Betalutin for the treatment of recurrent indolent NHL: new insights. Dr. Arne Kolstad 22 November 2017

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1 Betalutin for the treatment of recurrent indolent NHL: new insights Dr. Arne Kolstad 22 November 2017

2 Betalutin, a new anti-cd37 antibody radionuclide conjugate (ARC) lutetium-177: Beta-particle emitting radioactive nuclide with 6.7 days half-life 177 Lu Lilotomab: murine anti-cd37 antibody satetraxetan: Chelator that binds to lysine residues on lilotomab and chelates lutetium-177 2

3 New radionuclide: Lutetium-177 Feature 177 Lu 131 I (Bexxar) 90 Y (Zevalin) Retained inside the cells after internalization? Uptake of free radionuclide in body? Yes No Yes No Thyroid No Can be imaged Yes, low energy g-photons Yes, but high g-energy No Need for shielding and isolation of patients? Centralized production feasible? No Yes No Yes, half-life 6.7 days Yes, half-life 8 days No, too short half-life (2.7 d) 3

4 Betalutin - LYMRIT trial in patients with indolent NHL Started at Norwegian Radium Hospital in 2012 Phase 1/2a dose-escalation study to find the best dosing regimen for Betalutin More than 60 patients have been enrolled 23 centres are participating in the study Betalutin is produced at the Institute for Energy Technology (IFE) in Norway and at Centre for Probe Development and Commercialisation (CPDC) in Canada. 4

5 LYMRIT study: Different pre-treatment and pre-dosing regimens have been tested to optimize the dosing of Betalutin 5

6 Rituximab pre-treatment depletes B-cells Pre-B and mature B-cells are found in blood, bone marrow, lymph nodes, spleen, and tumours. CD20 and CD37 expression are highest on pre-b and mature B-cells Rituximab depletes B-cells before Betalutin treatment. Rituximab binds selectively to CD20 on B cells and activates B cell lysis CD20 Tumour Bone Marrow Bone Marrow Tumour CD37 Rituximab Spleen Lymph nodes Blood Stream 6

7 Lilotomab pre-dosing blocks CD37 on B-cells, mainly in the bone marrow and spleen Betalutin has high affinity for CD37 on B cells. With no pre-dosing, Betalutin uptake is high in bone marrow and spleen. Betalutin with no pre-dosing Lilotomab blocks CD37 in bone marrow and spleen. Higher Betalutin blood concentration may also increase uptake in tumour. Betalutin with pre-dosing Bone Marrow Tumour Bone Marrow CD20 Betalutin Bone Marrow Tumour Bone Marrow Lilotomab Tumour Tumour CD37 Spleen Spleen Blakkisrud et al. 2017, submitted to European Journal of Nuclear Medicine and Molecular Imaging. 7

8 Centres from 9 countries across Europe are participating Norway Oslo Dr Kolstad Trondheim - Dr. Fagerli Bergen Prof Tore Gjertsen Spain Madrid - Dr Provencio Pulla Salamanca - Dr Garcia-Sancho Sweden Umeå - Dr. Erlansson Linkøping - Dr. Lagerløf Borås - Dr. Andersson UK Manchester - Prof. Illidge Poole - Dr. Bayne Glasgow - Dr. O Rourke Bristol - Dr. Beasley Austria Innsbruck - Dr. Willenbacher Linz - Dr. Welterman Vienna - Prof. Raderer Croatia Zagreb Dr Aurer Czech Republic Ostrava - Prof. Hajek Olomouc - Prof. Papajik Italy Firenze - Prof. Bosi Bologna - Prof. Zinzani Poland Kraków - Prof. Jurczak Warsaw - Prof. Jedrzejczak Warsaw Dr Walewski 8

9 Key eligibility criteria 1. Histologically confirmed (by WHO classification) relapsed/refractory incurable non-hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA, marginal zone, small lymphocytic, lymphoplasmacytic and mantle cell 2. Age 18 years 3. A pre-study WHO performance status of Life expectancy 3 months 5. <25% tumor cells in bone marrow biopsy 6. Measurable disease by radiological methods 9

10 ICML 2017: Poster presentation (June 2017) LYMRIT 37-01: Updated results of a phase I/II study of 177 Lu-lilotomab satetraxetan, a novel CD37-targeted antibody-radionuclideconjugate in relapsed NHL patients Kolstad A et al., Abstract

11 Patient characteristics All patients (n=59) FL (n=44) Other (n=15) Median age, years (range) 65, n (%) 69 (40 88) 43 (73%) 69 (40 80) 31 (70%) 68 (57 88) 12 (80%) Male/female 33 (56%)/ 26 (44%) 25 (57%)/ 19 (43%) 8 (53%)/ 7 (47%) Ann Arbor stage at diagnosis* I/II III/IV Unknown/not reported 4 (13%) 19 (63%) 7 (23%) 4 (21%) 12 (63%) 3 (16%) 0 (0%) 7 (64%) 4 (36%) Prior regimens, median (range) 2 prior regimens 2 prior rituximab regimens Prior alkylating agent 3 (1-8) 40 (68%) 32 (54%) 48 (81%) 2 (1-8) 31 (70%) 24 (54%) 34 (77%) 3 (1-7) 9 (60%) 8 (53%) 14 (93%) Bulky disease >5 cm, n (%) 25 (42%) 22 (50%) 3 (20%) WHO performance status 0/1 35/24 29/15 6/9 * Information collected for Phase 2 patients only (N: all=30; FL=19) Kolstad A et al. ICML 2017, abstract

12 Safety summary The most common grade 3/4 adverse events were reversible thrombocytopenia and neutropenia Dose-limiting toxicities were prolonged but reversible neutropenia and thrombocytopenia (8 patients), and hematuria associated with thrombocytopenia (1 patient). The recommended dose for expansion of Betalutin in Arm 1 with a lilotomab pre-dose of 40 mg was 15 MBq/kg. A phase 2 expansion cohort enrolled 30 patients. The recommended dose for expansion of Betalutin in Arm 4 with a lilotomab pre-dose of 100 mg/m 2 was 20 MBq/kg. Patients are being enrolled in a phase 2 cohort. Treatment-emergent SAEs occurring in 2 or more patients were thrombocytopenia (n=2), atrial fibrillation (n=2), and lymphoma progression (n=2). Eighteen months after subsequent treatment with bendamustine (24 months after Betalutin), MDS/AML was reported in 1 patient with prior alkylating agent exposure There were no on-study treatment-related deaths 12

13 Grade 3/4 treatment emergent AEs in 2 patients (n=59) Adverse event n (%)* Neutropenia 32 (54%) Leukopenia 29 (49%) Thrombocytopenia 28 (47%) Lymphopenia 24 (41%) Infection Urinary tract infection (1) Sepsis/neutropenic sepsis (2) Pharyngitis (1) Pneumonia (1) 5 (8%) Lymphoma progression 3 (5%) * 7 patients had not had hematologic recovery at the time of data cut-off Kolstad A et al. ICML 2017, abstract

14 A higher lilotomab pre-dose in Arm 4 resulted in less hematologic toxicity (higher platelet counts) compared to Arm 1 40 mg llo + 15 MBq/kg Betalutin 40 mg llo + 20 MBq/kg Betalutin 100 mg/m 2 llo + 15 MBq/kg Betalutin 100 mg/m 2 llo + 20 MBq/kg Betalutin Kolstad A et al. ICML 2017, abstract

15 The same pattern was observed with neutrophil counts (higher in Arm 4 compared to Arm 1) 40 mg llo + 15 MBq/kg Betalutin 40 mg llo + 20 MBq/kg Betalutin 100 mg/m 2 llo + 15 MBq/kg Betalutin 100 mg/m 2 llo + 20 MBq/kg Betalutin Kolstad A et al. ICML 2017, abstract

16 Overall response by lymphoma subtype ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease Kolstad A et al. ICML 2017, abstract

17 Best percent change in tumour size from baseline (n=45) 87% of all patients had a reduction in tumour size Percentage change in tumor size (SPD)* ** Patients Follicular Marginal zone Mantle cell * SPD= sum of the products of the diameters **Change in size of target lesion is beyond the scale for this figure (n=2) Kolstad A et al. ICML 2017, abstract

18 Imaging results: FDG PET/CT and SPECT/CT scans show tumour targeting of Betalutin Baseline FDG PET/CT scan showing tumour locations Day 4 SPECT/CT scan showing radioactivity uptake in tumours Kolstad A et al. ICML 2017, abstract

19 Dosimetry: Lilotomab pre-dosing blocks bone marrow uptake and increases tumour uptake of Betalutin A reduced red marrow uptake can be observed for patients in Arms 1 and 4 compared to patients who did not receive pre-dosing with lilotomab (Arms 2+3). The ratio of tumour to red marrow absorbed dose was significantly higher in both Arm 1 and Arm 4 compared to the group that did not receive unlabelled lilotomab. Blakkisrud et al., JNM, 2017 Blakkisrud et al., submitted to EJNMMI,

20 LYMRIT data to be presented at the upcoming ASH congress Single-agent Betalutin is highly active and well tolerated in recurrent inhl: 64% ORR and 24% CR rate in the 55 evaluable inhl patients 81% ORR (CR 28%) in 21 FL patients in Arm 1 (of 32 inhl patients evaluated); Median duration of response (DoR) of 15 months in FL patients Preliminary data from six FL patients from Arm 4 are encouraging (50% ORR, CR 17%) No unexpected safety findings, the safety profile is both predictable and manageable - Updated data will be presented at the meeting (data cut off date for abstract was 3 July 2017) Abstract 2769 Abstract title: 177 Lu-Lilotomab Satetraxetan, a Novel CD37-Targeted Antibody-Radionuclide Conjugate in Relapsed Non-Hodgkin s Lymphoma (NHL): Updated Results of an Ongoing Phase I/II Study (LYMRIT 37-01) Authors: Kolstad, A et al. Session Name: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma Clinical Studies: Poster II Date: Sunday, December 10, 2017 Presentation Time: 6:00 PM - 8:00 PM Location: Georgia World Congress Center, Bldg A, Lvl 1, Hall A2, Atlanta, GA, USA 20

21 Summary Single-agent Betalutin is highly active in recurrent indolent NHL: Overall response rate of 64% (CR 28%) for all evaluable patients High response rates in relapsed FL (ORR 70%, CR 27%) Overall, 87% of all patients in the study had a reduction in tumour size Primary grade 3/4 toxicities were reversible neutropenia and thrombocytopenia that are mediated by pre-dosing with cold antibody lilotomab. With its promising clinical profile and ready-to-use formulation, Betalutin has the potential to be a novel, safe and effective therapy for recurrent B-cell NHL. 21