Theragnostics Neuroendocrine and Prostate Cancer

Transcription

1 Theragnostics Neuroendocrine and Prostate Cancer

2 Target Audience: Pharmacists ACPE#: L01-P Activity Type: Knowledge-based Target Audience: ACPE#: Activity Type:

3 Disclosures Financial: Employed by Advanced Accelerator Applications (AAA) / Novartis The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

4 Learning Objectives 1. To understand clinical indications and utilization of 68Ga - DOTATATE imaging in NETs 2. To understand clinical indications and utilization of 177 Lu- DOTATATE Target Audience: therapy in NETs 3. To understand potential clinical benefits and research ACPE#: applications of 177 Lu-PSMA 4. To understand benefits of Theragnostics in NM space Activity Type:

5 Impact of Theragnostics Patients Physicians Payors More effective care through personalized interventions Reduce or eliminate unnecessary treatment Better diagnose and stage disease Select optimal therapies Monitor treatment response and disease progression Reduce costs from unnecessary treatments Improve patient management & outcomes 5

6 Improving Patient Management through Unique Theragnostic Platform Same Targeting Molecule Ga-68 labeled Ga-68 PET Lu-177 labeled Lu-177 PRRT / RLT Diagnosis Selection for PRRT / RLT or other treatment Follow-up ELECTRONS TREAT TUMORS FROM WITHIN GAMMA RAYS DETECTED BY PET/CT CAMERA PRRT = Peptide Receptor Radionuclide Therapy RLT = RadioLigand Therapy 6

7 Oncology Theragnostics Pipeline Product Indications Preclinical Phase I Phase II Phase III Filing Marketed Status Lutetium Lu 177 dotatate* Neuroendocrine tumors Therapeutic Phase III Netter-1 study in NETs Orphan Drug Designation Approved in EU for GEP-NETs NDA in US under review Ga-68 dotatate/ edotreotide Neuroendocrine tumors NETSPOT : PET Diagnostic SOMAKIT-TOC : PET Diagnostic PET diagnostics for localization of NETs Orphan Drug Designation Approved in US and EU 177Lu PSMA-R2 Prostate cancer Therap. Exclusive license from John s Hopkins for series of candidates in prostate cancer Clinical studies planned for Ga PSMA-R2 Prostate cancer PET Diag. Exclusive license from John s Hopkins for series of candidates in prostate cancer Clinical studies planned for Lu NeoBOMB1 GIST Prostate cancer Breast cancer Therapeutic GRPR antagonist Exclusive license from Erasmus MC and Demokritos University Clinical studies planned in GIST, BC and PC 68Ga NeoBOMB1 GIST Prostate cancer Breast cancer PET Diagnostic * USAN lutetium Lu 177 dotatate / INN: lutetium ( 177 Lu) oxodotreotide GRPR antagonist Exclusive license from Erasmus MC and Demokritos University Clinical studies planned in GIST, BC and PC 7

8 Neuroendocrine Tumors (NETs) 8

9 9 Neuroendocrine tumors (NETs) are a heterogeneous group of relatively rare tumors1 NETs consist of a spectrum of malignancies that can arise from neuroendocrine cells throughout the body NETs may be grouped according to the embryologic origin of the primary site: Foregut: respiratory tract, stomach, duodenum, biliary system, and pancreas Midgut: small bowel, appendix, cecum, and proximal colon Hindgut: distal colon and rectum 1 Alexandraki, K.I., et al.; Endocrine 2012, 41,

10 10 GI tract and pancreas are the most frequent localizations of NETs1 Neuroendocrine cells are widely distributed throughout the body NETS can appear in almost every organ or tissue The most frequent localization is the digestive system followed by bronchopulmonary NETs, including thymus and then unknown origin 1Dasari A, et al. JAMA Oncol. 2017

11 11 NETs have historically been considered as rare tumors Incidence has been increasing (>600% over the last 4 decades) and NETs are now the second most prevalent gastrointestinal cancer after colon cancer; more prevalent than pancreatic, gastric, esophageal or hepatic cancer or any two of these combined 1Dasari A, et al. JAMA Oncol. 2017

12 NETs are Heterogeneous EXTENT OF DISEASE Low tumor burden/resectable Widely metastatic High tumor burden/unresectable Liver dominant PACE OF GROWTH Stable Progressive PRIMARY SITE Foregut Midgut Hindgut Pancreas GRADE / DIFFERENTIATION Low-grade Int.-grade High-grade Well diff. Poorly diff. HORMONE STATUS Functional Non-Functional SSTRs High expression Low/absent expression 12

13 13 Delayed Diagnosis Results in Most Patients Being Metastatic Upon Diagnosis1 60% of NETs are non-functioning or asymptomatic Metastatic disease is increasingly prevalent in GI-NETs and PNETs At initial diagnosis, 40-50% of patients present with metastases 1Alexandraki, K.I., et al.; Endocrine 2012, 41,

14 14 NETs pose high morbidity burden on patients and survival rates have not increased with current treatments GEP-NETs constitute a lifethreatening disease and are associated with debilitating clinical symptoms 1,2 5-Year Survival Among Various NET Tumors, SEER (Lawrence et al. 2011) A recent survey of oncologists reported that nearly one third of patients were managed by watch and wait, also indicative of the unmet need in this disease state 3 Percent Kanakis and Kaltsas Pape et al Casciano 2013

15 15 Treatment Options for NETs are Dependent on diagnosis and Extent of Disease Somatostatin Analogues (SSA): SSAs are synthetic forms of somatostatin They bind to the somatostatin receptors (SSTRs) overexpressed by NETs Like somatostatin, they inhibit hormone release by the target cells, resulting in symptoms relief 80% of NETs overexpress SSTRs Some guidelines may recommend SSAs for NETs symptom control or as antiproliferative therapy Inhibitors of mammalian target of Rapamycin (mtor): Everolimus: adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic. Not indicated for the treatment of patients with functional carcinoid tumors. Tyrosine kinase inhibitors (TKIs): Sunitinib: progressive, well-differentiated pancreatic neuroendocrine tumors (pnet) in patients with unresectable locally advanced or metastatic disease. Surgery: Only curative treatment, mainly used in grade 1 or grade 2 Radiofrequency ablation: Can relieve symptoms in 70% of cases for approximately 1 year and provide local liver control in most patients Radioembolization and chemo-embolization: Recommended as 1st line treatment in patients with progressive or symptomatic tumors of midgut origin if metastases are confined to the liver and 2nd line treatment for liver metastases of PNETs

16 Diagnostic Challenges NETs Heterogeneous No unique and specific clinical presentation (vague symptoms) Diagnosis is often delayed by 5-7 years 1 60 to 70% of patients have metastatic diseases at diagnosis 1 Diagnosis is complex and multimodal based on 2 Clinical symptoms (non-functioning vs functioning tumors) Biological Markers Specific: 5-HIAA, PNETS hormones Non specific: Chromogranins, Neuron Specific Enolase Pathology (differentiation, proliferation, primary) Imaging (primary location, staging) 1. Alexandraki & Kaltsas Endocrine 2012, 41: 40-52; 2. Oberg Exp Rev Endocrinol Metab 2011, 6 (1):

17 Non-Functioning NETs The majority of NETs are non-functioning GEP-NETs No specific clinical symptoms related to a specific secretion Either truly non-functional or the secretion is not clinically relevant Tumors can be asymptomatic until their volume provokes mass effects Pain, discomfort, anorexia, weight loss, jaundice Late diagnosis Intestinal NETs are often revealed by non-specific abdominal pain or emergency clinical presentations Obstruction / Perforation / Bleeding Late diagnosis due to aspecific, misleading symptoms (different for lung NETs) 17

18 Functioning NETs (Carcinoid Syndrome) The carcinoid syndrome is the most typical clinical manifestation of GEP NETs: 1,2 Diarrhea (60-80%) 1, Flushing (60-85%) 1, Abdominal pain, Sweating, Bronchial wheezing (due to bronchospasm: pseudo-asthma) 10% 1 Due to the release and interaction of hormones (that have effects on intestinal motility (diarrhea) and on vasoconstriction), mainly 2 Serotonin, Prostaglandins, Histamine, Tachykinins Serotonin (5-HT), derived from the amino acid tryptophan, is stored and secreted by some NE cells; it is inactivated in the liver into 5- hydroxyindoleacetic acid (5-HIAA) 2 1. Pape et al. Neuroendocrinology 2012, 95: ; 2.Strosberg Best Practice & Research Clinical Gastroenterology 2012, 26:

19 Somatostatin Receptor Imaging Somatostatin Regulatory peptide widely distributed in the human body, nervous system and GI track Somatostatin receptors (SSTRs): Overexpressed in Most NETs, but most commonly in gastro-enteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs Other tumors express somatostatin receptors: pituitary adenoma, meningioma, paraganglioma, small cell lung cancer, MTC

20 Somatostatin Receptor Imaging Synthetic Somatostatin analogs (SSAs): 1 st line treatment is Octreotide Radioactive Labeled Somatostatin Analogs: 68 Ga-dotatate (NETSPOT ) 111 In-pentetreotide (OctreoScan ) 20

21 NETSPOT Indications NETSPOT after radiolabeling with Ga 68, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients 1 Initial staging for patients with neuroendocrine tumors Restaging, detecting recurrence, and monitoring of response to therapy in patients with NETs Detection of unknown primary neuroendocrine tumor in patients with known metastatic NETs 1 NETSPOT Prescribing Information 2016

22 Reconstitution Procedure 22

23 Normal Biodistribution sstr2 expressing organs Higher uptake pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands Lower uptake thymus and lung No uptake cerebral cortex or in the heart 111In- pentetreotide 68Ga-dotatate

24 Examples of Functional Imaging and MRI Primary tumor in the terminal ileum (green arrows). Liver metastases not visible on 111In-pentreotide scan. 111In-Pentetreotide 68Ga-DOTATATE PET/CT MRI 24

25 Clinical Studies w/ Impact on Patient Management and Change in Outcome Safety and Efficacy of 68Ga-DOTATATE PET/CT for Diagnosis, Staging and Treatment Management of Neuroendocrine Tumors. Deppen SA, et al. J Nucl Med May;57(5): Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. Sadowski SM, et al. J Clin Oncol. 2015; 34: Impact of 68Ga-DOTATATE PET/CT on the Management of Neuroendocrine Tumors: The Referring Physician s Perspective Herrmann K, et al. The J. of Nuclear Medicine. 2015, 56(1): The Role of 68 Ga-DOTATATE PET in Patients with Neuroendocrine Tumors and Negative or Equivocal Finding on 111 In-DTPA-Octreotide Scintigraphy. Srirajaskanthan R, et al. J Nucl Med 2010 June;51(6): Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. Sadowski SM, et al. J Clin Oncol. 2015; 34: High management impact of Ga-68 DOTATATE(GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. Hofman MS, et al. J of Med Imaging and Rad Onc 56(2012): Impact of 68 Ga-DOTATATE PET-CT on the surgical management of primary neuroendocrine tumors of the pancreas or ileum. Ilhan H, et al. Ann Surg Oncol. (2015) 22:

26 Peptide Receptor Radionuclide Therapy (PRRT) 26

27 Peptide Receptor Radionuclide Therapy (PRRT) PRRT involves the systemic administration of a specific radiopharmaceutical to deliver cytotoxic radiation to a tumor1 The radiopharmaceutical is composed of a β- emitting radionuclide, chelated to a peptide1 The peptide is designed to target cell surface receptors, such as somatostatin receptors1 Structure of a radiopharmaceutical2 The affinity for SSTRs and the specificity of binding ensures a high level of specificity in the delivery of radiation to the tumor 1. Zaknun et al. Eur J Nucl Med Mol Imaging 2013, 40: Bergsma et al. Best Practice & Res Clin Gastroenterol 2012, 26:

28 Efficacy of PRRT Tumor response (%) in patients with GEP NETs treated with PRRT Study Ligand n CR+PR SD PD Valkema In-DTPA-octreotide Anthony In-DTPA-octreotide Bodei Y-DOTATOC Waldherr Y-DOTATOC Waldherr Y-DOTATOC Valkema Y-DOTATOC Bushnell Y-DOTATOC Pfeifer Y-DOTATOC Cwikla Y-DOTATATE Kwekkeboom Lu-DOTATATE Sward Lu-DOTATATE Garkavij Lu-DOTATATE Bodei Lu-DOTATATE Van der Zwan et al. Eur J Endocrinology,2015, 172: R1-8 28

29 lutetium Lu 177 dotatate Binds specifically to malignant cells that overexpress sstr2 receptors The clearance through the kidney pathway is rapid: on average 70% of the administered radioactivity is found in the urine at 24h β-emitting radionuclide - Intermediate energy with beta particle Decays with a half-life of 6.7 days Pathway penetration of 2 mm Low abundance gamma ray, which permits diagnostic imaging

30 30 lutetium Lu 177 dotatate is the First Approved Peptide Receptor Radionuclide Therapy (PRRT) for NETs 1 Indication: LUTATHERA is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. 1 Contraindication: None. 1 1 LUTATHERA [prescribing information]. January 2018.

31 31 Structure of lutetium Lu 177 dotatate lutetium Lu 177 dotatate is a molecularly targeted radiation therapy that involves the systemic administration of a radiolabeled peptide designed to target specific cell surface receptors with high affinity and specificity 1 Structure of lutetium Lu 177 dotatate 1 LUTATHERA [prescribing information]. January 2018.

32 32 Lutetium Lu 177 Dotatate Delivers Cytotoxic Radiation1 1LUTATHERA [prescribing information]. January 2018.

33 33 Lutetium Lu 177 Dotatate Administration 1 LUTATHERA [prescribing information]. January 2018.

34 34 Lutetium Lu 177 Dotatate Treatment Regimen1 LUTATHERA (200 mci) is administered as an intravenous infusion over minutes every 8 weeks for a total of 4 doses (4 x 200 mci = 800 mci) 1LUTATHERA [prescribing information]. January 2018.

35 NETTER-1 (Phase III) A multicentre, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with 177 Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumours 35

36 36 NETTER-1: International, multicenter, randomized, comparatorcontrolled, parallel-group Phase III study 1 1 Strosberg J, et al. N Engl J Med. 2017; 376:

37 37 NETTER-1: Inclusion and Exclusion Criteria1 1Strosberg J, et al. N Engl J Med. 2017; 376:

38 NETTER-1 Phase III: Study Endpoints Primary objective Compare Progression Free Survival (PFS) after treatment with lutetium Lu 177 dotatate plus 30 mg octreotide LAR (symptoms control) vs treatment with high dose (60 mg) octreotide LAR Secondary objectives Compare the Objective Response Rate between study arms Compare the Overall Survival between study arms Compare the Time to Progression between study arms Evaluate the safety and tolerability of lutetium Lu 177 dotatate Evaluate the health related quality of life (QoL) as measured by the EORTC QLQ-G.I.NET21 questionnaire 38

39 Dose Modifying Toxicity Patients who completed Tx phase, N=103* Nb of Patients (%) Number of administrations 4 79 (77%) 3 6 (6%) 2 12 (12%) 1 5 (5%) 0 1 (1%) All treated patients, N=111 Nb of Patients (%) Dose modifying toxicity No DMT 103 (93%) DMT 8 (7%) (*) without patients still under treatment (n=8) or no treatment 39

40 40 NETTER-1: included a well-balanced patient characteristics 1 1 Strosberg J, et al. N Engl J Med. 2017; 376:

41 Lu 177 dotatate demonstrated markedly longer progression-free survival 1 41 Median PFS for lutetium Lu 177 dotatate was not reached Median PFS for long acting octreotide 60 mg was 8.5 months PFS Events Lutetium Lu 177 dotatate = 27 events Octreotide LAR 60 mg = 78 events Indicates 79% risk reduction for disease progression or death (HR 0.21 [95% CI, 0.13, 0.32], P<0.0001) 1 1 LUTATHERA [prescribing information]. January 2018.

42 42 Preliminary Evidence Suggests an Overall Survival Benefit 1 Interim OS analysis showed a 48% reduction in estimated risk of death (HR 0.52; 95% CI, ) 2 Lutetium Lu 177 dotatate = 27 deaths Octreotide LAR 60 mg = 43 deaths O'Brian Fleming threshold for statistical significance at first interim analysis = Data not sufficiently mature to provide estimation of median OS in either arm 2 1 LUTATHERA [prescribing information]. January Strosberg J, et al. N Engl J Med. 2017; 376:

43 43 Lu 177 dotatate demonstrated consistent benefits across stratification and prognostic factors2 Consistent treatment benefits with Lu 177 dotatate were observed irrespective of stratification and prognostic factors, including: Levels of radiotracer uptake on somatostatin receptor scintigraphy (SRS) Tumor grade Age Gender Tumor marker levels 1Strosberg J, et al. N Engl J Med. 2017; 376:

44 44 Lu 177 dotatate demonstrated 3X greater ORR than Octreotide LAR 60 mg The response rate was 13% in the Lu 177 dotatate group compared with 4% in the Octreotide LAR 60 mg control group (P=0.0148) 1 Notable given that response rates above 5% have not been observed in large randomized clinical trials of other systemic therapies in this patient population 2 1 LUTATHERA [prescribing information]. January Strosberg J, et al. N Engl J Med. 2017; 376:

45 NETTER-1 Safety and Tolerability 2 Lu 177 dotatate and Octreotide LAR 30 mg (n=111) Octreotide LAR 60 mg (n=110) Any adverse event 106 (96%) 95 (86%) Related to treatment 95 (86%) 34 (31%) Serious adverse events 29 (26%) 26 (24%) Related to treatment 10 (9%) 1 (1%) Withdrawals due to adverse events 7 (6%) 10 (9%) Related to treatment 5 (5%) 0 (0%) 1 Strosberg J, et al. N Engl J Med. 2017; 376:

46 46 Lu 177 Dotatate Demonstrated Limited Acute Side Effects1 1LUTATHERA [prescribing information]. January Bone marrow toxicity (myelo-/hematotoxicity): reversible / transient reductions in blood counts affecting all lineages Most common adverse events in Lu 177 dotatate group: nausea and vomiting due to amino acid infusions. Resolved upon completion of the infusions. Adverse events leading to premature withdrawal from the trial: 7 patients (6%) in Lu 177 dotatate group 10 patients (9%) in control group

47 47 NETTER-1: Hematologic Events Were Transient1 Short term hematologic events (neutropenia, leukopenia, cytopenia, thrombocytopenia) almost always come back to their normal level before the next treatment; patient recovers by the next dose For patients in which this does not occur, there is a well established dose-modification regimen Long term hematologic events (Myelodysplastic syndrome, acute leukemia) were observed in <2% of patients (Phase I/II)2 1Strosberg J, et al. N Engl J Med. 2017; 376: T, et al. Clin Cancer Res. 2017;23(16): Brabander

48 NETTER-1: Grade 3-4 Hepatotoxicity 1 Lu 177 dotatate and Octreotide LAR 30mg (N = 111) Octreotide LAR (N = 110) AST increase 4% 0% ALT increase 4% 0% Bilirubin increase 2% 0% GGT increase (at inclusion respectively 11% and 9%) 18% 13% (CTCAE V4.0; Safety Set) 1 Strosberg J, et al. N Engl J Med. 2017; 376:

49 NETTER-1: Creatinine Clearance1 1Strosberg J, et al. N Engl J Med. 2017; 376:

50 lutetium Lu 177 dotatate Biodistribution and Elimination About 75% of the injected activity cleared from the plasma with a half-life of 5 min in patients with low tumor burden About 90% of the injected activity cleared from the plasma with a half-life of 25 minutes in patients with high tumor burden The clearance is through the kidney pathway; on average, 70% of the administered radioactivity is found in the urine at 24 h The long terminal elimination half-life (2 to 7 days) corresponds to a small percentage of the administered radioactivity (below 1%) 50

51 Time to deterioration (TTD) in HRQoL We present the Quality of Life (QoL) results obtained in the NETTER-1 study comparing treatment with 177 Lu-DOTATATE to Octreotide LAR on the time to clinically relevant change (deterioration) in health related QoL (HRQoL). The method used for this assessment is a time-to-event methodology, where the event is defined as a deterioration in the patient s QoL. Time to QoL deterioration (TTD): Time from randomization to the first QoL deterioration 10 points for each patient in the corresponding domain scale. For each domain a Kaplan-Meier plot was produced showing time to event by treatment arm. Kaplan-Meier methods were used to generate a point estimate of the median time to event with corresponding 95% confidence interval (CI). The main analysis was conducted in the population that comprises all randomized patients as per intent to treat (ITT) principles

52 QoL improvement in NETTER-1 Phase III Trial1 Global Health Status TTD HR 0.406; p= Physical Functioning TTD HR 0.518; p= Strosberg Role Functioning TTD HR 0.580; p= J, et al. QoL Abstract. NANETS

53 QoL improvement in NETTER-1 Phase III Trial1 Diarrhea TTD Pain TTD HR 0.473; p= HR 0.566; p= Strosberg Fatigue TTD HR 0.621; p= J, et al. QoL Abstract. NANETS

54 Phase I/II Long-Term Efficacy, Survival, and Safety of [ 177 Lu-DOTA 0, Tyr 3 ]octreotate in Patients with Gastroenteropancreatic and Bronchial Neuroendocrine Tumors 54

55 Safety and Efficacy data: Patients treated between pts 100 mci 177 Lu- DOTATATE 810 Dutch patients 696 bronchial and GEPNETs 610pts 100mCi treated according to all inc. criteria 443 pts 600 mci 177 Lu- DOTATATE before 2013 Safety analysis Efficacy and survival analysis 55

56 Safety, n=610 Acute Toxicities: CTCAE Grade 3/4: Total hematological toxicities 10% Thrombocytopenia 5% Leukopenia 5% Lymphopenia 50%, 26% at 3 mo f/u, 6% at 30 mo f/u Hemoglobin 4% Aminotransferases (AST, ALT), 3% Creatinine 0.3% Chronic Toxicities Acute Leukemia 0.7%, observed 55 month after first therapy MDS 1.5% (no Hx of alkylating agents), observed 28 months after first therapy Renal failure 1%, most likely unrelated No liver failure 56

57 Efficacy n= month median F/U from first treatment ORR 39% SD 43% PD 12% In patients with midgut and pancreatic NETs with PD at baseline, disease control rate was 84% and 81%, respectively. 57

58 Overall Survival by Primary Tumor Pancreas best survival 58

59 Risk Factors Affecting Survival Risk Factors Elevated ALP Liver metastasis Bone metastasis Extensive Disease Poor KPS Best response: PD 59

60 Erasmus compared to NETTER-1 60

61 61 2,268 patients across 11 countries, including the US, have been treated with Lu 177 dotatate (as of 12/31/2017) 1 US Early Access Program was initiated in institutions enrolled in the Early Access Program (EAP) Number of Patients List of EAP sites is available on ClinicalTrials.gov (ID = NCT ) *Austria, Estonia, Finland, Greece, Portugal, Spain, Switzerland, Denmark United States United Kingdom France Other European Countries* 1 Data on File. Advanced Accelerator Applications 2018

62 Lutathera (Lu-177 Dotatate) Approved by FDA: January, 2018 Approved indications treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP- NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults. 62

63 Oncology Theragnostics Pipeline Product Indications Preclinical Phase I Phase II Phase III Filing Marketed Status Lutetium Lu 177 dotatate* Neuroendocrine tumors Therapeutic Phase III Netter-1 study in NETs Orphan Drug Designation Approved in EU for GEP-NETs NDA in US under review Ga-68 dotatate/ edotreotide Neuroendocrine tumors NETSPOT : PET Diagnostic SOMAKIT-TOC : PET Diagnostic PET diagnostics for localization of NETs Orphan Drug Designation Approved in US and EU 177Lu PSMA-R2 Prostate cancer Therap. Exclusive license from John s Hopkins for series of candidates in prostate cancer Clinical studies planned for Ga PSMA-R2 Prostate cancer PET Diag. Exclusive license from John s Hopkins for series of candidates in prostate cancer Clinical studies planned for Lu NeoBOMB1 GIST Prostate cancer Breast cancer Therapeutic GRPR antagonist Exclusive license from Erasmus MC and Demokritos University Clinical studies planned in GIST, BC and PC 68Ga NeoBOMB1 GIST Prostate cancer Breast cancer PET Diagnostic * USAN lutetium Lu 177 dotatate / INN: lutetium ( 177 Lu) oxodotreotide GRPR antagonist Exclusive license from Erasmus MC and Demokritos University Clinical studies planned in GIST, BC and PC 63

64 Prostate Specific Membrane Antigen (PSMA)

65 Prostate Specific Membrane Antigen (PSMA) NIH Definition A type II membrane protein originally characterized by the murine monoclonal antibody (mab) 7E11-C5.3 and is expressed in all forms of prostate tissue including carcinoma. If combined with the appropriate bifunctional chelate, PSMA could be used to diagnose and/or treat prostate cancer including metastatic disease. Important to maintain specificity of PSMA once the chelate is attached

66 PSMA -Prostate Specific Membrane Antigen The American Cancer Society estimates that each year approximately 161,360 new cases of prostate cancer will be diagnosed and about 26,730 men will die of the disease. -2 nd most common cancer in men Accurate risk assessment both sensitivity and specificity in staging and re-staging is key More effective treatments needed for advanced metastatic disease Prostate Specific Membrane Antigen (PSMA), a transmembrane protein amplified on the surface of >95% of prostate cancer cells. 66

67 PSMA-R2: AAA-PSMA R2 molecule was originally developed by Johns Hopkins University - The US provisional filed on March The patent protects a formulation composed by: A Chelator A linker encompassing the one of Lu-2 (now PSMA-R2) Glu-Urea-Lys PSMA binding moiety AAA is developing PSMA-R2 for both diagnostics ( 68 Ga-PSMA-R2) and therapeutics ( 177 Lu-PSMA-R2) Theragnostics: same chelator (Dota) for both Ga 68 and Lu

68 PSMA R2: Summary of in vitro and in vivo results PSMA R2 - Preclinical development completed In vitro plasma stability: Plasma Levels in human and animal species tested at least 2 hours. In silico log P: liposolubly In vivo biodistribution (%ID/g) for -PSMA-R2: Tumor uptake: at 1h and at 4h Kidney uptake: at 0.5h Tumor-to-kidney Salivary glands uptake Biodistribution data form JHU of 177 Lu-labelled compound is in line with the corresponding 68 Ga-labelled compound In vivo efficacy: Survival of the animals at 70 days, reduction in tumor volume, Complete Tumor Remission and Tumor Recurrence assessed Extended single dose toxicity in rats: 177 Lu--PSMA-R2 : toxicity at doses at least 100 times higher than the one foreseen in human 68 68

69 68Ga-PSMA-R2 Preclinical development completed 68Ga-PSMA-R2 Phase 1 trial is expected to start in 1Q2018 Clinical Plans for 68 Ga-labelled compound: Patients with positive PSMA tumors Metastatic disease, positive lymph nodes (to receive accurate curative surgery) of being treated curatively with radiotherapy - radiotherapy planning Planning change patient management in men with Ready to enter Clinical development Feasibility and site selection completed (4 sites in USA) Phase 1/2 clinical trial to start enrolling soon 69

70 177Lu-PSMA-R2 Has potential to improve outcomes in castrate resistant prostate cancer patients at biochemical recurrence (PSA rise) on 2nd generation anti-androgens after chemotherapy PSMA R2 - Preclinical development completed IND Package submitted Ready to enter Clinical development Higher tumor uptake / higher tumor-to-target organ AUC ratio / higher radiosensitivity of the prostate tumor, which could justify avoiding individual dosimetry and supports the one-dose-fits-all approach and 3 dose regimen Feasibility and site selection completed (~15 sites in USA and EU) Phase 1/2 clinical trial to start enrolling soon Patient selection based on 68 Ga-labelled compound 70

71 NeoBOMB 1

72 NeoBOMB1: Targeting Gastrin-Releasing Peptide Receptors (GRPRs) New generation antagonist bombesin analogue, which binds selectively and with high affinity to GRPRs expressed by several types of tumors (e.g. prostate, breast or gastro-intestinal stromal tumors) GRPRs are considered relevant molecular targets for receptor mediated tumor imaging and treatment. Bombesin antagonists have superior pharmacokinetic and toxicological properties when compared to their agonist counterparts Labeled with suitable radio-metals, NeoBOMB1 can be a high-performance imaging tool for diagnosis and therapy of GRPR-positive malignancies Ongoing Phase I/IIa MITIGATE study in patients with advanced TKI-treated gastrointestinal stromal tumors (GIST) 72

73 NeoBOMB1 Clinical Plans for 68 Ga-labelled compound Basket Phase 2 clinical trial starting soon (EU) Clinical Plans for 177 Lu-labelled compound Basket Phase 1a/b clinical trial starting soon (EU) 73

74 The Ga 68 Kit Approach Cold Kit approach PSMA-R2, NeoBOMB1 is the same as NETSPOT Utilizes the eluate of commercially available Ga-68 generators directly, without the need for complex synthesis apparatus Same Distribution NETWORK 74

75 Thank You!

76 1. Assessment Question 1. What is an approved indication for Lu-177 DOTATATE in the United States? A. Metastatic Target Audience: cancer to the liver. B. Treatment of somatostatin receptor-positive GEP-NETs C. Metastatic ACPE#: neuroendocrine cancer to bone D. Endocrine blight Activity Type:

77 2. Assessment Question 2. PSMA with an appropriate chelate could be used to treat: A. Metastatic Target Audience: melanoma refractory to chemotherapy B. Primary and metastatic malignant bladder cancer C. Metastatic ACPE#: malignant substantial glioma D. Primary and metastatic prostate cancer Activity Type: