Slide 1: Phase 2 VIBRANT Top-line Results in CRSwNP
No Image Phase 2 VIBRANT Top-line Results in CRSwNP September 2, 2025 © 2025 Upstream Bio, Inc.
Slide 2: Disclaimer
No Image Disclaimer This presentation contains “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, each as amended. These statements may be identified by words such as “aims,” “anticipates,” “believes,”
Slide 3: Agenda
No Image Agenda Introduction Rand Sutherland, MD Chief Executive Officer VIBRANT Aaron Deykin, MD Phase 2 Top-line Results Chief Medical Officer and Head of R&D Looking Ahead Rand Sutherland, MD Chief Executive Officer © 2025 Upstream Bio, Inc. Rand Sutherland, MD Chief Executive Officer Analyst Q&A
Slide 4: Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP
No Image Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP Study drug dosed every 12 weeks, treatment period 24 weeks Met primary endpoint, with NPS reduction of -1.8 (p<0.0001) Met key secondary endpoints, Phase 2 VIBRANT including NCS reduction of -0.8 (p=0.0003*) and 76% reduction
Slide 5: Verekitug dosed every 12 weeks delivered clinical activity similar to tezepelumab
No Image Verekitug dosed every 12 weeks delivered clinical activity at week 24 similar to tezepelumab dosed every 4 weeks Injections per year 4 13 26 2 0.5 0.0 0.0 NPS change from baseline -0.3 -0.3 Verekitug -0.4 -0.5 Tezepelumab TE = -0.5 -0.5 Dupilumab Depemokimab -1.0 TE = -1.8 -2.0 TE = -1.7 -1
Slide 6: About Upstream Bio
No Image About Upstream Bio Clinical-stage Developing the only known antagonist of the TSLP receptor immunology company → Verekitug’s pharmacology is unique and characterized by rapid, focused on severe complete and sustained occupancy of the TSLP receptor, for up to respiratory diseases 24 weeks af
Slide 7: Verekitug blocks TSLP receptor assembly and reduces TSLP-driven inflammation
No Image Verekitug blocks TSLP receptor assembly and potently reduces TSLP-driven inflammation → Inhibition of TSLP signaling reduces type 2 and non-type 2 inflammation, as well TSLP TSLP TSLP as fibrotic responses → Verekitug blocks the formation of the heterodimeric TSLP receptor and reduces key d
Slide 8: CRSwNP: A TSLP-driven disease with substantial unmet need
No Image CRSwNP: A TSLP-driven disease with substantial unmet need 1 → CRSwNP is a chronic inflammatory disease of the upper airway, marked by nasal and sinus inflammation and the presence of nasal polyps → Severe disease significantly impacts quality of life, often necessitating surgery and systemi
Slide 9: Phase 2 VIBRANT Trial in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)
No Image Phase 2 VIBRANT Trial in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) Aaron Deykin, MD Chief Medical Officer and Head of R&D © 2025 Upstream Bio, Inc.
Slide 10: VIBRANT Phase 2 trial design
No Image VIBRANT Phase 2 trial design Enrolled 81 patients with CRSwNP in the US and Europe Randomized, double-blind, placebo-controlled Phase 2 study with a 24-week treatment period (NCT06164704) Key inclusion criteria: Primary endpoint: Verekitug + SoC* Change in NPS → History of nasal polyp (NP)
Slide 11: VIBRANT ITT population disposition
No Image VIBRANT ITT population disposition 93% of subjects completed the study 81 participants randomized Verekitug Placebo n=41 n=40 Not dosed* n=1 Received Received Verekitug Placebo n=40 n=40 Withdrawn from study N=5 Lack of efficacy: 1 Investigator decision: 1 © 2025 Upstream Bio, Inc. Consent
Slide 12: Baseline characteristics were balanced across treatment groups
No Image Baseline characteristics were balanced across treatment groups Slightly higher blood eosinophils observed in placebo group Verekitug Placebo (n=) Placebo Verekitug (n=) Total (n=81) Age (years), mean (SD) 49.8 (13.26) 49.6 (13.42) 49.7 (13.25) CRSwNP duration (years), mean (SD) 13.7 (9.92)
Slide 13: Verekitug was generally well tolerated
No Image Verekitug was generally well tolerated Adverse Event Category, n, subjects (%) Verekitug (n=40) Placebo (n=40) Any treatment-emergent adverse events (TEAE) 27 (67.5) 26 (65.0) → Overall, incidence of AEs was similar across Any TEAEs related to study treatment 1 (2.5) 3 (7.5) treatment group
Slide 14: Most common TEAEs consistent with CRSwNP symptoms
No Image Most common TEAEs in the study population (>5%) were consistent with CRSwNP symptoms These occurred more frequently in the placebo group TEAE, by Preferred Term, n, subject (%) Verekitug Placebo Upper respiratory tract infections 3 (7.5) 6 (15) Sinusitis 2 (5) 3 (7.5) Nasopharyngitis 2 (5)
Slide 15: Significant and clinically meaningful improvements in NPS and key secondary endpoints
No Image Verekitug led to significant and clinically meaningful improvements in NPS and key secondary endpoints, including reduction in need for surgery or systemic corticosteroids Verekitug Placebo Treatment difference Primary -1.8 (-2.51, -1.03) NPS change from baseline* -2.1 (0.26) -0.3 (0.27) En
Slide 16: Significant reductions in NPS and NCS over 24 weeks
No Image Verekitug dosed every 12 weeks led to significant reductions in NPS and NCS over 24 weeks Endoscopic NPS change Total NCS change* NPS change from baseline Significant reduction in NCS observed at week 2 (p<0.01)† NCS change from baseline -1.8 (-2.51, -1.03), p <0.0001 -0.8 (-1.17,-0.37) p=0
Slide 17: Clinical effect in NPS across all subgroups
No Image Verekitug demonstrated clinical effect in NPS across all subgroups Subgroups Verekitug Placebo Least Squares Mean Difference (95% CI) n n Overall 41 40 -1.8 (-2.51 to -1.03) Age (years) <65 36 34 -1.8 (-2.68 to -0.98) ≥65 5 6 -0.7 (-2.91 to 1.44) Sex Male 26 26 -2.1 (-3.08 to -1.19) Female
Slide 18: VIBRANT population similar to CRSwNP studies of other biologics
No Image VIBRANT population generally similar to CRSwNP studies of other biologics Verekitug Tezepelumab1 Dupilumab2 Depemokimab3 Ph 2 VIBRANT Ph 3 WAYPOINT Ph 2 Ph 3 ANCHOR 1/2† Patients (n) 81 408 60 528 Age years (mean) 49.7 49.7 48.4 52 CRSwNP duration years, (mean) 12.7 12.8 9.6 12 Patients wit
Slide 19: Verekitug dosed every 12 weeks delivered clinical activity similar to tezepelumab
No Image Verekitug dosed every 12 weeks delivered clinical activity at week 24 similar to tezepelumab dosed every 4 weeks Injections per year 4 13 26 2 0.5 0.0 0.0 NPS change from baseline -0.3 -0.3 Verekitug -0.4 -0.5 Tezepelumab TE = -0.5 -0.5 Dupilumab Depemokimab -1.0 TE = -1.8 -2.0 TE = -1.7 -1
Slide 20: Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP
No Image Top-line results for Phase 2 VIBRANT study of verekitug in CRSwNP Study drug dosed every 12 weeks, treatment period 24 weeks Met primary endpoint, with NPS reduction of -1.8 (p<0.0001) Met key secondary endpoints, Phase 2 VIBRANT including NCS reduction of -0.8 (p=0.0003*) and 76% reduction
Slide 21: Looking Ahead
No Image Looking Ahead Rand Sutherland, MD Chief Executive Officer © 2025 Upstream Bio, Inc.
Slide 22: Verekitug has the potential to advance the standard of care in CRSwNP
No Image Verekitug has the potential to advance the standard of care in CRSwNP and other respiratory diseases → Verekitug delivered significant effects on the primary and key secondary CRSwNP endpoints in the VIBRANT trial → This broad clinical activity was delivered at a differentiated dosing inter
Slide 23: CRSwNP and Severe Asthma: Biological, Epidemiological and Clinical Overlap
No Image CRSwNP and Severe Asthma Biological, Epidemiological and Clinical Overlap Shared biology with central role of TSLP driving Common biologic therapies and activation of common cytokine pathways1-4 Shared Epidemiology1 magnitude of response5 Nasal polyps In patients with CRSwNP Anti-TSLP Anti-
Slide 24: Thank you to our trial participants and investigators
No Image Thank you to our trial participants and investigators Met primary endpoint, with NPS reduction of -1.8 (p<0.0001) Met key secondary endpoints, Phase 2 VIBRANT including NCS reduction of -0.8 (p=0.0003*) and 76% reduction in need for surgery/steroids (p=0.03*) 100 mg Q12W vs placebo Generall
Slide 25: Q&A
No Image Q&A © 2025 Upstream Bio, Inc.