Clinical development of bone-seeking / alpha-particle p p emitting g 223Ra Current status

NOVEL TREATMENT OF PATIENTS WITH BONE METASTASES FROM HORMONE REFRACTORY PROSTATE CANCER – in Phase-3 Phase 3 Slides not to be reproduced without permission of author

Acknowledge: PhD Roy H. Larsen cofo nder of ATI and Professor Sten Nilsson, founder Nilsson Karolinska Hospital

ALGETA – team

Collaborating Clinical Sites

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Radium-223 Øyvind S. Bruland Professor of Clinical Oncology

R Alpharadin

Clinical Results Aspects of the Tumorbiology Basis for targeting

Skeletal Metastases is very common The Clinical Problem

• Pain

• Pathological fracture • Spinal cord & cauda equina compression • Cranial nerve entrapment • Hypercalsemia • Bone marrow suppression • Impaired p mobility y & QoL Q

E.Munch: ”The Scream”, 1893

Shortcomings in the current treatment of Skeletal Metastases • Lack of effective cytotoxic agents to combat overt & disseminated disease • External radiotherapy is an effective local palliative treatment modality • However, with low therapeutic index – Impair/destroy p y “in field red bone-marrow”

Multiple metastatic lesions

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Metastatic Prostate Cancer Bone mets dominate – less visceral metastases t t Skeletal mets govern the prognosis – ….. cause of death! Pancytopenia Pronounced P d Bl Blastic-/ i / Sclerotic phenotype E.Munch – ”Death as The Helmsman”

Widespread Disease • Bone scintigraphy in a 60 year old ld patient with multiple skeletal k l t l metastases t t from prostate cancer

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Bone-seeking Radiopharmaceuticals Biodistribution - ”a a class-effect class effect” Diagnostic (photons): • 99mTc MDP

– Ratios in osteosclerotic/-blastic lesions:

• Metastases/normal bone 4-10 • Metastases/soft / tissues up p to 300

Palliation (electrons): • 89 Sr - MetastronR (Amersham) • 153 Sm EDTMP - QuadrametR (Cytogen/Shering) • 186/188 Re HEDP (Mallinkrodt) Therapeutic (alpha particles): • 223 Ra - AlpharadinR (Algeta)

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Why use ™ Intravenously

223Ra?

targeted to skeletal metastases

Radium is a natural bone seeker – like Strontium - no need for carrier molecule ™Veryy strongg cytotoxicity y y in targeted g areas/cells due to high LET ™ A cost efficient alpha particle emitter Small molecule ((cationic form)) - compared p to monoclonal antibodies Slides not to be reproduced without permission of author

Targeted Radionuclide Therapy • % injected amount of radioactivty reaching the target • Biodistribution Bi di t ib ti – Routes of excretion – Other organs/tissues than cancer being targeted?!?

• Kinetics of targeted radioisotope at the targeted sites • Microdistribution of radionuclide within a targeted l i lesion • Radiobiological effects of the radioisotope • Fate of the decay-products – radioactive daughters • Dosimetry Radium-223 has unique properties that ”fits” the situation in HRPC Slides not to be reproduced without permission of author

Phase I (Nilsson et al. 2005 Clin Cancer Res) 25 patients with advanced breast or prostate ccancer ce completed co p e ed study s udy – No o SAE S „ 5 dose levels levels:: 46 - 250 kBq kBq/kg /kg „ Single i.v ii.v. v. injection „ Pain palliation observed in more than 50% of the patients also observed at the first dose level patients, „ 4 pts. became without the need for opioids „ DLT & MTD not reached „ Strong rreduction eduction in serum alkaline phosphatase „ No significant i ifi hematological h l i l toxicities i ii „

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Uniquely advantageous clearance mechanism

Baseline 99mTc -MDP MDP

Day 2 Imaging g g based on

Day 6 223

Ra

•

Cleared rapidly, directly into gut (no apparent hepatobiliary excretion)

•

Spares kidney – radiation dose low

•

N evidence No id off mucositis iti – drug d held h ld within ithi intestinal i t ti l content t t

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Confirmed uptake of radium-223 in bone metastasis Radium-223 image

Standard bone scan Bone metastasis

Baseline imaging dose

99mTc-MDP

Abundant gamma rays

After radium-223 injection

Imaging based on

223 Ra

Few gamma rays

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Simple injection of Alpharadin Radium-223 will target areas of new bone formation in bone metastases, being rapidly taken up from the blood circulation

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BC1-02 phase II: study design

RAND DOMIZE

Alpharadin 50 kBq/kg b.w. q4 wks

HRPC patients Local EBRT

Saline placebo q4 wks

n = 64

Treatment

4 injections q 4 weeks

Bone markers, PSA

W12

W16

M6

Follow-up of long term toxicity, and survival

Skeletal Related Events (SRE), pain, bone markers, PSA, safety, sa ety, survival su a

M9

M12 Study unblinded

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M 18

M24

BC1-02 phase II: significant increase in survival Phase II BC1-02 trial

• Median survival 46.4 weeks in the placebo group and 65.3 weeks in the Alpharadin group; 4.5 months difference. Hazard ratio 2.103, p = 0.017. (Lancet Oncology, 2007) • 30% (10pts) of the patients were alive at 24 months in the Alpharadin group versus 13% (4 pts) in the placebo group

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PSA: decreased during treatment period and beyond

Maximum treatment duration

• Rapid reduction of PSA • Reduction spans treatment period and beyond • Extend treatment duration - sustain reduction Slides not to be reproduced without permission of author

Significant effects on all relevant biomarkers R l ti Relative change h ffrom baseline b li to t 4 weeks k after ft last l t injection i j ti Alpharadin1

Placebo1

P-value

Bone ALP (bone formation marker)

-66% 66%

+9%