Announcement PDF ASX RELEASE 31st July 2025 Investor Webinar Presentation: Phase 3 Update and Probability of Success Paradigm Biopharmaceuticals Ltd (ASX: PAR) (“Paradigm” or “the Company”), a late-stage drug development company focused on delivering new therapies to address unmet medical needs, advises that the investor webinar, held today, provided an update on the Company’s global Phase 3 clinical trial (PARA_OA_012) of injectable pentosan polysulfate sodium (iPPS) for knee osteoarthritis. The presentation used during the webinar is now available and attached to this announcement. A recording of the session will be made available shortly on the Paradigm website: https://paradigmbiopharma.com/performance-progress/#announcements About Paradigm Biopharmaceuticals Paradigm Biopharmaceuticals Ltd. (ASX: PAR) is a late-stage drug development company driven by a purpose to improve patients’ health and quality of life by discovering, developing, and delivering pharmaceutical therapies. Paradigm’s current focus is developing iPPS for the treatment of diseases where inflammation plays a major pathogenic role, indicating a need for the anti-inflammatory and tissue regenerative properties of PPS, such as in osteoarthritis (phase 3). Forward Looking Statements This Company announcement contains forward-looking statements, including statements regarding anticipated commencement dates or completions dates of preclinical or clinical trials, regulatory developments, and regulatory approval. These forward-looking statements are not guarantees or predictions of future performance, and involve known and unknown risks, uncertainties, and other factors, many of which are beyond our control, and which may cause actual results to differ materially from those expressed in the statements contained in this presentation. Readers are cautioned not to put undue reliance on forward-looking statements. Authorised for release by the Paradigm Board of Directors. FOR FURTHER INFORMATION PLEASE CONTACT: Simon White Director of Investor Relations Tel: +61 404 216 467 Paradigm Biopharmaceuticals Ltd. ABN: 94 169 346 963 Level 15, 500 Collins St, Melbourne, VIC, 3000, AUSTRALIA Email: investorrelations@paradigmbiopharma.com Paradigm Biopharma PHASE 3 CLINICAL TRIAL WEBINAR JULY 2025 DR. DONNA SKERRETT | CMO MR PAUL RENNIE | MD Paradigm Biopharma JUL 2025 2 Disclaimer This document, together with any information communicated by Paradigm Biopharmaceuticals Ltd ASX:PAR (known as “Paradigm”, “Paradigm Biopharma” or “the Company”), in any presentation or discussion relating to this document (collectively, “Information”) is confidential, and has been prepared by the Company on the condition that it is for the exclusive information and use of the recipient. The Information is proprietary to Paradigm and may not be disclosed to any third party or used for any other purpose without the prior written consent of the Company. Except as otherwise expressly stated in this presentation, Paradigm has not authorised any person to give any information or make any representation which is not contained in this presentation. Any such information or representation not contained in this presentation must not be relied upon as having been authorised by, or on behalf of, Paradigm. The Information should not to be relied upon for the making of any investment decision. Any investment in Paradigm is subject to a number of investment risks including the possibility of loss of capital invested and no return of income or payment of dividends. Neither Paradigm nor any other entity or person in or associated with Paradigm guarantees any return (whether capital or income) or generally the performance of Paradigm or the price at which its securities may trade. In particular, this presentation is not a recommendation, offer or invitation to subscribe for or purchase Paradigm securities. This presentation is not exhaustive of all of the information a potential investor or their professional advisers would require. This presentation does NOT constitute a “Prospectus" or a "Disclosure Document” (as defined in the Corporations Act 2001 (Cth) (“Corporations Act”)) and has not been, and will not be, lodged with the Australian Securities and Investments Commission or any other regulatory authority. Accordingly it is not required to contain, and may not necessarily contain, all of the information that a Prospectus or like Disclosure Document would be required to contain pursuant to the Corporations Act. This presentation does not take into account any specific objectives, financial situation or needs of investors. For these and other reasons, you are strongly recommended to obtain your own up to date independent legal, financial and investment advice – those acting without such advice do so at their own risk. 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These risks and uncertainties include, but are not limited to: (i) the possible delays in and the outcome of pre clinical and clinical trials, (ii) risks relating to possible partnering or other like arrangements, (iii) the potential for delays in regulatory approvals, (iv) the unknown uptake and market penetration of any potential commercial products and (vi) other risks and uncertainties related to the Company’s prospects, assets / products and business strategy. This is particularly the case with companies such as Paradigm which operate in the field of researching, discovering, developing and commercialising potential treatments or other therapies. You are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof and Paradigm does not undertake any obligation to revise and disseminate forward-looking statements to reflect events or circumstances after the date hereof, or to reflect the occurrence of or non-occurrence of any events. In addition, the past performance of Paradigm cannot be assumed as indicative of the future performance. There is NO guarantee of future performance, Including that Paradigm will achieve its stated objectives / milestones, that its forecasts will be met or that forward looking statements will be realised - actual results and future outcomes will in all likelihood differ from those outlined herein. Neither Paradigm nor any of its advisers, agents or employees make or give any express or implied representation, warranty or guarantee that the information contained in this presentation or otherwise supplied by or on behalf of Paradigm is complete or accurate or that it has been or will be audited or independently verified, or that reasonable care has been or will be taken in compiling, preparing or furnishing the relevant information. Paradigm does not take any responsibility for any inference, interpretation, opinion or conclusion that any person may draw or form from this presentation. To the maximum extent permitted at law, Paradigm and all of its representatives, directors, partners, employees or professional advisers exclude all direct and indirect liability arising out of or in connection with any use or reliance of the information contained or described within this presentation. Other than to the extent required by law (and only to that extent), the Parties do not make any representation or give any assurance, guarantee or warranty (express or implied) as to, nor assume any responsibility or liability for, the authenticity, origin, validity, accuracy, suitability or completeness of, or any errors in or omissions from, any information, statement or opinion contained in this Presentation or any accompanying, previous or subsequent material or presentation. Not an offer This presentation may not be released to US wire services or distributed in the United States. The new fully paid ordinary shares in Paradigm have not been, and will not be, registered under the US Securities Act of 1933 and may not be offered or sold in the United States except in transactions exempt from, or not subject to, the registration requirements of the US Securities Act and applicable US state securities laws. The distribution of this presentation in the United States and elsewhere outside Australia may be restricted by law. Persons who come into possession of this presentation should observe any such restrictions as any non-compliance could contravene applicable securities laws. See “International Offer Restrictions" for more information Paradigm Biopharma JUL 2025 Executive Summary Background Paradigm Biopharmaceuticals (ASX: PAR) is a late-stage drug development company focused on delivering new treatments for diseases with high unmet medical need. Our lead program, injectable pentosan polysulfate sodium (iPPS), is being developed for osteoarthritis (OA), a debilitating condition affecting millions worldwide. To develop and commercialise first-in-class therapies for musculoskeletal diseases, targeting inflammation, pain relief, and disease modification. Mission Market potential • Late-stage clinical development with Phase 3 trial commenced in the US and AUS. • Robust clinical and real-world data supporting iPPS. • Addressing one of the largest unmet needs in musculoskeletal medicine. 3 Paradigm Biopharma JUL 2025 Phase 3 OA program commencement – Site Activation, First Participant Consent Australia First Participant Consented in US 2025 Recent NewsFlow New IP Acquisition – Building out Paradigm OA portfolio. Funding Secured to provide runway through many significant milestones. 4 Paradigm Biopharma Advancing iPPS Toward a Differentiated OA Therapy Robust data and regulatory momentum 01 SAFETY & EFFICACY PROFILE • Strong efficacy and safety shown across a broad dataset • Durable benefits sustained to 12 months in Phase 2 studies • Imaging and biomarker data suggest effects beyond symptom relief 02 PHASE 2 AND REAL-WORLD EVIDENCE • Multiple Phase 2 studies underpin Phase 3 program, showing consistent efficacy across patient types and timepoints • Real-world insights from Australia's SAS program show long-term benefits with repeat courses 03 MECHANISM OF ACTION • Demonstrated across preclinical models and human studies • Anti-inflammatory, cartilage-protective, and matrix-restoring properties • Biomarker data from Phase 2 suggests activity beyond symptom relief underpin a well-defined path through Phase 3 04 OPTIMISED PHASE 3 PROGRAM • Fast Track designation granted by FDA • Protocol refined following extensive FDA engagement (Type C and D meetings) • Endpoints, statistical powering, and assessment windows aligned with regulatory expectations JUL JUL2005 2025 5 Paradigm Biopharma Drug Development Phase Success Rates Only about 12% of drugs entering Phase I ultimately receive regulatory approval, highlighting the high attrition rate in drug development. • The biggest drop-off occurs in Phase II, where just over one-third of candidates advance, often due to efficacy or safety issues. • Success rates rebound in later stages, with over 60% of drugs in Phase III progressing to regulatory submission. • Once a drug is submitted for approval, the likelihood of approval is high (around 86%). 6 Drug Development Phase Success Rate 86.5 Success Rate % • 02/12/21 JUL 2025 62.5 62 34.5 12 I - II II - III III - NDA NDA - Approval I - Approval Phase Source: "Benchmarking R&D success rates of leading pharmaceutical companies" (Drug Discovery Today, 2025) Osteoarthritis Pivotal PH3 Trial Paradigm Biopharma Study Overview A Phase 3, Doubleblind, Placebocontrolled, Multicenter Study to Evaluate Treatment Effect of Pentosan Polysulfate Sodium Compared with Placebo in Participants with Knee Osteoarthritis Pain. Trial Type: Phase 3 Study Drug: Pentosan Polysulfate Sodium (PPS) - Injectable Patient Population: Adults with moderate to severe knee osteoarthritis with pain Study Centres: Total: 65 sites Ø Australia: 15 sites Ø United States: 50 sites Number of Participants: Enrollment goal: 466 participants Ø Randomised 1:1 PPS to Placebo 29/12/20 JUL 2025 8 Paradigm Biopharma Phase 3 Objectives Key objectives for the Phase 3 PARA_OA_012 study Primary Objectives • To evaluate the treatment effect of PPS on knee pain in participants with knee OA pain. (Weekly Average ADP Day 112) Key Secondary Objectives • To evaluate the treatment effect of PPS on knee pain function in participants with knee OA pain. (WOMAC Day 112) • To evaluate the effect of PPS treatment on PGIC in participants with knee OA pain. (PGIC Day 112) • To evaluate the efficacy of PPS treatment on knee pain, function, stiffness, and overall, in participants with knee OA pain Secondary Objectives • • • WOMAC Pain and function assessments at multiple timepoints to Day 404 IPPS effects on Rescue Medication use Structural changes via X-Ray and MRI from baseline day 168, 404 JUL29/12/20 2025 9 Paradigm Biopharma PARA_OA_012 29/12/20 JUL 2025 10 Optimised Endpoint Design and Pain Scoring • Following FDA discussions, the primary efficacy endpoint is now assessed 8 weeks post-final injection, aligning with recent OA and chronic pain studies and reflecting the durable therapeutic effect of iPPS. • Independently scored and self reported by patient. • Pain is assessed via daily scores recorded through a smart device and averaged weekly to minimise day-to-day variability and ensure a more robust signal of clinical benefit. • A 14-day pre-dosing familiarisation period allows participants to practise consistent reporting and ensures compliance from the outset. • Automated daily alerts at a standardised time of day promote highquality data capture and time-aligned pain scoring. Paradigm Biopharma. JUL 2025 PARA_OA_012 Phase 3 trial design Follow-up Period: 52 weeks Treatment Period: 6 weeks Screening PPS 2 mg/kg N = 233* Placebo N = 233* Day 1 39 First Injection Last Inj. 56 84 112 Interim Analysis 140 168 224 280 336 404 End of Study Primary endpoint: Change from baseline in weekly ADP NRS pain score at Day 112. Secondary endpoints: Function, PGIC, rescue medication, biomarkers of disease progression, including MRI & X-Ray. *May be subject to change 11 Paradigm Biopharma. JUL 2025 PARA_OA_012 Phase 3 Site Locations by State United States 50 sites Australia 15 sites 12 Paradigm Biopharma JUL JUL2005 2025 13 PARA_OA_012 Considerations in Evaluating Probability of Success NRS 0-10 endpoint, average daily pain • What is a meaningful difference – statistical or clinical (anchor to PRO) • FDA recommended endpoint to ”reduce recall bias and capture day to day variability” Magnitude of Effect • How does the change from baseline in pain score relate to benchmarks of clinical meaning or MCII, MCID, PRO anchors such as PGIC Effect size-distribution based method of meaningful difference • Assessment of mean difference between groups corrected for standard deviation • What is relationship of ES to study power, sample size, and probability of success FDA: Analgesic Indications: Developing Drug and Biological Products — Guidance for Industry, February 2022. PRO: Patient Reported Outcomes MCII: Minimal Clinically Important Improvement MCID: Minimal Clinically Important Difference Paradigm Biopharma 29/12/20 JUL 2025 PARA_OA_005 Magnitude: NRS 0-10, absolute and %Change from Baseline NRS Med % CBL 4-6 7-8 iPPS Day 53 iPPS Day 81 -33.33 -16.67 NRS-valid and reliable measure of pain intensity -36.67 -14.29 -8.33 -28.57 • NRS assessed for prior 48 hours • Clinical MCID is one unit difference or 15% NRS (6) • 2-point reduction or 30% NRS anchors with clinically important PGIC change • PGIC MCID is one unit difference at 3 month (6) • Clinically important PGIC is much improved and very much improved (5) Absolute pain NRS -1.81 (2.31) -1.22 (2.32) 4-6 7-8 -1.61 (2.17) -2.28 (2.63) -1.15 (2.19) -1.81 (2.04) KOOS ADL Med %CBL 4-6 7-8 35.91 26.67 37.85 29.39 26.67 26.11 PGIC mean 4.42, 87% ≥5 14 Paradigm Biopharma 29/12/20 JUL 2025 PARA_OA_008 Magnitude: WOMAC, %Change from Baseline1 iPPS Day 56 iPPS Day 112 Pain -49.33* -45.05 Function -49.38* -46.58* Stiffness -45.51 -47.45 Overall -48.97 -46.02 1 MMRM-mixed model repeated measures • Sustained improvements in both pain and function scores were observed in the iPPS twice-weekly treatment group • These improvements* exceeded the Minimum Clinically Important Improvement (MCII) thresholds(2,3): • • • Pain reductions in the iPPS group approached the “substantial improvement” benchmark of 50% recommended by IMMPACT(1): • • • Pain: 17% Function: 12% 49% reduction at Day 56 45% reduction at Day 112 Patient Global Impression of Change (PGIC) 7point scale: • • • Day 365: 3.55 (2.11) vs 2.06 (1.70), p = 0.005 Day 112: 4.07 (2.16) vs 3.10 (2.26) Day 56: 3.93 (2.09) vs 3.15 (2.30) 15 Paradigm Biopharma 29/12/20 JUL 2025 16 PARA_OA_012 Endpoint: Observed effect size for Pain Scores (Scale 0-10) Time Para_005 Para_OA_008 Pooledweighted Day 39 0.33 0.38 0.34 Day 56 (53 for 005) 0.25 0.66 0.34 Day 112 (109 for 005) 0.20 0.46 0.30 Day 168 (165 for 005) 0.28 0.26 0.28 Study Population Considerations • SC 2mg/kg twice weekly x 6 Patient Populations • 005 BML 95%, KL 3-4~ 80% • 008 BML 70%, KL 3-4 79% Subgroup Observations • NRS 4-6 (70%) and KL4 (28%) improved pain responses in 005. Effects sizes form the basis for sample size calculations Paradigm Paradigm Biopharma Biopharma PARA_OA_012 – Probability of Success Clinically Important response on NRS Scale • • • Sample Size: ~466 participants with moderate to severe knee OA (KL Grade 2–4), randomised 1:1 Primary Endpoint: Change from baseline in weekly average pain (NRS 0–10) at Day 112 Standard Deviation (SD): Estimated between 2.0 and 2.5 for NRS change Effect Size (ES) and Detectable Differences • For ES = 0.3: • Difference between means = 0.6 (SD 2.0) • Difference between means = 0.75 (SD 2.5) • For ES = 0.2: • Difference between means = 0.4 (SD 2.0) • Difference between means = 0.5 (SD 2.5) Clinical and Statistical Relevance • MCID (Minimal Clinically Important Difference): ~1 point or 15% on NRS • Power Assumptions: • N=233 per group detects ES = 0.2 for SD 2–2.5 • Minimum observed effect size for significance at final analysis: 0.18 (N=466, p<0.024, 1-sided) JUL JUL2005 2025 17 Paradigm Biopharma PARA_OA_012 Interim & Final Analysis Interim analysis (IA) is planned after pain intensity data are available from 50% of total planned sample size 466 (randomised 1:1). Outcomes of IA could be: • • Early conclusion of futility if an observed effect size of 0.1 (between-group difference in means divided by SD). Early conclusion of efficacy if an observed effect size of 0.39 (p-value < 0.002, O’Brien-Fleming type 1 error spending function to control the overall type 1 error at 0.025 1-sided. If neither a futility or efficacy conclusion can be reached at the IA, the trial will continue to the final analysis with planned N=466 and require p<0.024, 1-sided for success. 29/12/20 JUL 2025 18 Paradigm Biopharma JUL 2025 19 News flow & catalysts Upcoming Clinical Catalysts Event Target Date PARA_OA_012 – First participant dosed US and Aus Q3 CY2025 PARA_OA_012 – 50% Recruitment of participants 2H CY2025* PARA_OA_012 – 100% Recruitment 1H 2026* PARA_OA_012 Interim Analysis – 50% participants reach Day 112 Mid-CY2026* *The above is a statement of current intentions as at the date of this presentation. Investors should note that the above upcoming events are subject to funding or new circumstances. Paradigm Biopharma Paul Rennie Managing Director Email: prennie@paradigmbiopharma.com Simon White Director IR Email: swhite@paradigmbiopharma.com For more information please visit: paradigmbiopharma.com JUL 2025 20 References: 1. Robert H. Dworkin, Dennis C. Turk, Kathleen W. Wyrwich,, Dorcas Beaton. Interpreting the Clinical Importance of Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT Recommendations https://www.jpain.org/issue/S15265900(07)X0083-X 2. Angst F, Aeschlimann A, Michel BA, Stucki G. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. Journal of Rheumatology. 2002;29(1). https://doi.org/10.3899/jrheum.151415 3. Bellamy N, Hochberg M, Tubach F, Martin-Mola E, Awada H, Bombardier C, et al. Development of multinational definitions of minimal clinically important improvement and patient acceptable symptomatic state in osteoarthritis. Arthritis Care Res (Hoboken). 2015;67(7). https://doi.org/10.1002/acr.22538 4. Hawker : https://doi.org/10.1002/acr.20543 5. Farrar: https://doi.org/10.1016/s0304-3959(01)00349-9 6. Salaffi: https://doi.org/10.1016/j.ejpain.2003.09.004