SAD/MAD Safety and PK Study of RBN-3143 in Healthy and Atopic Dermatitis Subjects

NCT05215808 | Unknown Phase 1

• 1 other identifier: RBN-3143-21-001
• Study Type: interventional
• Target: 72
• Locations: 2 countries
• Sites: 6

Brief Summary

RBN-3143 Background: PARP proteins are members of a family of seventeen ADP-ribosyltransferase (ART) enzymes that regulate cellular processes including gene expression, protein degradation, and multiple cellular stress responses. RBN-3143 is a PARP-14 inhibitor. PARP14 is over-expressed in tissues with inflammatory diseases. RBN-3143 is a novel, orally administered PARP14 inhibitor that was developed to be evaluated as therapy for a range of inflammatory diseases, with an initial focus on Atopic Dermatitis. Study Overview: The study consists of 2 parts. Part A: This part of the study is being conducted in a clinical research unit (CRU) and is enrolling healthy adult subjects to determine the safety of RBN-3143; its absorption, metabolism, and excretion (what the body does to this drug); and will assess its potential pharmacodynamic properties (what the drug does to the body). There are 3 subsections to this part of the study. The first segment was conducted in a double-blind manner (neither the investigator nor subject knew if placebo or RBN-3143 was given) to assess dosing regimens of RBN-3143 when taken in a fasted state (before food). The last two segments are currently recruiting and are Open Label (all subjects will receive RBN-3143) and will assess RBN-3143 when taken with food, with pantoprazole, a medication that decreases the amount of acid in the stomach, and with midazolam. Part B: In early 2023 the second part of the study will be conducted in patients with moderate to severe atopic dermatitis to measure the pharmacodynamic activity of RBN-3143 and evaluate preliminary efficacy of 28 days administration of the study drug. All patients will receive the same dose of RBN-3143.

Conditions

Atopic Dermatitis

Keywords

Normal Healthy Volunteers; Atopic Dermatitis

Outcome Measures

Primary Outcomes (1)

• Safety determined by DLTs

  Incidence rate of Dose limiting Toxicities (DLTs) of RBN 3143

  30 days

Secondary Outcomes (6)

• Cmax of RBN-3143

  Predose through 72 hours

• Tmax of RBN-3143

  Predose through 72 hours

• AUC of RBN-3143

  Predose through 72 hours

• T1/2 of RBN-3143

  Predose through 72 hours

• CYP3A4 Assessment

  Through Day 19

Study Arms (4)

RBN-3143

EXPERIMENTAL

RBN-3143 in single ascending dose followed by multiple ascending dose cohorts, randomized 3:1 ratio

Drug: RBN-3143

Placebo

ACTIVE COMPARATOR

Placebo randomized in 1:3 ratio with ascending RBN-3143 single and multiple dosing

Drug: RBN-3143

Pantoprazole

OTHER

Open Label PPI cohort to evaluate concurrent administration of pantoprazole on RBN-3143 pharmacokinetics

Drug: RBN-3143

Midazolam

OTHER

Open Label DDI Cohort (12 subjects) to evaluate the effect of RBN-3143 on the exposure of midazolam, a sensitive CYP3A4 substrate

Drug: RBN-3143

Interventions

RBN-3143 DRUG

Oral Administration of tablets

Midazolam; Pantoprazole; Placebo; RBN-3143

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy male or female subjects between 18 and 65 years of age (inclusive at the time of informed consent)
• Body mass index (BMI) between ≥18 and ≤30 kg/m2 (inclusive) at Screening
• Good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at Screening and/or before administration of the initial dose of study drug
• Clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator
• Willingness and ability to speak, read, and understand English, and provide written informed consent
• Must be a non-smoker or former smoker. Subjects must have negative cotinine results in drug tests at Screening and Baseline
• Females must be:
• Non-pregnant Non-lactating Must use a non-hormonal, acceptable, highly effective double contraception from Screening until study completion, including the Follow-up Period
• Acceptable non-hormonal double contraception is defined as a condom AND one other form of the following:
• An IUD (non-hormonal)
• Documented evidence of surgical sterilization at least 6 months prior to Screening (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy for women or vasectomy for men \[with appropriate post-vasectomy documentation of the absence of sperm in semen\] provided the male partner is a sole partner)
• Women of child-baring potential (WOCBP) must have:
• A negative pregnancy test at Screening and Day -1 and be willing to have additional pregnancy tests as required throughout the study
• Post-menopausal Women:
• Women not of childbearing potential must be:

You may not qualify if:

• Any medical condition that is considered by the Investigator or delegate that may interfere with study assessments, may adversely affect the subject's participation in the study, may make the subject's participation in the study unreliable, or be of such severity as to present an increased risk to the subject because of participation in the study.
• Prior or ongoing medical conditions, physical findings, laboratory abnormality or a history of neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease that is considered as significant by the Investigator or delegate, and in the Investigator's opinion, could adversely affect the safety of the subject
• Abnormal ECG findings at Screening that are considered by the Investigator to be clinically significant:
• Significant history of cardiovascular disease
• ECG results showing QTcF \>450 msec or the presence of clinically significant abnormalities as determined by the investigator (Screening or Day -1)
• Elevation of blood pressure (BP), i.e., supine systolic BP \>140 mmHg and/or diastolic BP \>90 mmHg, or heart rate \>100 beats per minute at rest
• Use of any prescription medication within 14 days of dosing or over-the-counter (OTC) medication (including vitamins) within 48 hours of dosing or intends to use any prescription medication or OTC medication during the study that may interfere with the evaluation of study medication. Co-administration of medications known to have high risk of prolonging the QT interval are also prohibited. The use of other concomitant medications that present a low risk of QT prolongation may be considered, with the approval of the Medical Monitor. Simple analgesia (paracetamol, nonsteroidal anti-inflammatory drug \[NSAID\]) may be permitted at the discretion of the Investigator or delegate. Use of a low dose corticosteroid and β2 agonist inhalers to treat concomitant Asthma are allowed.
• Ingestion of herbal medicines within 3 weeks before Screening, and grapefruit, grapefruit juice, star fruit or orange marmalade (made with Seville oranges) within 2 weeks prior to dosing, or intends to use any of these products during the study
• Relevant dietary restrictions or unwilling to consume standard meals provided.
• Ingestion of caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) on days scheduled for full PK sample collection from 10 hours prior to the start of dosing through 12 hours post-dose. Must refrain from the consumption of alcohol for 2 days prior to Day 1 through the end of the study
• A history of substance abuse or dependency or history of recreational intravenous (IV) drug use over the last 1 year (by self-declaration); or a positive ethanol breath test, urine cotinine, or urine drug screen at Screening and at Day -1
• A positive test for hepatitis C antibody (HCV), hepatitis B surface antigen (HBsAg), human immunodeficiency virus (HIV) antibody, or COVID-19 (if conducted, at the Investigator's discretion) at Screening
• Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the Follow-up Period
• Use of any investigational product (IP) or investigational medical device within 30 days prior to Screening, or 5 half-lives of the product (whichever is the longest) or participation in more than 4 investigational drug studies within 1 year prior to Screening
• Donated or lost a significant volume of blood (\>450 mL) within 4 weeks prior to the first study drug administration

Sponsors & Collaborators

• Ribon Therapeutics, Inc.: lead

Study Sites (6)

Veracity Clinical Research

Woolloongabba, Queensland, Australia

RECRUITING

CMAX Clinical Research Pty Ltd

Adelaide, SA 5000, Australia

RECRUITING

Optimal Clinical Trials

Auckland, New Zealand

RECRUITING

Waitemata Clinical Research

Auckland, New Zealand

RECRUITING

New Zealand Clinical Research (NZCR)

Christchurch, 8011, New Zealand

RECRUITING

Southern Clinical Trials Tasman

Nelson, New Zealand

RECRUITING

Related Publications (9)

• Caprara G, Prosperini E, Piccolo V, Sigismondo G, Melacarne A, Cuomo A, Boothby M, Rescigno M, Bonaldi T, Natoli G. PARP14 Controls the Nuclear Accumulation of a Subset of Type I IFN-Inducible Proteins. J Immunol. 2018 Apr 1;200(7):2439-2454. doi: 10.4049/jimmunol.1701117. Epub 2018 Mar 2.

  PMID: 29500242 BACKGROUND

• Cho SH, Raybuck A, Wei M, Erickson J, Nam KT, Cox RG, Trochtenberg A, Thomas JW, Williams J, Boothby M. B cell-intrinsic and -extrinsic regulation of antibody responses by PARP14, an intracellular (ADP-ribosyl)transferase. J Immunol. 2013 Sep 15;191(6):3169-78. doi: 10.4049/jimmunol.1301106. Epub 2013 Aug 16.

  PMID: 23956424 BACKGROUND

• Cohen MS, Chang P. Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat Chem Biol. 2018 Feb 14;14(3):236-243. doi: 10.1038/nchembio.2568.

  PMID: 29443986 BACKGROUND

• Goenka S, Boothby M. Selective potentiation of Stat-dependent gene expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor. Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4210-5. doi: 10.1073/pnas.0506981103. Epub 2006 Mar 6.

  PMID: 16537510 BACKGROUND

• He H, Bissonnette R, Wu J, Diaz A, Saint-Cyr Proulx E, Maari C, Jack C, Louis M, Estrada Y, Krueger JG, Zhang N, Pavel AB, Guttman-Yassky E. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol. 2021 Jan;147(1):199-212. doi: 10.1016/j.jaci.2020.05.048. Epub 2020 Jul 21.

  PMID: 32709423 BACKGROUND

• Iwata H, Goettsch C, Sharma A, Ricchiuto P, Goh WW, Halu A, Yamada I, Yoshida H, Hara T, Wei M, Inoue N, Fukuda D, Mojcher A, Mattson PC, Barabasi AL, Boothby M, Aikawa E, Singh SA, Aikawa M. PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation. Nat Commun. 2016 Oct 31;7:12849. doi: 10.1038/ncomms12849.

  PMID: 27796300 BACKGROUND

• Mehrotra P, Hollenbeck A, Riley JP, Li F, Patel RJ, Akhtar N, Goenka S. Poly (ADP-ribose) polymerase 14 and its enzyme activity regulates T(H)2 differentiation and allergic airway disease. J Allergy Clin Immunol. 2013 Feb;131(2):521-31.e1-12. doi: 10.1016/j.jaci.2012.06.015. Epub 2012 Jul 25.

  PMID: 22841009 BACKGROUND

• Mehrotra P, Krishnamurthy P, Sun J, Goenka S, Kaplan MH. Poly-ADP-ribosyl polymerase-14 promotes T helper 17 and follicular T helper development. Immunology. 2015 Dec;146(4):537-46. doi: 10.1111/imm.12515. Epub 2015 Sep 28.

  PMID: 26222149 BACKGROUND

• Vyas S, Chesarone-Cataldo M, Todorova T, Huang YH, Chang P. A systematic analysis of the PARP protein family identifies new functions critical for cell physiology. Nat Commun. 2013;4:2240. doi: 10.1038/ncomms3240.

  PMID: 23917125 BACKGROUND

MeSH Terms

Conditions

Dermatitis, Atopic

Condition Hierarchy (Ancestors)

Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• Thomas Polasek, MD

  CMAX Clinical Research Pty Ltd

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Clinical Operations Manager

CONTACT

617-914-8596; clinicaltrials@ribontx.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 3:1 Randomization ratio of RBN-3143 to Placebo
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: single dose ascending cohorts followed by multiple dose ascending cohorts

Study Record Dates

• First Submitted: January 18, 2022
• First Posted: January 31, 2022
• Study Start: March 7, 2022
• Primary Completion: June 30, 2024
• Study Completion: September 30, 2024
• Last Updated: October 23, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2); NZ (4)