Betalutin : a modern approach to treating NHL patients. Arne Kolstad Oslo University Hospital Norway

Transcription

1 Betalutin : a modern approach to treating NHL patients Arne Kolstad Oslo University Hospital Norway 1

2 Speaker credentials Senior Consultant of Medical Oncology and Radiotherapy, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Area of expertise: Malignant lymphoma Chairman of the Norwegian Lymphoma Group Leader of Oslo University Hospital Focus Area Cancer Immunotherapy Principal investigator of clinical trials with radioimmunotherapy, autologous and allogeneic stem cell transplantation and cancer vaccines in lymphoma Member of Nordic Nanovector's Scientific Advisory Board 2

3 Designing novel therapies for NHL Non-Hodgkin lymphoma the majority are B-cell lymphomas B-cells have several target antigens for novel therapies T cell 15% B cell 85% NHL = non-hodgkin lymphoma. 3

4 Currently approved radioimmunotherapy (RIT) agents target CD20 Two radioimmunotherapy (RIT) agents (Zevalin and Bexxar ) are currently approved for NHL Both agents target CD20 Patients with B-cell NHL receive anti-cd20 antibody therapy as standard RIT targeting CD20 may not be as effective in patients who have been treated with anti- CD20 antibodies RIT targeting CD20 are not extensively used in treatment of NHL despite documented effects Target for Zevalin and Bexxar NHL = non-hodgkin lymphoma. 4

5 Targeting a different antigen may improve efficacy Targeting a different antigen than CD20 may be more effective in patients who have received prior anti-cd20 therapy CD37: the treatment target for Betalutin Development of HH1 (anti-cd37) and 177-Lu- HH1 (Betalutin ) at Oslo University Hospital Radiumhospitalet Betalutin is an antibody radionucleotide conjugate (ARC) which targets CD37 5

6 Betalutin targets CD37 - an important therapeutic target for NHL HH1: antibody that targets the CD37 antigen that is expressed on B- cell lymphocytes and corresponding NHLs HN S C N H HOOC HOOC N N 177 Lu N N COOH COOH Lutetium-177: Beta-particle emitting radioactive nuclide with 6.7 days half-life Tetraxetan: Linker that binds to lysine residues on HH1 and that chelates Lutetium-177 NHL = non-hodgkin lymphoma. 6

7 Anti-CD37 (HH1) is internalized while anti-cd20 (rituximab) is not Anti-CD37 Anti-CD20 Internalization of HH1 results in more localized radioactivity and less radiotoxicity to the surrounding cells 7

8 Important characteristics of Betalutin compared with prior analogues Half-life matches circulation time of the HH1 antibody, for effective biodistribution before either the antibody is recycled or the payload decays Low energy beta-emitter Betalutin Zevalin Bexxar T ½ 6.7 d 2.7 d 8.0 d Mean beta-energy 0.13 MeV 0.93 MeV 0.18 MeV Penetration depth 0.25 mm 3.6 mm 0.7 mm Antigen CD37 CD20 CD20 Targets a different antigen to other drugs for NHL CD37-based therapies in relapsed lymphoma patients that do not respond to standard CD20- based therapy (rituximab) provide greater anticipated activity and a potential synergistic effect Limited range of the particles minimizes exposure to healthy cells ARC = antibody radionuclide conjugate; RIT = radioimmunotherapy. 8

9 ARCs are an improvement over prior agents in this space Carrier-free "Ready to use formulation Specific activity ( MBq/mg) Clinical dosage: 10mg/patient A single injection, ready-to-use formulation, for easy administration in an outpatient setting ARC = antibody radionuclide conjugate; MBq = megabecquerel; RIT = radioimmunotherapy. 9

10 Progress in the clinical development plan of Betalutin Betalutin is a novel ARC in clinical development by Nordic Nanovector for the treatment of B cell NHL A total of 31 patients have been enrolled in to the LYMRIT Phase 1/2 study, including 12 patients in Phase 2 The latest trial data were presented at the AACR congress in April 2016 on the 21 evaluable patients at the time of the poster submission ARC = antibody radionuclide conjugate; NHL = non-hodgkin lymphoma. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

11 A total of 29 patients have been enrolled to date Lymrit Phase 1/2 trial Phase 1 Phase 2 Pivotal Phase 2 PARADIGME trial Arm 1 10MBq/kg (- HH1 + R0) N = 1 MBq = Megabecquerel (radioactivity measurement unit) HH1 = CD37 B-cell seeking antibody R0 = rituximab predosing on day 0 N = Number of patients = Completed step 10MBq/kg (+ HH1 50mg) N = 3 Arm 2 Arm 3 Arm 4 20MBq/kg (+ HH1 50mg) N = 3 15MBq/kg (- HH1) N = 2 15MBq/kg (- HH1 + R0) N = 3 15MBq/kg (+ High dose HH1) N = 3 15MBq/kg (+ HH1 50mg) N = 6 10MBq/kg (- HH1) N = MBq/kg or 20MBq/kg* (- HH1 + R0) N = MBq/kg or 20MBq/kg* (+ High dose HH1) N = 3 15MBq/kg (+ HH1 50mg) N = >9 Discontinued for futility 17.5MBq/kg* (+ HH1 50mg) N = >3 First Patient: 2H 2017 Dose TBD N=85 Last Patient: 2H 2018 Regulatory submission: 1H 2019 * Dose decision based on safety data and Safety Review Board s recommendation PARADIGME dose decision: 1Q

12 Centres from 13 countries across Europe are participating Phase I & II 11 centres Norway Oslo Dr Kolstad Trondheim - Dr. Fagerli Bergen Prof Bjørn Croatia Zagreb Dr Aurer Italy Bologna - Prof. Zinzani Milan Dr Ciceri Poland Warsaw Dr Walewski Spain Madrid - Dr Provencio Pulla Salamanca - Dr Garcia-Sancho Sweden Umeå - Dr. Erlansson UK Manchester - Prof. Illidge Phase II 14 centres Austria Innsbruck - Dr. Willenbacher Linz - Dr. Welterman Vienna - Prof. Raderer Czech Republic Ostrava - Prof. Hajek Olomouc - Prof. Papajik Prague - Prof. Trnéný Italy Firenze - Prof. Bosi Poland Kraków - Prof. Jurczak Warsaw - Prof. Jedrzejczak Sweden Linkøping - Dr. Lagerløf Borås - Dr. Andersson UK Poole - Dr. Bayne Glasgow - Dr. O Rourke Bristol - Dr. Beasley 12

13 The right pre-treatment and pre-dosing regimens are the key to Betalutin s success (arms 1 and 2) 50 mg HH1 Rituximab Rituximab 375 mg/m mg/m 2 Betalutin Day -28 Day -21 Day -14 Day 0 Rituximab Rituximab 375 mg/m mg/m 2 Betalutin Pre-treatment Pre-dosing Treatment Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

14 The right pre-treatment and pre-dosing regimens are the key to Betalutin s success (arms 3 and 4) Rituximab 375 mg/m 2 Arm 3 Rituximab 375 mg/m 2 Betalutin Day -28 Day -21 Day -14 Day 0 Treatment phase Betalutin Arm 4 High dose HH1 Pre-treatment Pre-dosing Treatment Repetto et al. Abstract number 3245, ASH 2015; Dahle et al. Abstract number P162, EANM

15 The majority of patients had FL and had received multiple prior treatments Characteristics Arm 1 Arm 2 Phase 2 Total Dose level 10 MBq/kg N=3 15 MBq/kg N=6 20 MBq/kg N=3 10 MBq/kg N=2* 15 MBq/kg N=2 15 MBq/kg N=5 N=21 Median age (years) Range Male 3 (100%) 5 (83%) 1 (50%) 1 (50%) 1 (50%) 1 (20%) 14 (67%) Female 0 1 (17%) 1 (50%) 1 (50%) 1 (50%) 4 (80%) 7 (33%) Primary diagnosis - FL 3 (100%) 5(83%) 2 (100%) 2 (100%) 2 (100%) 4 (80%) 19 (90%) - MCL 0 1 (17%) (20 %) 2 (10%) Prior treatments median (range) 5 (1-8) 2.5 (1-5) 1 (1-2) 2 (2-2) 3 (2-4) 2 (1-2) 2 (1-8) *First patient received 250 mg/m 2 rituximab on day -7 and day 0 prior to Betalutin and is included in this group. FL = follicular lymphoma, MBq = megabecquerel, MCL = mantle cell lymphoma. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

16 A typical patient profile for the LYMRIT study Older adults (range years) Histologically-confirmed, relapsed, incurable FL CD37-positive Less than 25% of tumor cells in the bone marrow Typically received several previous treatments for lymphoma, including: Rituximab Alkylating chemotherapy FL = follicular lymphoma. 16

17 Imaging was performed to track lymph node volume at regular intervals CT = computer tomography; FDG PET/CT = fluorodeoxyglucose positron emission tomography-computer tomography. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

18 Response level (%) Efficacy data presented at AACR confirms Betalutin s strong potential % % 32% 16% 21% ORR CR PR SD PD ORR = Overall response rate, CR = Complete response, PR = Partial response, SD = Stable disease, PD = Progressive disease Tumor response assessed according to Cheson criteria Highly favourable response rate in a heavily pre-treated population One patient had confirmed transformed lymphoma at 3 months. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

19 Betalutin resulted in reduced tumor volume for most patients Maximum change in the sum of products of the diameters (SPD) of up to six of the largest tumor nodules for each patient from baseline. Reduction in tumor volume of >50% was seen in most patients *Patient with transformed disease. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

20 Patients Competitive duration of response is emerging from a single treatment Arm 1: 10 MBq/kg Arm 1: 15 MBq/kg Arm 1: 20 MBq/kg Arm 2: 10 MBq/kg Arm 2: 15 MBq/kg Phase 2: 15 MBq/kg Response end Time since start of treatment (months) Continued response Duration of response (DoR) of all patients with response assessment (12/21). Triangles represent start of response (either partial and complete). Durable responses: DoR exceeding 12 months in most responders MBq = megabecquerel. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

21 A highly favorable, predictable and manageable safety profile was observed Most adverse events were hematological, and included thrombocytopenia and neutropenia Adverse events Arm 1 Arm 2 Phase 2 Total Dose levels 10 MBq/kg N=3 15 MBq/kg N=6 20 MBq/kg N=3 10 MBq/kg N=2* 15 MBq/kg N=2 15 MBq/kg N=5 N=21 CTCAE grade** Platelet count decrease Neutrophil count decrease *First patient received 250 mg/m 2 rituximab on day -7 and day 0 prior to Betalutin and is included in this group. **CTCAE grade version 4. Serious adverse events rated as possibly or probably related to Betalutin : epistaxis, pulmonary infection and sepsis were reported in one patient each and two cases of atrial fibrillation CTCAE = common terminology criteria for adverse events; MBq = megabecquerel. Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

22 Thrombocytopenia was transient and reversible Platelet count decrease following Betalutin treatment 15MBq/kg Betalutin with HH1 (patient ) 15MBq/kg Betalutin without HH1 (patient ) Adapted from Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

23 Neutropenia was transient and reversible Neutrophil count decrease following Betalutin treatment 15MBq/kg Betalutin with HH1 (patient ) 15MBq/kg Betalutin without HH1 (patient ) Adapted from Kolstad A, et al. Poster version of the Abstract LB-252. Presented at AACR Annual Meeting, New Orleans, April 16-20,

24 Betalutin demonstrates a durable response Complete metabolic response (FDG PET/CT) at 3 months in patient with FL at 20 MBq/kg Complete metabolic response (FDG PET/CT) at 6 months in patient with FL at 15 MBq/kg Patient is still in complete remission 24 months after Betalutin treatment Patient is still in complete remission 18 months after Betalutin treatment FDG PET CT = fluorodeoxyglucose positron emission tomography-computer tomography; MBq = megabecquerel; SPECT = single-photon emission computerized tomography. 24

25 Summary Betalutin, a single dose, ready-to-use formulation, that binds to a novel target, CD37, for the treatment of NHL Most adverse events were hematological (thrombocytopenia and neutropenia), which were transient and reversible Promising efficacy and durable responses were observed Betalutin targets a different antigen than CD20 and has the potential to be a novel, safe and effective therapy for B-cell malignancies NHL = non-hodgkin lymphoma. 25