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Tri-Lab Research Effort to Provide Accelerator-Produced 225 Ac for Radiotherapy:

Unveiling the progress and projections of the accelerator-produced 225Ac for alpha therapy, tapping into clinical trials and increased customer demand, aiming at revolutionizing cancer treatment.

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Tri-Lab Research Effort to Provide Accelerator-Produced 225 Ac for Radiotherapy:

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  1. Tri-Lab Research Effort to Provide Accelerator-Produced 225Ac for Radiotherapy: Overview and Summary Kevin John Los Alamos National Laboratory September 19-20, 2018 Annual Program Review

  2. Brief Background Update on October 2017, Review Answering the Charge Overview of the Tri-Lab Effort Summary of Effort to Date Outline ORNL 225Ac Finished Product

  3. Brief Background

  4. Expanding the Alpha Therapy Toolkit: 225Ac Xofigo (radium-223 dichloride, Bayer)- First FDA approved alpha therapy agent in 2013 225Ac, t1/2 = 10 day, Ea = 5-8 MeV Multiple clinical trials (lymphoma, melanoma, glioma and neuroendocrine tumors) in the US and Europe focused on 225Ac direct application or on the use of 213Bi via an 225Ac/ 213Bi generator Interest in 225Ac direct labeling applications increasing based on recent prostate cancer work and FDA orphan drug status of Actimab-A for treatment of AML (Actinium Pharmaceuticals, Inc.) Significant uptick in the number of customers interested in the 225Ac supply chain

  5. Recent 225Ac Clinical Work Clemens Kratochwil, University Hospital Heidelberg – J. Nuc. Med., v57, 2016, pp 1941-1944 NOTE: This study was conducted with 229Th-derived 225Ac

  6. Current worldwide supply of 225Ac is estimated at 1200-1700 mCi/yr* derived from 229Th/ 225Ac generators Patient doses, as informed by clinical trials, are estimated at: 225Ac: 0.3-5 mCi per patient kg (25-400 mCi/patient) 213Bi: 1 mCi per patient kg (Optimum generator loading estimated at 100-150 mCi225Ac) Demand projected to be 30-50 Ci/yr** 225Ac Supply and Demand Projection of Ac-225 demand assuming multiple, approved Ac-225 and Bi-213 drugs and robust clinical R&D programs • *International Atomic Energy Agency. Technical Meeting Report “Alpha Emitting Radionuclides and Radiopharmaceuticals for Therapy” IAEA Headquarters Vienna, Austria, June 2013 • **US DOE Offices of Nuclear Energy and Nuclear Physics “2008 Workshop on The Nation’s Needs for Isotopes: Present and Future” Rockville, MD August 2008

  7. * Theoretical maximum value assumed for production with 450 µA on target resulting from successful completion of IPF Accelerator Improvement Project. J.W. Weidner et al. Appl. Radiat. Isot. 70 (2012) 2602 J.W. Engle et. al. Phys. Rev. C. 88 (2013) 014604 J.W. Engle et. al. Radiochim. Acta 102 (2014) 569 J.R. Griswold et. al. Appl. Radiat. Isot. 118 (2016) 366 Accelerator Production via 232Th(p,x)225Ac – Initial R&D Promised Significant Impact AIP investments at IPF and BLIP have increased our projected production capacity

  8. 8 Basis of the Tri-Lab Effort: Leveraging UniqueIsotope Program Facilities, Capabilities and Expertise to Address 225Ac Supply LANL Isotope Production Facility (IPF) at LANSCE; 100 MeV incident energy up to 250 mA for routine production ORNL - Approximately 25 years of experience in the isolation of 225Ac from fissile 233U via 229Th BNL Linac at the Brookhaven Linac Isotope Producer (BLIP) 160 μAintensity to targets at incident energies ranging from 66-202 MeV

  9. 8 Management Overview – Leveraging World-Class Expertise DOE Office of Nuclear Physics Acquisition Executive DOE NP: J. Gillo Laboratory Champions ORNL: D. Dean, BNL: B. Mueller, LANL: D. Rej Federal Program Manager DOE NP: E. Balkin Mission Integration, Infrastructure ORNL: D. Stracener BNL: C. Cutler LANL: E. Birnbaum NIDC: M. Ferren Ac-225 Technology Research and Integration Effort – Contract Project Manager LANL: K. John Customer / Product Requirements, Product Evaluation & QA NIDC: W. Runde NIDC: A. Brown Chemistry Development & Demonstration • ORNL: R. Copping • BNL: J. Fitzsimmons, D. Kim • LANL: M. Fassbender Targetry Development & Demonstration LANL: M. Nortier, E. Vermeulen, J. Cooley BNL: D. Medvedev Materials and Final Product Evaluation and Production LANL: K. John Transportation Logistics • NIDC: K. Felker Project Management LANL: D. Jones • ORNL: J. Cunningham • BNL: R. Grubb ES&H LANL: K. John ORNL: M. Dunsmore BNL: E. Lessard LANL: L. Bitteker

  10. Updates Since Last Review

  11. Develop a “Plan B” for the planned BNL facility modifications should the SLI funding not materialize and present to the Office of Nuclear Physics (NP) by the end of the calendar year. -Plan B report submitted on 12/21/17 (see read-ahead materials), NP communicated adequacy of response on 5/7/18. Prior to initiating Stage 2, update the PMP to include the most up to date plans for Stage 2, as presented at the review, in terms of scope, and cost and schedule. Include the new project profile, including contingency. -A Stage 2 update to the PMP and associated RLS was submitted on 12/21/17 (see read-ahead materials), NP communicated adequacy of response on 5/7/18. Updates Since Oct 2017 Review

  12. Generate a cost-benefit analysis for facility upgrades that takes into consideration several options and associated implementation and life cycle costs to each. The analysis should articulate the justification and prioritization for the establishment of modifications and processing capabilities and should consider options such as the costs to develop a new shipment strategy to ship Ci-level targets from LANL or BNL to ORNL; and the irradiation of large targets versus multiple stacks. Submit to NP by May 1, 2018. -A facility/shipping alternatives analysis was submitted on 5/1/18 (see read-ahead material), NP communicated adequacy of response on 6/20/18. Updates Since Oct 2017 Review

  13. Refine the Stage 3 cost range and present at the next annual review. Updates Since Oct 2017 Review Note: we will submit a detailed, bottom-up Stage 3 estimate as part of the Stage Gate 2 review Refine the Stage 3 cost range and present at the next annual review.

  14. The LANL team should develop a plan for handling alpha waste and present status at the next Ac-225 Tri-Lab annual review. -LANL has developed a report to address this recommendation that details our understanding of current waste streams for the existing process and the anticipated needs of scale-up -This has been translated into the pre-conceptual engineering design process sheets that provide anticipated waste streams and value-added byproducts Update Since May 2018 LANL S&T Review

  15. Answering the Charge

  16. Significance and merit of the research effort • K. John, R. Copping, M. Nortier presentations and technical breakout session (program management plans) Status of the technical effort • Scope: K. John presentations and project management breakout • Merit: K. John, R. Copping, M. Nortier presentations and technical breakout • Feasibility: C. Cutler, D. Stracener, E. Birnbaum, K. Felker presentations and facility/ES&H breakout • QA: K. John, R. Copping, M. Nortier, A. Brown presentations Answering the Charge: Technical, Cost, Schedule and Management Review – Meeting the Charge

  17. Feasibility of budget, schedule including workforce availability • Read ahead materials (monthly/quarterly reports, Stage 2 RLS), K. John presentations and project management breakout session Transitioning to operations, establishing production plans • Read ahead materials (QA documentation), K. John, K. Felker and C. Cutler, D. Stracener, E. Birnbaum presentations (operations) and R. Copping and M. Nortier presentations (production) Technical, Cost, Schedule and Management Review – Meeting the Charge

  18. Effectiveness of the proposed management structure and approach to ES&H • K. John presentations, breakout sessions (risk and opportunity management plan + register) Other issues relating to the Ac-225 effort • breakout sessions Technical, Cost, Schedule and Management Review – Meeting the Charge

  19. Overview of the Tri-Lab Effort

  20. The overall effort is staged in order to systematically address technical and logistical risks • Stage 1-Initial support for preliminary product assessments: Routine production of 5-50 mCi of 225Ac and/or 225Ac/213Bi generators in order to establish product equivalency and to develop specifications for accelerator-produced material. • In addition to product assessment focus, Stage 1 will also concentrate on refining our understanding of the effort’s overall risk profile through a series of technical campaigns and candid assessments of overall facility, transportation, staffing resources and QA infrastructure. • Outcomes of these assessments will be critical inputs for go/no-go decisions and will serve to define the work scope for Stages 2 and 3. 19 PMP Overview – A Staged Effort Using a Risk Based Planning Approach

  21. Description of Stage 1 All level 1 and 2 milestones met and Stage 1 was executed under budget and roughly 1 year ahead of schedule Significant technical progress related to target design experience and chemical process optimization Stage 1 irradiations have provided us with invaluable logistical experience and delivered a means to supply material for materials evaluation campaigns and biodistribution/dosimetry/toxicity studies

  22. Stage 2-Intermediate stage effort in support of initial clinical trials: Routine production of 50-100 mCi of 225Ac for direct application studies and for development of 225Ac/213Bi generator studies with focus on dosimetry and toxicity. A key parallel effort associated with Stage 2 is the co-location of production and processing capabilities and may include facility upgrades or modifications as identified in Stage 1. Stage 3-Final preparations for routine production: Routine production of 100-1000mCi of 225Ac for support of multiple users of direct application of 225Ac and/or 213Bi generators at multiple sites. 21 PMP Overview Continued – Stages 2 and 3

  23. 22 STAGE 2 50-100 mCi Continued Production/Processing STAGE 3 100-1000 mCi Complete Facility Mods Implement Facility Mods and ES&H/QA Policies Routine Production SG-1 SG-2 SG-3 Final Prep for Routine Production SG-4 Project Complete Receive DOT Type B Container April, 2025 April, 2024 Oct, 2017 Sept, 2020 Complete ES&H/QA Documents Implement Chemistry/ Targetry Scale-up Next Annual Progress Review Scheduled for Sept 2019

  24. 23 Stage 2 Focus • General focus on increasing production frequency and volume in anticipated support of clinical trials • Continued improvements to the design and preparation of thorium targets and radiochemical processing optimization • Continued improvement of shipping capabilities and performance • Submittal of a Drug Master File to inform the FDA, helps our customer base and protects our process • Starting to execute facility vision with eye toward Stage 3 processing • Continued focus on stakeholder and customer interactions. First-in-human study using 225Ac-PSMA-617 derived from a 229Th- cow

  25. Summary of Effort to Date

  26. Production Summary We’ve produced over 1800 mCi of 225Ac at EOB and distributed over 235 mCi of accelerator produced 225Ac/213Bi as part of the Tri-Lab Effort, additional material used for chemistry, targetry and QC method development 15 separate batches have been processed with multiple shipments per batch resulting in distribution to 15 different customers/evaluators, many repeat shipmentsThe Tri-Lab effort has generated multiple publications and patents (see US patents 9,951,399 and 9,555,140)Forward Stage 2 focus on increasing production frequency and volume in concert with guidance from NIDC Target processing at ORNL, Building 4501 Hot Cell Facility

  27. We have had an ongoing dialog with FDA – some highlights below: Accelerator-produced 225Ac for direct labeling and 213Bi generator application will be viewed by FDA as an Active Pharmaceutical Ingredient (API) The Tri-Lab Effort has supported initial dosimetry/toxicity studies aimed at determining impact of 227Ac content; ultimate determination rests on drug developers as they develop their Investigational New Drug Applications (IND) FDA has urged us to develop an accelerator-produced 225Ac Drug Master File -DMF development is in process and will be submitted in mid-late Stage 2 We will continue to work with NP, NIDC and the 225Ac user community to address issues and concerns 26 FDA and End-user Interactions (Ariel Brown) 2018 special issue of Current Radiopharmaceuticals “In conclusion, our data demonstrates that accelerator-produced 225Ac is suitable for the development of pre-clinical and clinical targeted radionuclide therapy”

  28. 27 Targetry Demonstration (Meiring Nortier) We must design targets capable of withstanding the proton beams delivered at IPF and BLIP in anticipation of Ci-level production. Continued focus on optimization of thermal contact between Th target material and target cladding at LANL. BNL target designs are nearly ready for Ci-level production. Forward focus on the development of target fabrication defense-in-depth to address LANL Sigma facility single-point-failure. BNL 3rd generation thick Th target undergoing post-irradiation examination after “cook-and-look” experiment. Note that 1 of the 3 Th puck segments had to be aggressively loosened in order to be removed from the cladding

  29. 25 Chemistry Demonstration (Roy Copping) Our understanding and control of the chemical process has developed dramatically under the Tri-Lab effort 225Ac is routinely isolated in high yield/purity Exciting developments regarding Th-debulking – required for Stage 3 target masses (>50-100g Th) -Anticipating a downselect process in 2019 -Implementation of preferred alternative in a hot cell process by 2020 Draft chemistry process flow sheet developed at the May 2014 Chemistry Workshop (Blue- LANL Scope, Orange- BNL Scope, Green- ORNL Scope) Current chemistry process flow sheet as presented at the August 2018 Chemistry Workshop

  30. 29 Transportation Logistics (Kevin Felker) Fast-tracked the purchase order for the amendment of the SARP for the Croft 3977A – amendment in process New unit(s) will be ordered pending outcome of SARP amendment process in Stage 2 Special form capsule approach developed as a compensatory measure under the revised Stage 1 cost/schedule – new cask and container received, used for LANL-to-ORNL shipments; will be sufficient through Stage 2 for LANL Pursuing use of SFC at BNL and next generation design (W vs DU)

  31. 30 Facilities (Multiple Talks) ORNL 4501 adequate for Stage 2 – depending on process frequency Stage 3 and beyond will require co-location of production and processing operations Stage 1 gap analysis has evolved into a Stage 2 facility integration strategy focusing on the BNL MEL hot cell facility and LANL green field concept -additional ORNL preferred alternative will be considered for defense in depth and for alternative method(s) of production Staged, strategic resource needs are reflected in the Stage 2 RLS and cost/schedule estimates for facility concepts will be presented ORNL, Bldg 4501 Hot Cell BNL, MEL Hot Cell Facility

  32. Approx. 36,000 hours charged to the Tri-Lab effort since April 2015 – no safety or security issues (no DARTs/TRCs or ORPS-reportable events) Overall effort is well understood now with BNL/LANL target irradiations, ORNL processing, shipping logistics and waste forward path – no significant changes anticipated for entirety of Stage 2 We’ll need to devote additional attention to safety as we focus on increased production volume/frequency Knowledge from Stage 1 built into Stage 2 RLS Stage 2 effort will focus on Stage 3 readiness (i.e., modifications to AB documents, Type B container implementation, etc.) 31 ES&H, Waste Streams

  33. Stage 2 launched Jan. 2018 with a focus on increasing production frequency/volume with an eye toward supporting clinical trials Strong focus on technical advances moving forward from a research concentration toward an emphasis on production development Stressing an emphasis on the execution of an integrated facility vision to ensure that we are ready to support our anticipated, enhanced production efforts Significant challenges remain with respect to the impact of Ac-227 impurity (perceptions, facility licensing, patient waste disposition) -we are working with FDA and NRC to address these concerns; feedback has been positive/supportive to date 32 Summary

  34. Addressing the Supply Chain: Various 225Ac/229Th Production Routes

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