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Placebo
50 mg
100 mg
SAFETY AND PHARMACOKINETICS OF N91115 IN PATIENTS WITH CYSTIC FIBROSIS HOMOZYGOUS
FOR THE F508DEL-CFTR MUTATION
1
1
Donaldson, S for the SNO-4 Multicenter Study Group. University of North Carolina, Chapel Hill, NC, USA
200 mg
*Pharmacokinetic endpoints are discussed in poster 250:
“The
Pharmacokinetics of N91115, an Inhibitor of S-Nitrosoglutathione
Reductase, in Cystic Fibrosis Patients”
There were no significant effects on other safety parameters measured at
Baseline and predose on Day 1, 7, 14, 21, and 28 including:
• 12-lead ECGs
• Laboratory chemistry and hematology parameters including liver
functions tests, white blood cell counts and absolute neutrophil counts
• Certain changes in hsCRP were reported as AEs by the investigator,
however, there were no changes in hsCRP levels on N9115 compared
with placebo when all the data were analyzed
• There were three adverse events of decreased body weight reported in
the 200 mg dose group, however there were no changes in body
weight in any of the dose groups when all the weight data were
analyzed
• Sputum cultures in patients who could spontaneously produce sputum
done at Baseline and on Day 28
N91115 is being studied as a potential, novel therapy for CF with the
initial target population being patients who are homozygous for the
F508del-CFTR mutation. N91115 is a CFTR stabilizer that modulates CFTR
through a different but complementary mechanism of action to correctors
and potentiators such as VX-661, lumacaftor and ivacaftor. The effects of
N91115 on CFTR function are mediated through preservation of GSNO,
the human body’s most abundant low molecular weight S-nitrosothiol or
“SNO”. While SNOs are normally present in the human airway,
concentrations tend to be reduced in CF patients (Grasemann et al. 1999)
Figure 4: Change from Baseline in Sweat Chloride for Each
Subject on Days 7, 14, 21, and 28
Placebo
No changes in spirometry parameters were observed during the study in
intent to treat or per protocol analyses (Figure 3). Three subjects were
excluded in the per protocol group for significant changes in study
medications (2 on N91115) and discontinuation of study drug for a
serious adverse event (1 patient on placebo).
Figure 1: N91115 Significantly Increases and Prolongs CFTR
Activity in Combination with Lumacaftor/Ivacaftor
50 mg
100 mg
Figure 3: Percent Predicted FEV1 (ppFEV1) is Shown as a Mean
(95% CI) Absolute Change from Baseline for Each Treatment
Arm.
200 mg
Day 7 - Baseline
Data on file at Nivalis Therapeutics, Inc.
Figure 2: N91115 Significantly Increases the Plasma Membrane
(PM) Density of F508del-CFTR Expressed in the Human Bronchial
Cell Line CFBE41oA
B
1000
400
*
200
0
DMSO
VX-809
**
600
4
2
8
0
-2
-4
-6
-8
7
14
Day 14 - Baseline
Day 21 - Baseline
Day 28 - Baseline
Figure 5: Within Group Mean Change (95% CI) from Baseline in
Sweat Chloride at Day 28
21
28
Table 3: Summary of Absolute and Relative Changes in ppFEV1
Placebo
50 mg
100 mg
200 mg
6
4
2
0
-2
-4
-6
-8
-10
Day 28-Baseline
Day
D2828
-D1- Baseline
Dose of N91115 BID
N=
Mean (SD)
Baseline Characteristics
Median
Mean (SD)
Median
100
200
12
10 (83)
12
9 (75)
13
9 (69)
14
4 (29)
100
12
200
13
-2.2 (4.4)
-1.7
0.1 (6.1)
-0.6
-3.5 (4.7)
-3.5
0.6 (5.9)
2.2
Age, y, mean (SD)
28.0 (8.0) 30.8 (6.6) 26.5 (7.7) 26.8 (8.1) 27.9 (7.6)
BMI, kg/m2, mean (SD)
22.8 (2.4) 21.5 (2.3) 23.2 (3.8) 24.2 (3.8) 23.0 (3.3)
Sweat Chloride mmol/L,
mean (SD)
102 (14)
98 (8)
101 (9)
107 (9)
102 (10)
ppFEV1, mean (SD)
Range
83.5
(26.0)
48 - 119
78.1
(20.1)
48 - 113
72.4
(21.7)
42 - 105
76.6
(20.3)
42 - 109
77.5
(21.8)
42 - 119
-2.1 (3.5)
-2.0
0.3 (4.3)
-0.5
-2.5 (3.6)
-2.0
0.2 (4.1)
1.0
-
2.3
1.1
-1.3
-1.8
2.8
3.9
-
2.4
1.5
-0.4
0
2.3
3.0
Median
All
Patients
51
32 (63)
ppFEV1: Absolute treatment
response (versus placebo) at Day 28
Mean
Median
Dose of N91115 BID
Sweat Chloride: Change from
Baseline at Day 28 (n)
Mean (SD)
Placebo
12
11 (92%)
1
50
12
11(92%)
0
100
13
12 (92%)
1
200
14
12 (86%)
1
Median
1
0
0
0
Median
5 (42%)
0
1 (8%)
2 (17%)
2 (17%)
1 (8%)
3 (23%)
0
0
6 (43%)
2 (14%)
3 (21%)
1 (8%)
1 (8%)
1 (8%)
0
1 (8%)
1 (8%)
0
3 (21%)
0
0
1 (8%)
1 (8%)
0
0
1 (8%)
1 (8%)
0
0
0
0
2 (15%)
0
0
1 (8%)
0
0
1 (7%)
2 (14%)
2 (14%)
2 (14%)
3 (21%)
2 (14%)
Sweat Chloride: Treatment
response (versus placebo) at Day
28
Mean
CFQR Mean change from
Baseline (n)
Respiratory Domain Mean (SD)
Eating Domain Mean (SD)
Patient Global Impression of
Change (n)
n (%) much improved
1
1
p=0.11;
2
p=0.09
•
N91115 was well-tolerated with no dose limiting toxicities up to 200
mg Q12H administered over 28 days
The effect on sweat chloride at 200 mg may suggests a “threshold
dose effect” and higher doses are warranted
Preclinical data combined with the favorable safety profile in healthy
subjects and CF patients support the next step in clinical development:
a Phase 2 Study assessing the safety and efficacy of N91115 added to
lumacaftor/ivacaftor over 12 weeks in patients homozygous for
F508del-CFTR.
•
•
Table 4: Selected Exploratory Endpoints are Summarized as Day
28 Change from Baseline
Table 2: Adverse Event Summary
•
References
Exploratory Endpoints
Safety
Conclusions
•
ppFEV1: Relative treatment response
(versus placebo) at Day 28
Mean
N91115 mg BID
50
50
12
ppFEV1: Absolute
Change from Baseline at Day 28
Table 1: Demographic and Baseline Characteristics of the Study
Population
Placebo
Placebo
11
ppFEV1: Relative Change from
Baseline at Day 28
Courtesy of Dr. Guido Veit and Dr. Gergely Lukacs, McGill University
hsCRP↑
Dyspnea
Nasal congestion
Oropharyngeal pain
Weight ↓
Wheezing
200
*
200
0
100
Visit Day
400
VX-661
N=
Patients with any adverse event, n (%)
Patients with any serious adverse event,
n
Discontinuation due to adverse event
Adverse Event by Preferred Term
Cough
Chest discomfort
Fatigue
Pulmonary exacerbation of CF
During 28-day treatment period
During 14-day withdrawal period
50
800
* P < 0.05, ** P < 0.01
N=
Female (%)
0
1
VX-661 +
VX-770
600
**
VX-661
800
*
VX-809 +
VX-770
*
*
VX-809
1000
*
DMSO
N91115
VX-770
DMSO
N91115
1200
DMSO
1200
6
Mean Change in Sweat Chloride
(mmol/L ± 95% CI)
Δ ppFEV1 (mean ± 95% CI)
% Predicted FEV1 Mean Absolute Change from Baseline
N91115 mg BID
Background and Rationale
Sweat testing was performed at Baseline; Days 7, 14, 21, and 28; and the
follow up visit (Day 42). Baseline and follow-up sweat chloride data were
available for 47 patients. As illustrated in the waterfall plots, more patients
in the 200 mg Q12H dose group had decreases in sweat chloride from
Baseline than in the other dose groups (Figure 4). No rebound effect was
noted after 14 days of treatment withdrawal with a sustained effect on
sweat chloride observed at Day 42. The reason for the sustained effect
after 14 days of withdrawal is unclear. The mean changes from Baseline
on Day 28 are summarized in Figure 5. The data suggest that 200 mg
may be a threshold dose for the sweat chloride signal with placebo
differences for the mean change of -5.2 mmol/L (95% CI -11.7, 1.4; p =
0.11) at 28 days.
Safety
When N91115 is added to lumacaftor/ivacaftor in F508del-CFTR human
bronchial epithelial (HBE) cells, a significant net increase in chloride
secretion is observed over the lumacaftor/ivacaftor combination alone
(Figure 1). Additionally, N91115 increases the surface expression of CFTR
when added to lumacaftor or VX-661 in combination with ivacaftor (Figure
2). These effects are consistent with a distinct, complementary
mechanism of action of N91115 versus current correctors and
potentiators, and support the use of a GSNOR inhibitor as part of CFTR
modulator therapy.
PM density (% of DMSO)
Background: Preservation of S-nitrosoglutathione (GSNO), through
inhibition of its primary catabolizing enzyme, S-nitrosoglutathione
reductase (GSNOR), may provide a novel therapeutic strategy in cystic
fibrosis (CF). In experimental models, N91115 has been shown to
significantly increase the activity and cell surface expression of F508delCFTR when added to CFTR correctors or corrector/potentiator
combinations. N91115 has also been shown to partially restore CFTR
function in the intestines of CF mice and to inhibit inflammatory mediators
in models of tobacco smoke and elastase induced lung injury.
Objectives: The primary objective of the present study was to assess
the safety of three different doses of oral N91115 administered twice daily
over 28 days in CF patients who were homozygous for the F508del-CFTR
mutation. Secondary and exploratory objectives included the assessment
of pharmacokinetics and the exploration of potential pharmacodynamic
biomarkers of GSNOR inhibition.
Methods: This was a double-blind, randomized, placebo controlled,
parallel group, dose-ranging study. A total of 48 patients were planned for
enrollment with equal randomization to placebo or N91115 at doses of
50 mg, 100 mg, or 200 mg administered Q12H for 28 days. The treatment
phase was followed by a 14 day washout period. Safety assessments were
based on clinical evaluations, laboratory tests, adverse events, spirometry,
and 12-lead ECGs. Additional safety oversight was provided by an
independent Data Monitoring Committee. Secondary endpoints included
pharmacokinetic parameters of N91115 and its primary metabolite.
Exploratory endpoints included sweat chloride, systemic biomarkers of
inflammation, body weight, PGIC, and the CFQ-R.
Results: A total of 51 patients homozygous for F508del-CFTR were
enrolled among the 4 treatment groups. Demographic and baseline
characteristics are shown in Table 1. The frequency of adverse events was
similar among the treatment groups (Table 2). There were 3 treatment
emergent serious adverse events (infective pulmonary exacerbations of CF
or PEs), 1 in the placebo group, and 1 each in the N91115 100 and 200
mg dose groups. The PE in the patient on placebo resulted in study drug
discontinuation. No PEs, serious or non-serious, occurred in the 200 mg
dose group during the treatment phase, however, 3 patients in that dose
group experienced a PE (1 serious, 2 non-serious) during the follow-up
phase.
There were no adverse effects on safety parameters including 12-lead
ECGs, laboratory chemistry and hematology parameters (including WBC
and ANC), sputum microbiology, or spirometry. The pharmacokinetic
profile of 200 mg Q12H N91115 demonstrated exposure to free drug that
was 2-fold the effective dose of N91115 in murine models. No effects on
systemic inflammatory biomarkers were observed. A modest trend toward
improvement in sweat chloride after 28 Days was observed in the 200 mg
dose group (mean change compared with placebo of -5.2 mmol/L, p =
0.11), and the data suggest that 200 mg may be a possible threshold
dose for sweat chloride effects.
Conclusions: N91115 was safe and well tolerated with no dose limiting
toxicities and no significant safety findings across a comprehensive set of
safety parameters. The study was not designed to assess the efficacy of
N91115 on FEV1, nevertheless, the absence of an adverse effect is
encouraging and supports the assessment of this endpoint in larger
studies of longer duration. A larger sample size and longer treatment
duration are also likely required to demonstrate any effect on
inflammatory biomarkers in this stable CF population. The emergence of
sweat chloride as a possible pharmacodynamic biomarker is encouraging.
The sweat chloride data suggest an onset of effect at the highest dose
studied. This dose provides approximately 4-fold the total N91115
exposure compared with effective doses in in vivo murine models,
however, due to protein binding differences between mouse and man, the
exposure to free drug is approximately 2-fold. This combined with the
safety profile of N91115 has informed dose selection for Phase 2 where a
higher dose group is planned in addition to a 200 mg Q12 dose group.
These doses of N91115 will be added to a background regimen that
includes Orkambi™ (lumacaftor and ivacaftor) in Phase 2.
PM density (% of DMSO)
Abstract
Depleted levels of SNOs may be attributed, in part, to GSNO reductase
(GSNOR), the major catabolic enzyme of GSNO. N91115 preserves GSNO
through selective and reversible inhibition of GSNOR. GSNO and GSNOR
inhibition (GSNORi) have been shown to exert their effects on CFTR
processing and stability through modification of chaperone function
(Marozkina et al. 2010), a mechanism that is entirely different from
correctors and potentiators of CFTR. Consistent with this distinct
mechanism, the effects of N91115 on CFTR function and cell surface
expression have been found to be additive to those of lumacaftor and
ivacaftor.
Placebo
50
100
200
11
11
13
12
1.1 (9.1)
-1.9 (7.3)
0.4 (7.4)
-1.0
-3.0
-2.0
-4.1 (5.7)1
-5.0
-
-2.7
-2.0
-0.4
-1.0
-5.2
-4.0
12
12
13
14
0 (5.8)
-1.85 (4.3)
0.93 (9.42)
0 (4.73)
12
12
13
14
2 (17%)
1 (8%)
1 (8%)
5 (36%)
-2.6 (11.5)
1.6 (10.5)
-0.86 (11.53) 2.38 (7.77)2
Grasemann et al., J Pediatr 1999; 135(6):770-772
Marozkina et al. PNAS 2010; 107(25):11393-11398