A Phase 1, Randomized, Double-Blind, Placebo-Controlled Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacology of GSM-779690T in Healthy Adult Participants
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Ascending Dose Study to Evaluate the Safety, Tolerability and Pharmacology of GSM-779690T in Healthy Adult Participants
This is a randomized, double-blinded, placebo-controlled dose escalating first in human study to evaluate the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) of GSM-779690T. The study will have two parts: a single ascending dose (SAD) component and a multiple ascending dose (MAD) component. The goal of this study is to learn if GSM-779690T is safe and to assess the effects on levels of specific Aβ peptide isoforms in adults.
SAD: A total of 48 healthy volunteers are planned to be consented and enrolled to receive a single oral dose of GSM-779690T at increasing strengths or placebo in Cohorts 1 through 6.
MAD: A total of 48 healthy volunteers are planned to be consented and enrolled to receive multiple oral doses of GSM-779690T (doses will be informed by SAD data) in Cohorts 7 through 10. Cohort 10 will include healthy older-adults.
Participants who have signed an informed consent and meet screening eligibility requirements will be randomly assigned to receive a single oral dose of GSM-779690T or placebo with a 3:1 (active: placebo) ratio at each dose level. The decision to escalate between dose levels in the SAD and to proceed to the MAD will be based on Data Review Committee review of prior cohorts, safety, tolerability, and PK data. The study treatment, GSM-779690T, and all protocol assessments will be administered at the study site by trained study site personnel.
Participants must meet all the following inclusion criteria to be eligible for enrollment:
Healthy, cognitively typical, and aged 20-45 years (inclusive).
Current Mini Mental State Examination (MMSE) score between 27 and 30 (inclusive) at screening.
Able to provide their own written informed consent.
Able to read, speak and understand English to ensure compliance with cognitive testing and study visit procedures.
Must be ambulatory and be willing to remain domiciled in the clinic for the required study procedures.
Contraception requirements:
a. Women of childbearing potential (WOCBP) must agree to use a highly effective method of birth control (confirmed by the investigator) from enrollment, throughout the study duration, at 1 week after last dose of study treatment, and have a negative pregnancy test result at screening. Highly effective methods of birth control (those that can achieve a failure rate of less than 1% per year when used consistently and correctly) include: (i) Combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, or transdermal, (ii) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, or implantable, (iii) Intrauterine device, (iv) Intrauterine hormone-releasing system, (v) Bilateral tubal occlusion, (vi) Sexual abstinence, ie, refraining from heterosexual intercourse (vii) Vasectomised sexual partner (provided that partner is the sole sexual partner of the WOCBP study participants and that the vasectomized partner has received medical assessment of the surgical success).
b. Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or who are postmenopausal. The following age-specific requirements apply: (i) Women < 50 years old will be considered postmenopausal if they have been amenorrhoeic for >12 months following cessation of exogenous hormonal treatment and FSH levels are in the postmenopausal range (>40 IU/L). Until FSH is documented to be within menopausal range, the patient should be treated as a WOCBP.
(ii) Women > 50 years old will be considered postmenopausal if they have been amenorrhoeic for >12 months following cessation of all exogenous hormonal treatment.
c. Males with childbearing partners must be willing to practice sexual abstinence or use double-barrier protection during study treatment and until 1 week after the last dose of study treatment.
The same Inclusion Criteria as listed above for the phase 1A SAD study applies to the adult cohorts (aged 20-45 years, inclusive) in phase 1B MAD Study. The following additional inclusion criteria apply to the older-adult Cohort 10 only:
8. Healthy, cognitively typical, aged 60-75 years (inclusive).
9. Older participants (Cohort 10) must be living in the community (includes long-term assisted living facilities but excludes long-term care nursing facilities).
10. If applicable, older-adult participants (Cohort 10) diagnosed with chronic cardio- or metabolic diseases must have the condition well controlled (in the opinion of the investigator) to include a stable regimen for four (4) weeks prior to Dose Day 1. Some medications are permitted to treat common disorders, such as but not limited to hypertension, type II diabetes, dyslipidemia, and hypothyroidism.
11. Participants must have low likelihood of brain amyloid presence based on an amyloid probability score 2 (APS2) of < 47.5 calculated by PrecivityAD2™ test using the plasma sample collected at screening visit.
Participants meeting any of the following criteria must be excluded in the study:
History of any current or clinically significant gastrointestinal, renal, hepatic, bronchopulmonary, neurological, psychiatric, cardiovascular, endocrinological, ophthalmologic, hematological or allergic disease or metabolic disorder.
Note: Older participants in Cohort 10 may be eligible if the chronic condition is well controlled per opinion of the clinical investigator.
Use of any concomitant medications is prohibited, other than prescribed birth control methods stable 4 weeks prior to screening.
Note: Older participants in Cohort 10 who are taking stable dose regimen (4 weeks prior to Dose Day 1) may be eligible upon review and approval by the Medical Monitor.
A history of a psychiatric disorder such as schizophrenia, bipolar disorder or major depression according to the criteria of the most current version of the Diagnostic and Statistical Manual of Mental Disorders (DSM).
Any evidence of current suicidal ideation or any previous suicide attempt as evaluated by the Columbia-Suicide Severity Rating Scale (C-SSRS).
Diagnosis of a neurodegenerative disease or dementia, including but not limited to Alzheimer's disease (AD), Parkinson's disease and Huntington's disease.
A history of a seizure disorder.
Impaired hepatic function with any of the following lab abnormalities on screening:
Renal function with an estimated glomerular filtration rate (eGFR) less than 90 mL/minute/1.73 m2 Note: less than 80 mL/minute/1.73 m2 in older participants enrolling in Cohort 10.
Presence of crystalluria in urinalysis at screening.
A clinically significantly abnormal 12-lead ECG result, including but not limited to: heart rate < 50 or > 100 beats per minute (bpm), QRS > 160 ms, QTcF > 450 ms in men & 460 ms in women, or any clinically significant arrhythmia including Mobitz type II second-degree atrioventricular (AV)(Hay block) block and bifascicular block.
A seated systolic blood pressure of < 100 or > 140 millimeters of mercury (mm Hg) or diastolic blood pressure of < 60 or > 90 mm Hg.
Postural change at 3 min upon standing from seated position of:
Cancer or malignant tumor within the past 3 years, except patients who underwent potentially curative therapy with no evidence of recurrence. Patients with stable untreated prostate cancer or skin cancers are not excluded.
Current acute or chronic Hepatitis A, B, C or HIV infection.
Alcohol abuse, alcohol dependence, or drug abuse in the past 5 years per most current version of the DSM.
Participation in another clinical trial with an investigational agent and have taken at least one dose of study medication, unless unblinded on placebo, within 3 months (12 weeks) or 5 drug half-lives (whichever is longer), prior to screening. (The end of a previous investigational trial is the date the last dose of an investigational agent was taken).
Previous treatment (within 1 year) with an investigational small molecule with anti-amyloid properties or passive immunization against Aβ or previous treatment with an active immunization against amyloid.
Positive result from a urine drug test at screening (screened for Amphetamines, Barbiturates, Cocaine metabolites, 3,4-Methylenedioxymethamphetamine (MDMA), Tricyclic Antidepressants (TCA), Phenylcyclohexyl Piperidine (PCP), Cotinine, Opiates, Benzodiazepines, Cannabinoids (THC), Methamphetamine, Methadone, Oxycodone (OXY)).
Not willing to abstain from consuming products containing caffeine (including chocolate), xanthine, citrus or alcohol from Day 1 through the end of the PK study.
SAD Cohorts 5, 6 and MAD Cohorts 9, 10: Contraindication to lumbar puncture (LP) This includes but is not limited to participants with a known allergy to the local anesthetics used in the LP, infection or inflammation of the skin or skin disease at or in proximity to the LP site; abnormal coagulation parameters, including platelet count, INR, PT and/or PTT, History of lumbar spine surgery or chronic low back pain for participants in the SAD Cohorts 5 and 6 and the MAD Cohorts 9 and 10.