Phase 1 Study to Evaluate the Safety and Tolerability of Intravenously Administered PYC-003

Official title

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

Overview

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.

Detailed description

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.

Part D will be an extension study for participants that complete Part C where participants will continue receiving doses for up to 96 weeks.

Interventions

• Drug PYC-003
  A peptide-phosphorodiamidate morpholino oligonucleotide conjugate administered as a single intravenous infusion

Primary outcome measures

• [Part A, B, C and D] Number of participants experiencing treatment emergent adverse events (AE) as assessed by CTCAE V5.0 [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in vital signs (body temperature) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in vital signs (systolic and diastolic blood pressure) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in vital signs (pulse rate) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in vital signs (respiratory rate) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in 12-lead ECG (QT Interval) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in 12-lead ECG (QRS Duration) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in 12-lead ECG (QTcF Interval) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in 12-lead ECG (PR Interval) [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Changes from baseline in 12-lead ECG (Heart Rate) [Time frame: Up to 98 weeks]

Secondary outcome measures (10)

• [Part A, B, C and D] Peak plasma concentration (Cmax) of PYC003 [Time frame: Up to 98 weeks]
• [Part A, B, C and D] Time to maximum observed plasma drug concentration (Tmax) of PYC003 [Time frame: Up to 98 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) [Time frame: 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) [Time frame: Up to 36 weeks]
• [Part A, B and C] Area under the plasma concentration-time curve, from time zero extrapolated to infinity (AUC0-inf) [Time frame: 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) [Time frame: Up to 36 weeks]
• [Part A, B and C] Apparent half life of PYC-003 (T1/2) [Time frame: Up to 36 weeks]
• [Part A, B and C] Apparent elimination constant (Kel) of PYC-003 [Time frame: Up to 36 weeks]
• [Part A, B and C] Apparent clearance (CL) of PYC-003 [Time frame: Up to 36 weeks]
• [Part A, B and C] Apparent volume of distribution (Vz) of PYC-003 [Time frame: Up to 36 weeks]

Eligibility criteria

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 Exclusion Criteria

• 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 -1.
• 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.

13\. Able and willing to attend the necessary visits to the study site.

14\. Able and willing to adhere to alcohol and nicotine-containing product restrictions

15\. 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 B and Part C (ADPKD Participant) Key Exclusion Criteria

• Females who are pregnant, breastfeeding, or plan to become pregnant during the course of the study.
• Presence of potentially confounding genetic mutations (per genotyping by a NATA accredited or equivalent diagnostic laboratory)including, but not limited to, the presence of PKD2, HNF1B, GANAB, IFT140, and/or DNAJB 11 mutations.
• Use of (or anticipated use of) Tolvaptan and/or metformin administration within 30 days prior to the first administration of IP until study completion.
• 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.
• Any renal or systemic pathology other than ADPKD or any other condition or prior therapy that in the opinion of the PI or designee would make the participant unsuitable for this study.
• Has only 1 kidney or has 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.
• Has received (or is anticipated to receive) cell therapy, gene therapy, or RNA therapy for any renal condition.
• 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 ECG findings at Screening, Day -3 to Day -1, or predose that are considered by the PI or designee to be clinically significant.
• Abnormal vital signs findings at Screening that are considered by the PI or designee to be clinically significant.

Note: A hypertensive participant is eligible if on a stable antihypertensive regimen for ≥ 28 days prior to first administration of IP and the blood pressure adequately controlled (per PI discretion) prior to first administration of IP.

• 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.
• 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.
• Urine protein: creatinine ratio (UPCR) of > 50 mg/mmol.
• Hematuria (urine protein: creatinine ratio > 30 mg/mmoL, or hematuria > ++ on dipstick, or > 100 cells per high-power field on microscopy) and/or urinary abnormalities at Screening deemed by the PI or designee to be of moderate or higher severity.
• Renal complications (eg, cyst rupture or cyst infections) within 6 weeks prior to first administration of IP.
• 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.
• 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 D will be an extension study for participants that complete Part C.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

Australia · 10 centers

• South Coast Renal, Brockway House, Level 1, Suite 8, 82-86 Queen Street, — Southport
• Concord Repatriation General Hospital — Concord
• Liverpool Hospital, Clinic G-Reception 133, Level 1, Clinical Building, Burnside Drive — Liverpool
• Scientia Clinical Research — Randwick
• Sydney Adventist Hospital — Wahroonga
• Westmead Hospital, Clinical Research Unit, Level 6, B Wing/Building, Hawkesbury Road — Westmead
• Mater Hospital Brisbane — South Brisbane
• St Vincent's Hospital Melbourne — Fitzroy
• … and 2 more centers

Hong Kong · 1 center

• Prince of Wales Hospital — Shatin

New Zealand · 1 center

• Pacific Clinical Research Network Auckland — Takapuna

Identifiers

NCT: NCT06714006 · PYC-003-CL-001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗