September 7, 2023 1 P01: Imaging, Dosimetry and Radiobiology for α-emitter Radiopharmaceutical - PowerPoint Presentation

1. September 7, 20231P01: Imaging, Dosimetry and Radiobiology for α-emitter Radiopharmaceutical TherapyGeorge Sgouros, Ph.D.Director of Radiological Physics Division (RPD)Professor, Department of Radiology, Johns Hopkins University

2. DisclosuresConsultantAbdera Therapeutics, Bayer, PointBiopharma, Precirix, RayzeBioScientific Advisory BoardOrano Med, Convergent Therapeutics, PrecirixFounder, StakeholderRadiopharmaceutical Imaging and Dosimetry, LLC (Rapid)

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7. Main Challenge“Don’t Let the Perfect be the Enemy of the Good”Define Good

8. Results of trialsALSYMPCA: 14 vs 11.2 months; 2.8 mo OSNETTER–1:No significant improvement in OSVISION: 15.3 vs 11.3 months; 4 mo OSTheraP – Pluvicto equivalent to cabazitaxel (19.1 vs 19.6 mo OS)

9. Success rate of oncologic drugsChi Heem Wong, Kien Wei Siah, Andrew W Lo Estimation of clinical trial success rates and related parametersBiostatistics, Volume 20, Issue 2, April 2019, Pages 273–286 97% of cancer drugs that are evaluated in humans fail

10. “Don’t Let the Passably Adequate be the Enemy of the Better”

11. Radiopharmaceutical Therapy Current implementation

12. Radiopharmaceutical Therapy Ideal Implementation

13. Treatment planning-based Radiation DeliveryRadioactive ChemotherapyPhase 1 benefit v risk (B/R)is limitedPhase 2,3B/R generally > Phase 1,2Simplified Quantitative ImagingDosimetry forαRPT that accounts forµscale distributionMacro2µ activity apportionmentoptimize combo Tx, pick responders Radiobiology and PK modelingµscale S valuesP2P1P3Core UseEmpirical/observational“Everything is numbers” (almost) DCAP1DCBAP2DCBAP3DCAP4CURRENTFUTUREAAdminBPath/HistopathCBiostats/Data MgmtDPatient Studies/Clin TrialsCoresAccount for αRPT scaleP4BB

14. Underpinnings of the Alpha P01Alpha-particle-emitter radiopharmaceutical therapy (αRPT) is a new and fundamentally different therapeutic modality. Can deliver highly potent, α-particles to disseminated cancer cells. Does not rely on understanding the signaling pathways. Radiation delivery modality; radiation type is impervious to resistant mechanisms that limit other cancer therapies. Clinical implementation of αRPT can benefit by imaging and dosimetry-driven treatment planning.

15. Underpinnings of the Alpha P01In the context of αRPT this translates to answering the following two questions: 1: Where does the αRPT localize and for how long? This is fundamentally an imaging and dosimetry question. No one cancer treatment modality is curative and patients differ in their potential therapeutic response and toxicity. 2: Can the unique radiobiologic properties of α-emitters be used, in combination with dosimetry-driven treatment planning:To identify agents most likely to improve response? Identify patient populations that will most benefit from αRPT?

16. Why is a program project needed?αRPT dosimetry is multidisciplinary imagingpharmacokineticsradiation biologyphysicsαRPT dosimetry is complexmicroscale effectshigh potencyDNA DSB repair modulationαRPT dosimetry is essentialtoxicity vs undertreatmentcombination w/ DNA DSBr modulatorscombination with radiotherapyCoordinated effort will be more scientifically and financial efficientfaster and greater scientific return per $ spent

17. Alpha P01 ProjectsP1: Alpha-emitter Imaging for dosimetry and treatment planning: (Yong Du, Eric Frey (Rapid Sub contract)Rigorously validated Quantitative SPECT for α-emittersReduce number of time-points requiredExtract genomic/histo info from imaging P2: Macro to μ S-values (Wesley Bolch)Generate anatomical models of micro-scale anatomyCalculate micro-scale S values for α-particlesAssess variability of S valuesP3: Macro to μ Apportionment (Rob Hobbs)Calculate partition coefficients to apportion macro activity to micro substructuresTwo species (murine, porcine)Validate via dose-response studyP4:Radiobioeffect modeling of αRPT (George Sgouros)Relate absorbed dose to DNA DSB repair kinetics and responseImpact of germline, somatic mutationsImpact of DNA DSB repair pathway inhibitors

18. Alpha P01 CoresA - Administrative (George Sgouros)B - Path/Histopath (Kathy Gabrielson)C- Biostats/Data Mgmt (Hao Wang)D - Patient Studies/Clin Trials (Ana Kiess)

19. Integration*P1: Alpha-emitter Imaging for dosimetry and treatment planning(Core D) Patient imaging, (Core B)  genomic, expression pattern biopsies(P2, P3)  M2μ to get absorbed doseTumor, normal tissue absorbed dose vs response  (P4) P2: Macro to μ S-values(Core D)  Patient dose-limiting tissues(Core B) substructures that drive toxicity(P1) Tissues that concentrate activity by imagingμ S-values  (P3, P1)P3: Macro to μ apportionment factors(P2)  μ S-values (P1)  Quantitative imaging(Core B)  Animal path/histo(Core D)  macroscopic organ activitiesM2μ  (P1, P4)Identify microscale regions that are uniform  (P2)P4:Radiobioeffect modeling of αRPT(Core B)  biopsy repair pathway(Core D)  access to clinical trial involving biopsies and repair inhibitors (Hopkins UWash trial of 223Ra)(P1)  tumor normal tissue absorbed vs responseImpact of repair pathway deficiencies on dose vs response (P1)*All projects use Cores A (admin) and C (biostats)

20. Advisory CommitteeZaver Bhujwalla (Hopkins)Experience managing large grants (P50, P30)Cancer imaging, VC radiology researchTed Deweese (Hopkins)Chair of Rad Onc, Vice Dean clin affairsRadiobiologyRick Jones (Hopkins)Experience managing P01Director BMT program, SKCCCThomas (Rock) Mackie (U Wisconsin)Medical Physicist in Rad Onc3-D treatment planning, developer of tomotherapy, Pinnacle System treatment planningMike Sathekge (University of Pretoria, South Africa)Head, Nuclear Medicine DepartmentNuclear Medicine physician – alpha-, beta-emitter PSMA therapyKatarina Sjogren-Gleisner (Lund University, Sweden)Clinical radiotherapy medical physicist, radiopharmaceutical dosimetry expertICRU RPT dosimetry Committee memberMicheal Zalutsky (Duke U)Radiochemist, alpha-emittersTranslation to clinic

21. Project 1: Alpha-emitter Imaging for dosimetry and treatment planning​Yong Du (JHU) and Eric Frey (Rapid)September 7, 2023Project 121

22. Specific AimsThe overall goal is to develop a workflow that uses images for dosimetry and treatment planning for alpha-emitter radiopharmaceutical therapy (aRPT). Develop and validate quantitative SPECT imaging of alpha-emitters.Optimize and simplify imaging protocol for accurate dosimetry. Statistically analyze the relationships between quantitative images, dosimetry, dose-response, therapy outcome. 9/7/2023Project 122

23. Overview9/7/2023Project 123

24. Project 2: Macro-to-Micro Radionuclide S ValuesPI: Wesley Bolch

25. Project 2 – Macro-to-Micro Radionuclide S ValueMathematical framework of the micro-to-macro (MTM) formalism: MIRD Schema at the macro-scale tissue level: MIRD Schema at the micro-scale tissue level – microscale S value:  MIRD Schema at the micro-scale tissue level – activity apportionment factors fMTM  Macroscale source region – what you can measure in the patient via traditional NM imagingMicroscale source region – what you can measure via tissue histology in an animal modelMicroscale target region – what cell population you think is responsible for organ toxicity (modeling)MacroscalerS = LiverrT = LungsMicroscalerS = Blood of Hepatic arteryrT = Hepatocytes

26. Project 3: Macro-to-micro ApportionmentRobert HobbsSeptember 7, 202326

27. ApportionmentMeasure (isotope) activity conc aij(t) in compartments AND whole organMultiply by fraction of occupancy fi to apportion fraction of activity gi to compartmentsBound RPT and free daughters (e.g. 213Bi)Hobbs et al. Phys Med Biol ’12

28. Project 4 - Radiobioeffect modeling of αRPTGeorge SgourosSeptember 7, 202328

29. Two genes are synthetic lethal if mutation of either alone is compatible with viability but mutation of both leads to death. So, targeting a gene that is synthetic lethal to a cancer relevant mutation should kill only cancer cells and spare normal cells.Kaelin WG, Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5(9):689-98; Hartwell Science 1997Bkg/RationalenormaltumorαRPT (D2)αRPT (D1<D2)Synthetic Lethality

30. P01 Core D – Patient Studies CoreAna Ponce Kiess, MD, PhDNov 9, 2020

31. Specific AimsThis core will provide the patient data needed to perform the work described in each project.Aim 1: To acquire and maintain patient images and associated clinical data for use by the investigatorsAim 2: To propose and lead sub-studies of ongoing clinical trials required for each projectAim 3: To coordinate collaboration among clinical investigators, study sponsors and P01 investigatorsAim 4: To enhance the potential to collect patient data from routine RPT patient therapy and future clinical trials of RPT agents

32. Core C: Biostatistics CoreLeader:Hao Wang, Ph.D.

33. Specific AimsAim 1: Provide comprehensive statistical consultations and collaborations for all Projects and Cores. Aim 2: Collaborate with the Patient Studies Core D to ensure that clinical trials have appropriate design, monitoring, sample collection, data management and analysis. Aim 3: Spearhead the development of centralized facilities and protocols for data storage, management, and dissemination.

34. Core B: Pathology CoreLeader:Kathy Gabrielson D.V.M., Ph.D., DACVP

35. Specific AimsAim 1: Collaborate with each project to ensure that all animal models have appropriate design, monitoring, sample collection, data management and analysis. Aim 2: Provide comprehensive gross and histopathology consultations and collaborations for all Projects. Compare PET/CT and SPECT/CT imaging to gross or histopathology. Aim 3: Work with Core D to acquire and pathologically characterize retrospectively or prospectively collected human tissue samples from relevant αRPT clinical trials.Aim 4: Validate and implement in situ molecular assays to quantify DNA damage and repair on animal and human tissues with a centralized facility for digital imaging, quantification, data storage, management, and dissemination.

36. Core A – AdministrativeGeorge Sgouros

37. Specific AimsProvide overall scientific leadership and managerial oversight, including integration of research activities across the projects and cores. This includesBudgetary oversightSupport for manuscript preparation, submission, registrationSupport for preparation of progress reportsFacilitate/coordinate resource sharingDisseminate results across projects, Work w/ industry and other stakeholders to implement findingsThe longer-term objective of this core and the overall program PI is to foster interactions and collaborations across disciplines, departments and institutions, at both the administrative and faculty member level that will endure beyond the P01 period and lead to breakthroughs in basic, translational, and clinical research related to αRPT.

38. AA =7.4 MBq, 1 of 2SPECT/CT imaging *Optimal AA (dose) for 2 0f 2AA=OAA2 of 2*“Optimal” Administered Activity (OAA): RM absorbed dose (AD) ≤ 2 Gy and kidney AD ≤ 23 Gy; other (SG) require data/analysisNormal tissue dosimetryPBMC γH2AX eval2-STEP αRPT7-15 days

39. AcknowledgmentsRemco BastiaannetMahmood HasanRob HobbsZhi LiIoanna LiatsouJoe PiccoloEmmanuel AntonarakisPhuoc TranRebecca KriminsJun LuoTamara LotanMike CarducciBill NelsonKaren HortonR01CA187037U01EB031798P01CA272222

40. Treatment planning-based Radiation DeliveryRadioactive ChemotherapyPhase 1 benefit v risk (B/R)is limitedPhase 2,3B/R generally > Phase 1,2Simplified Quantitative ImagingDosimetry forαRPT that accounts forµscale distributionMacro2µ activity apportionmentoptimize combo Tx, pick responders Radiobioeffect modelingµscale S valuesP2P1P3Core UseEmpirical/observational“Everything is numbers” (almost) DCAP1DCBAP2DCBAP3DCAP4CURRENTFUTUREAAdminBPath/HistopathCBiostats/Data MgmtDPatient Studies/Clin TrialsCoresAccount for αRPT scaleP4BB