Fusion Protein Technology Potential Treatment for Hemophilia 1. Recombinant Factor VIII-Fc Development Program 2. Rec

1. Fusion Protein Technology �Potential Treatment for Hemophilia1. Recombinant Factor VIII-Fc Development Program 2. Recombinant Factor IX-Fc Development Program26 September 2009, WFH Global Forum, MontrealGlenn Pierce MD, PhD

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3. 4 From Insight to Exploration to Application Syntonix founded in 1998 based on Harvard and Brandeis research Neonatal Fc receptor, FcRn, found in human epithelial and endothelial cells Use rFc fusions for transport of proteins Explored alternative delivery routes, e.g. pulmonary, oral In 2003 focused on injectable, long lasting versions of drugs for the treatment of hemophilia Drug delivery focus initially; explored a number of molecules � IFNa, IFNb, EPO, FSH Culminated in Ph I EPOFc trial for pulmonary delivery Worked, with bioavailability and no tox issues However, discontinued as result of ambiguity about regulatory path (inhalable insulin was stuck at that point) and safety concerns emerging around EPO Developed monomeric Fc to improve pK, shifted focus to improved pK via IV delivery and settled on FIXFc as priority Partnered with BVT to enable next step in development Biogen originally considered investment, but liked technology and potential so much we decided to acquire and then run as a subsidiary Goal is maintain focus on unique attributes of hemophilia, but make expertise and resources available to facilitate clinical progressDrug delivery focus initially; explored a number of molecules � IFNa, IFNb, EPO, FSH Culminated in Ph I EPOFc trial for pulmonary delivery Worked, with bioavailability and no tox issues However, discontinued as result of ambiguity about regulatory path (inhalable insulin was stuck at that point) and safety concerns emerging around EPO Developed monomeric Fc to improve pK, shifted focus to improved pK via IV delivery and settled on FIXFc as priority Partnered with BVT to enable next step in development Biogen originally considered investment, but liked technology and potential so much we decided to acquire and then run as a subsidiary Goal is maintain focus on unique attributes of hemophilia, but make expertise and resources available to facilitate clinical progress

4. 5 Biogen Idec�s Pipeline and Therapeutic Areas BIIB employs more than 4K people, w/ annual revenues greater than 4bb USD. Biogen Core in MS treatment, with emphasis on building long term relationships Make a long-term commitment to advance standard of care w/ ongoing investment IDEC Developed Rituximab, launched with Genentech � ongoing expansion in Immunology Tackle challenge of hemophilia patients with inhibitors Therapeutic area focus � areas of high unmet needBIIB employs more than 4K people, w/ annual revenues greater than 4bb USD. Biogen Core in MS treatment, with emphasis on building long term relationships Make a long-term commitment to advance standard of care w/ ongoing investment IDEC Developed Rituximab, launched with Genentech � ongoing expansion in Immunology Tackle challenge of hemophilia patients with inhibitors Therapeutic area focus � areas of high unmet need

5. 6 Rationale for Longer Acting Fusions: rFactor IX and rFactor VIII Immunoglobulin G antibodies exhibit long half-lives, on the order of weeks Protection from catabolism through interactions with FcRn Interaction site localized to the constant domain of IgG (Fc) Fusion of proteins with Fc domain confers extended half-life via FcRn interaction A Factor IX (FIX) or Factor VIII (FVIII) product with a longer half life could reduce the dosing frequency required to maintain prophylaxis Improved management of hemophilia Biogen Idec has developed an improved configuration for Fc fusion proteins, and applied this technology to FIX and FVIII

6. 7 The Neonatal Fc Receptor: FcRn Crystal Structure: Martin WL, West AP, Gan L and Bjorkman PJ Molecular Cell, 2001, 7, 867. Simister NE, Rees AR. Isolation and characterization of an Fc receptor from neonatal rat small intestine. Eur J Immunol 1985; 15: 733-8 Brambell FWR, Hemmings WA, Morris IG. A theoretical model of ?-globulin catabolism. Nature 1964 Sep; 203: 1352-5 Ghetie V, Hubbard JG, Kim JK, Tsen M-F, Lee Y and Ward ES Abnormally short serum half-lives of IgG in 2-microglobulin-deficient mice. Eur J Immunol 1996 Mar; 26 (3): 690-6 Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A 1996 May; 93: 5512-6 Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D. Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin; possible protective role of FcRn. Immunology 1996; 89: 573-8 Crystal Structure: Martin WL, West AP, Gan L and Bjorkman PJ Molecular Cell, 2001, 7, 867. Simister NE, Rees AR. Isolation and characterization of an Fc receptor from neonatal rat small intestine. Eur J Immunol 1985; 15: 733-8 Brambell FWR, Hemmings WA, Morris IG. A theoretical model of ?-globulin catabolism. Nature 1964 Sep; 203: 1352-5 Ghetie V, Hubbard JG, Kim JK, Tsen M-F, Lee Y and Ward ES Abnormally short serum half-lives of IgG in 2-microglobulin-deficient mice. Eur J Immunol 1996 Mar; 26 (3): 690-6 Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A 1996 May; 93: 5512-6 Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D. Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin; possible protective role of FcRn. Immunology 1996; 89: 573-8

7. 8 Therapeutic Utility of Fc Fusion Proteins Numerous recombinant Fc fusion proteins approved for clinical use Traditional Fc fusion proteins are dimeric Enbrel (Etanercept, TNFaR, 1998) Amevive (Alefacept, LFA-3, 2003) Orencia (Abatacept, CTLA-4, 2005) Arcalyst (Rilonacept, IL-1R, 2008) Nplate (Romiplostim, TPO peptide, 2008) Well established safety profile for chronic therapy Several more in clinical trials Biogen Idec has previous experience in developing Fc fusion proteins for clinical use Well established approach to improving half-life for a range of effector molecules Enbrel � Immunex/Amgen Amevive � Biogen (divested to Astellas) Orencia � BMS (w/ next generation molecule in devt) Arcalyst � Regeneron Nplate � Amgen Multiple other fusion molecules in development If questions about theoretical tox concerns No our knowledge, any tox issues seen have been attributed to effector function, not Fc mediated Possible line of questioning: other than Nplate, all are immunosuppressants ADCC � antibody mediated cell-dependent cytotoxicity FCgRIII receptor stimulate release of cytotoxic molecules from Natural Killer (NK) cells to kill antibody covered target cells Concentration of fusion-factors much lower than circulating IgG levels (10-20 ug/ml vs. 10-12 mg/ml) Did competitive binding studies � demonstrated blocking of Fc binding at IgG levels 10X lower than circulating levels Created a-gly EPOFc and IFNaFc molecules that bound FcRn but not FcgR No increase in activity, which would have been expected if target cells were being killed by ADCCWell established approach to improving half-life for a range of effector molecules Enbrel � Immunex/Amgen Amevive � Biogen (divested to Astellas) Orencia � BMS (w/ next generation molecule in devt) Arcalyst � Regeneron Nplate � Amgen Multiple other fusion molecules in development If questions about theoretical tox concerns No our knowledge, any tox issues seen have been attributed to effector function, not Fc mediated Possible line of questioning: other than Nplate, all are immunosuppressants ADCC � antibody mediated cell-dependent cytotoxicity FCgRIII receptor stimulate release of cytotoxic molecules from Natural Killer (NK) cells to kill antibody covered target cells Concentration of fusion-factors much lower than circulating IgG levels (10-20 ug/ml vs. 10-12 mg/ml) Did competitive binding studies � demonstrated blocking of Fc binding at IgG levels 10X lower than circulating levels Created a-gly EPOFc and IFNaFc molecules that bound FcRn but not FcgR No increase in activity, which would have been expected if target cells were being killed by ADCC

8. 9 rFVIIIFc, a Monomeric Fc Fusion Syntonix created a novel configuration: �monomeric� Fc fusions have a single effector molecule attached to Fc Monomer technology has been applied to FVIII for the treatment of Hemophilia A Regulatory filings underway First in Human Study will initiate shortly

9. 10 rFVIIIFc Structure and Characterization Final BDD-FVIIIFc fusion is a 220 kDa protein 90 kDa HC, 105 kDa LC-Fc, 25 kDa Fc alone Produced in HEK 293 cells Posttranslational modifications generally comparable to existing FVIII products Specific activity comparable to other FVIII products rFVIIIFc: 8000 to 10,000 IU/mg = 1760 to 2200 IU/nmol Advate: 4000 to 10,000 IU/mg = 1120 to 2800 IU/nmol Xyntha: 5500 to 9000 IU/mg = 935 to 1530 IU/nmol Refacto: 9110 to 13,700 IU/mg = 1549 to 2329 IU/nmol For Refacto it said 1370- I added a 0For Refacto it said 1370- I added a 0

10. 11 rFVIIIFc in FVIII-deficient Mice

11. 12 rFVIIIFc in Hemophilia A Dogs � Single IV Dose Y axes messed upY axes messed up

12. 13 ReFacto�/rFVIIIFc Crossover Study in FVIII-Deficient (Hemophilia A) Dogs Whole blood clotting times were corrected to normal range after 125 IU/kg dose Correction for ~65-72 hr with ReFacto and ~90-120 hr for rFVIIIFc Half-life of FVIIIFc is twice that for ReFacto in chromogenic assay 1% clotting activity at ~60 hr for ReFacto and ~110 hr for rFVIIIFc Correlates with ELISA data for FVIIIFc protein concentrations Inhibitors (anti-FVIII Ab�s) measurable in both dogs by 168 hr

13. 14 rFIXFc, a monomeric Fc fusion

14. 15 rFIXFc Domain Structure and Postranslational Modifications PRO: Propeptide cleaved by processing enzyme Cotransfected with additional for full processing GLA: contains 12 g-carboxylated glutamic acid (Gla) residues Produced in HEK293 cells due to greater capacity for g-carboxylation ACT PEP: activation peptide cleaved to yield active protease Other modifications: N- and O- glycosylation, Asp b-hydroxylation, Tyr sulfation, Ser phosphorylation

15. 16 Intravenous Pharmacokinetics of rFIXFc in FIX-Deficient Mice Can we get an r in front of FIXFc?Can we get an r in front of FIXFc?

16. 17 rFIXFc in FIX-Deficient Dogs Y legends messed upY legends messed up

17. 18 Six Month rFIXFc Toxicology Study in Monkeys

18. 19 Summary of Pharmacokinetics of rFIXFc and rFIX in Various Species

19. 20 FcRn Mediates Protection from Catabolism

20. 21 rFIXFc and rFVIIIFc Clinical Goals Demonstrate of prolonged protection from bleeding Maintenance of FVIII/FIX trough levels with similar or reduced number of breakthrough bleeds with less frequent administration Establishment of similar FVIII/FIX protective levels for surgery Fulfillment with the regulatory requirements globally for licensure

21. 22 Path Forward Complete ongoing rFIXFc Ph I/IIa trial and transition to global pivotal licensure studies Initiate First In Human study for rFVIIIFc � Phase I/IIa Study Initiate rFVIIIFc Integrated Ph II/III trial � licensure study Evaluate the potential of this technology to impact treatment of hemophilia worldwide