31 slides from Actinium Pharmaceuticals, Inc. (delaware)'s technical presentation, Oct 21, 2014
Slide 1: Radioimmunotherapy of AML with Actimab-A and Iomab-B
Radioimmunotherapy of AML with Actimab-A and lomab-B Joseph G. Jurcic, MD Professor of Medicine at CUMC Director, Hematologic Malignancies Columbia University Medical Center
Slide 2: Outline
Outline AML background Current front-line treatment approaches Emerging therapies for older patients Targeted a-particle therapy with Actimab-A Current management for relapsed AML Conditioning with lomab-B before HCT
Slide 3: Development of AML
Development of AML Normal Hematopoiesis Leukemogenesis =a — Or sun eet cup * Laukennia: 1. Lack of Differentiation == / \ Neutrophil ) ® (.). @ = = f_o a @® 7/~*@ ® ee ® 2. Increased Proliferation ® ©
Slide 4: AML Survival by Age
AML Survival by Age 1095 1460 1825 2190 2555 2920 3285 3650 Days from Diagnosis, Juliusson G et al. Blood 2009;113:4179-4187.
Slide 5: AML: Cytogenetics Determines Survival
AML: Cytogenetics Determines Survival 1004 754 _-4, 48:21), 15:17), inv (16) LAWL Lea Bel | | +8, "other numerical changes", normal karyotypes ih 25 4 1 | 504 | Percent 5q-/-5, 11423 changes, 7q-/-7, "other structural changes" a 0 2 4 6 8 Bloomfield CD et al. Cancer Res 1998;58:4173-4179.
Slide 6: Risk Status Based on Cytogenetic and Molecular Abnormalities
Risk Status Based on Cytogenetic and Molecular Abnormalities Risk Status Cytogenetics Molecular Abnormalities Better-risk inv(16) or t(16;16) Normal cytogenetics: t(8;21) NPM1 mutation in the (15:17) absence of FLT3-ITD or isolated biallelic CEBPA mutation Intermediate-risk Normal cytogenetics +8 al
Slide 7: Phases of AML Therapy
Phases of AML Therapy * Induction — Cytarabine + anthracycline * Postremission — Consolidation chemotherapy — Hematopoietic cell transplantation (HCT)
Slide 8: Treatment Outcome by Age
Treatment Outcome by Age Age <56 yo 56-65 yo 66-75 yo >75 yo No. of patients 368 246 274 80 Response, no. (%) CR 235 (64) 113 (46) 108 (39) 26 (33) Resistant disease 99 (27) 91 (37) 401 (37) 29 (36) Median survival, mo. 18.8 9.0 6.9 Sh) (95% Cl) (14.9-22.6) (8.1-10.2) (5.4-7.7) —(1.4-6.1) Median DFS
Slide 9: % of Total Incidence
% of Total Incidence 2012 AML Incidence by Age Group 25% 20% 15% 10% 5% 0% <20 20-34 35-44 45-54 55-64] 65-74 75-84 85+ Age of Diagnosis Source: NCI SEER US Cancer Database, AML.
Slide 10: Low-Dose Cytarabine in Older AML Patients
Low-Dose Cytarabine in Older AML Patients % still alive 100 —— LDAra-C ee Co HU 75 4 \ \ No. No. Obs.— Patients Events Exp. 50 { LD Ara-C 103 100 —22.0 HU 99 99 20 aE A, 2 = 0.0009 { _— YC, ee ~—_, 0 te Y 0 1 2 3 Years from entry Burnett AK ef al. Cancer 2007; 109:1114-1124.
Slide 11: Recently Studied Newer Agents For Older AML Patients
Recently Studied Newer Agents For Older AML Patients Response Drug Class (CR+CRp) Comments Tipifarnib’ Faresyltransferase 22/158 (14%) Median survival — 5 mos. inhibitor Serious AEs — 47% Low-dose Nucleoside analogue 10/26 (38%) 1-year survival — 21% Clofarabine? Clofarabine/ Nucleoside analogues 36
Slide 12: Hypomethylating Agents for Older AML Patients
Hypomethylating Agents for Older AML Patients Azacitidine Decitabine ]- 5-Day Regimen (CashenAF et al. JCO2010; 28:556-561.) — 24% CR — Median survival 7.7 mos. — Median time to response 3 cycles * 10-Day Regimen (Blum wet al. PNAS2010: 107:7473-7478.) - 47% CR — Median survival 12.8 mos. Fenaux P e
Slide 13: Novel Low-Intensity Therapies
SGI-1101 Novel Low-Intensity Therapies 67 patients with relapsed/refractory or untreated older AML patients randomized to 60 or 90 mg/m? SQ x 5 days 8/50 (16%) of relapsed/refractory patients had CRc (CR + on CRp + CRi). Decitabine 9/17 untreated patients achieved CRc. No difference in responses rat
Slide 14: Alpha- vs. Beta-Particle Radioimmunotherapy
Alpha- vs. Beta-Particle Radioimmunotherapy ) OC ~~“ Blood Vessel
Slide 15: 213Bi-Lintuzumab: A 1st Generation a-Emitting Antibody Conjugate
213Bi-Lintuzumab: A 1%t Generation a-Emitting Antibody Conjugate * Patients received 16-95 mCi in 3-7 fractions ¢ Lintuzumab doses adjusted to a specific activity of 12-15 mCi/mg ro TO Day 1 4 ¢ Myelosuppression lasted 12-41 days (median, 22 days) * Transient liver function abnormalities seen in 6 p
Slide 16: Results by Disease Status for 213Bi-Lintuzumab
Results by Disease Status for 213Bj-Lintuzumab Doses 2 1 mCi/kg Disease Status N° cr cRp PR Overall Patients Response Untreated AML, 9 Untreated relapse Me 2 2 2 6(33%) 1° refractory, Refractory relapse Z p 0 0 0 Rosenblat TL et al. Clin Cancer Res 2010; 16:5303-5311.
Slide 17: Actinium-225: An a-Particle Nanogenerator
Actinium-225: An a-Particle Nanogenerator 225Ac—> 2p, —, 217ap —, 213—; —CL, Stable 10 days 4.9 min 0.032sec 46min \sotopes oe eo 1000000, Use of 213Bi is limited by: 100000 — Short half-life E 10000 — Need for an on-site generator B 1000 rd 100 ; é 225Ac can be conjugated to ag) antibodies using DO
Slide 18: Phase I Trial of 225Ac-Lintuzumab (Actimab-A)
Phase | Trial of 225Ac-Lintuzumab (Actimab-A) 875 + 18 patients with relapsed or nls refractory AML received 0.5-4 125 yCi/kg 400 ¢ Dose-limiting toxicity was prolonged myelosuppression 75 « No renal toxicity was seen « Bone marrow blasts reduced in 10/15 (67%) evaluable % Change in Marrow Blasts ny
Slide 19: LDAC + Actimab-A in Older AML Patients
LDAC + Actimab-A in Older AML Patients Day 1 10 14 18 29 =; + Bone marrow blast reductions seen in 4 patients (57%) after 1st cycle « Mean blast reduction was 58% (range, 34-100%) + Median number of cycles given was 2 (range, 1-4) % Change in Marrow Blasts * Median time to progression was 2.5 months
Slide 20: Managing Relapsed AML
Managing Relapsed AML
Slide 21: Salvage Therapy for Relapsed AML
Salvage Therapy for Relapsed AML No FDA-approved regimens Standard chemotherapy — High-dose cytarabine — Etoposide/mitoxantrone + cytarabine (MEC) — Fludarabine/cytarabine/G-CSF + idarubicin (FLAG-Ida) — Cladribine/cytarabine/G-CSF + idarubicin (CLAG-Ida) — Hypomethylating agents Investigational the
Slide 22: Outcomes after Salvage Chemotherapy for Relapsed AML
Outcomes after Salvage Chemotherapy for Relapsed AML o H — FLAG/FLAG-IDA (n=65) HiDAC (n=22) — Hypomethylating agents (n=34) LoDAC/HU/Pall. (n=25) MEC (n=44) ° © fi ° a L ° Bb 1 Ss o 2 ° = a o — S c S n So ho 1 Time (months) Roboz GJ et al. JCO 2014;32:1919-1926.
Slide 23: Recent Phase III Trials for Relapsed AML
Recent Phase III Trials for Relapsed AML Elacytarabine Time (months) Roboz GJ et al. JCO 2014;32:1919-1926. Vosaroxin Vosaroxin Placebo +Ara-C + Ara-C P-value (n=356) —_ (n=355) MedianOS 7.5mos 6.1 mos 0.06 cR 30.1% 16.3% < 0.001 30-day - vy mortality fo% ese Grade 23 a 4 See 55.5% 35.7% http://ir.s
Slide 24: Overall survival after HCT in CR2
ae fe nS 2 g Va S > 3 a 3 ia. 2 3 4 Time from Transplant, Years Foreman SJ, Rowe JM. Blood 2013; 121:1077-1082. OS after HCT in CR2 for patients 18-50 yo: — 6m: ~80% — 12m: ~70% — 2y:~60% BUT: Only ~15% enter CR2, so OS for all patients is: — 6m: ~12% — 12m: ~10% — 2y:~10%
Slide 25: Impact of Disease Burden on HCT Outcomes
Impact of Disease Burden on HCT Outcomes Median Median Disease burden Ne: Ci survival PFS patients (mos.) (mos.) Morphologic & cytogenetic 8 10.4 78 remission Morphologic remission only 6 46 2.9 Overt relapse 38 9) 2.8 Kebriaei P et al. Bone Marrow Transplant 2005; 965-970.
Slide 26: Rationale for RIT in HCT Regimens
Rationale for RIT in HCT Regimens ¢ AML is highly radiosensitive. ¢ TBI is effective in HCT regimens at high doses. ¢ TBI cannot be safely dose escalated. * RIT can increase radiation doses to leukemia cells and normal bone marrow without increasing doses to normal tissues. * lomab-B consists of an
Slide 27: Iomab-B biodistribution and radiation dose
DAML - Remission BIAML - RelapseiRetractry GBAML- Secondary BMos Treatment at MTD (24 Gy to liver) delivers ~36 Gy to marrow and ~100 Gy to spleen. Pagel JM et al. Blood 2009; 114:5444-5453.
Slide 28: Outcomes after Iomab-B at MTD
Outcomes after lomab-B at MTD Overall Survival Disease—Free Survival Non—Relapse Mortality ‘Relapse | Censor FJ 3 9 Ic eococrcocoee + = = 2 Years after Transplant Pagel JM et al. Blood 2009; 114:5444-5453.
Slide 29: Compelling Results Enable Pivotal Phase III Trial
Compelling Results Enable Pivotal Phase Ill Trial * Complete response rate: 100% + Non-relapse mortality (NRM): + Engraftment by Day 28: 100% — Day 100: 10% ¢ Transplant related mortality: ~ Eh ae en 14% (same as RIC) myeloablative conditioning) All relapsed/refractory AML patients > 50 —_Rel/ref AM
Slide 30: Iomab-B Pivotal Trial Schema
lomab-B Pivotal Trial Schema Not Fail 7 enrolled Screening, including HLA typing Pass \ Enrolled Primary Endpoint: Durable CR rate, lasting at least 6 months. No CR Off Study Crossover mMN-ZO0O0Z>Pa Bone marrow aspirate and biopsy performed in all patients at ~1 and/or 2 months after the last day of
Slide 31: Conclusions
Conclusions Actimab-A * a-particle immunotherapy results in efficient single-cell tumor kill. * Single-agent 2"3Bi-lintuzumab has anti-leukemic activity and produced remissions when given with cytarabine. « 225Ac-lintuzumab (Actimab-A) showed safety and efficacy ina phase | trial and is under study