XTMAB-16 for Sarcoidosis
Recruiting in Palo Alto (17 mi)
+33 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Xentria, Inc.
Must be taking: Prednisone, Methotrexate, Azathioprine, others
Must not be taking: TNFα inhibitors, Rituximab
Disqualifiers: Pregnancy, CNS sarcoidosis, Congestive heart failure, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?A phase 1b/2 study of XTMAB-16 in patients with pulmonary sarcoidosis
Will I have to stop taking my current medications?
The trial requires that you continue taking your current medications like prednisone, methotrexate, azathioprine, mycophenolate, leflunomide, chloroquine, or hydroxychloroquine at a stable dose. You should not stop these medications unless advised by the study investigator.
Is XTMAB-16 safe for humans?
The safety of XTMAB-16 in humans is still being studied, but early clinical trials have been conducted to determine safe dose levels. It is a type of anti-TNF antibody, similar to other treatments that have been used for conditions like sarcoidosis, but specific safety data for XTMAB-16 is limited.
12345How is the drug XTMAB-16 different from other sarcoidosis treatments?
XTMAB-16 is unique because it is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody with a distinct molecular structure, designed to inhibit granuloma formation and suppress inflammation in sarcoidosis. Unlike other treatments, it is still in clinical development and not yet approved by the FDA for any condition.
56789Eligibility Criteria
Adults aged 18-80 with pulmonary sarcoidosis, able to follow the study plan, weighing 45-160 kg, and on stable doses of certain medications can join. They must not have been hospitalized recently or be likely to need hospitalization during the trial. Participants should not have other significant health issues like uncontrolled diabetes or hypertension, recent malignancies (except some skin cancers), severe reactions to biologics, active infections including COVID-19 and TB, or require certain treatments for sarcoidosis.Inclusion Criteria
I am taking a low to moderate dose of prednisone or similar medication, and can follow a specific plan to reduce it.
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
You tested negative for COVID-19 using a PCR or rapid antigen test before the screening.
+7 more
Exclusion Criteria
I have had cancer other than non-melanoma skin cancer or cervical carcinoma in-situ in the last 2 years.
I haven't donated or lost significant blood, or received a transfusion in the last 3 months.
I have not taken rituximab or repository corticotropin in the last year.
+28 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment Part A
Participants receive XTMAB-16 at varying doses or placebo every 2 or 4 weeks for 12 weeks
12 weeks
Treatment Part B
Participants receive XTMAB-16 at the established dose or placebo for 24 weeks
24 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing XTMAB-16 against a placebo in patients with pulmonary sarcoidosis. It's an early-stage study (phase 1b/2) designed to evaluate how safe XTMAB-16 is and how well it works compared to a non-active treatment.
5Treatment groups
Experimental Treatment
Group I: Part B - XTMAB-16 (dose established in Part A) for 24 weeks or PlaceboExperimental Treatment1 Intervention
Group II: Part A - XTMAB-16: 4 mg/kg every 4 weeks (Q4W) for 12 weeks or PlaceboExperimental Treatment1 Intervention
Group III: Part A - XTMAB-16: 4 mg/kg every 2 weeks (Q2W) for 12 weeks or PlaceboExperimental Treatment1 Intervention
Group IV: Part A - XTMAB-16: 2 mg/kg every 4 weeks (Q4W) for 12 weeks or PlaceboExperimental Treatment1 Intervention
Group V: Part A - XTMAB-16: 2 mg/kg every 2 weeks (Q2W) for 12 weeks or PlaceboExperimental Treatment1 Intervention
XTMAB-16 is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as XTMAB-16 for:
- Pulmonary sarcoidosis (Orphan Drug Designation)
🇪🇺 Approved in European Union as XTMAB-16 for:
- Pulmonary sarcoidosis (Orphan Drug Designation)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Xentria Investigative SiteDetroit, MI
Xentria Investigative SiteMinneapolis, MN
Xentria Investigative SiteHouston, TX
Xentria Investigative SiteCharlottesville, VA
More Trial Locations
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Who Is Running the Clinical Trial?
Xentria, Inc.Lead Sponsor
References
[Sarcoïdosis and anti-TNF: a paradoxical class effect? Analysis of the French Pharmacovigilance system database and literature review]. [2019]To identify and characterize the observations of sarcoidosis occurring during anti-TNF blockade collected in the French Pharmacovigilance system database and reported in the literature.
Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: A multicenter study of 132 patients. [2018]The off-label use of TNF antagonists in refractory sarcoidosis is increasingly reported but data on their efficacy and safety are still insufficient.
Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish registry of biologics BIOBADASER and a systematic review. [2022]To evaluate the safety, efficacy, and effectiveness of TNF antagonists in patients with sarcoidosis.
The CD4+ lymphopenic sarcoidosis phenotype is highly responsive to anti-tumor necrosis factor-{alpha} therapy. [2018]The treatment options for patients with sarcoidosis are presently limited, and it is unclear which treatments are most effective for any given patient. We have identified a sarcoidosis phenotype characterized by CD4(+) lymphopenia and resistance to conventional immunosuppressants, such as corticosteroids and methotrexate. Based on recent reports linking tumor necrosis factor (TNF)-alpha to regulatory T-cell (Treg) dysfunction, we hypothesized that sarcoidosis-associated CD4(+) lymphopenia would resolve with anti-TNFalpha treatment. Five consecutive patients with CD4(+) lymphopenia were treated with a chimeric anti-TNFalpha antibody (infliximab). Clinical disease manifestations and peripheral blood T-cell subsets were assessed before and after infliximab treatment. All patients experienced significant increases in absolute peripheral blood lymphocyte and CD4(+) T-cell counts and demonstrated improvement in clinical disease manifestations in response to infliximab. No change in the distribution of T-cell subsets was noted. The presence of CD4(+) lymphopenia identifies a distinct sarcoidosis phenotype that is particularly responsive to anti-TNFalpha therapy.
Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment. [2023]Background: Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established in vitro sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. Objective: To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. Methods: First, XTMAB-16 activity was evaluated in an established in vitro model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the in vitro granuloma model. Results: XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, in vitro secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the in vitro granuloma model with a half maximal inhibitory concentration (IC50) of 5.2 and 3.5 μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the in vitro IC50 concentrations. Conclusion: The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.
Role of CD4+ T cells in sarcoidosis. [2021]Activated pulmonary CD4(+) T lymphocytes of the Th-1 type are essential for the inflammatory process in sarcoidosis, and IFN-gamma production is crucial for the characteristic granuloma formation. Both the T cells and their inflammatory mediators may constitute possible targets for immunotherapy. A particular T-cell subset, the T-cell receptor (TCR) AV2S3(+) bronchoalveolar lavage (BAL) CD4(+) T cells, is found at dramatically increased levels in the BAL fluid of human leukocyte antigen (HLA)-DRB1*0301-positive and/or HLA-DRB3*0101-positive patients with sarcoidosis. The AV2S3(+) BAL CD4(+) T cells strongly associate with the sarcoid inflammation, and future studies on this particular T-cell subset to reveal their specificity may lead to the identification of sarcoidosis-specific antigen(s). T-cell subpopulations with regulatory functions (i.e., natural killer T cells and T regulatory cells) have recently been described as abnormal in sarcoidosis. Dysfunctional regulatory T cells may allow T effector cells to contribute to the formation of granulomas, and they may thus be relevant for the inflammatory process in this disease. These findings are exciting news and will be of help in designing new treatment strategies.
Sarcoidosis Th17 cells are ESAT-6 antigen specific but demonstrate reduced IFN-γ expression. [2021]Sarcoidosis is a granulomatous disease of unknown etiology. Many patients with sarcoidosis demonstrate antigen-specific immunity to mycobacterial virulence factors. Th-17 cells are crucial to the immune response in granulomatous inflammation, and have recently been shown to be present in greater numbers in the peripheral blood and bronchoalveolar lavage (BAL) fluid (BALF) of sarcoidosis patients than healthy controls. It is unclear whether Th-17 cells in sarcoidosis are specific for mycobacterial antigens, or whether they have similar functionality to control Th-17 cells.
The Roles of T Helper 1, T Helper 17 and Regulatory T Cells in the Pathogenesis of Sarcoidosis. [2022]Sarcoidosis is a systemic granulomatous disorder of unidentified etiology, with a heterogeneous clinical presentation. It is characterized by a reduced delayed-type hypersensitivity to tuberculin and common antigens. The balance between Th1, Th17 and Regulatory T(Treg) cells controls T-cell proliferation and activation.The Th17/Treg ratio in the peripheral blood and bronchoalveolar lavage fluidis increased in patients with active sarcoidosis. Amplified IL-17A expression in granulomas and the presence of IL-17A+, IL-17A+IL-4+ and IL-17A+IFN-γ+ memory T helper cells in the circulation and BAL indicate Th17 cell involvement in granuloma induction and/or maintenance in sarcoidosis. Sarcoidosis should therefore be considered as a Th1/Th17 multisystem disorder and anti-IL-17/Th17 approaches that control and reduce IL-17Amay be an option, therefore, for the treatment of sarcoidosis.Here we provide a short overview as to the role of Th17 cells as critical cells in the pathogenesis of sarcoidosis.
Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. [2019]The lung-draining mediastinal lymph nodes (MLNs) are currently widely used to diagnose sarcoidosis. We previously reported that T-helper (Th) 17.1 cells are responsible for the exaggerated interferon-γ production in sarcoidosis lungs. In this study, we aimed to investigate 1) whether Th17.1 cells are also increased in the MLNs of sarcoidosis patients and 2) whether frequencies of the Th17.1 cells at diagnosis may correlate with disease progression.MLN cells from treatment-naive pulmonary sarcoidosis patients (n=17) and healthy controls (n=22) and peripheral blood mononuclear cells (n=34) and bronchoalveolar lavage fluid (BALF) (n=36) from sarcoidosis patients were examined for CD4+ T-cell subset proportions using flow cytometry.Higher proportions of Th17.1 cells were detected in sarcoidosis MLNs than in control MLNs. Higher Th17.1 cell proportions were found in sarcoidosis BALF compared with MLNs and peripheral blood. Furthermore, BALF Th17.1 cell proportions were significantly higher in patients developing chronic disease than in patients undergoing resolution within 2 years of clinical follow-up.These data suggest that Th17.1 cell proportions in pulmonary sarcoidosis can be evaluated as a diagnostic and/or prognostic marker in clinical practice and could serve as a new therapeutic target.