A Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenously Administered PYC-003, a Peptide-phosphorodiamidate Morpholino Oligonucleotide Conjugate, in Healthy Adult Participants and Adult Participants With Confirmed PKD1 Mutation-associated Autosomal Dominant Polycystic Kidney Disease
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 166
- 试验地点
- 18
- 主要终点
- (Part A and B) Number of participants with treatment-related adverse events as assessed by CTCAE V5.0
研究概览
简要总结
This is a Phase 1, First-in-Human study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of PYC-003 in healthy adult participants and adult participants with confirmed PKD1 mutation-associated Autosomal Dominant Polycystic Kidney Disease (ADPKD) There are 4 parts in this study, i.e. Part A, Part B, Part C and Part D.
详细描述
Part A (SAD - Healthy) will be conducted as a randomized, double-blind, placebo-controlled, SAD study to assess the safety, tolerability, PK, PD, and immunogenicity of PYC-003 in healthy adult participants.
The anticipated number of participants across 5 Part A (SAD - Healthy) cohorts is approximately 40 participants.
On Day 1, each participant will receive the investigational product (IP; ie, PYC-003 or placebo), as a single intravenous (IV) infusion.
Part B (SAD - ADPKD) will be conducted as an open-label single ascending dose (SAD) study to assess the safety, tolerability, PK, PD, and immunogenicity of PYC-003 in adult participants with confirmed PKD1 mutation-associated ADPKD. The anticipated number of participants across 5 Part B (SAD - ADPKD) cohorts is approximately 30 participants. On Day 1, each participant will receive PYC-003 as a single IV infusion.
Part C (MAD-ADPKD) will be conducted as an open label multiple ascending dose (MAD) study to assess the safety, tolerability, PK, PD, and immunogenicity of PYC-003 in adult participants with confirmed PKD1 mutation-associated ADPKD. The anticipated number of participants across 4 Part C (MAD - ADPKD) cohorts is approximately 48-96 participants. Each participant will receive PYC-003 as an IV infusion either once every 6 weeks for 13 weeks or once every 8 weeks for 17 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Part A will be randomized, double-blind, placebo-controlled, Single Ascending Dose study.
Part B, Part C and Part D will be an open-label study.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Part A (SAD - Healthy Volunteers) Key Inclusion Criteria
- •Adult aged 18 to 60 years (inclusive)
- •At the discretion of the PI or designee, in good general health, with no significant medical history, and have no clinically significant abnormalities on physical examination at Screening
- •BMI ≥ 18.0 and ≤ 32.0 kg/m2 and weight ≥ 50 kg.
- •Non-smoker and must not have used any tobacco or nicotine products within 2 months prior to Screening.
- •Clinical laboratory values within normal range or deemed not clinically significant by the PI
- •eGFR ≥ 80 mL/min/1.73 m2 via the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) 2021 calculation
- •Woman of childbearing potential (WOBCP) must agree to use an acceptable, highly effective, double barrier method of contraception from the start of Screening until study completion.
- •Males must be surgically sterile (vasectomized for at least 6 months prior to first IP administration) or, if engaged in sexual relations with a WOCBP, must agree to use an acceptable, highly effective, double barrier method of contraception from the start of Screening until study completion.
- •Females must agree not to donate ova from the first administration of IP until 30 days following study completion.
- •Males must agree not donate sperm from the first administration of IP until 90 days following study completion.
- •Able and willing to attend the necessary visits to the study site.
- •Able and willing to adhere to caffeine, alcohol, and nicotine-containing product restrictions
- •Able and willing to provide written informed consent after the nature of the study has been explained and prior to the commencement of any study procedures.
- •Part A (SAD - Healthy Volunteers) Key
排除标准
- •Females who are pregnant, breastfeeding, or plan to become pregnant during the course of the study.
- •Underlying physical or psychological medical condition that, in the opinion of the PI or designee, would make the participant unlikely to comply with the protocol or complete the study per protocol.
- •Has only 1 kidney or has received a kidney transplant.
- •Blood donation or had significant blood loss (> 500 mL) within 30 days prior to the first administration of IP.
- •Plasma donation within 7 days prior to the first administration of IP.
- •Fever (body temperature > 38°C) or symptomatic viral or bacterial infection within 2 weeks prior to first administration of IP.
- •Infections requiring parenteral antibiotics within 6 months prior to Screening.
- •Positive test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), HIV antibody.
- •History of life-threatening infection (e.g., meningitis).
- •Vaccination with a live vaccine within 4 weeks prior to the first administration of IP.
- •Poor venous access.
- •History of severe allergic or anaphylactic reactions, or sensitivity to the IP or its constituents.
- •History of malignancy, except for non-melanoma skin cancer excised more than 1 year prior to Screening and cervical intraepithelial neoplasia that has been successfully cured more than 2 years prior to Screening.
- •Abnormal electrocardiogram (ECG) findings at Screening, Day -3 to Day -1, or predose that are considered by the PI or designee to be clinically significant.
- •History or presence of a condition associated with significant immunosuppression.
- •Exposure to any drugs that cause significant immunosuppression (including experimental therapies as part of a clinical study) within 4 months or 5 half-lives (whichever is longer), prior to Screening.
- •ALP, AST, and ALT > 1.5 × ULN at Screening or Day -3 to Day -
- •History of borderline to low blood magnesium and potassium levels and/or Screening or Day -3 to Day -1 blood magnesium level < 0.7 mmol/L and potassium levels < 3.5 mmol/L.
- •Active infection of the urinary tract (ie, kidney, bladder).
- •Positive toxicology screening panel (urine test including qualitative identification of amphetamines, barbiturates, benzodiazepines, cocaine, methamphetamine, methadone, opiates, phencyclidine, tetrahydrocannabinol [THC], tricyclic antidepressants), or alcohol breath test.
- •History of substance abuse or dependency or history of recreational IV drug use over the last 5 years (by self-declaration).
- •Regular alcohol consumption defined as > 14 standard drinks per week for females and > 21 standard drinks for males (where 1 standard drink = 375 mL of mid-strength beer [3.5% alcohol/volume], 100 mL wine [13.5% alcohol/volume] or 30 mL of spirits [40% alcohol/volume]) or > 4 standard drinks on any single day.
- •Unwilling to abstain from alcohol for 48 hours prior to admission to the study site and for 48 hours prior to any follow-up visits.
- •Use of any investigational medical device or investigational drug within 30 days or 5 half-lives of the investigational drug (whichever is longer) prior to the first administration of IP.
- •Use of (or anticipated use of) the following:
- •Any prescription drugs (other than hormonal contraception; oral contraceptive pills, long-acting implantable hormones, injectable hormones, a vaginal ring, or an intrauterine device [IUD]) within 14 days prior to the first administration of IP and during the course of the study without prior approval of the PI and MM.
- •Any over-the-counter medication, herbal remedies, supplements or vitamins within 7 days prior to the first administration of IP and during the course of the study without prior approval of the PI and MM. Note: Paracetamol (i.e., up to 2000 mg per day) may be used for minor ailments during the study, at the discretion of the PI, without prior consultation with the MM.
- •Unwilling to refrain from strenuous exercise (including weightlifting) for 48 hours prior to admission to the study site and for 48 hours prior to any follow-up visits.
- •Anything that the PI considers would jeopardize the safety of the participant, prevent complete participation in the study, or compromise interpretation of study data.
- •Part B and Part C (ADPKD Participants) Key Inclusion Criteria
- •Male or female aged 18 to 65 years (inclusive) at the time of informed consent.
- •ADPKD diagnosis as confirmed by the presence of genetic mutations associated with ADPKD, including, but not limited to, the presence of PKD1 mutation. Note: Where genotyping is not included the medical history for a participant, genotyping may be completed at Pre-Screening.
- •Class 1C, 1D, or 1E per Mayo Imaging Classification System for Predicting Kidney Outcomes in ADPKD (Irazabal et al. 2015) (based upon prior magnetic resonance imaging [MRI] or computed tomography [CT] scan obtained prior to Screening, or MRI obtained during Pre-Screening).
- •BMI ≥ 18.0 and ≤ 35.0 kg/m2 and weight ≥ 50 kg.
- •Non-smoker and must not have used any tobacco or nicotine products within 2 months prior to Screening.
- •Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 via the CKD EPI 2021 calculation
- •8. Hematology and serum chemistry results at Screening that meet the following criteria:
- •Platelets > 150 × 10^9/L
- •Total white blood cell count > 3.0 × 10^9/L
- •Absolute neutrophil count > 1.5 × 10^9/L
- •Hemoglobin > 110 g/L for females and > 120 g/L for males
- •Total and direct bilirubin < 1.5 × ULN, unless elevated bilirubin is associated with a known benign condition (e.g., Gilbert's syndrome)
- •Alanine aminotransferase (ALT) < 1.5 × ULN
- •Aspartate aminotransferase (AST) < 1.5 × ULN
- •Alkaline phosphatase (ALP) < 1.5 × ULN
- •Gamma-glutamyl transferase < 2 × ULN
- •9.WOCBP must agree to use an acceptable, highly effective, double barrier method of contraception from the start of Screening until study completion
- •10. Males must be surgically sterile (vasectomized for at least 6 months prior to first administration of IP) or, if engaged in sexual relations with a WOCBP, must agree to use an acceptable, highly effective, double barrier method of contraception from the start of Screening until study completion
- •11. Females must agree not to donate ova from the first administration of IP until 30 days following study completion.
- •12.Males must agree not donate sperm from the first administration of IP until 90 days following study completion.
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研究组 & 干预措施
Part A (SAD - Healthy)
Part A will be conducted as a randomized, double-blend, placebo-controlled, Single Ascending Dose Study in healthy adult participants. On Day 1, each participant will receive the investigational product (IP; i.e., PYC-003 or placebo), as a single intravenous (IV) infusion. All Part A (SAD - Healthy) cohorts will first dose 2 sentinel participants in a blinded manner on Day 1.
干预措施: PYC-003 (Drug)
Part B (SAD - ADPKD)
Part B will be conducted as an open-label Single Ascending Dose study in adult participants with confirmed PKD1 mutation-associated ADPKD. On Day 1, each participant will receive PYC-003 as a single IV infusion.
干预措施: PYC-003 (Drug)
Part C (MAD - ADPKD)
Part C (MAD - ADPKD) will be conducted as an open-label MAD study in adult participants with confirmed PKD1 mutation-associated ADPKD. Each participant will receive PYC-003 as an IV infusion either once every 6 weeks for 13 weeks (i.e., dosing on Day 1, Day 43, and Day 85) or once every 8 weeks for 17 weeks (i.e., dosing on Day 1, Day 57, and Day 113).
干预措施: PYC-003 (Drug)
结局指标
主要结局
(Part A and B) Number of participants with treatment-related adverse events as assessed by CTCAE V5.0
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD. The incidence, severity, and relatedness of TEAEs and treatment-emergent SAEs will be recorded
(Part A and B) To evaluate the changes in ECG QRS duration from baseline via 12-lead ECG (local) following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in ECG QT interval from baseline via 12-lead ECG (local) following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in baseline body temperature following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in Heart rate via 12-lead ECG (local) following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in ECG PR interval from baseline via 12-lead ECG (local) following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes physically via complete and symptom-directed physical examination following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD Complete and symptom-directed physical examinations are to be performed by a licensed physician. Complete physical examinations include general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes.
(Part A and B) To evaluate the changes in ECG QTcF interval from baseline via 12-lead ECG (local) following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in baseline systolic and diastolic blood pressure following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes from baseline in serum potassium, serum magnesium, serum sodium, serum osmolality, serum cystatin C, and serum creatinine following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in standard renal and hepatic clinical chemistry parameters following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in baseline pulse rate following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes in baseline respiratory rate following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
(Part A and B) To evaluate the changes from baseline in urine potassium, urine magnesium, urine creatinine, and urine osmolality following a single dose of PYC-003 administered intravenously
时间窗: 24 weeks
To evaluate the safety and tolerability of PYC-003 following a single dose administered intravenously to healthy adult participants and adult participants with confirmed PKD1 mutation-associated ADPKD
[Part A, B and C] Number of participants experiencing treatment emergent adverse events (AE) as assessed by CTCAE V5.0
时间窗: Up to 36 weeks
The incidence, severity, and relatedness of treatment emergent adverse events and treatment-emergent Serious Adverse Events will be recorded An AE is any event, side-effect, or other untoward medical occurrence that occurs in conjunction with the use of a medicinal product in humans, whether or not considered to have a causal relationship to this treatment. An AE can, therefore, be any unfavourable and unintended sign (that could include a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
[Part A, B and C] Changes from baseline in vital signs (body temperature)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in vital signs (systolic and diastolic blood pressure)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in vital signs (pulse rate)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in vital signs (respiratory rate)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in 12-lead ECG (QT Interval)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in 12-lead ECG (QRS Duration)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in 12-lead ECG (QTcF Interval)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in 12-lead ECG (PR Interval)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in 12-lead ECG (Heart Rate)
时间窗: Up to 36 weeks
[Part A, B and C] Changes from baseline in physical examination findings
时间窗: Up to 36 weeks
Complete physical examinations include general appearance, head, ears, eyes, nose, throat, dentition, thyroid, chest (heart, lungs), abdomen, skin, neurological, extremities, back, neck, musculoskeletal, and lymph nodes. Abbreviated physical examinations will be symptom directed.
(Part A, B and C) Changes from baseline in hepatic clinical chemistry parameters (ALT, AST, ALP and GGT)
时间窗: Up to 36 weeks
ALT (Alanine Transaminase), AST (Aspartate Transaminase) ALP (Alkaline Phosphatase) and GGT (Gamma-glutamyl transferase) will be tested
(Part A, B and C) Changes from baseline in standard renal clinical chemistry parameters (eGFR)
时间窗: Up to 36 weeks
estimated Glomerular filtration rate (eGFR) will be calculated via the CKD EPI 2021 calculation
(Part A, B and C) Changes from baseline in serum potassium, serum magnesium, and serum sodium
时间窗: Up to 36 weeks
(Part A, B and C) Changes from baseline in serum cystatin C
时间窗: Up to 36 weeks
(Part A, B and C) Changes from baseline in serum and urine creatinine
时间窗: Up to 36 weeks
(Part A, B and C) Changes from baseline in serum and urine osmolality
时间窗: Up to 36 weeks
(Part A, B and C) Changes from baseline in urine magnesium and urine potassium
时间窗: Up to 36 weeks
次要结局
- [Part A, B and C] Peak plasma concentration (Cmax) of PYC003(Up to 36 weeks)
- [Part A, B and C] Time to maximum observed plasma drug concentration of PYC003(Up to 36 weeks)
- [Part A, B and C] Area under the plasma concentration-time curve, from time zero to 24 hours post dose of PYC-003 (AUC0-24)(Up to 36 weeks)
- [Part A, B and C] Area under the plasma concentration-time curve, from time zero to the last time point with measurable analyte concentration after PYC-003 dose (AUC0-last)(Up to 36 weeks)
- [Part A, B and C] Area under the plasma concentration-time curve, from time zero extrapolated to infinity (AUC0-inf)(Up to 36 weeks)
- [Part A, B and C] The percentage of the AUC that was extrapolated beyond the last observed data point (AUC%extrap)(Up to 36 weeks)
- [Part A, B and C] Apparent half life of PYC-003 (T1/2)(Up to 36 weeks)
- [Part A, B and C] Apparent elimination constant (Kel) of PYC-003(Up to 36 weeks)
- [Part A, B and C] Apparent clearance (CL) of PYC-003(Up to 36 weeks)
- [Part A, B and C] Apparent volume of distribution (Vz) of PYC-003(Up to 36 weeks)
- (Part A and B) The peak plasma concentration, Cmax of PYC-003 following a single dose administered intravenously(24 weeks)
- (Part A and B) The peak plasma concentration, Tmax (time to maximum observed plasma drug concentration) of PYC-003 following a single dose administered intravenously(24 weeks)
- (Part A and B) The Plasma PK parameter, t½ (half life) of PYC-003 will be determined following a single dose administered intravenously to adult participants(24 weeks)
- (Part A and B) The Plasma PK parameter, AUC0-24 (Area under the plasma concentration versus time curve over the last 24 hour) of PYC-003 will be determined following a single dose administered intravenously(24 weeks)
- (Part A and B) Plasma PK parameter, AUC0-inf (extrapolated area under concentration-time curve) of PYC-003 will be determined following a single dose administered intravenously to adult participants(24 weeks)
- (Part A and B) The Plasma PK parameter, AUC%extrap (the area under the curve) of PYC-003 will be determined following a single dose administered intravenously(24 weeks)
- (Part A and B) The Plasma PK parameter, kel (elimination rate constant) of PYC-003 will be determined following a single dose administered intravenously(24 weeks)
- (Part A and B) The Plasma PK parameter, Vz (Volume of distribution) of PYC-003 will be determined following a single dose administered intravenously(24 weeks)
- (Part A and B) The Plasma PK parameter, CL (Total drug clearance from plasma) of PYC-003 will be determined following a single dose administered intravenously(24 weeks)