Randomized, Double‑Blind, Placebo‑Controlled Trial of Oral CHIT1 Inhibitor OATD‑01 in Patients with Active Pulmonary Sarcoidosis (KITE Study)

Trial ID: 2023-506642-23-01
Protocol: OATD-01-C-03
Sponsor: Molecure S.A.

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Diseases & Conditions

Pulmonary sarcoidosis

Objectives

The primary objective of this study is to evaluate the response to a 12-week treatment with **OATD-01**, an oral inhibitor of chitinase-1, by assessing the reduction of granulomatous inflammation in the pulmonary parenchyma. This is measured using [18F]FDG PET/CT imaging in subjects with active pulmonary sarcoidosis. The clinical relevance of this objective lies in its potential to provide a novel therapeutic approach for managing inflammation in pulmonary sarcoidosis, a condition characterized by the formation of granulomas in the lungs, which can lead to impaired lung function and quality of life.

Secondary objectives include:

Quantifying the change in granulomatous inflammation in pulmonary parenchyma, mediastinal/hilar nodes, and extrathoracic locations using [18F]FDG PET/CT imaging SUV.
Evaluating pulmonary function following treatment with OATD-01.
Assessing the quality of life of subjects post-treatment.
Determining the overall safety and tolerability of OATD-01.
Characterizing the cardiac safety of OATD-01.
Evaluating the risk for clinically relevant phospholipidosis in male subjects.
Assessing thyroid and renal function in subjects.
Characterizing the pharmacokinetic (PK) exposure of OATD-01 to assess PK parameters and allow for an exploratory post-hoc PK/PD analysis.

These secondary objectives aim to provide a comprehensive understanding of the effects of OATD-01 on various physiological and safety parameters, which is crucial for determining its overall therapeutic potential and safety profile in treating active pulmonary sarcoidosis.

Participants

The clinical trial involves a total of **46 participants** diagnosed with **active pulmonary sarcoidosis**. The study population includes both male and female subjects aged **18 years and older**. Participants are required to have a diagnosis of active and currently symptomatic pulmonary sarcoidosis, either treatment-naïve or previously treated but currently untreated. The selection criteria ensure that participants have parenchymal pulmonary involvement as evidenced by [18F]FDG PET/CT imaging. The trial population was selected based on specific diagnostic criteria, including bilateral hilar adenopathy or perilymphatic nodules, among others. Participants are expected to have a **Body Mass Index (BMI)** within the range of 18 - 46 kg/m². Lifestyle considerations include the requirement for participants to use effective methods of birth control to avoid pregnancy or fathering a child during the study period. The trial includes a vulnerable population, and all participants must provide written informed consent before the initiation of any study procedures.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of OATD-01, an oral inhibitor of chitinase-1, in the treatment of **active pulmonary sarcoidosis**. The trial will span a duration of 12 weeks, with the primary objective being the assessment of granulomatous inflammation reduction in the pulmonary parenchyma, as evaluated by [18F]FDG PET/CT imaging. Participants will be randomly assigned to receive either OATD-01 or a placebo, with the study drug administered in the form of film-coated tablets. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to evaluate the overall outcomes.

Participants are expected to be involved in the study for the entire 12-week treatment period, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The inclusion criteria require participants to be adults aged 18 years or older with a confirmed diagnosis of active pulmonary sarcoidosis, evidenced by specific imaging and clinical criteria. The study will also monitor secondary endpoints, including changes in forced vital capacity, quality of life scores, and the occurrence of treatment-emergent adverse events. The trial is set to commence recruitment in April 2024, with an estimated completion date in March 2026. Participants will be required to comply with protocol requirements, including the use of effective birth control methods, and provide written informed consent prior to any study procedures.

Treatment

The clinical trial involves the administration of **OATD-01**, an experimental medication developed by OncoArendi Therapeutics S.A. OATD-01 is formulated as **film-coated tablets** and is designed to be taken orally. The active substance in OATD-01 is **5-(4-((2S,5S)-5-(4-chlorobenzyl)-2-methylmorpholino)piperidin-1-yl)-1H-1,2,4-triazol-3-amine**, a chemical compound that functions as an inhibitor of chitinase-1 (CHIT1). The dosage regimen for OATD-01 is set at a maximum daily dose of 25 mg, with the treatment period extending up to 12 weeks. The primary objective of the trial is to evaluate the reduction of granulomatous inflammation in the pulmonary parenchyma of subjects with active pulmonary sarcoidosis, as assessed by [18F]FDG PET/CT imaging.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this randomized, double-blind, placebo-controlled study. The placebo is administered in a manner consistent with the experimental medication to maintain the study's blinding and integrity. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the efficacy and safety of OATD-01. The administration schedule for the placebo mirrors that of the experimental drug, ensuring that participants receive identical treatment regimens in terms of frequency and duration.

Efficacy

The efficacy of the investigational product OATD-01 in the treatment of active pulmonary sarcoidosis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the response to treatment from baseline to the end of treatment (EOT), which will be evaluated as either a complete or partial response based on criteria determined for each subject. Secondary endpoints include the evaluation of **granulomatous inflammation** using [18F]FDG PET/CT imaging. This will be quantified by the percent change in maximum, mean, and peak standardized uptake values (SUVmax, SUVmean, SUVpeak), as well as the volume of lesions in pulmonary parenchyma, mediastinal/hilar nodes, and extrathoracic locations.

Additional secondary endpoints involve measuring the absolute change in Forced Vital Capacity (FVC, % predicted) and Forced Expiratory Volume in the first second (FEV1). The change in quality of life will be assessed using the Kings Sarcoidosis Questionnaire General and Lung (KSQ GENERAL and LUNG) scores. The occurrence of treatment-emerging adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) will also be monitored. Other parameters include changes in the Fatigue Assessment Scale total score, mean changes in vital signs, and any clinically significant abnormalities in 12-lead electrocardiography (ECG) or 24-hour ECG. The study will also track heart rhythm abnormalities, clinically significant abnormalities in sperm parameters, free testosterone concentration, and thyroid and renal function parameters. Mean plasma concentrations of OATD-01 will be measured at various post-baseline timepoints through sparse sampling.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female subject aged ≥18 years at Screening
Diagnosis of active and currently symptomatic pulmonary sarcoidosis, either treatment-naïve or previously treated but currently untreated, with diagnostic criteria adapted from Official American Thoracic Society Clinical Practice Guideline 2020 and with limitations described in the exclusion criteria section: • Bilateral hilar adenopathy (BHA) on any chest X-ray within 3 months or chest CT* within 12 months prior to enrolment OR • Perilymphatic nodules, peribronchial thickening (on chest CT*), or upper lobe or diffuse infiltrates (on any chest imaging) within 3 months prior to enrolment and at least one of the three: - known previous positive biopsy from any body site showing pathologic features consistent with sarcoidosis, obtained at any point in the past - history of or active Lupus pernio or Heerfordt’s syndrome positive BAL result with the ratio of CD4+ to CD8+ T-lymphocytes higher than 3.5 supported by a documented positive opinion on diagnosis of sarcoidosis by an independent expert, assigned by sponsor, based on a highly suggestive clinical and radiological picture * to avoid CT-derived excessive cumulative radiation, a minimum interval of 12 weeks (or longer as defined by local standards) is to be respected between any chest (High Resolution-)CT performed pre-study before the informed consent and the planned baseline [18F]FDG PET/CT at screening.
Parenchymal pulmonary involvement evidenced by [ 18F]FDG PET/CT imaging at Screening (or performed at the study site within 3 months prior to enrolment under certain conditions detailed in section 7.2.2.8)
Body Mass Index within the range of 18 - 46 kg/m2
Subjects willing to avoid pregnancy or fathering a child and agree to use acceptable effective methods of birth control (per recommendations from Heads of Medicines Agencies - Clinical Trials Facilitation and Coordination Group) defined as those, alone or in combination, that result in a low failure rate for the entire duration of the study including: • Woman of nonchildbearing potential* • Woman of childbearing potential* who has a negative serum pregnancy test at Screening and at any timepoint before the first study drug dose on Day 1 and who agrees to take highly effective contraceptive measure to avoid pregnancy (with a failure rate of less than 1% per year when used consistently and correctly) from Screening until 7 months after EOT. As highly effective contraceptive measures are considered: - combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation :  oral  intravaginal  transdermal - progestogen-only hormonal contraception associated with inhibition of ovulation:  oral  injectable  implantable - intrauterine device - intrauterine hormone-releasing system - bilateral tubal occlusion - vasectomised partner** - sexual abstinence*** • Man who agrees to use double barrier contraception (condoms - or diaphragm/ cervical cap used by their female partner- plus spermicidal agent: foam, gel, film etc.) to avoid fathering a child from Screening until 100 days after EOT, or is surgically sterilized. *A woman is considered of childbearing potential i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. **Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. ***Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
Capable of understanding and complying with protocol requirements
Written informed consent given by the subject before the initiation of any study procedures Note: A witnessed consent is not all

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Exclusion Criteria

Severity and/or phenotype of sarcoidosis requiring immediate (or within the next 3 months) initiation of treatment with a corticosteroid, corticotropin, methotrexate, anti-TNF agent, azathioprine, JAK inhibitor, mycophenolate, or leflunomide.
Alcohol consumption above 20 units/week for men and 10 units/week for women
Known allergy to excipients of the study drug
Any contraindication to cardiac MRI and PET/CT procedures, including severe claustrophobia and known hypersensitivity to the contrast medium (limited to contraindication solely to PET/CT in case cardiac sarcoidosis is evaluated based on a pre-study cardiac MRI in line with the exclusion criterion no. 2)
Severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, thyroid, renal or metabolic disease) at Screening, or other condition, which in the opinion of the investigator, would compromise the safety of the subject or the subject’s ability to participate in the study
Current smoker of >5 cigarettes or e-cigarettes per day or user of nicotine releasing alternatives (patches, chewing gums etc.)
Unable to take oral medications
History of or active Löfgren’s syndrome
Participation in another clinical study within 1 month prior to screening
Subject deprived of liberty by a judicial or administrative decision, subject admitted to a social institution or who is under a measure of legal protection, subject hospitalized without consent or who is in an emergency situation
Established alternative diagnosis of a non-infectious or infectious systemic disease, or suspicion thereof, undermining the suspicion/diagnosis of sarcoidosis
Total serum bilirubin >1.5 x upper limit of normal (ULN), with the exception of previously documented Gilbert syndrome, or alanine aminotransferase (ALT) or asparagine aminotransferase (AST) > 2.5 x ULN, or alkaline phosphatase (ALP) >1.5 x ULN, or liver failure and/or cirrhosis or subjects with moderate to severe hepatic impairment (i.e., Child-Pugh score ≥7)
If performed pre-study, mediastinal and/or hilar lymph node biopsy result suggestive of an alternative diagnosis to sarcoidosis (taking into account the Key Pathological Features of Sarcoidosis by the Official American Thoracic Society Clinical Practice Guideline 2020)
Clinically significant lung disease other than sarcoidosis (including but not limited to tuberculosis, asthma, Chronic Obstructive Pulmonary Disease, interstitial lung disease, lung cancer) or any current inflammatory or immunological systemic disease other than sarcoidosis
Known repeated demonstration of QTcF interval prolongation (>450 ms in a male and QTc >470 ms in a female) at Screening
Systemic or inhaled pharmacological treatment for sarcoidosis with: a. corticosteroids/corticotropin: current treatment or received within 3 months prior to enrolment b. methotrexate, anti-TNF agents, azathioprine, JAK inhibitors, mycophenolate, leflunomide, or any investigational therapy that is potentially disease-modifying: current treatment or received within 4 months prior to enrolment
Primary systemic treatment indication being an extrapulmonary location of sarcoidosis (e.g., neurological)
Subjects currently treated with P-glycoprotein and/or BCRP strong inhibitors
Subjects currently treated with drugs that are sensitive substrates of OCT1, MATE1, MATE2K, OAT3 with a narrow therapeutic index
Concomitant use or need for treatment with a drug known for QT prolongation effect or a thiazide diuretic
History or current diagnosis of cardiac arrhythmia (other than non-sustained supraventricular arrhythmia)
Creatinine clearance (CrCL) <60 mL/min (by CockcroftGault formula
Heart failure (New York Heart Association class III or IV) and/or known myocardial hypertrophy or Left Ventricle Ejection Fraction <50% in the cardiac MRI (criteria for use of a pre-study cardiac MRI apply accordingly as set out under exclusion criterion no. 2)
Subjects currently treated with strong CYP3A4 inhibitors and/or inducers
PET imaging, or other diagnostic or therapeutic procedure with administration of a radiopharmaceutical, performed within 6 weeks before Screening.
Known neurosarcoidosis or small fiber neuropathy or medical conditions causing primary ataxia
Subjects currently treated with pirfenidone or nintedanib
Cardiac sarcoidosis (known or diagnosed at Screening using cardiac Magnetic Resonance Imaging [MRI]) except for well documented currently inactive cardiac sarcoidosis Note: Cardiac sarcoidosis may be evaluated based solely on a pre-study cardiac MRI result if negative for active disease and performed not earlier than 12 months prior to enrollment, as long as no clinically relevant cardiac symptoms or signs (i.e., ECG abnormalities) developed since the time of this MRI
Hypokalemia (<3.6 mmol/L, mmol/L) or hypocalcemia (<2.1 mmol/L) at Screening
Marked fasting hyperglycemia or uncontrolled diabetes at Screening with plasma glucose exceeding 8.3 mmol/L, or other contraindication to [18F]FDG administration and/or PET procedure (including body temperature >37°C and any metabolic disease affecting the energy metabolism of muscles) as described in the separately provided PET protocol
Pregnancy, breastfeeding, or planning to become pregnant or breastfeed, oocyte or sperm donation and cryopreservation during the study and 7 months after EOT. For the purposes of detecting pregnancy occurrence after EOT, the Sponsor will provide urine pregnancy test to subjects to perform at home at monthly intervals after the end of the study last follow-up visit for up until 7 months post last administration of the study drug. The subjects will be advised to report to the sponsor any pregnancies occurring in that time.
Known positivity for Human Immunodeficiency Virus (HIV 1/2 antibodies), hepatitis B virus (HBV), or hepatitis C virus (HCV), or detected at screening
Subjects with psychiatric disorder that could affect the conduct of the study and/or compliance with the study treatment

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Denmark	Recruiting	01 Apr 2024	4
France	Recruiting	01 Apr 2024	10
Germany	Recruiting	01 Apr 2024	10
Greece	Recruiting	01 Apr 2024	9
The Netherlands	Recruiting	01 Apr 2024	—
Norway	Recruiting	01 Apr 2024	17
Netherlands	—	—	15