Upstream Bio (NASDAQ:UPB) reported top-line results from its Phase II VALIANT trial evaluating verekitug in adults with severe asthma, highlighting statistically significant reductions in annualized asthma exacerbation rate (AAER) with multiple dosing regimens and a safety profile the company said was consistent with prior studies.
VALIANT results: exacerbations, lung function, and biomarkers
CEO Dr. Rand Sutherland said the placebo-controlled, randomized study followed patients for up to 60 weeks and met its primary endpoint, demonstrating “statistically significant and clinically meaningful” AAER reductions with two less-frequent dosing regimens: 100 mg every 12 weeks (four times per year) and 400 mg every 24 weeks (twice per year). A third, lower-dose regimen (100 mg every 24 weeks) also showed a statistically significant effect on AAER but did not show consistent improvements across other endpoints, according to management.
- 100 mg every 12 weeks: 56% reduction in AAER
- 400 mg every 24 weeks: 39% reduction in AAER
- 100 mg every 24 weeks: 49% reduction in AAER
While the trial was not powered to detect statistically significant differences in secondary endpoints at week 60, the company said the 100 mg every-12-weeks and 400 mg every-24-weeks groups showed clinically meaningful improvements in lung function and reductions in exhaled nitric oxide (FeNO), a biomarker associated with airway inflammation.
Management highlighted that the 100 mg every-12-weeks regimen was associated with a 122 mL improvement in FEV1 and a 20.4 parts-per-billion reduction in FeNO, described as a 43.5% mean reduction from baseline. The 400 mg every-24-weeks regimen was associated with a 139 mL FEV1 improvement and a 26.3 ppb FeNO reduction, described as a 44.9% reduction from baseline.
Study design and week-24 secondary endpoint analysis
Chief Medical Officer Dr. Aaron Deykin said VALIANT was a Phase II randomized, double-blind, placebo-controlled, parallel-group trial enrolling adults with severe asthma across the U.S. and 14 other countries. Eligibility included documented asthma history, FEV1 between 30% and 80% of predicted with reversible airflow obstruction, ongoing symptoms despite standard-of-care therapy, and a history of exacerbations in the prior 12 months.
A total of 478 participants were randomized across four arms using a double-dummy design:
- Verekitug 100 mg every 12 weeks (high dose), 121 patients
- Verekitug 400 mg every 24 weeks (medium dose), 118 patients
- Verekitug 100 mg every 24 weeks (low dose), 120 patients
- Placebo, 119 patients
The trial used a variable treatment period in which all subjects received at least 24 weeks of treatment, with some followed up to a maximum of 60 weeks. Deykin said the study had 90% power to detect a 50% reduction in AAER for each active arm compared to placebo, but was not powered for secondary endpoints measured at week 60.
To address data availability, the company pre-specified analyses of secondary endpoints at week 24, which Deykin said had the largest dataset. At week 24, the company reported statistically significant, generally dose-related placebo-adjusted improvements in FEV1, FeNO, and asthma control questionnaire (ACQ) with the 100 mg every-12-weeks and 400 mg every-24-weeks regimens. Management also said treatment effects on biomarkers and lung function appeared early—FeNO reductions were described as evident by week 2—and were maintained through 60 weeks.
Safety and immunogenicity
Upstream Bio said verekitug was “generally well-tolerated” across dosing regimens, with treatment-emergent adverse events (TEAEs) and serious TEAEs reported as similar across groups. Deykin noted there was a numerically higher incidence of serious adverse events in the placebo group, and no deaths were reported. He added that adverse events described as bronchitis occurred more frequently in the high- and medium-dose verekitug groups compared to placebo.
The company also discussed anti-drug antibodies (ADAs), reporting that ADAs were observed in 50% to 60% of subjects. Deykin said ADA prevalence and titers were stable over time, did not vary by dose group, and were not associated with differences in adverse events. He added that while ADAs can impact exposure, the efficacy results were observed “net of that,” and the company did not see a pattern suggesting a changing ADA effect over time. One subject randomized to placebo experienced anaphylaxis during the study, according to management.
Next steps: integrated analysis, Phase III planning, and other programs
Sutherland said the company plans a “comprehensive integrated analysis” of data from VALIANT and its Phase II VIBRANT study in chronic rhinosinusitis with nasal polyps (CRSwNP), which the company previously said delivered positive top-line results in September. Management said the goal is to inform dose optimization and selection across severe asthma and CRSwNP, followed by interactions with regulators to align on Phase III development strategy and initiate Phase III trials in both indications in parallel.
In Q&A, management emphasized that dose selection is still under evaluation and will be driven by pharmacology and exposure-response modeling across studies. Deykin said earlier Phase I modeling suggested 100 mg every 12 weeks could provide maximal efficacy, but the company intends to revisit this using the larger Phase II dataset and would consider higher doses if modeling suggests additional upside.
Upstream Bio also discussed its Phase II VENTURE trial in COPD, which Sutherland said is “actively enrolling” and is now more than 60% complete, exceeding internal timelines. Management said it plans to continue enrollment as-is for now while it evaluates whether learnings from asthma and CRSwNP have any implications for the COPD program.
On formulation, Deykin said the company would not conduct Phase III with vials, and instead plans to use a prefilled syringe while developing an autoinjector in parallel, with the stated goal of launching with both an autoinjector and prefilled syringe.
About Upstream Bio (NASDAQ:UPB)
Upstream Bio, Inc is a clinical-stage biotechnology company focused on the development of next-generation prophylactic vaccines and immuno-oncology therapies. Leveraging a proprietary viral vector platform, the company aims to deliver optimized antigen payloads that stimulate robust and durable immune responses against both infectious diseases and cancer targets. Upstream Bio’s approach emphasizes safety, manufacturability and potential for rapid scale-up to address emerging public health challenges.
The company’s research and development pipeline includes multiple viral vector-based candidates in early clinical and preclinical stages.
