A Study to Evaluate the Safety and Pharmacokinetic Properties of LASN01 in Healthy Subjects and in Patients With Pulmonary Fibrosis or Thyroid Eye Disease

Study Overview
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Brief Summary
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LASN01 is a novel, fully human antibody directed against the human IL-11 receptor that is being developed to address the fibro-inflammatory pathology of pulmonary fibrosis and TED. This study is a four-part trial consisting of Parts A, B, C and D. The primary objective of this study is to evaluate the safety, tolerability, and the secondary objective is to evaluate the immunogenicity and pharmacokinetics of single and multiple doses of LASN01 in healthy participants and in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrosing interstitial lung disease (PF-ILD) or Thyroid Eye disease (TED).

Detailed Description
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This clinical trial (LASN01-CL-1101) consists of 4 parts, each part containing adaptive design elements that can be modified. Part A will comprise a single-dose administration in healthy participants in 5 dose cohorts. Part B will comprise a multiple-dose administration in healthy participants in 2 dose cohorts. Part C will comprise a multiple-dose administration in a single cohort of approximately 8 to 12 participants. Part D will comprise a multiple-dose design in a single cohort of approximately 8 to 12 participants. In each part of the study, participants will be randomized to receive IV doses of LASN01 or placebo.

Official Title
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A Phase 1, Randomized, Double-blind, Placebo-controlled, Single and Multiple Ascending Dose Study to Determine the Safety, Tolerability, Immunogenicity and Pharmacokinetic Properties of LASN01 in Healthy Subjects and in Patients With Pulmonary Fibrosis or Thyroid Eye Disease

Conditions
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Pulmonary Fibrosis, Thyroid Eye Disease

Intervention / Treatment
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* Drug: LASN01
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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I. Participant Inclusion Criteria- Parts A, B, C, and D Female participants must be nonpregnant, nonlactating, and either postmenopausal for ≥12 months, surgically sterile for ≥6 months, or agree to use 2 effective methods of contraception or a highly effective method of contraception. Males must be surgically sterile for ≥6 months or agree to highly effective methods of contraception. Able to comprehend and willing to sign an ICF and understand and comply with the requirements of the study. Part A and Part B only Males or females, 18 through 60 years of age, inclusive Body weight ≥110 pounds (≥50 kg); body mass index (BMI) within the range of 18 through 32.0 kg/m2 In good health as determined by the Investigator Part C only Male and female patients >40 years of age (IPF patients) or ≥21 years of age (PF-ILD patients) IPF-specific Inclusion Criteria: A diagnosis of IPF IPF has been stable for ≥3 months at Screening PF-ILD-specific Inclusion Criteria: Patients with physician diagnosed ILD who fulfill ≥1 of the following criteria for PF-ILD within 24 months of the Screening visit despite treatment with approved and/or unapproved medications used in clinical practice to treat ILD. Fibrosing lung disease on HRCT performed within 3 years of the Screening Visit For patients with underlying CTD: stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks before the Screening visit FVC ≥45% predicted Part D only Age 18 through 80 years, inclusive Clinical diagnosis of Graves' disease associated with active TED Moderate-to-severe active TED Less than 15 months from onset of TED in the study eye No previous medical treatment for TED with the exception of local supportive measures, mycophenolate and oral or injectable steroids, immunomodulating therapies, and/or orbital irradiation/radiotherapy II. Participant Exclusion Criteria Parts A, B, C, and D Any acute or chronic condition that would limit the participant's ability to participate in and complete this clinical study Part A and Part B only Significant history or clinical manifestation of any significant endocrine, metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, or psychiatric disorder History of significant hypersensitivity; intolerance; or allergy to any drug compound, food, or other substance; or history of anaphylaxis or angioedema Positive serum test for HIV or hepatitis infection Currently receiving any antibiotics for upper or lower respiratory tract infections Use of any prescription drug or vaccine within 21 days before Check-in with the exception of hormonal contraceptives and vaccines. Any prescription biologic within 3 months or 5 half-lives (whichever is greater) before Check-in Participation in any other investigational study drug trial in which an investigational study drug was administered within 30 days before randomization or an investigational biological study drug was administered within 3 months before Check-in Part C only History of clinically relevant cardiovascular disease that could jeopardize a patient's health during the course of the study Patients with concurrent active malignancy other than adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix IPF-specific Exclusion Criteria: FVC <45% predicted of normal or a forced expiratory volume during the first second of the forced breath (FEV1)/FVC ratio of <0.7 Extent of emphysema in the lungs exceeds fibrosis Currently receiving pirfenidone or nintedanib if on treatment for <3 consecutive months or needed dose modification due to AEs in the last 3 months PF-ILD-specific Exclusion Criteria: Diagnosis of IPF Diagnosis of sarcoidosis Significant pulmonary arterial hypertension FVC <45% predicted of normal or a FEV1/FVC ratio of <0.7 Previous treatment with pirfenidone Part D only Any previous use of anti-insulin-like growth factor 1 receptor monoclonal antibody (eg, teprotumumab) at any time Patients with 2 mm proptosis decrease between Screening and Baseline, or a 1-point decrease on the CAS 7-point scale in any 2 weeks during the Screening period Patients with decreased best corrected visual acuity due to optic neuropathy, new visual field defect, or color defect secondary to optic nerve involvement within the last 6 months before Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LASN01<br> | Drug: LASN01<br>* Escalating doses of LASN01 will be given in different cohorts of Parts A, B, C and D.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Escalating doses of matching placebo will be given in different cohorts of Parts A, B, C and D.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events receiving LASN01 compared to placebo |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1-Day 141 in Part D | 
| Number of participants with abnormal clinically significant clinical laboratory results |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| Number of participants with abnormal clinical vital signs |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1-Day 141 in Part D | 
| Number of participants with abnormal clinically significant 12-lead electrocardiogram (ECG) parameters |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| Number of participants with abnormal clinically significant results from physical examination |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameter assessed by serum LASN01 concentration at specified timepoints for maximum plasma concentration (Cmax) |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| PK parameter assessed by serum LASN01 concentration at specified timepoints for time to peak concentration (T max) |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| PK parameter assessed by serum LASN01 concentration at specified timepoints for area under curve (AUC) |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| PK parameter assessed by serum LASN01 concentration at specified timepoints for clearance volume (CL) |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| PK parameter assessed by serum LASN01 concentration at specified timepoints for terminal phase volume (Vz) |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| PK parameter assessed by serum LASN01 concentration at specified timepoints for half life ( t1/2). |  | Day 1-Day 57 in Part A, Day 1-Day 71 in Part B, Day 1-Day 127 in Part C, Day 1- Day 141 in Part D | 
| Change in proptosis in the study eye compared to baseline as assessed by MRI |  | Day 1-141 |