Upstream Bio, a clinical-stage biotech company advancing new therapies to treat inflammation, has initiated a phase 1b multiple ascending dose study of UPB-101 in asthma patients with the dosing of the first patient.
Meanwhile, a possible way to tackle one of the underlying causes of asthma has been developed by researchers from Aston University and Imperial College London in the U.K.
In tests in mice, the researchers were able to virtually eliminate asthmatic symptoms within two weeks and return their airways to near normal.
Just under 5.5 million people in the UK receive treatment for asthma and around 1,200 people die of the disease each year.
Asthma causes the airways to become thickened and constricted, resulting in symptoms such as wheezing and shortness of breath.
Current treatments, including steroids, provide short term relief from these symptoms, by either relaxing the airways or reducing inflammation. However, no current drugs address the structural changes asthma makes to the airway and lungs, in order to offer a longer-lasting treatment.
Lead researcher, Jill Johnson, from Aston University’s School of Biosciences, said: “By targeting the changes in the airway directly, we hope this approach could eventually offer a more permanent and effective treatment than those already available, particularly for severe asthmatics who don’t respond to steroids. However, our work is still at an early stage and further research is needed before we can begin to test this in people.”
The research focused on a type of stem cell known as a pericyte, which is mainly found in the lining of blood vessels. When asthmatics have an allergic and inflammatory reaction, for example to house dust mites, this causes the pericytes to move to the airway walls. Once there, the pericytes develop into muscle cells and other cells that make the airway thicker and less flexible.
This movement of the pericytes is triggered by a protein known as CXCL12. The researchers used a molecule called LIT-927 to block the signal from this protein, by introducing it into the mice’s nasal passages. Asthmatic mice treated with LIT-927 had a reduction in symptoms within one week and their symptoms virtually disappeared within two weeks.
The researchers also found the airway walls in mice treated with LIT-927 were much thinner than those in untreated mice, closer to those of healthy controls.
The team are now applying for further funding to carry out more research into dosage and timing. They believe that, should this research be successful, it will still be several years before the treatment could be tested in people.
The research was published in Respiratory Medicine.
Upstream Bio’s UPB-101 is a monoclonal antibody designed to block the thymic stromal lymphopoietin receptor (TLSPR) and thus inhibit TSLP-driven inflammation. TSLP is a cytokine and a key driver of inflammatory response in asthma and other allergic and inflammatory diseases.
“The Upstream team is excited to bring UPB-101 to asthma study participants. Our goals with this study are to further explore the impact of UPB-101 on relevant pharmacodynamic measures, and to inform the dose regimen selection for phase 2 investigation,” said Aaron Deykin, chief medical officer and head of research and development.
“TSLP receptor blockade is a novel approach to inhibiting TSLP-induced activation of multiple downstream pathways in asthma and is anticipated to have broad utility across many inflammatory phenotypes of patients. It is an emerging class of biologics for patients with moderate to severe asthma who, despite treatment with standard inhaled medications, still experience ongoing exacerbations and debilitating, sometimes life-threatening symptoms.”
The phase 1b study is a randomized, double-blind, placebo-controlled, multiple ascending dose study. The completion of the study is expected in 2023. The study is designed to further characterize UPB-101 based on a previous phase 1 single ascending dose study of healthy volunteers completed by Astellas Pharma.
In the single ascending dose study, the company said UPB-101 demonstrated a promising profile on safety, pharmacokinetics, and pharmacodynamics measures. In pre-clinical studies, UPB-101 demonstrated inhibition of cytokine production from both CD4+ T cells and ILC2, and completely suppressed skin allergic reactions in a non-human primate model, suggesting it may be effective against multiple types of inflammation.
“Advancing UPB-101 to a multiple ascending dose trial in asthma patients marks a key milestone for our team. We anticipate that UPB-101’s unique mechanism targeting the TSLP receptor upstream of the inflammatory cascade has the potential to benefit patients living with uncontrolled asthma and other inflammatory indications,” said Sam Truex, CEO.
About TSLP and TSLPR blockade
Thymic stromal lymphopoietin (TSLP) is a cytokine that is a key driver of the inflammatory response in major allergic and inflammatory diseases, such as asthma, where TSLP expression is elevated across lung tissues and blood compared with healthy individuals and correlates with airway obstruction and disease severity. In addition, genome-wide association studies have identified associations between asthma risk and polymorphisms in the TSLP gene.
TSLP activation is one of the first events in the inflammatory cascade stimulated by allergens, viruses, and other triggers, initiating the upregulation of downstream targets such as IL-4, IL-5, IL-13, IL-17 and IgE. Because TSLP is a target upstream in the inflammatory cascade, there is opportunity to address disease at its root, prior to the influence of other disease-related cytokines.
Blocking the TSLP receptor presents an opportunity for a single treatment to impact the drivers of multiple pathological inflammatory processes across a broad set of diseases.