Primary:- To evaluate the safety and tolerability of NT-0167 in healthy volunteersSecondary:- To evaluate the pharmacokinetic (PK) profile of NT-0167 in healthy volunteers after the administration of single ascending (SAD) and multiple ascending…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
inflammatory disorders and neurodegenerative diseases
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
* Treatment-emergent (serious) adverse events ((S)AEs)
* Clinical laboratory tests
o Haematology
o Chemistry
o Urinalysis
o Coagulation
o Thyroid function tests
* Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Respiratory Rate (breaths/min)
* Electrocardiogram (ECG)
o Heart Rate (HR) (bpm), PR-, QRS-, and QTcF-intervals
o Morphological abnormalities
* Holter ECG (not in Food cohort)
* Physical examination
* Weight (only during MAD cohorts)
Pharmacokinetic endpoints
* AUCinf, AUClast, CL/F, Cmax, t1/2, tlag, tmax, Vz/F
Pharmacodynamic endpoints
* Inflammasome-driven cytokines in whole blood challenge assay:
o IL-1*
o IL-18
o IL-6
o TNF
Secondary outcome
N.A.
Background summary
Inflammasomes are large multiprotein complexes which play a key role in innate
immunity by participating in the production of the pro-inflammatory cytokines
interleukin-1* (IL-1*) and IL-18 [Guo et al, 2016]. These related cytokines
cause a wide variety of biological effects associated with infection,
inflammation and autoimmune processes. They are both produced as inactive
precursors, pro-IL-1* and pro-IL-18, and share a common maturation mechanism
that requires caspase-1. Caspase-1 itself is synthesized as a zymogen,
pro-caspase-1, that undergoes autocatalytic processing resulting in two
subunits that form the active caspase-1. Activation of caspase-1 occurs within
the inflammasome following its assembly.
The best characterised inflammasome is the NLRP3 (NOD-, LRR- and pyrin domain
containing protein 3; also known as NALP3 and cryopyrin) inflammasome. It
comprises the NLR protein NLRP3, the adapter ASC (apoptosis-related speck-like
protein) and pro-caspase-1. The general consensus is that maturation and
release of IL-1* requires two distinct signals: the first signal leads to
synthesis of pro-IL-1* and other components of the inflammasome, such as NLRP3
itself; the second signal results in the assembly of the NLRP3 inflammasome,
caspase-1 activation and IL-1* maturation and secretion.
Activation of the NRLP3 inflammasome can be triggered by numerous stimuli which
may be chemically and structurally very different. Triggering molecules
(pathogen-associated molecular patterns, PAMPs), such as bacterial
lipopolysaccharide and fungal zymosan, can activate the NLRP3 inflammasome and
induce IL-1* secretion in the presence of adenosine triphosphate (ATP) [Guo et
al, 2016]. Besides PAMPs, the NLRP3 inflammasome can be activated by molecules
associated with stress or danger, including crystalline and particulate
substance (danger-associated molecular patterns, or DAMPs).
NLRP3 inflammasome activation inhibitors are being developed for the treatment
of a range of inflammatory disorders including CAPS, NASH, inflammatory bowel
disease and neurodegenerative diseases (e.g. Alzheimer*s disease and
Parkinson*s disease). Clinical evidence through IL-1* modulation, NLRP3
gain-of-function mutation-driven diseases and non-clinical evidence through
genetic manipulation and pharmacological inhibition suggests that efficacy can
be achieved across a range of chronic diseases by inhibition of NLRP3
inflammasome activation. CP-456,773 [Dostert et al, 2009], a prototype molecule
originally discovered by Pfizer in the 1990s and subsequently shown to be an
NLRP3 inflammasome inhibitor in 2015 [Primiano et al, 2016] provides additional
clinical proof of concept as this molecule was progressed to a Phase II
rheumatoid arthritis study and showed evidence of a pharmacodynamic response.
Nodthera is developing a small molecule inhibitor of NLRP3, preventing the
assembly of the inflammasome. This compound, NT-0167, is a differentiated
molecule from the Pfizer compound CP-456,773. NT-0167 is a potent and selective
NLRP3 inflammasome inhibitor in LPS/ATP stimulated human peripheral blood
mononuclear cells and human blood, compared to CP-456,773, NT-0167 shows a
considerable improvement in human blood activity due to reduced plasma protein
binding. It shows efficacy in a single dose acute LPS/ATP mouse model and in an
MSU-mediated air-pouch inflammation model in mice inducing a decrease in IL-1*
compared to control, indicating inhibition of the inflammasome. To describe the
human target coverage for NT-0167, a PK/PD model was built based on the
available mouse and human PK/PD data with CP-456,773. According to this model,
the dose that is predicted to give 80% target coverage of NT-0167 at trough is
200mg QD or 100mg BID, which is projected to achieve a Cmax of 4584ng/mL
(9.96uM total; 158ng/mL (0.69µM free) and AUCt of 71429ng.h/mL (155.3µM.h
total; 4929ng.h/mL (10.7µM.h free). NT-0167 had no effect on hemodynamic or ECG
parameters or body temperature, compared with vehicle controls treatments in a
conscious minipig study at doses up to 300mg/kg. NT-0167 had no measurable
impact on behavioural or physiological parameters in the Irwin rat study up to
1000mg/kg. In a conscious rat respiratory study, NT-0167 did not induce test
article-related changes in any of the respiratory parameters measured up to
1000mg/kg. NT-0167 showed no liability for QT prolongation in a GLP-compliant
hERG study with 3% inhibition at 30 µM. In the GLP-compliant 28-day rat study
following dosing of NT-0167, the no observed adverse effect level (NOAEL) was
1000 mg/kg/day, the mean combined (male and female) Cmax value at Day 22 was
459 ug/mL and the AUC0-t value was 3490 ug·h/mL (representing a 48-fold safety
margin over the projected AUCt at 200mg QD). In the GLP-compliant 28-day
minipig study following dosing of NT-0167, the no observed adverse effect level
(NOAEL) was 1000 mg/kg/day, the mean combined (male and female) Cmax value at
Day 22 was 122 ug/mL and the AUC0-t value was 605 ug·h/mL (representing a
8.5-fold safety margin over the projected AUCt at 200mg QD).
The current first-in-human study will evaluate the safety/tolerability,
pharmacokinetics and pharmacodynamics of single and multiple ascending doses of
NT-0167 in healthy volunteers.
Study objective
Primary:
- To evaluate the safety and tolerability of NT-0167 in healthy volunteers
Secondary:
- To evaluate the pharmacokinetic (PK) profile of NT-0167 in healthy volunteers
after the administration of single ascending (SAD) and multiple ascending doses
(MAD);
- To evaluate the pharmacodynamic (PD) properties of NT-0167 in healthy
volunteers after single ascending and multiple ascending doses based on ex vivo
inflammasome challenges;
- To evaluate the effect of food on the PK profile and tolerability of NT-0167
after a single dose administration.
Study design
This study comprises up to 6 randomized, double-blind, placebo-controlled, SAD
cohorts, and up to 4 randomized, double-blind, placebo-controlled, MAD cohorts.
Each cohort will consist of 8 subjects: 2 subjects will receive placebo and 6
will receive active NT-0167. Before starting the MAD cohorts, an assessment of
the effect of food intake on the PK of the Investigational Medicinal Product
(IMP) will be studied in the subjects from one of the SAD cohorts.
Intervention
NT-0167
SAD: 10 - 2000 mg
Food cohort: 300/1000/2000 mg
MAD: 100 mg - 200 mg
Study burden and risks
The pharmacological and toxicological profile of NT-0167 observed in
pre-clinical studies suggest that administration to humans in a carefully
monitored study is acceptable. As with any new investigational product, the
administration of NT-0167 may be associated with unforeseen and serious risks.
Intense clinical monitoring will therefore be employed to ensure subject
safety. In addition to this, risks to participating volunteers will be
minimised by the strict adherence to inclusion and exclusion criteria, gradual
dose escalation, and the implementation of study and dose escalation pausing
rules which may lead to stopping the study.
The study design has been used previously in many entry-into-man studies and is
accepted by scientists and regulatory authorities. All study drug
administrations will be done in the clinic under medical supervision. The
subjects receiving any study drug will remain in the clinic for at least 48
hours after each study drug administration. Thus, the subjects can be closely
monitored for any adverse signs during the different treatments. Therefore,
providing the protocol is adhered to, careful observation and medical
management will minimize any associated risk in this study.
Mansion House, Chesterford Research Park, Little Chesterford Suite 8
Saffron Walden CB10 1XL
GB
Mansion House, Chesterford Research Park, Little Chesterford Suite 8
Saffron Walden CB10 1XL
GB
Listed location countries
Age
Inclusion criteria
Eligible subjects must meet all of the following inclusion criteria at
screening:
1. Signed informed consent and willing and able to comply with the study
protocol;
2. Healthy men or women of non-child bearing potential (WONCBP), 18 to 55 years
of age (inclusive) at screening. The health status is verified by absence of
evidence of any clinically significant active or uncontrolled chronic disease
following a detailed medical history, a complete physical examination including
vital signs, laboratory measurements, and 12-lead ECG;
3. Female subjects must be of non-childbearing potential in accordance with one
of the following definitions:
* Surgically sterile (by hysterectomy and/or bilateral oophorectomy and/or
bilateral salpingectomy) as documented by a surgical report or by ultrasound, or
* Post-menopausal (age-appropriate spontaneous amenorrhoea for *12 months and
follicle-stimulating hormone (FSH) * 40 IU/mL together with the absence of oral
contraceptive use for >12 months);
4. Male volunteers agree to use barrier protection when they engage in sexual
relations with women of child-bearing potential (WOCBP) or lactating women for
the duration of their participation in the study and until 90 days after EOS.
5. Body mass index (BMI) between 18 and 32 kg/m2, inclusive, and with a minimum
bodyweight of 50 kg;
6. Has the ability to communicate well with the Investigator in the Dutch
language and willing to comply with the study restrictions.
7. Have the intention to be reachable by mobile phone or e-mail during the
whole study period
Exclusion criteria
Eligible subjects must not meet any of the following exclusion criteria at
screening or pre-dose:
1. Lactating females;
2. Female volunteers with a positive pregnancy test at screening or baseline
prior to IMP administration;
3. Evidence (including symptoms, physical signs, and/or laboratory values) of
any active or chronic disease or condition that could interfere with, or for
which the treatment might interfere with, the conduct of the study, or that
would pose an unacceptable risk to the subject in the opinion of the
investigator;
4. Any confirmed or suspected disease or condition associated with immune
system impairment, including auto-immune diseases, HIV, asplenia or recurrent
severe infections.
5. Use of chronic (more than 14 days) immunosuppressant or immunomodulatory
drugs within the 6 months prior to IMP administration, or isolated
(non-chronic) use within 30 days prior to IMP administration;
6. Any history of severe allergic reaction(s);
7. Any confirmed significant drug hypersensitivity reactions (including skin
reactions or anaphylaxis), or known allergies (non-active hay fever is
acceptable);
8. History of clinically significant systemic disorders including
haematological, renal, endocrine, gastrointestinal, hepatic, cardiovascular,
pulmonary, dermatological and neurological disorders, or other conditions which
could interfere with the interpretation of the study results or compromise the
health of the volunteers;
9. Any history of psychiatric condition that may affect participation in the
study or preclude compliance with the protocol;
25. Receipt of any vaccination with 3 months of IMP administration.
26. Participation in an investigational drug, vaccine or device study within 3
months prior to first dosing or plans to participant in other investigational
drug, vaccine or device research during the study period.
27. Previous participation in a study with an investigational drug or device
involving the dosing of a biological targeted at any immune pathway within one
year prior to screening;
38. Any other known factor, condition, or disease that, in the opinion of the
Investigator, might interfere with treatment compliance, study conduct or
interpretation of the results, or may compromise volunteer safety.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004228-39-NL |
| CCMO | NL72337.056.19 |