TAT-11, Ottawa

Consideration toward Safety Guidance for Targeted Alpha Therapy in Japan

Tsuneo YANO1), Koki HASEGAWA2), Tatsuhiko SATO3),1) Akiko HACHISUKA4), Koichi FUKASE5), Yoko HIRABAYASHI6)

April 2nd, 2019

1) QiSS-Targeted Alpha Therapy Research, Research Center for Nuclear Physics, Osaka University 2) Center for Instrumental Analysis, Kyoto Pharmaceutical University 3) Nuclear Science and Engineering Center, Japan Atomic Energy Agency 4) Division of Biochemistry, National Institute of Health Sciences 5) Department of Chemistry, Graduate School of Science, Osaka University 6) Center for Biological Safety & Research, National Institute of Health Sciences

TAT-11, Ottawa Preclinical Safety Evaluation

1) to identify an initial safe dose and subsequent dose escalation scheme in human

2) to identify potential target organs for toxicity and to examine whether such toxicity is reversible

3) to identify safety parameters for clinical monitoring

We focused on both astatine 211At and actinium 225Ac as the alpha-emitters. We also discuss on initial human-dose and dose escalation, organ identification to suspect toxicity and evaluation items for monitoring upon considering physical half-lives, drug stabilities and accumulation into targeted cells. We also propose the selection method of TAT drug candidates which is satisfied with safety profile including delayed-type toxicities under our new evaluation system with histopathological examination. TAT-11, Ottawa Characteristics of Alpha Particle

extremely High LET very Short Range

Cell size: 10-100 mm

α-particle Range: 40-90 mm Vessel β α LET: 100keV/mm

Normal cells β-particle Range: 800-5000 mm LET: 0.8keV/mm

Tumor cells

TAT-11, Ottawa

Strategy for Safety Evaluation at Preclinical Stage

Problems to be solved 89Y- instead of 90Y- When stable isotope corresponding to alpha nuclide is existed, toxicity test is conducted by its labeled test compound. However, astatine 211At and actinium 225Ac do not have stable isotopes. Therefore, above mentioned strategy can not be applied.

Extended single-dose toxicity test Alternative strategy Guidance for Exploratory IND studies 2006 Safety evaluation with alpha nuclides labeled compounds including histopathological evaluation allows us to evaluate the toxicities at cellular level in mice. Delayed toxicity and recovery are revealed to perform histopathological evaluation over a long duration (1 week or 1 month) after injection. Microdosimetry

Cellular Effects by Alpha Particles

α 10～100mm

Not Integrated Integrated in the narrow space in the narrow space Little Hit Much Hit It is difficult to calculate cellular effect by the measurement because differences in cell dozens or so minute space

Direct Effect by Alpha Particles α Simulation is important

Apoptosis very short range （around 2-10 cells of diameter） In-direct Effect by Alpha Particles Oxidative stress or Abscopal effect ? Cleavage of Double-strand DNA by extremely high LET Need of Specific Dosimetry for TAT Treatment very short range → Accumulation is important in Organ microstructures (cavernosum, nephron etc.)

Mouse Kidney Dose evaluation is required taken with α-Camera at radiosensitive regions, (Hobbs et al.) Not the averaged absorbed dose in organs

α-Ray possess high ionization density → α-ray compared with γ-ray and β-ray causes the complexed DNA damage

Ionization density distribution around the electron and proton-carbon ion At the same dose, taking into account a high therapeutic efficacy (relative biological effectiveness), dose assessment is necessary TAT-11, Ottawa Microdosimetric simulation

Thanks to Dr. Robert F. Hobbs, Prof. George Sgouros Microdosimetry study developed by Johns Hopkins University was applied to several alpha-particle-emitting radiopharmaceuticals. It was applied on Ra-223 dichloride (Xofigo) which was the first alpha-emitter radiopharmaceutical that has received approval for the treatment of patients with castration-resistant prostate cancer metastasized to bone. It was implemented in a new clinical trial for treatment of patients with bone metastases in renal cell carcinoma. This approach was also illustrated for the immune checkpoint inhibitor, PD-L1 antibody to investigate as a means of alpha-particle emitter delivery in a combined immunological and alpha-particle emitter targeting strategy. Thanks to Prof. Alfred Morgenstern The newlyProposed proposed two microdosimetric Microdosimetry simulation models is developed by Japan Atomic Energy Agency on the basis of PHITS coupled with -Stochastic Microdosimetric Kinetic Model. PHITS-SMK Model Johns Hopkins Model

Particle and Heavy Ion PHITS GEANT4 Transport code System Simulation geometry Grid cell populations Fine structure of organs (nephrons, bone marrow cavity, etc.)

Minimum Target Size Cell nuclear domain Cell (～0.5μm) Drug Concentration Consider accumulation for Consider integration of Distribution each cell site and inter- each organ cellular heterogeneity microstructures

Estimated amount RBE or biological dose DVH at cellular level or S-value of microstructure

Complementary role is both TAT-11, Ottawa Cellular scale simulation for estimating RBE

PHITS-SMK Model will be established to adopt reliable extrapolation in preclinical studies for alpha-emitter radiopharmaceutical products as well as BNCT[1].

Cellular-scale dose distributions for typical α & β emitters calculated by PHITS

[1] Tatsuhiko Sato et al. Sci. Rep. 8, 988 (2018) New Evaluation System Biodistribution analysis by PET or SPECT using complementary nuclide labeling agents

JP Patent Appl. No. 2018-189191 & No. 2019-4146

Localization analysis by auto-radiography for animal tissues using alpha-camera or CR-39

Thanks to Prof. Lars Jacobsson, Dr. Tom Bäck Dose escalation studies Histopathological examination for delayed-type toxicities in preclinical animal studies

Establishment of microdosimetric simulation and verification of accuracy using an animal model

Extrapolation to human Important Aspects for Drug Development

Tsuneo Yano, Koki Hasegawa, Akiko Hachisuka, Koichi Fukase, Yoko Hirabayashi, Discussion on Translational Research of Drug Product for Targeted Alpha Therapy – Part 1 –, Pharmaceutical and Medical Device Regulatory Science, 49(10), 676-684 (2018). Safety Evaluation

Quality/GMP Synthesizer toward Medical Device application Efficacy Microdosimetry

Tsuneo Yano, Koki Hasegawa, Tatsuhiko Sato, Akiko Hachisuka, Koichi Fukase, Yoko Hirabayashi, Discussion on Translational Research of Drug Product for Targeted Alpha Therapy – Part 2 –, Pharmaceutical and Medical Device Regulatory Science, 50(3), 118-130 (2019). TAT-11, Ottawa International Standardization of Translational Research Guideline for TAT Drug Products

FDA-CDER Oncology Therapeutic Radiopharmaceuticals: Nonclinical Studies and Labeling Recommendations Guidance for Industry- Draft Guidance, June 2018

EMEA Guideline on the Non-clinical Requirements for Radiopharmaceuticals (Draft) 15 November 2018

Since both draft guidelines include alpha- and beta-emitter radiopharmaceutical products, we have to investigate TAT drug products more precisely and intensively.

Updated information on the progress for both guidelines would be very much appreciated by FDA and EMEA New Wave for Anti-tumor antibodies development

After being incorporated into tumor cells, Half theit clinical is necessary trials to cut with antibody novel and drug antibodies by lysosomal are enzymes in oncology, manyDisadvantage are terminated of ADC because (Antibody -ofDrug lack-Conjugate of efficacy)

carlumab - prostate cancer - diffuse large B-cell lymphoma/chronic lymphocytic leukemia - breast cancer - glioblastoma and non–small cell lung carcinoma (NSCLC) - gastric cancer ; fusion protein Phase 3 farletuzumab - - lung cancer - head and neck cancer zanolimumab - T-cell lymphoma - NSCLC - multiple myeloma - gastric cancer, NSCLC

F. Fahey, et.al, J. Nucl. Med, 55, 337-348 (2014). F. Fahey, et.al, J. Nucl. Med, 56, 1119-1129 (2015). New Wave for Anti-tumor antibodies development

Extra molecularNine design radiolabeled of cleavage is mAbsunnecessary relevant due to shortfor TRThalf-life of α emitter are currently inAdvantage commercially of TAT-antibody supported studies.

90Y-OTSA101 phase I 212Pb- [trastuzumab] phase I 177Lu-DOTA-HH1 [tetulomab] phase I/II or phase II 90Y-IMMU-102 [epratuzumab] phase I/II or phase II 225Ac-huM195 [] phase I/II or phase II 131I-chTNT-1/B [chTNT] phase I/II or phase II 131I-BC8 [BC8] phase I/II or phase I 177Lu-ATL-101 [J591] phase I/II or phase II 90Y-IMMU-107 [clivatuzumab] phase III

Four mAbs—trastuzumab, epratuzumab, lintuzumab, and J591 have been studied in cold as well as radiolabeled forms.

F. Fahey, et.al, J. Nucl. Med, 55, 337-348 (2014). F. Fahey, et.al, J. Nucl. Med, 56, 1119-1129 (2015). TAT-11, Ottawa Renaissance of terminated anti-tumor drug candidates

We think terminated anti-tumor drug candidates will be developed again as new therapeutic drugs through the process of TAT drug which is called “re-positioning”. We expect this report can provide how to think about the non-clinical safety issues for development of new TAT drugs in advance.

Renaissance of terminated anti-tumor drug candidates

Regulatory Science for TAT Future

JP Patent Appl. No. 2018-189191 & No. 2019-4146