Study of Multiple-Ascending-Dose Study of XTMAB-16 in Patients With Pulmonary Sarcoidosis With or Without Extrapulmonary Manifestations

• XTMAB-16 or Placebo (Drug): Infusion

Primary outcomes

• Rate of Adverse Events (AEs), including Serious Adverse Events (SAEs), Dose Limiting Toxicities (DLTs), and Adverse Events of Special Interests (AESIs) throughout the study duration [Throughout Study Duration, 20 weeks]: To evaluate the safety and tolerability of multiple ascending doses of XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations

Secondary outcomes

• Pharmacokinetic (PK) profile including trough concentration (Ctrough) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Pharmacokinetic (PK) profile including maximum concentration (Cmax) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Pharmacokinetic (PK) profile including average concentration (Caverage) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Pharmacokinetic (PK) profile including area under the curve (AUC) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Dose normalized maximum serum concentration (Cmax/D) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Dose normalized area under the concentration time curve over the dosing interval (AUCtau/D) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Dose normalized area under the concentration time curve from time 0 to the time of the last quantifiable concentration observed (AUClast/D) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Dose normalized area under the concentration time curve from time 0 extrapolated to infinity (AUCinf/D) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Pharmacodynamics (PD) markers, including: Angiotensin converting enzyme (ACE), Soluble IL-2 receptor (sIL 2R), C-reactive protein (CRP), Interleukin-1b (IL-1b) and Calcitriol (vitamin D 1, 25) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Occurrence and persistence of anti-drug antibodies (ADA) [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Mean percent change in forced vital capacity (FVC)% [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Change in King's Sarcoidosis Questionnaire (KSQ) - Lung Score [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• The King's Sarcoidosis Questionnaire (KSQ) - General Health. Results are given as a number between 1 to 100 with higher numbers indicating better health. The minimal clinically important difference (MCID) for KSQ remains unclear in sarcoidosis. [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• The Leicester Cough Questionnaire items are scored on a 7-point Likert scale. A total score (range 3 to 21) is also calculated by adding the domain scores together, with higher scores indicating better quality of life. The MCID for chronic cough is 1.3. [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• The Steroid Toxicity Questionnaire (STQ) is a simple 12 question tool used to characterize the toxicity associated with steroid use using a 4-point scale. The MCID remains unclear in sarcoidosis. Higher scores indicate greater steroid toxicity [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Observed dose limiting toxicities (DLT), rate of adverse events of special interest (AESI) throughout the study duration between dose levels and frequencies [Baseline to Week 12]: To determine the recommended Phase 2 dose level and frequency for XTMAB-16 in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Proportion of participants who achieve the targeted tapered dose of corticosteroid [Baseline to Week 12]: To observe the potential therapeutic effect of XTMAB-16 as measured by the ability to reduce background oral corticosteroid use
• Proportion of participants who achieve at least 50% reduction in dose of corticosteroid by Week 12 [Baseline to Week 12]: To observe the potential therapeutic effect of XTMAB-16 as measured by the ability to reduce background oral corticosteroid use
• Total (systemic) clearance after intravenous (IV) dose in the intended participant population [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Volume of distribution after intravenous (IV) dose and an estimate of the volume of distribution at steady state based on single dose IV data parameters in the intended participant population [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Terminal elimination phase half-life expressed in time units in the intended participant population [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Accumulation ratio repeat dosing [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Area under the effect-time curve from time 0 (predose) to the last quantifiable effect -concentration time point, t (AUEC0-t) [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Maximum observed effect (Emax, obs) [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Time to reach Emax, obs (tEmax, obs) [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Absolute and percent change in biomarkers from Baseline to End of Infusion (EOI), Interleukin-6 (IL-6) and Soluble Tumor Necrosis Factor α (sTNFα) [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Number and percentage of participants by cohort who test positive for XTMAB-16 anti-drug antibodies (ADA) and transient & persistent positive status at follow-up assessments [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations
• Number and percentage of participants by cohort who test positive for XTMAB-16 neutralizing antibody (nAb) and transient & persistent positive status at follow-up assessments [Baseline to Week 12]: To evaluate the pharmacokinetics (PK) profile of XTMAB-16 and the effects on immunogenicity and biomarkers in participants with pulmonary sarcoidosis with or without extrapulmonary manifestations

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

1. Participant between 18 to 80 years (inclusive) of age.
2. Weighs between 45 kg and 160 kg (99 to 353 lbs) at Screening.
3. Diagnosis of pulmonary sarcoidosis (at least 6 months before Screening) using the 2020 American Thoracic Society (ATS) Clinical Practice Guideline (Crouser et al, 2020), the European Respiratory Society (ERS) or the WASOG criteria including a compatible clinical and radiologic presentation with other causes of granulomatous disease ruled out (cutaneous and ocular involvement permitted).
4. Modified Medical Research Conference (mMRC) Dyspnea Scale of ≥ 1.
5. Receiving treatment of 7.5 to 25 mg/day of oral prednisone, or equivalent, during the screening period and, at the determination of the investigator, is capable of undergoing the protocol specific corticosteroid taper regimen.
6. Receiving treatment with methotrexate, azathioprine, mycophenolate, leflunomide, chloroquine, or hydroxychloroquine for at least 3 months before Screening that has been at a stable dose for 4 weeks before Screening. All efforts should be made to maintain stable background therapy at the Screening dose through the intervention period at the Investigator's discretion.
7. Willing to refrain from consumption of grapefruit or grapefruit juice \[pomelos, exotic citrus fruits, or grapefruit hybrids\] from screening visit until after the final dose.
8. Polymerase chain reaction (PCR) test or rapid antigen test negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Screening.
9. Able to provide written informed consent.
10. In the opinion of the Investigator, the participant is capable of understanding and complying with protocol requirements

Exclusion Criteria:

1. Pregnant or breastfeeding women or women who are planning to become pregnant during the study.
2. Participants > 65 years of age. (This exclusion criterion is only applicable for EU).
3. Known potentially significant fibrotic disease and/or active inflammation contained solely in the hilar region as shown by high-resolution computed tomography (HRCT), confirmed by a central reader. Participants with current active inflammation in the hilar region with concurrent inflammation outside the hilar region may be included.

   A historical HRCT performed within 6 months of screening may be submitted for diagnostic confirmation by central review. If a subject's last HRCT was from > 6 months of screening, an HRCT should be performed during screening for diagnostic confirmation by central review.
4. Any prior TNFα inhibitor therapy.
5. Clinically significant extra-pulmonary sarcoidosis requiring systemic therapy as determined by the investigator.
6. Baseline percent predicted forced vital capacity (FVC) of < 50%.
7. Prior treatment with rituximab or repository corticotropin injection within the previous 12 months.
8. Clinically significant Central Nervous System (CNS) sarcoidosis requiring therapy, except history of isolated seventh cranial nerve palsy or evidence of demyelinating neurologic disease.
9. Advanced congestive heart failure (New York Heart Association \[NYHA\] 3 or 4).
10. Current disease presentation consistent with Lofgren's syndrome (i.e., presence of the triad of erythema nodosum, bilateral hilar lymphadenopathy on chest X-ray, and joint pain).
11. Clinically significant pulmonary hypertension requiring treatment. Note: Clinically significant pulmonary hypertension requiring treatment would be defined as treatment with, i.e., prostacyclins, phosphodiesterase 5 inhibitors, and endothelin receptor antagonists.
12. Known hypersensitivity to any component of the formulation of XTMAB-16.
13. Live or messenger ribonucleic acid (mRNA) vaccination within 2 weeks before Day 1 or inoculation with a live or mRNA vaccine is planned during study participation.
14. Evidence of active or latent TB by interferon-gamma release assay (IGRA) or invasive fungal infections at Screening.
15. Known positive history of malignancy other than non-melanomatous skin cancer in the last 2 years, including in-situ carcinoma of the uterine cervix completely cured by radical surgery.
16. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, coronavirus disease (COVID-19), TB, or a known history of human immunodeficiency virus (HIV) infection at Screening.
17. Women of childbearing potential who are sexually active with a non-sterilized male partner and are not willing to adhere to highly effective birth control measures from the time of signing the informed consent, throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since the last dose of study drug.
18. Male participants who are non-sterilized and sexually active with a female partner of childbearing potential and are not willing to use highly effective contraception from the time of signing the informed consent throughout the duration of the study, and for 90 days after 5 half-lives have elapsed since last dose of study drug.
19. Clinically significant hepatic or renal disease, including uncontrolled diabetes at the discretion of the investigator.
20. Any severe prior reaction to any type of biologics or human blood product such as albumin, IgG, etc.
21. Concurrent emphysema.
22. Known hypercalcemia due to non-sarcoidosis conditions such as untreated hyperparathyroidism, at the discretion of the investigator.
23. Abnormal ECG: ventricular arrhythmias (non-sustained ventricular tachycardia (VT), multifocal or frequent premature ventricular contractions, bundle branch block, axis deviation, or abnormal Q waves). In the case of a QTcF (corrected QT interval by Fredericia) interval > 450 ms (men) or > 480 ms (women; participants with bundle branch block) or PR interval outside the range of 120 to 220 ms, the assessment may be repeated once for eligibility determination at Screening or Baseline.
24. Donation or loss of 450 mL or more of his or her blood volume (including plasmapheresis) or transfusion of any blood product within 90 days prior to dosing.
25. Known uncontrolled hypertension. Note: Uncontrolled hypertension is noted as blood pressure ≥ 160/100 mmHg despite antihypertensive therapy within 3 months of randomization.
26. Clinical signs and symptoms consistent with COVID-19, e.g., fever, dry cough, dyspnea, sore throat, fatigue, new smell or taste disorder or confirmed infection by appropriate laboratory test within the last 4 weeks prior to Screening.
27. In the opinion of the investigator, inability to tolerate corticosteroid taper.
28. Concurrent systemic steroid use for non-sarcoidosis conditions.
29. Concurrent known auto-immune disease requiring treatment.
30. Participation in another clinical trial of an investigational agent within 3 months (small molecule) / 6 months (biologics) or 5 half-lives (if known) of the agent, whichever is longer.
31. Any condition that required hospitalization within the 3 months prior to Day 1 or is likely to require so during the study.
32. Clinically significant abnormalities in the Screening physical exam, medical history, vital signs, ECG, or clinical laboratory tests that are not known to be due to concurrent sarcoidosis, and in the opinion of the Investigator and Medical Monitor should preclude the participant's participation in the clinical study.