CHICAGO--(BUSINESS WIRE)--Xentria, Inc., a biotech company focused on developing treatments to address unmet clinical needs, today announced the peer reviewed publication in Frontiers in Pharmacology of a biosimulation model for XTMAB-16, its sarcoidosis treatment candidate. The publication, entitled “Leveraging in vitro and pharmacokinetic models to support bench to bedside investigation of XTMAB-16 as a novel pulmonary sarcoidosis treatment” can be found here.
Partnering with Certara, Inc., (Nasdaq: CERT) a global leader in biosimulation, and lead investigator Elliott D. Crouser, M.D., Professor of Internal Medicine, Wexner Medical Center at The Ohio State University, Xentria used biosimulation to more accurately estimate a safe and effective dose for XTMAB-16 for its upcoming first in-patient clinical trial commencing early 2023.
“Estimating safe and effective human doses of any drug is an important part of the overall clinical development process but selecting the starting dose in humans is extremely complex - it must be low enough to be safe but high enough to avoid excessive dose escalations,” says Elliot Offman, Ph.D., Vice President at Certara. “By leveraging modeling technology that uses non-clinical data combined with XTMAB-16’s Phase 1 findings, we were able to work with Dr. Crouser to support clinical dosing regimens in the initial trial in the sarcoidosis patient population.”
XTMAB-16, which received orphan drug designation in November 2020, is being developed as a novel biologic with the proposed indication of treating sarcoidosis, a rare and debilitating condition that causes small patches of swollen tissue, called granulomas, to develop in organs of the body, including the skin, eyes, heart, and central nervous system. The multi-system condition has widely variable disease manifestations and outcomes which require targeted therapies that help prevent disease progression.
XTMAB-16 is a novel chimeric anti-tumor necrosis factor α antibody that was shown to be well tolerated in healthy volunteers and was further shown to suppress in vitro sarcoidosis granuloma formation in a dose-dependent manner.
In a Phase 1 clinical study, single escalating doses of XTMAB-16 were administered to healthy participants, and serially drawn serum samples were quantified for XTMAB-16 concentrations. A population pharmacokinetic modeling and simulation framework was applied to characterize XTMAB-16 concentration-time profiles in serum following administration to healthy volunteers. Applying biodistribution factors, the interstitial lung concentration was simulated to enable optimization of XTMAB-16 dose and regimen needed to achieve lung concentrations consistent with granuloma suppression observed in an in vitro model of sarcoidosis.
“This study represents a successful collaboration between industry and academia that benefits both our development program and the sarcoidosis research field overall,” says Thomas Matthews, Director of Clinical Research at Xentria. “We believe this is an incredible contribution to the field of sarcoidosis research and possibly represents the first time an in-vitro model has been used to help guide clinical trial dosing assumptions using sarcoidosis patient-profiles.”
As the company moves to initiating its first trial in patients with pulmonary sarcoidosis, the modeling framework will be used to simulate drug concentrations that may be needed to reach sarcoidosis lung tissue – and to be as confident as possible that clinical trial participants receive a safe and potentially effective dose from the outset.
“The research process demonstrates the extensive and innovative measures undertaken to examine a potentially safe and effective dose for treating this complex disease. As more data come in from the upcoming trial in patients living with sarcoidosis, we will continue to adjust the modeling for real-time tracking,” says Dr. Crouser.
“We are thrilled to build upon our academic collaboration with Dr. Crouser for the development of this innovative and compelling model in a rare disease patient population that currently has no FDA-approved treatments developed specifically for them,” says Noopur Singh, Director of Medical Affairs at Xentria. “Leveraging these pharmacokinetic simulations throughout clinical development could help us mitigate risk in the XTMAB-16 development program and accelerate the potential of a new treatment for patients living with sarcoidosis.”
Sarcoidosis is a chronic, multisystem inflammatory disorder of unknown etiology that is characterized by the formation of granulomas — clumps of inflammatory cells — in one or more organs in the body. Sarcoidosis affects people of all ages but is most common among people who are 20 to 39 years of age.
While sarcoidosis can occur in any organ, more than 90% of patients with sarcoidosis will have the lungs affected, which is called pulmonary sarcoidosis. Left undiagnosed or untreated, the condition of patients with pulmonary sarcoidosis could degenerate into a chronic, progressive disease. Chronic, unresolved lung inflammation may result in scarring (fibrosis) that permanently damages the lung tissue and can lead to lung failure and death. In this complicated cascade of pro-inflammatory cytokines, the enhanced expression of TNFα, a cytokine that plays a significant role in antigen-stimulated, cell-mediated immune responses, may promote the formation of harmful granulomas and fibrosis throughout the body in people with sarcoidosis.
XTMAB-16 is a chimeric human-murine anti-TNF monoclonal antibody being developed as a novel biologic product for the treatment of sarcoidosis. By blocking TNFα, XTMAB-16 may disrupt an important inflammatory pathway and help slow or stop granuloma formation. Preliminary preclinical data was recently published which suggested that XTMAB-16 reduces granuloma formation in peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis. The clinical relevance of this effect remains to be determined.
Established in 2020, Xentria works across biopharmaceutics communities creating innovative and authentic collaborations and partnerships that advance challenging drug development.
Xentria, derived from “centrality”, is dedicated to delivering customized approaches to ambitious drug innovation through meaningful patient engagement and effective partnerships.
Headquartered in Chicago, Xentria is taking the lead to support surging life sciences initiatives for global audiences, while nurturing diversity, individualism, and sustainability. To learn more about Xentria visit www.xentria.com.
Certara accelerates medicines using proprietary biosimulation software, technology, and services to transform traditional drug discovery and development. Its clients include more than 2,000 biopharmaceutical companies, academic institutions and regulatory agencies across 62 countries. For more information on Certara, please visit https://www.certara.com.