A Phase 1 (First in Human) Randomized, Double-blind, Placebo-controlled SAD, MAD Study With Oral REM0046127

A Phase 1 (First in Human) Randomized, Double-blind, Placebo-controlled SAD, MAD Study With an Adaptive Dose Design to Evaluate the Safety, Tolerability, and Pharmacokinetics of REM0046127 in Healthy Subjects

This is a phase 1 randomized double blind, first in human (FIH) study with the novel oral Alzheimer drug candidate REM0046127, which consists of two main parts, a single ascending dose (SAD) study with 7 cohorts followed by a multiple ascending dose (MAD) study with 2 cohorts.

SAD

As a baseline, 5 cohorts of 8 young healthy males are foreseen, with a repeat to assess food impact and an additional elderly cohort. Depending on the early FIH findings, the number of cohorts could be more or less. FIH studies include initially only males due to the incomplete nature of preclinical reproductive toxicology studies

• Treatment duration: single day

• Each cohort:

  • 2 volunteers on placebos, of which 1 sentinel
  • 6 volunteers on study drug, of which 1 sentinel

• Timing for each cohort will be about 21 days

  • Subjects will be screened for selection from day -21 to day -1 before starting the experimental phase of each cohort
  • First the 2 sentinels will be dosed
  • Following the review of sentinel safety and tolerability data through the Data Safety Monitoring Board (DSMB) after one day or 2 half-life times following the sentinel dosing, the remaining 1+5 subjects will be randomized and dosed approximately 7 days after the sentinels

MAD

• First cohort of 10 healthy young male subjects. This cohort can be initiated after the food interaction has been assessed in the last safe SAD cohort, and does not need to wait for the elderly cohort.

• Second cohort of 12 healthy elderly subjects:

  • The 1st cohort of healthy young male at about 75% of the Maximum Tolerated Dose (MTD) of the SAD
  • The 2nd cohort of healthy older male and female (not of child-bearing potential) at about 50 or 100% of the highest tolerable dose of the SAD, depending on the observations in the 1st MAD cohort to assess potential impact of age on Pharmacokinetics (PK)
  • Treatment duration: 7 days
  • Timing for each cohort will be about 35 days

• Subjects will be screened for selection from day -21 to day -1 before starting the experimental phase each cohort

• First the sentinels will be dosed

• Following the review of sentinel safety and tolerability data through the DSMB, the remaining subjects will be randomized and dosed approximately 14 days later

• According to plan the sentinels of the 2nd cohort will be dosed about 35 days after the sentinels of the 1st cohort.

Inclusion Criteria:

1. SAD/MAD: Young male subjects aged 18 to 45 years (limits included) willing and able to give their written consent to participate in the trial after having received information about the study design, the objectives of the project, the possible derivative risks, and their right to withdraw from the study at any time and for any reason

2. Elderly Cohorts: Elderly male and female (not of childbearing potential) subjects aged 55 to 80 (limits included) willing and able to give their written consent to participate in the trial after having received information about the study design, the objectives of the project, the possible derivative risks, and their right to withdraw from the study at any time and for any reason.

3. Women not of childbearing potential: Clinically significant abnormalities in screening laboratory tests, including:

   • Surgically sterile (bilateral tubal ligation, hysterectomy), or
   • Postmenopausal with last natural menses greater than 24 months

4. Electrocardiogram without clinically significant pathologic abnormalities and with corrected QT interval (cQT) values lesser than 450 ms

5. Normotensive as defined by Systolic Blood Pressure ≤ 150 mm Hg. Diastolic Blood Pressure ≤ 90 mm Hg without antihypertensive medication

6. Body Mass Index (BMI) between 18 and 30 kg/m2.

7. Body weight between 60 and 80 kg, inclusive

   Only for the elderly cohort of the MAD:

8. Participants may be taking medication for non-serious chronic diseases, provided that the dose of these concomitant medications has been stable within the previous 2 months

9. No suicidal ideation, as demonstrated by a score of "0" on the Columbia Suicide Severity Rating Scale (C-SSRS)

Exclusion Criteria:

1. Women of childbearing potential (WOCBP)

2. Failure to perform screening or baseline examinations

3. Any chronic medical condition (such as type 1 diabetes) requiring chronic treatment that might increase the risk to the subject or confound the interpretation of safety observations according to the clinical assessment of the investigator (physician)

4. Evidence of active infection requiring antibiotic therapy within 14 days prior to screening

5. Medical history of vasculitis or any autoimmune disease excluding seasonal allergic rhinitis and childhood history of atopic dermatitis

6. History of any treatment for cancer within the past 2 years, other than basal cell or squamous cell carcinoma of the skin

7. Seropositive for human immunodeficiency virus (HIV)

8. History of acute/chronic hepatitis B or C and/or carriers of hepatitis B (seropositive for Hepatitis B surface antigen [HbsAg] or anti-Hepatitis C [Hepatitis C Virus (HCV)] antibody)

9. Clinically significant abnormalities in screening laboratory tests, including:

   • Absolute neutrophil count < 1.4 x109
   • Absolute lymphocyte count < 1.2 x 109
   • Alanine transaminase (ALT) or aspartate transaminase (AST) > 1.5 x the upper limit of normal (ULN)
   • Lactate Dehydrogenase (LDH) > 1.5 x ULN
   • Total bilirubin level: Out of normal range 0-1.5 mg/dL
   • Estimated glomerular filtration rate (eGFR) < 60 mL/min
   • Haemoglobin (Hgb): out of normal range (male: 13,5-18,0 g/dL).
   • Haemoglobin (Hgb): out of normal range (female: 12,0-16,0 g/dL)

10. Use of an investigational drug within 2 months prior to dosing in this study

11. Any disorder that could interfere with the absorption, distribution, metabolism or excretion of drugs (e.g. small bowel disease, Crohn's disease, celiac disease, or liver disease)

12. Chronic kidney disease (defined as the presence of any degree of proteinuria on urine analysis and/or an eGFR of <60 ml/min using the (Modification of Diet in Renal Disease (MDRD) formula)

13. Psychiatric history of current or past psychosis, bi-polar disorder, major depression, or anxiety disorder requiring chronic medication within the past 5 years

14. History of substance abuse, including alcohol and nicotine or positive urine drug screen at screening visit

15. Any reason or opinion of the investigator that would prevent the subject from participation in the study

16. Inability to follow the instructions or an unwillingness to collaborate during the study

17. Male subjects with female partner of child-bearing potential who are unwilling or unable to adhere to contraception requirements

    Only for the elderly cohort of the MAD:

18. Chronic daily drug intake during the study period:

    • Benzodiazepines, neuroleptics or major sedatives
    • Antiepileptics
    • Centrally active anti-hypertensive drugs (clonidine, l-methyl-DOPA, guanidine, guanfacine, etc.)
    • Opioid containing analgesics

19. History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years

20. Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the volunteer or put the volunteer at special risk, such as:

    • Chronic liver disease, liver function test abnormalities or other signs of hepatic insufficiency (Alanine-Aminotransferase (ALT), Aspartate-Aminotransferase (AST), Gamma Glutamyl-Transferase (GT), alkaline phosphatase > 2.0 ULN)
    • Respiratory insufficiency
    • Heart disease (myocardial infarction, unstable angina, heart failure, cardiomyopathy within six months before screening)
    • Bradycardia (heartbeat <50/min) or tachycardia (heartbeat >95/min)
    • Hypertension (<180/95) or hypotension requiring treatment with more than 2 drugs
    • Atrioventricular (AV) block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcF-interval (males >450 and females >470 ms)
    • Uncontrolled diabetes defined by HbA1c >8.5
    • Renal insufficiency (serum creatinine > 2mg/dL) or creatinine clearance ≤ 30 mL/min according to Cockcroft-Gault formula).