To investigate the safety, tolerability and pharmacokinetics after multiple daily doses of YTX-7739
ID
Source
Brief title
Condition
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- Safety:
o Safety and tolerability of YTX-7739 will be measured by assessing the
severity and incidence of treatment-emergent adverse events (TEAEs), clinical
laboratory tests, ECGs, vital signs and physical examinations.
- Pharmacokinetic:
o The non-compartmental PK parameters of YTX-7739 will be estimated including
AUC, C(max), T(max), elimination half-life (t1/2) and elimination rate constant
(Ke).
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 regulates toxicity caused by
alpha-synuclein, the major protein component of Lewy body pathology and a key
genetic risk factor for Parkinson*s disease. In a variety of cellular assay
systems, inhibitors of the enzyme stearoyl-CoA-desaturase (SCD) reduce levels
of monounsaturated fatty acids and also reduce alpha-synuclein toxicity.
YTX-7739 is a novel, orally active inhibitor of SCD enzymatic activity, showing
preferential inhibition of the brain-predominant SCD5 isoenzyme (IC50 ~10nM)
and lower potency at the systemically distributed SCD1 isozyme (IC50 ~600nM).
Inhibition of SCD5 and SCD1 reduce levels of monounsaturated 16-Carbon and
18-Carbon fatty acids and reduce alpha-synuclein toxicity. Here, we aim to
explore the safety, tolerability and pharmacokinetic properties of YTX-7739, as
well as the pharmacodynamic response to YTX-7739, following 14-28 daily doses
in healthy adult volunteers and individuals with Parkinson*s Disease.
Study objective
To investigate the safety, tolerability and pharmacokinetics after multiple
daily doses of YTX-7739
Study design
This will be a randomized, double-blind, placebo-controlled multiple ascending
dose (MAD) study in healthy volunteers (Part A) and Parkinson*s Patients (Part
B).
Intervention
Part A:Cohort 1 : 25 mg OD YTX-7739 / matching placebo. The dose of cohort 2
and part B will be based on emerging data from cohort 1. Cohort A2 and cohorts
in part B will be dosed for 28 days. The maximum dose is 400 mg.
Study burden and risks
The safety, tolerability, pharmacology and food effect of single doses of up to
400 mg YTX-7739 has been studied in humans in the SAD study. YTX-7739 was safe
and well tolerated with few adverse events. All adverse events were mild or
moderate, of short duration and self-limiting. There were no serious or
unexpected adverse events. In this context the risk associated with exposure
after a single dose (taking into account the half-life of 30-91 hours in a fed
state) to YTX-7739 is considered acceptable. The safety profile observed after
single doses does not raise concerns for the multiple dose study. The target
exposures for the multiple dose study are well below the highest exposures
achieved in the SAD study, only the extent of exposure will be longer.
A potential risk is that the frequency and severity of adverse events may
increase after multiple dosing compared to a single dose. Key pharmacokinetic
findings from the SAD study have been taken into consideration in designing the
current MAD study in order to mitigate this risk.
The AEs that are expected to occur include eye dryness/irritation, skin dryness
and hair loss, all of which can be monitored well in the clinic. As discussed
in the Investigator*s Brochure, the AEs in the pre-clinical studies were mild
and reversible at the exposure levels that are targeted in this multiple dose
study.
A concern prior to the SAD study was a mild, transient prolongation (maximal
increase up to 27 msec,) in QTc observed in beagle dogs, that was not
associated with arrhythmia. This concern has been addressed by the Holter ECG
monitoring and concentration-QTcF modelling, which showed the upper CI of the
QTcF reaching the 10 ms threshold at a concentration of 2160 ng/mL. In the
multiple dose study, concentrations are targeted to stay around 800 ng/mL,
which is well below this threshold.
Subjects will undergo regular blood draws, meibum expressions and several
lumbar punctures during the study. Subjects in part A will eat a high-fat
(standard breakfast for part B) meal daily for the duration of the dosing
period. Ingredients for the breakfasts will be made available to the subjects
by CHDR. Variations on the high-fat meal composition will be available.
No benefit is expected for participants.
40 Guest Street, Suite 4410
Boston MA 02135
US
40 Guest Street, Suite 4410
Boston MA 02135
US
Listed location countries
Age
Inclusion criteria
Part A
1. Adult male or female subjects 18-55 years of age, inclusive.
Part B
2. Male or female subjects 40-75 years of age, inclusive, with a confirmed
diagnosis of Parkinson*s disease (Hoehn and Yahr grade 1-3).
Part A + B
3. Healthy status as defined by absence of evidence of any significant 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 and urinalysis, as judged by the investigator;
4. Body mass index (BMI) between 18-32 kg/m2, inclusive, and with a minimum
weight of 50kg and maximum weight of 120kg
5. If subject is a female, she agrees to report onset and duration of menses if
it occurs anytime during participation in the study (screening to end of study)
6. Evidence of a personally signed and witnessed informed consent document
indicating that the subject has been informed of all pertinent aspects of the
study;
Exclusion criteria
Part A:
1. Clinically significant findings as determined by medical history taking,
physical examination, fundoscopy, ECG, laboratory findings (abnormal lipid or
hormone profile) and vital signs;
2. Hemodynamic status at screening: systolic blood pressure <100 or >160 mmHg,
diastolic blood pressure <50 or >95 mmHg, heart rate <45 or >100 bpm measured;
Part B:
3. Clinically significant findings as determined by medical history taking, MRI
(Part B, cohort 4 only), physical examination, fundoscopy, ECG and vital signs,
other than Parkinson*s disease;
4. Any current, clinically significant, known medical condition other than
Parkinson*s disease. Patients with a diagnosis of neurological diseases, other
than Parkinson*s disease, including Alzheimer*s disease, Huntington*s disease,
vascular dementia, progressive supranuclear gaze palsy, multiple system
atrophy, drug-induced parkinsonism, essential tremor, primary dystonia,
epilepsy, etc., that are considered clinically relevant by the investigator.
5. Dementia indicated by MMSE <18 at Screening;
6. Use of drugs known to prolong QT interval;
7. Hemodynamic status at screening: results that are considered clinically
relevant by the investigator;
8. Part B, cohort 4 only: any contra-indication to performing a MRI (including
(an history of) a cardiac pacemaker, implanted cardiac defibrillator,
neurostimulator, hydrocephalus pomp, drug pump, stents or clips in vessels,
non-removable hearing aid, non-removable implants containing a magnet in the
jaw, tissue expander in the breast, IUD, metal splinters of fragments in the
body, non-removable medication patch, tattoo or permanent make-up applied less
than 6 weeks ago, non-removable piercing, non-removable hair extensions
containing metal);
9. An history of claustrophobia, tinnitus or hyperacusis;
10. Part B, cohor t4 only: an history of allergic reaction during previous
MRI examination;
11. History of repeated head injury; history of epilepsy or seizure disorder
other than febrile seizures as a child
12. Reside in a nursing home or assisted care facility
13. Concomitant disease or condition that could interfere with, or treatment of
which might interfere with, the conduct of the study, or that would, in the
opinion of the Investigator, pose an unacceptable risk to the participant in
this study or interfere with the participant's ability to comply with study
procedures or abide by study restrictions, or with the ability to interpret
safety data
14. Prior lack of response to dopaminergic medication (for example, levodopa or
a dopaminergic agonist)
15. Ccontinuous use of any of the following within 30 days prior to baseline:
antipsychotics (including clozapine and olanzapine), metoclopramide, alpha
methyldopa, clozapine, olanzapine, flunarizine, amoxapine, amphetamine
derivatives, reserpine, bupropion, buspirone, cocaine, mazindol,
methamphetamine, methylphenidate, norephedrine, phentermine,
phenylpropanolamine, and modafinil. Single use up to 7 days prior to the start
of the study is allowed for metoclopramide.
for all exclusion criteria please see protocol section 4.3, pages 51-53
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 | EUCTR2020-000034-17-NL |
| CCMO | NL72549.056.20 |
| OMON | NL-OMON20317 |