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1 First-in-disease therapies for patients with rare skin diseases Phase 2 TOIVA Topline Data in Cutaneous Venous Malformations December 15, 2025
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2 Forward Looking Statements This presentation contains forward-looking statements of Palvella Therapeutics, Inc. (“the Company”) within the meaning of the Private Securities Litigation Reform Act of 1995. Forward- looking statements include all statements that are not historical facts, and in some cases, can be identified by terms such as “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements contained in this presentation include, but are not limited to, statements regarding the Company’s future financial or business performance, conditions, plans, prospects, trends or strategies and other financial and business matters, the Company’s current and prospective product candidates and any additional indications or platform candidates, the Company's planned research and development activities, the Company's planned clinical trials, including timing of receipt of data from the same, the Company’s plan to meet with regulatory authorities, the planned regulatory framework for the Company's product candidates including the Company’s plans to pursue Breakthrough Therapy Designation, the strength of the Company's intellectual property portfolio, and projections of the Company’s future financial results and other metrics. Such forward- looking statements are subject to risks, uncertainties, and other factors which could cause actual results to differ materially from those expressed or implied by such forward looking statements. These forward-looking statements are based upon current estimates and assumptions of the Company and its management and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation. Factors that may cause actual results to differ materially from current expectations include, but are not limited to: competition, the ability of the Company to grow and manage growth, maintain relationships with suppliers and retain its management and key employees; the success, cost and timing of the Company’s product development activities, studies and clinical trials; changes in applicable laws or regulations; the possibility that the Company may be adversely affected by other economic, business or competitive factors; the Company’s estimates of expenses and profitability; the evolution of the markets in which the Company competes; the ability of the Company to implement its strategic initiatives and continue to innovate its existing products; and the ability of the Company to defend its intellectual property. Nothing in this Presentation should be regarded as a representation by any person that the forward-looking statements set forth herein will be achieved or that any of the contemplated results of such forward-looking statements will be achieved. You should not place undue reliance on forward-looking statements, which speak only as of the date they are made. The Company undertakes no duty to update these forward-looking statements. Industry and Market Data The Company may from time to time provide estimates, projections and other information concerning its industry, the general business environment, and the markets for certain conditions, including estimates regarding the potential size of those markets and the estimated incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties, and actual events, circumstances or numbers, including actual disease prevalence rates and market size, may differ materially from the information reflected in this presentation. Unless otherwise expressly stated, we obtained this industry, business information, market data, prevalence information and other data from reports, research surveys, studies and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data, and similar sources, in some cases applying our own assumptions and analysis that may, in the future, prove not to have been accurate. Trademarks This Presentation may contain trademarks, service marks, trade names and copyrights of other companies, which are the property of their respective owners. Solely for convenience, some of the trademarks, service marks, trade names and copyrights referred to in this Presentation may be listed without the TM, SM © or ® symbols, but the Company will assert, to the fullest extent under applicable law, the rights of the applicable owners, if any, to these trademarks, service marks, trade names and copyrights.
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3 Phase 2 TOIVA Topline Data: Today’s Presenters Michael Kelly, MD, PhD • Pediatric hematologist-oncologist at Cleveland Clinic • Study investigator in Phase 2 TOIVA study • Member of Palvella Medical and Scientific Advisory Board Bohan Wei VP Corporate Development & New Product Planning Wes Kaupinen Founder and CEO Jeff Martini, PhD Chief Scientific Officer
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4 Agenda EXECUTIVE SUMMARY DISEASE OVERVIEW PHASE 2 TOIVA TOPLINE RESULTS SUMMARY Q&A Wes Kaupinen, Founder and CEO Michael Kelly, MD, PhD, Cleveland Clinic Jeff Martini, PhD, CSO Michael Kelly, MD, PhD, Cleveland Clinic Wes Kaupinen, Founder and CEO
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5 • Achieved statistical significance on multiple pre-specified clinician-reported and patient- reported efficacy endpoints, including dynamic change endpoints and static severity endpoints • Overall Cutaneous Venous Malformations-Investigators’ Global Assessment (cVM-IGA): 7-point clinician-assessed change scale ranging from “Very Much Worse” (-3) to “Very Much Improved” (+3) • Mean effect size at week 12: +1.5 (p<0.001) • 73% of participants (11/15 participants) demonstrated 1-point improvement or greater at Week 12 • 67% of participants (10/15 participants) rated as either “Much Improved” (+2) or “Very Much Improved” (+3) at Week 12 • QTORIN rapamycin was generally well-tolerated, consistent with previous clinical trials Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; Intent-to-Treat (ITT) population analyzed with no imputation of values for missing data. QTORIN Rapamycin for Cutaneous Venous Malformations: Phase 2 TOIVA Topline Data Planned discussions with FDA in early 2026 regarding the potential for Breakthrough Therapy Designation and a Phase 3 pivotal study
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6 Dr. Michael Kelly, Cleveland Clinic Pediatric hematologist-oncologist at Cleveland Clinic • One of the leading physician-scientists advancing modern, mutation- informed treatment paradigms in the vascular anomalies field • Involved in over 100 clinical trials for novel oncology and vascular anomaly therapeutics • More than two decades of clinical and research experience in care of patients with complex venous, lymphatic, and mixed vascular malformations • Treated thousands of vascular anomaly patients, including those with cutaneous venous malformations and microcystic lymphatic malformations • Clinical investigator in Phase 2 TOIVA trial evaluating QTORIN rapamycin for the treatment of cutaneous venous malformations • Consultant to Palvella and investigator in the Phase 3 SELVA trial evaluating QTORIN rapamycin for microcystic lymphatic malformations Michael Kelly, MD, PhD
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7 Disease Overview Dr. Michael Kelly, Cleveland Clinic QTORIN Rapamycin for Cutaneous Venous Malformations
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8 Cutaneous Venous Malformations: High Unmet Medical Need One of the most significant unmet medical needs in vascular malformations field Most common vascular malformation, affecting estimated > 75k patients in the U.S.1 Chronic, lifelong disease course 1. Gallagher et al, Orphanet Journal of Rare Diseases, (2025).
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9 Cutaneous Venous Malformations: Relentless Cycle of Microthromboses and Functional Loss Abnormal Vessels Bleeding Chronic Micro- thromboses Height (elevation/ engorgement) Phleboliths (painful calcium deposits) TEK/PIK3CA/Other VM Mutations mTOR Hyperactivation Endothelial Dysfunction Therapeutic goal: slow/halt the biological progression and/or improve clinical signs of disease Appearance (visualization/ color) No Spontaneous Regression Sources: Eng et al, American Journal of Medical Genetics Part C: Seminars in Medical Genetics, (2025); Fujino et al, Lymphatic Research and Biology, (2024); Hirose et al, Human Pathology, (2024).
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10 Constitutively Active Biological Signaling is Not Addressed by Non-specific, Episodic Treatments Sclerotherapy Laser Surgery ⮽ Does not address underlying causal biology of disease ⮽ Highly invasive and traumatic ⮽ Any improvement likely to be limited and short- term Disease will reliably recur, often more extensively than before Sources: Ali S, Mitchell SE Semin Intervent Radiol. 2017 Sep;34(3):288-293; Hassanein, AH, Plastic and Reconstructive Surgery 125(6):p 48, June 2010. Image Source: Vein Health Medical Clinic.
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11 Phase 2 TOIVA Topline Results Dr. Jeff Martini, Chief Scientific Officer Dr. Michael Kelly, Cleveland Clinic QTORIN Rapamycin for Cutaneous Venous Malformations
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12 Venous Malformations: Progress Towards the Potential First Targeted Therapy for Unaddressed Cutaneous Disease Known Genetics / Clear Biology Real-world Evidence Real-world evidence supports rapamycin’s off-label use in primarily internal manifestations of VMs… …however, poor patient outcomes persist in cutaneous disease Limaye et al (2009, 2015) Teng et al (2025) QTORIN RAPAMYCIN On Target, In Tissue Phase 2 TOIVA Data (2025) Plausible mechanism 3.9% concentration Dermal penetration Extensive CMC package QTORIN 3.9% rapamycin anhydrous gel is for investigational use only and has not been approved or cleared by the FDA or by any other regulatory agency. The safety or efficacy has not been established for any use.
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13 Phase 2 TOIVA Study in cVMs: 24-Week Study Single-arm, baseline-controlled, QD dose, age 6+ Safety and Tolerability Efficacy (no pre-specified primary endpoint): cVM-IGA (7-point clinician change scale), cutaneous VM multi-component static scale (cVM-MCSS), other clinician- and patient-reported outcomes Statistics: Intent-to-Treat (ITT) population, based on available data at each time point and analyzed per statistical analysis plan Key Entry Criteria: Enriched for patients with cutaneous disease and confirmed by third party eligibility consult team; genetics not required Enrollment: 16 participants enrolled and dosed; 1 dosed participant lost to follow up Sites: Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; ITT analyzed with no imputation of values for missing data. Single arm, QTORINTM rapamycin treatment (QD) Efficacy Evaluation Period 12 weeks Screening / Baseline Visit Exit Interview with participant Entry Interview with participant Treatment Extension Period 12 weeks Today’s Results
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14 Statistically Significant Improvements on Dynamic Change Scales Note: 7-point scales ranging from -3 to +3; positive values indicate improvements from baseline Participants (n=15) at Week 12 Mean Change / p-value Overall Cutaneous Venous Malformations Investigator Global Assessment (cVM-IGA) +1.5 (p < 0.001) cVM-IGA Height/Engorgement +1.3 (p < 0.001) cVM-IGA Appearance (visualization/color of affected veins) +1.5 (p < 0.001) cVM-IGA Bleeding +0.7 (p = 0.045) Overall Patient Global Impression of Change (PGI-C) +1.1 (p < 0.001) Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; ITT analyzed with no imputation of values for missing data. cVM-IGA Ulceration assessed with no disease present at baseline.
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15 Overall cVM-IGA: 73% of Participants Demonstrated Improvement at Week 12 Single-arm, baseline-controlled, QD dose, age 6+ • Overall cVM-IGA: 7-point clinician-assessed dynamic change scale ranging from “Very Much Worse” (-3) to “Very Much Improved” (+3) • Mean effect size at week 12: +1.5 (p<0.001) • 73% of participants (11/15 participants) demonstrated at least a 1- point improvement on the Overall cVM-IGA at Week 12 • 67% of participants (10/15 participants) were rated as either “Much Improved” (+2) or “Very Much Improved” (+3) on the Overall cVM-IGA at Week 12; represented in these 10 participants were: i. Genetically confirmed TEK mutations ii. Genetically confirmed PIK3CA mutations iii. Non-TEK/PIK3CA mutation or unconfirmed genotype • Based on analysis of data at Week 12, the Company does not anticipate requiring confirmed genotypes or genetic testing in future studies Overall cVM-IGA at Week 12 (n=15) Internal threshold to progress to Phase 3: ~30% Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; ITT analyzed with no imputation of values for missing data. 1. Genetic testing was not required as part of the protocol; Palvella is continuing efforts to collect genetic data on trial participants. 73% 0% 25% 50% 75% 100% 1-Point Improvement or Greater Percentage of participants
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16 Overall cVM-IGA: Rapid, Time Dependent Response Observed % of Participants with At Least a 2-point Improvement on Overall cVM-IGA 31% 50% 67% 0% 25% 50% 75% 100% Week 0 Week 4 Week 8 Week 12 Percentage of Participants Single-arm, baseline-controlled, QD dose, age 6+ Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; ITT analyzed with no imputation of values for missing data.
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17 Statistically Significant Improvements on Key Static Severity Scales Note: 5-point scales ranging from 1 to 5; negative values indicate improvements from baseline Participants (n=15) at Week 12 Mean Change / p-value Overall Clinician Global Impression of Severity (CGI-S) -1.0 (p < 0.001) cVM-MCSS (Cutaneous VM Multi-Component Static Scale) Severity of Height/Engorgement -1.3 (p < 0.001) cVM-MCSS Severity of Appearance (visualization/color of affected veins) -1.1 (p < 0.001) Overall Patient Global Impression of Severity (PGI-S) -0.5 (p = 0.027) Note: Statistical significance (p<0.05) is nominal as there was no adjustment for multiplicity amongst efficacy endpoints. Data analyzed per statistical analysis plan; ITT analyzed with no imputation of values for missing data. CGI-S Ulceration assessed with no disease present at baseline. CGI-S Bleeding assessed with limited disease present at baseline.
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18 Site: CHOP Investigator: Dr. Denise Adams Participant Age: 17 Mutation: TEK cVM-IGA at Week 12: Very Much Improved (+3) Week 12Baseline Phase 2 Results: Visible Improvement Participant Qualitative Interview: “I’ve definitely noticed some improvements…it’s definitely had a positive effect…It’s more comfortable to wear a bra now…I’ve had less pain in that specific area” Note: Selective photos.
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19 Site: Cleveland Clinic Investigator: Dr. Michael Kelly Participant Age: 13 Mutation: PIK3CA cVM-IGA at Week 12: Much Improved (+2) Week 12 Phase 2 Results: Visible Improvement Note: Selective photos. Week 12Baseline Participant Qualitative Interview: “It’s slowed down bleeding and the color has changed…There’s a bump on my leg that went away…it shrunk in size and now it’s not there really”
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20 Phase 2 Results: Safety and Tolerability • QTORIN rapamycin was generally well-tolerated, similar to previous clinical trials • Most common Treatment-Emergent Adverse Events were application site reactions (erythema, 25%) • All Treatment-Related Adverse Events were moderate or mild (no severe events) • Majority of AEs were mild • No SAEs related to study drug • No unexpected AEs Rapamycin levels were below the lower limit of quantification (2 ng/mL) in systemic circulation on a standard lab assay for all participants at all timepoints in the study Significantly below 5 ng/mL which is the lower boundary where rapamycin begins to exert immunosuppressive effects
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21 Summary Wes Kaupinen Chief Executive Officer QTORIN Rapamycin for Cutaneous Venous Malformations
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22 QTORIN Rapamycin has the Potential to Be the First FDA- Approved Therapy for Cutaneous Venous Malformations Achieved statistical significance on multiple pre-specified clinician-reported and patient- reported efficacy endpoints, including 73% of participants (11/15 participants) demonstrated a 1-point improvement or greater on Overall cVM-IGA at Week 12 Planning for near-term discussions with FDA regarding potential for Breakthrough Therapy Designation and a Phase 3 pivotal study, as well as the newly announced Plausible Mechanism Pathway QTORIN rapamycin has the potential to become the first FDA-approved therapy and standard of care for the estimated more than 75,000 individuals with cutaneous venous malformations in the U.S. 1 The Phase 2 results further support Palvella’s “pipeline-in-a-product” strategy for QTORIN rapamycin, with programs advancing in microcystic LMs, cVMs, and angiokeratomas 2 3
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23 Striving to be first for rare disease patients Thank You