TSLP x IL-13 x IL-4

– Treatment with verekitug led to rapid PD effects which were sustained for up to 24 weeks, supporting evaluation of dosing intervals of once every 12 or 24 weeks in ongoing Phase 2 clinical trials – – PK/PD modeling predicts substantially higher clinical potency of verekitug compared to reported tezepelumab data – WALTHAM, Mass., Sept. 09, 2024 (GLOBE NEWSWIRE) -- Upstream Bio, Inc., a clinical-stage company developing verekitug, an investigational antagonist of the Thymic Stromal Lymphopoietin (TSLP) receptor, today presents additional clinical data from its 32-week, Phase 1b multiple ascending dose trial of verekitug (UPB-101) in adults with asthma at the European Respiratory Society (ERS) Congress 2024 being held in Vienna, Austria. New data from pooled verekitug-treated asthma patient cohorts demonstrated substantial reductions in biomarkers of inflammation including IL-5 (Interleukin 5) and IgE (immunoglobin E), in line with previously reported effects on blood eosinophils and fractional exhaled nitric oxide (FeNO). Predictive modeling based on observed pharmacodynamic (PD) and pharmacokinetic (PK) parameters suggests that verekitug may exhibit high potency in asthma patients, with an approximately 1.5-fold greater maximal predicted reduction of FeNO compared to that reported for tezepelumab. PK/PD modeling predicts that verekitug 100 mg once every 12 weeks (Q12W) and 400 mg once every 24 weeks (Q24W) dosing regimens could maintain trough serum levels above FeNO EC90 levels for >95% of the dosing interval, supporting testing of these dosing regimens in the ongoing Phase 2 VALIANT clinical trial for verekitug in severe asthma. As previously reported, verekitug was well tolerated at all dose levels tested. Verekitug also demonstrated rapid and substantial treatment effects, including 100% TSLP receptor occupancy after one dose, up to 54% reduction in FeNO and up to 65% reduction in blood eosinophils at 12 weeks. These findings were sustained for up to 24 weeks after the last dose. “We are pleased to share data supporting the potential for a differentiated product profile for verekitug, the only known antagonist in clinical development targeting the TSLP receptor,” said Aaron Deykin, M.D., Upstream Bio's Chief Medical Officer and Head of R&D. “TSLP receptor inhibition with verekitug has led to rapid, substantial and sustained reductions in disease-related biomarkers that are known to predict a reduction in exacerbations, which are clinically meaningful to patients with asthma. The data and related PK/PD modeling suggest significant potency and support our evaluation of dosing intervals of every 12 or 24 weeks in our ongoing Phase 2 VALIANT clinical trial in severe asthma. We look forward to further understanding the potential of verekitug to improve clinical outcomes and enhance patient care.” Oral data presentation details are as follows: Date and Time: September 9, 2024, 2:50 p.m. CESTPresentation Title: 32-week data from a multiple ascending dose trial with verekitug, a novel antibody to the human TSLP receptor (TSLPR), in adults with asthmaSession Title: Recent advances in biological treatments for asthma and chronic obstructive pulmonary disease A digital version of the presentation can be found on Upstream’s website. About the Phase 1b MAD Study The multiple ascending dose (MAD) study was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled adults with mild to moderate asthma and elevated blood eosinophils. Four dosing cohorts were included: 100 mg every 4 weeks, 200 mg every 4 weeks, 300 mg every 12 weeks and 25 mg single dose. Participants were observed for 32 weeks following randomization (NCT05448651). About TSLP and TSLP Receptor 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 disruption of TSLP signaling has been clinically validated as an effective therapeutic strategy. TSLP activation is one of the first events in the inflammatory cascade stimulated by allergens, viruses and other triggers, initiating the activation 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, 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. About Verekitug Verekitug is a novel recombinant fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that potently binds to the TSLP receptor and inhibits proinflammatory signaling initiated by TSLP. Verekitug is the only known antagonist in clinical development targeting the TSLP receptor. Three Phase 1 clinical trials have been completed for verekitug across a total of 120 participants, including 32 patients with asthma. In the Phase 1 single ascending dose (SAD) and Phase 1b multiple ascending dose (MAD) clinical trials, verekitug was well tolerated, demonstrated no evidence of clinically meaningful immunogenicity, showed a predictable and consistent pharmacokinetic profile, and had high subcutaneous bioavailability. Results of the Phase 1b MAD trial also demonstrated that verekitug is a potent inhibitor of the TSLP receptor and has the potential for an extending dosing interval compared to currently available treatments. Verekitug is currently being evaluated in two placebo-controlled, multi-national, randomized Phase 2 clinical trials. The VALIANT trial is a Phase 2 clinical trial in an estimated 436 patients with severe asthma, in which verekitug is administered at dosing intervals of either once every 12 weeks or once every 24 weeks with a primary endpoint of annualized asthma exacerbation rate (NCT06196879). The VIBRANT trial is a Phase 2 clinical trial in approximately 70 patients with chronic rhinosinusitis with nasal polyps (CRSwNP), in which verekitug is administered at a dosing interval of once every 12 weeks with a primary endpoint of change from baseline in nasal polyp score at week 24 (NCT06164704). About Upstream Bio Upstream Bio is a clinical-stage biotechnology company developing treatments for inflammatory diseases, with an initial focus on severe respiratory disorders. Upstream Bio is developing verekitug, the only known antagonist currently in clinical development that targets the receptor for Thymic Stromal Lymphopoietin (TSLP). The focus of Upstream Bio is to maximize verekitug’s unique attributes to address the substantial unmet needs of patients with severe asthma and CRSwNP that are underserved by today’s standard of care. Beyond these initial indications, Upstream Bio believes verekitug has broad potential in other inflammatory diseases, and it intends to leverage verekitug’s differentiated attributes to develop it as a potential therapy for diseases where TSLP signaling has been shown to play a significant role.

– In a multiple-ascending dose (MAD) study in patients with asthma, up to 54% reduction in fractional exhaled nitric oxide concentration (FENO) was observed with administration of verekitug, with treatment effects sustained up to 24 weeks after last dose – – Verekitug displayed a favorable safety and tolerability profile without evidence of clinically meaningful immunogenicity over 32 weeks – – Data to date support dosing intervals of 12 and 24 weeks in Phase 2 – WALTHAM, Mass., May 22, 2024 (GLOBE NEWSWIRE) -- Upstream Bio, Inc., a clinical-stage company focused on the development of verekitug, a potential first-in-class antagonist of the Thymic Stromal Lymphopoietin (TSLP) receptor that may deliver best-in-class efficacy for people with severe asthma and related diseases, today presented clinical data from its dose-ranging study of verekitug (UPB-101) in adults with asthma, at the American Thoracic Society International Conference being held in San Diego, CA. In all doses of verekitug, a rapid and complete TSLP receptor (TSLPR) occupancy within 2 weeks after the first dose was observed, and in doses >100 mg, TSLPR occupancy was sustained for up to 24 weeks after the last dose. As a result, a substantial reduction of FENO within 2 weeks after the first dose was observed in all doses of verekitug. With 100 mg of verekitug, a 54% reduction of FENO from baseline that was sustained for up to 24 weeks after the last dose was observed. Similar rapid, substantial and sustained reductions were observed in blood eosinophils, a type of white blood cell found in increased numbers in many patients with asthma. FENO is an accepted biomarker for underlying Type 2 lung inflammation in patients with asthma; higher levels of FENO are associated with an increased risk for future asthma exacerbations. Verekitug was well-tolerated at all dose levels tested; the most common treatment emergent adverse event was headaches. “These clinical data add to the growing scientific evidence that blocking the TSLPR may be an effective and durable approach to blocking the TSLP signaling pathway driving inflammatory diseases such as severe asthma. The rapid, substantial and sustained reduction in FENO and blood eosinophils observed for up to 24 weeks supports verekitug’s potential to deliver significant beneficial effects on clinical outcomes with potential administration every 12 or 24 weeks,” said Aaron Deykin, M.D., Upstream Bio's Chief Medical Officer and Head of R&D. “The clinical results presented today further support translation of our preclinical data to patients with severe asthma and suggest that the high potency of verekitug could lead to a potentially differentiated treatment profile with respect to both dosing interval and efficacy,” said Rand Sutherland, M.D., Upstream Bio’s Chief Executive Officer. “We continue to advance our two Phase 2 trials of verekitug in severe asthma and in chronic rhinosinusitis with nasal polyps, with the goal of observing continued durable effect with extended dosing intervals, a treatment paradigm that has the potential to advance care for patients with these diseases.” The MAD study was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled adults with mild to moderate asthma and elevated blood eosinophils. Four dosing cohorts were included: 100 mg every 4 weeks, 200 mg every 4 weeks, 300 mg every 12 weeks and 25 mg single dose. Participants were observed for 32 weeks following randomization (NCT05448651). A digital version of the poster can be found on Upstream’s website. 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 disruption of TSLP signaling has been clinically validated as an effective therapeutic strategy. TSLP activation is one of the first events in the inflammatory cascade stimulated by allergens, viruses and other triggers, initiating the activation 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, blocking the TSLP receptor (TSLPR) presents an opportunity for a single treatment to impact the drivers of multiple pathological inflammatory processes across a broad set of diseases. About Verekitug Verekitug is a novel recombinant fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that binds to the TSLPR and inhibits proinflammatory signaling initiated by TSLP. Verekitug is currently being evaluated in two Phase 2 clinical trials, the VALIANT trial in patients with severe asthma (NCT06196879) and the VIBRANT trial in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT06164704). In preclinical studies, verekitug demonstrated high occupancy of the TSLPR and potent inhibition of TSLP signaling. Additionally, verekitug inhibited cytokine production from both CD4+ T cells and ILC2 cells, and completely suppressed skin allergic reactions in a non-human primate model, suggesting that it may be effective against multiple types of inflammation. Three clinical trials have been completed for verekitug, including a Phase 1 single-ascending dose (SAD) clinical trial and a Phase 1b multiple-ascending dose (MAD) clinical trial. In these trials, verekitug was well tolerated, had no clinically meaningful immunogenicity, showed a predictable and consistent pharmacokinetic profile, and had high subcutaneous bioavailability. About Upstream Bio The focus of Upstream Bio is to maximize the potential of verekitug as a potential first-in-class antagonist of the TSLP receptor that may deliver best-in-class efficacy for people with severe asthma, CRSwNP, and other related diseases. Beyond these initial indications, Upstream Bio believes verekitug has broad potential in other inflammatory diseases, and it intends to leverage verekitug’s differentiated attributes to develop it as a potential therapy for diseases where TSLP signaling has been shown to play a significant role.

AstraZeneca and Amgen are currently planning their Phase III programme for Tezspire (tezepelumab) in chronic obstructive pulmonary disease (COPD), with the latest data on the monoclonal antibody providing more food for thought. Sharon Barr, executive vice president of biopharmaceuticals R&D at AstraZeneca, said “encouraging” results suggest potential efficacy “in a broad range of people with COPD irrespective of emphysema, chronic bronchitis and smoking status.”However, the failure of the Phase IIa COURSE study to meet its primary endpoint may mean that the late-stage programme focuses on those with a high blood eosinophil count (BEC), at least initially. Dave Singh, lead investigator of the trial, previously suggested to FirstWord that AstraZeneca and Amgen may choose to “define the primary population as maybe 250 or 200 [cells/μL] while also enrolling a subgroup with lower BEC to have a look at a bigger sample size. The primary population would be your first licence and then including other patients might open the door for the future.” The companies announced top-line results from COURSE last month, with Tezspire leading to a 17% numerical reduction in the annual rate of moderate-or-severe COPD exacerbations compared to placebo at week 52, which was not a statistically significant difference. In a prespecified subgroup of patients with BEC ≥150 cells/μL, the reduction was 37%, which just crept over the line for significance.However, additional findings reported Monday at the American Thoracic Society (ATS) conference showed that in the small number of patients with BEC ≥300 cells/µL, Tezspire led to a numerical reduction of 46% in the rate of moderate-or-severe exacerbations. Further subgroup analyses of the COURSE trial also showed that the therapy led to numerical improvements in lung function as measured by forced expiratory volume (FEV1) of 63mL and 146mL in the BEC ≥150 and ≥300 cells/μL groups respectively, compared to placebo.Play it safe on patient populationSpeaking shortly after the COURSE data were first top-lined, Singh said “I am just speculating but I think [AstraZeneca and Amgen] might go a bit conservative and make sure the Phase III trials are successful because COPD is not a crowded marketplace. They might not follow Dupixent and focus on patients with BEC of [300 cells/μL].”Sanofi and Regeneron’s Dupixent (dupilumab), which targets the IL-4 and IL-13 pathways, significantly reduced annual exacerbations by 30% and 34% versus placebo when added to standard inhaled therapy in COPD patients with BEC of ≥300 cells/µL. The companies are seeking FDA approval in this subgroup, with a decision expected by June 27. “They were obviously studied in different COPD populations so far but, based on what we see now, there is every reason to believe that” Tezspire will be as effective as Dupixent in these patients.Enough to differentiate?Analysts at Jefferies highlighted the every four week dosing of Tezspire compared to every two weeks for Dupixent as a potential point of differentiation. However, despite AstraZeneca and Amgen’s therapy being seen as efficacious as Dupixent, Barclays analysts said “we're sceptical it's enough to offer differentiation…particularly given the latter's meaningful head start.”Tezspire, which inhibits the action of the key epithelial cytokine TSLP,  is currently approved in the US and the EU for the add-on maintenance treatment of adult and paediatric patients aged 12 years and older with severe asthma. Meanwhile, Phase III studies are also under way in chronic rhinosinusitis with nasal polyps and eosinophilic esophagitis, with results expected later this year.