Study of AT-02 in Healthy Volunteers and Subjects With Systemic Amyloidosis

• Status: Not yet recruiting
• Trial end date: 2023-09-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a multicenter, international, two-part, Phase 1 study designed to evaluate the safety, tolerability, and PK of rising single doses of AT-02 in healthy volunteers (HV) and in subjects with systemic amyloidosis (SA).

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Attralus, Inc.
• Collaborator: Novotech (Australia) Pty Limited

Criteria

Inclusion Criteria:

Eligibility Criteria for Healthy Volunteers:

Healthy volunteers are eligible to be included in the study only if all the following criteria apply:

1. Understands the study procedures and can give signed informed consent

2. Male or female between >18 and <56 years of age.

3. Willing and able to comply with this protocol and informed consent and be available for the entire duration of the study.

4. Willing to abstain from alcohol and strenuous physical activity (i.e., strenuous or unaccustomed weightlifting, running, bicycling, etc.) from 48 hours prior to study treatment administration until discharge from the clinical unit and prior to each outpatient visit.

5. In good general health, determined by no clinically significant findings in the opinion of the Investigator from medical history, physical examination, 12-lead electrocardiogram (ECG), clinical laboratory findings, and vital signs at Screening and Phase 1 unit Check-in.

6. Has body mass index (BMI) of 18 to 32 kg/m2, inclusive.

7. Women of childbearing potential (WOCBP)

1. WOCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.

2. Must not be breastfeeding, lactating, or planning a pregnancy during the study period.

3. WOCBP who are not exclusively in same-sex relationships must agree to remain abstinent (complete avoidance of heterosexual intercourse) or use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, during the treatment period and for at least 105 days after the last dose of study intervention.

8. Postmenopausal females:

a) Postmenopausal females under the age of 55 years must have a documented serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause

9. Women of non-childbearing potential (WONCBP) and female participants with vasectomized male partners:

a) WONCBP must agree to remain abstinent (complete avoidance of intercourse) or the male partners of WONCBP participants must wear a condom to protect against the transfer of study intervention through bodily fluids during the treatment period and for at least 105 days after the last dose of study intervention.

10. Male participants:

1. Male participants must inform their female sexual partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner.

2. Male participants with female sexual partners who are WOCBP must agree to remain abstinent (complete avoidance of heterosexual intercourse) or use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, during the treatment period and for at least 165 days after the last dose of study intervention.

3. Male participants must not donate sperm for at least 165 days after the last dose of study intervention.

4. Male participants with potentially postmenopausal partners who are under the age of 55 years must use condoms unless their partner's postmenopausal status has been confirmed by FSH level.

5. Male participants in same-sex relationships or in relationships with WONCBP must agree to remain abstinent (complete avoidance of intercourse) or use a condom to prevent exposure of the partner to study intervention through ejaculate/seminal fluid during the treatment period and for at least 165 days after the last dose of study intervention.

Eligibility Criteria for Subjects with Systemic Amyloidosis:

Subjects with systemic amyloidosis are eligible to be included in the study only if all the following criteria apply:

1. Understands the study procedures and can give signed informed consent

2. Male or female more than18 years of age.

3. Has a confirmed diagnosis of AL, ATTR, or other form of systemic amyloidosis, based on any one of the following:

1. A histologic confirmation with a biopsy containing deposits of apple-green birefringent, Congophilic material or other amyloid staining (i.e., thioflavin T or sulfated alcian blue) with confirmatory immunohistochemistry, mass spectrometry or identification of an amyloidogenic genetic variant;

2. Genetic screening with presence of amyloid-related pathology; or

3. Amyloid-specific imaging study (e.g., bone scintigraphy and echocardiogram/CMR consistent with ATTR cardiac amyloid)

4. Subjects with AL systemic amyloidosis must have achieved a hematologic very good partial response (VGPR) or complete response (CR) based on their most recent assessment (e.g., difference in free light chains less than 40 mg/L) and within 12 months of Screening and may be receiving maintenance daratumumab.

5. Subjects with ATTR systemic amyloidosis may be receiving a TTR silencer (e.g., inotersen, vutrisiran, or patisiran) or a stabilizer (e.g., tafamadis or diflunisal), but not both.

6. Women of childbearing potential (WOCBP):

1. WOCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug.

2. Must not be breastfeeding, lactating, or planning a pregnancy during the study period.

3. WOCBP who are not exclusively in same-sex relationships must agree to remain abstinent (complete avoidance of heterosexual intercourse) or use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, during the treatment period and for at least 105 days after the last dose of study intervention.

7. Postmenopausal females:

a. Postmenopausal females under the age of 55 years must have a documented serum follicle stimulating hormone (FSH) level >40 mIU/mL to confirm menopause

8. Women of non-childbearing potential (WONCBP) and female participants with vasectomized male partners:

a. WONCBP must agree to remain abstinent (complete avoidance of intercourse) or the male partners of WONCBP participants must wear a condom to protect against the transfer of study intervention through bodily fluids during the treatment period and for at least 105 days after the last dose of study intervention.

9. Male participants:

1. Male participants must inform their female sexual partners who are WOCBP of the contraceptive requirements of the protocol and are expected to adhere to using contraception with their partner.

2. Male participants with female sexual partners who are WOCBP must agree to remain abstinent (complete avoidance of heterosexual intercourse) or use adequate contraceptive methods, defined as use of a condom by the male partner combined with use of a highly effective method of contraception by the female partner, during the treatment period and for at least 165 days after the last dose of study intervention.

3. Male participants must not donate sperm for at least 165 days after the last dose of study intervention.

4. Male participants with potentially postmenopausal partners who are under the age of 55 years must use condoms unless their partner's postmenopausal status has been confirmed by FSH level.

5. Male participants in same-sex relationships or in relationships with WONCBP must agree to remain abstinent (complete avoidance of intercourse) or use a condom to prevent exposure of the partner to study intervention through ejaculate/seminal fluid during the treatment period and for at least 165 days after the last dose of study intervention.

Exclusion Criteria:

• Healthy volunteers are excluded from the study if any of the following criteria apply:

1. Subject is mentally or legally incapacitated, has a history of psychosis, or has significant emotional problems at the time of the study according to the Investigator.

2. Subject has a history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, or neurologic disease according to the Investigator or reported history of HIV infection.

3. Subject has a history of poorly controlled asthma or a history of anaphylaxis or other significant allergy in the opinion of the Investigator

4. Subject has a history of any ongoing medical condition requiring treatment with prescription medication within the past two (2) weeks.

5. Subject's estimated creatinine clearance/glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is ≤80 mL/min.

6. Subject has clinically significant abnormalities on pre-study clinical examination or laboratory safety tests. Laboratory safety assessments (e.g., serum chemistry, hematology, coagulation) will be performed at Screening and on Day -1 (if Screening is prior to Day -1) to confirm eligibility. Screening safety labs may be repeated at the Investigator's discretion.

7. Hemoglobin <12 gm/dL or seropositivity for hepatitis B surface antigen, or hepatitis C antibodies at Screening.

8. Has received heparin or heparin analogs (e.g., enoxaparin, dalteparin, fondaparinux) within seven (7) days prior to Day 1.

9. Use of any prescription or OTC medications including food supplements and herbal medications (e.g., St. John's wort), except for contraceptive medications, a daily multivitamin, and/or as needed (prn) acetaminophen/paracetamol (not exceeding 2 grams/day) within seven (7) days prior to study treatment administration.

10. History of malignancy, except adequately treated basal or squamous cell carcinoma or in situ carcinoma of the uterine cervix.

11. History of drug allergy or drug hypersensitivity, or intolerance of IV or subcutaneous injections.

12. Any female who is pregnant or breastfeeding, or any female who is planning to become pregnant during the study and follow-up periods.

13. Any condition that, in the Investigator's opinion, may compromise study participation, present a safety risk to the subject, or may confound the interpretation of the study results.

14. A QT duration corrected for heart rate by Fridericia's formula (QTcF) >450 millisecond (msec) based on averaged QTcF values of triplicate ECGs (obtained at 1-minute intervals at Screening).

15. Subject has had surgery, experienced significant blood loss, or donated a unit of blood within the last 30 days.

16. Subject has donated a unit of plasma in the last seven (7) days.

17. Subject has participated in another clinical study within the last four (4) weeks or within five (5) half-lives of the prior study drug, whichever is longer.

• Subjects with systemic amyloidosis are excluded from the study if any of the following criteria apply:

1. Is pregnant or breastfeeding.

2. Is mentally or legally incapacitated, has significant emotional problems at the time of the study, or has a history of psychosis.

3. Receiving hemodialysis or peritoneal dialysis.

4. Myocardial infarction within 3 months of Screening.

5. New York Heart Association Class III or IV heart failure.

6. Heart failure not predominantly caused by cardiac amyloid.

7. Any severe uncorrected cardiac valve disease.

8. Respiratory insufficiency requiring oxygen therapy.

9. Currently receiving or has received within three (3) months prior to Screening:

melphalan, bortezomib, thalidomide, lenalidomide, rituximab, or cyclophosphamide.

10. Has received heparin or heparin analogs (e.g., enoxaparin, dalteparin, fondaparinux) within seven (7) days prior to administration of AT-02.

11. Active malignancy with exception of adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, in situ cervical cancer, low risk prostate cancer with Gleason score less than 7 and prostate specific antigen less than 10 mg/mL, any other cancer from which the subject has been disease-free for greater than and equal 2 years.

12. Uncontrolled or active infection.

13. Autoimmune disease requiring treatment with immunosuppressive/modulating treatment in the last year.

14. History of solid organ transplantation or ventricular assist device.

15. Suspected or known drug or alcohol abuse, serious psychiatric or any other medical condition, which, in the opinion of the Investigator, makes the subject unsuitable.

16. Has any concurrent illness that, in the opinion of the Investigator, might confound the results of the study or pose additional risk to the subject.

17. Subject's screening alanine transaminase (ALT) or aspartate transaminase (AST) is greater than 2.5x upper limit of normal (ULN).

18. Subject's screening NT-proBNP is greater tha equal 6000 pg/mL.

19. Subject's screening estimated creatinine clearance/eGFR using the CKD-EPI equation is less than 30 mL/min.

20. Subject is currently participating in an interventional clinical study or has participated in another clinical study within the last four (4) weeks or within five (5) half-lives of the prior study drug, whichever is longer.