
CONCLUSIONS
RESULTS
BI 409306 concentrations (nmol/L)
STUDY ENDPOINTS
cGMP changes from baseline
RANDOMIZED, DOUBLE-BLIND, PLACEBOCONTROLLED, PARALLEL-GROUP PROOF OF MECHANISM STUDY TO ASSESS THE PHARMACOKINETICS AND PHARMACODYNAMIC EFFECT OF DIFFERENT SINGLE ORAL DOSES OF BI 409306 IN HEALTHY MALE VOLUNTEERS
*Treated set included all treated subjects. All values are n (%). 1 The investigator assessed the possible causal relationship between an adverse event and the study medication. AE, adverse event
4. Bonkale WL et al. Neurosci Lett. 1995;187:5–8. 5. García-Osta A et al. ACS Chem Neurosci. 2012;3:832–44.
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