CAPITAL MARKETS DAY. Building an Alpha-pharmaceutical Pipeline based on Targeted Thorium-227 Conjugates. Thomas Ramdahl, PhD EVP & CTO

Transcription

1 CAPITAL MARKETS DAY Building an Alpha-pharmaceutical Pipeline based on Targeted Thorium-227 Conjugates Thomas Ramdahl, PhD EVP & CTO

2 The Alpha-pharmaceutical Pipeline Targeting high value opportunities in cancer therapy Market moving towards antibody-payload technologies Alpha-pharmaceuticals have unique advantages over other payloads Algeta is building an alpha-pharmaceutical pipeline: demonstrated efficacy in validated models further chemistry and chelation programs initiated increasing core capabilities accessing specific targeting molecules leveraging internal strengths in alpha conjugation building a strong proprietary position 2

3 Antibody-based Cancer Therapies are Top Sellers Drug 2009 sales Growth Herceptin 4.8 billion 8% Avastin 5.8 billion 21% Rituxan/MabThera 5.6 billion 6% Erbitux 1.6 billion N/A At exchange rate 1 CHF = USD (Herceptin, Avastin, Rituxan) and Euro = USD (Erbitux), summing sales of Merck and BMS 3

4 Next-generation Products will Incorporate Payloads There is strong & growing interest in arming antibodies with active payloads BMS/Medarex developing anti-cd 70 Antibody Drug Conjugate (ADC) Sanofi-Aventis developing SAR 3419 (anti-cd 19) Genentech developing T-DM1 a second generation Herceptin 4

5 Targeting the Cancer Cell via Tumor-specific Antigens The target: Cell surface markers (Antigens) Cancer cells Tumor vasculature 5

6 Conjugates use Different Cell-killing Mechanisms Alpha-pharmaceuticals: Alpha radiation externally penetrates and kill cells Antibody drug conjugates need internalization for release of toxin Source: Seattle Genetics 6

7 Changing the Payload to the Alpha Emitter Thorium-227 Alpha has the optimal characteristics for potent cell-killing: High energy radiation Difficult to repair DNA double strand breaks Short range 2-10 cell diameters ( µm) Minimal damage to surrounding normal tissue Alpha particle induces DNA double strand break 7

8 Cross-fire and Inherent Bystander Effect of Alpha Radiation There are not targets on all cells due to tumor cell heterogeneity Drug conjugate Alpha-pharmaceutical Hitting several cells Single cell effect 8

9 Potentially More Efficient Cell-killing from Alpha Radiation Alpha-pharmaceutical Drug conjugate Dead cells in dotted lines Viable cells in solid lines 9

10 Alpha Emitters Effective in Difficult-to-Treat Tumors Effective against chemo-resistant cells Effective against quiescent cells in G 0 1 Surviving Fraction Control NHIK 3025 NHIK 3025 DOX (MDR+) Chemo-resistant NHIK 3025 Plateau Quiescent Alpha Dose dose to medium to medium (Gy) (Gy) Also effective against radio-resistant cells and under hypoxic conditions. There is no known tumor resistance mechanism to alpha emission 10

11 Characteristics of Targeted Therapies Targeted cellkilling No reliance on patients immune effector mechanisms Toxic payload Alphapharmaceuticals Drug conjugates Naked antibodies No need for internalisation No need for cleavable linker Inherent bystander effect Overcomes restistance 11

12 Thorium-227 Conjugate Thorium-227 excellent profile for conjugation Half-life 18.4 days Produced from a simple generator system Targeting molecules Wide variety available Conjugation chemistry crucial Thorium-227 is fixed with a chelator Algeta has key expertise 12

13 Demonstration of Specific Targeting of Thorium Conjugate Biodistribution of 227 Th-DOTA-rituximab (CD20 antigen specific) in nude mice with Raji lymphoma xenografts (CD20 positive) NCR mice with raji xenograft 227Th-DOTA-MabThera % ID/g %ID/gram h 24h 7d 21d 10 0 Blood Lung Liver Spleen Kidney S. Intestines L. Intestines Femur Skull Tumor Specific CD20 targeting by thorium conjugate Organ 13

14 Thorium Conjugate in vivo Efficacy Proof of Concept Treatment of mice with Raji tumor xenografts (CD20 positive) with different antibodies Source: Adapted from Dahle et al., Blood

15 Thorium-227 Conjugates Potentially Well Tolerated Tox study in mice at therapeutic doses (Th-rituximab example): Treatment WBC (10 9 /l) Platelets (10 9 /l) RBC (10 12 /l) Normal values 5.4 ± ± ± 0.4 Control 5.7 ± ± ± kbq/kg 4.9 ± ± ± kbq/kg 3.6 ± ± ± kbq/kg 4.0 ± ± ± kbq/kg 2.8 ± ± ± 0.2 Blue color = Significantly different from control Source: Dahle et al., Eur.J.Nucl.Med.Imaging,

16 Strategic Aims for Pipeline Programs Increased focus on product development Leverage chelator expertise for optimal product performance Access specific targeting carrier molecules through partnering Continually strengthen our alpha-pharmaceutical capabilities and proprietary position 16

17 Leveraged Chelator Expertise for Optimal Performance Existing Technology Thorium New Technology Thorium P R O T E I N P R O T E I N Proof of concept studies used public domain chelating chemistry (DTPA, DOTA) to attach thorium to antibodies Need to optimize points of attachment Strong in-house know-how Maximise binding strength by using all available points of attachment Rapid binding and enhanced stability Proprietary 17

18 Leveraged Chelator Expertise for Optimal Performance Existing Technology P R O T E I N Thorium New Technology P R O T E I N Thorium Proof of concept studies used public domain chelating chemistry (DTPA, DOTA) to attach thorium to antibodies Need to optimize points of attachment Strong in-house know-how Maximise binding strength by using all available points of attachment Rapid binding and enhanced stability Proprietary 18

19 Strengthening Capabilities and Proprietary Position Strengthening capabilities: New Board member: adds extensive experience in biologicals (including as Head, Oncology Disease Biology Leadership Team, Hoffmann-La Roche) Strengthened chelation and chemistry teams; recruiting key antibody expertise Enhancing proprietary position: Patent and non-patent know-how barriers to entry New Board Member Kapil Dhingra Prosecuting patents on thorium labelling methodologies Building know-how around thorium production techniques Establishing proprietary chelator technologies 19

20 Accessing Specific Targeting Molecules Focus on in-licensing to provide Algeta with marketing rights in US and beyond targeting high value opportunities Attractive technology out-licensing/ co-development not excluded Technical Selection Criteria: Antigen specificity Pharmacokinetics Biodistribution Excretion Risk minimization strategy: Known and validated tumor target antigens Diversify across more than one antibody format Current status: Very positive response partners recognise Algeta s unique offer Multiple discussions on-going 20

21 Summary: the Alpha-pharmaceutical Pipeline Targeting high value opportunities in cancer therapy Market moving towards antibody-payload technologies Alpha-pharmaceuticals have unique advantages over other payloads Algeta is building an alpha-pharmaceutical pipeline: demonstrated efficacy in validated models further chemistry and chelation programs initiated increasing core capabilities accessing specific targeting molecules leveraging internal strengths in alpha conjugation building a strong proprietary position 21