* Part A: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of increasing doses of YTX-7739 in healthy subjects. * Part B: To study the effect of food on pharmacokinetics of YTX-7739 in a selection of subjects who…
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Considering the exploratory nature of this study, the primary endpoints will be
the incidence and severity or AEs or treatment emergent AEs.
Secondary outcome
NA
Background summary
There are currently no disease-modifying drugs available for the major
age-related neurodegenerative diseases, including Parkinson*s disease (PD). The
lack of therapies results from a poor understanding of disease biology,
unproven predictive value of animal models, challenges in translating
pharmacology from animals to man and difficulties in patient stratification and
assessment of clinical response. These challenges are exacerbated by a lack of
novel drug targets and drug molecules. Yumanity Therapeutics uses a proprietary
discovery platform that seeks to identify novel drug targets and drug molecules
that protect cells from toxicity caused by the accumulation of misfolded
proteins. Using this platform, the Yumanity team determined that elevated
cellular levels of monounsaturated fatty acids (namely oleic acid (C18:1n9) and
palmitoleic acid (C16:1n7)) regulates toxicity caused by *-synuclein, the major
protein component of Lewy body pathology and a key genetic risk factor for
Parkinson*s disease. Oleic and palmitoleic acids are obtained through diet and
also endogenously produced by the endoplamatic reticulum resident enzyme,
stearoyl-CoA-desaturase (SCD). In a variety of cellular assay systems, SCD
inhibitors reduce levels of monounsaturated fatty acids and also reduce *-
synuclein toxicity. This inhibition of SCD activity in brain, plasma, skin and
other tissues can be quantified as the fatty acid desaturation index (FA-DI),
which is the ratio of unsaturated to saturated fatty acids in a given tissue.
YTX-7739 is a novel, orally active inhibitor of SCD enzymatic activity, showing
inhibition of the brain-predominant SCD5 isoenzyme and the widely distributed
SCD1 isozyme. Inhibition of SCD5 and SCD1 reduce levels of monounsaturated
16-Carbon and 18-Carbon fatty acids and reduce *-synuclein toxicity (Vincent,
Tardiff et al. (2018); Fanning et al., (2018).
Here, we aim to explore the safety, tolerability, pharmacokinetic and
pharmacodynamic properties of YTX-7739 in healthy adult volunteers (part A) as
a prelude to further study this molecule as a potential disease modifying
therapy for Parkinson*s disease and related neurological disorders. In part B,
we aim to assess the effect of food on the pharmacokinetics of YTX-7739. In
part C, we aim to explore the pharmacokinetics of low doses of YTX-7739 after
administration in a fed state. Part C is being performed based on preliminary
results of parts A and B.
Study objective
* Part A: To investigate the safety, tolerability, pharmacokinetics and
pharmacodynamics of increasing doses of YTX-7739 in healthy subjects.
* Part B: To study the effect of food on pharmacokinetics of YTX-7739 in a
selection of subjects who participated in the SAD study.
* Part C: To study the pharmacokinetics of low doses of YTX-7739 after
administration in a fed state in healthy subjects
Study design
This study will comprise threefour parts. Part A will be a randomized,
double-blind, placebo-controlled single ascending dose (SAD) in 40 to 48
healthy adults using a parallel design. Part B will be a food-effect study in
which the subjects from the two highest dose cohorts of part A will be
administered YTX-7739 on a second occasion. Part C will be an open label, all
active treatment study of pharmacokinetics of low doses of YTX-7739 in a fed
state.
Intervention
5mg, 10mg, 20mg, 30mg, 100mg, 250mg, 400mg or placebo
Study burden and risks
The proposed study involves exposure of healthy human volunteers to single oral
doses of YTX-7739, an experimental drug that inhibits the enzyme
stearoyl-CoA-desaturase. As discussed in the Investigators Brochure, single
oral doses of YTX-7739 were very well tolerated in animals. The primary concern
requiring additional precautions was a mild, transient prolongation (maximal
increase 26 msec) in QTc. QTc interval prolongation was most evident at the
highest dose of 120 mg/kg/day in dogs, which had associated exposures of 10160
ng/mL (Cmax) and 167500 ng*hr/mL (AUClast). In animals, this mild effect of
prolonging QTc was not associated with arrhythmia.The risks to the safety posed
by administration of single oral doses of YTX-7739 are small and will be
mitigated by inclusion of sentinel subjects in the first dosing cohort,
initiation of dosing at a dose level expected to result in plasma
concentrations of YTX-7739 greater than 10X below the concentrations that may
produce an effect on QTc or any other known safety concern, holter monitoring
and incorporation of careful safety and tolerability review prior to each dose
escalation. As both parts include healthy volunteers, no benefit is expected.
Healthy subjects in the current study fall in a low risk category for
complications of COVID-19, the disease caused by the SARS-CoV-2 virus. To
prevent SARS-CoV-2 infections among trial participants, measures and procedures
based on the advice issued by the Dutch Centre for Infectious Disease Control
(RIVM) and COVID-19 measures declared by the Dutch government will be adhered
to as outlined in CHDR SOP GGECOVID. Site trial staff in direct contact and/or
within 1.5 m distance of study subjects will receive additional protection via
the use of Personal Protective Equipment (PPE) and disinfectants. All trial
subjects will be screened for SARS-CoV-2 with a PCR: 1) prior to the admission
at the clinical unit; 2) in case of symptoms possibly related to COVID-19.
Healthy subjects will be excluded from the study when tested positive for
SARS-CoV-2.
Based on the mechanism of action of YTX-7739 and the available information in
the Investigators Brochure, there is currently no reason to believe that the
investigational drug could 1) increase the susceptibility of trial participants
to the SARS-CoV-2 virus, or 2) worsen or mask any COVID-19 signs, symptoms or
complications. Pre-clinical data does not show evidence of any
immunocompromising or respiratory effects. The clinical safety data from parts
A and B of this trial shows no YTX-7739 related abnormalities in hematology,
vital signs and physical examination. Overall, a single dose of YTX-7739 was
well tolerated and adverse events occurred with comparable frequency in
subjects receiving YTX-7739 and in subjects receiving placebo. The doses
planned for part C of the study are 20 to 40 times lower than the highest dose
administered in parts A and B.
Guest Street 40, Suite 4410
Boston MA 02135
US
Guest Street 40, Suite 4410
Boston MA 02135
US
Listed location countries
Age
Inclusion criteria
1. Healthy male and female subjects 18-45 years of age, inclusive. Healthy
status is defined by absence of evidence of any active acute or chronic disease
or illness following a detailed medical and surgical history, a complete
physical examination including vital signs, 12-lead ECG, hematology, blood
chemistry, coagulation and urinalysis;
2. Body mass index (BMI) between 18-35 kg/m2, inclusive, and with a minimum
weight of 50kg and maximum weight of 120kg;
3. Evidence of a personally signed, dated and witnessed informed consent
document indicating that the subject has been informed of all pertinent aspects
of the study;
4. Able and willing to give written informed consent and to comply with all
study restrictions.
Exclusion criteria
1. Legal incapacity or inability to understand or comply with the requirements
of the study;
2. Clinically significant findings, as judged by the investigator, as
determined by medical history taking, physical examination, ECG and vital signs;
3. Subjects with a borderline QTcF of > 450 ms for males and > 470 ms for
females at screening or a history of long QT syndrome;
4. Hemodynamic status at screening: systolic blood pressure <100 or >160 mmHg,
diastolic blood pressure <60 or >95 mmHg or heart rate <45 or >100 bpm
5. Any current, clinically significant, known medical condition, as judged by
the investigator.
6. Pregnant, lactating or breast-feeding women;
7. Have a urine drug screen detecting illicit drug(s) of abuse (morphine,
benzodiazepines, cocaine, amphetamine, THC) or positive alcohol breath test at
screening;
8. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab)
or human immunodeficiency virus antibody (HIV Ab) at screening;
9. Consumption of, on average, >8 units/day of (methyl)xanthines (e.g., coffee,
tea, cola, chocolate) and/or not able to refrain from use during each stay at
the CHDR clinic;
10. History or clinical evidence of alcoholism or drug abuse;
11. Smoking of >5 cigarettes/day or equivalent prior to screening and/or not be
able to refrain from smoking cigarettes during each stay at the CHDR clinic;
12. Use of prescription, illicit or herbal medication within 7 days or 5
half-lives prior to the first day of dosing, except contraception,and
paracetamol. Other current and recent (within 1 month prior to the screening)
treatments will be allowed, if judged by the investigator to have no clinical
relevance;
13. Participation in a clinical trial with an investigational drug or device
within 90 days of first dosing or more than 4 times in the previous year;
14. Loss or donation of blood * 500 mL within 3 months before screening;
15. Subjects of childbearing potential who are unwilling or unable to use a
highly effective method of barrier contraception for the duration of the study
and for at least 90 days after their last dose of study treatment.
16. All males who are unwilling to practice effective contraception and abstain
from sperm donation during the study and who are not willing and able to
continue contraception and abstain from sperm donation for at least 90 days
after their last dose of study treatment.
17. Any confirmed significant allergic reactions (urticaria or anaphylaxis)
against any drug, or multiple drug allergies (non-active hay fever is
acceptable).
18. Part C, Cohort 7 only: History of spinal cord compression, any other
current abnormalities in the lumbar region (skin infection, structural
abnormalities in lower spine, etc.), or any other issue that, in the opinion of
the investigator, would make CSF collection unsafe
19. Positive SARS-CoV-2 PCR analysis prior to first dosing.
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 | EUCTR2019-003169-16-NL |
| CCMO | NL71070.056.19 |