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Antibody Technologies and Attrition Rates – an industry analysis 2013

Released by La Merie Publishing on March 24, 2013

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Antibody Technologies and Attrition Rates

Addendum: Antibody Data Sheets – 15/15

ID No. Drug Codes INN Brand Name Page No. 483 REGN1500 583 484 REGN668; SAR-231893 Dupilumab 584 485 REGN727; SAR-236553 Alirocumab 585 486 REGN88; SAR-153191 Sarilumab 586 487 MORAb-0028 587 488 IQ-DAA (IQNLF + 588 IQNPA) 489 P2G12 589 490 TB-402; Mab-LE2E9Q 590 491 SDZ OST-577; Ostavir Tuvirumab 591 492 SDZ MSL 109; EV 2-7; Sevirumab 592 Protovir 493 mAb C23 Regavirumab 593 494 HIV antibody cocktail 594 C2F5 + C2G12 + C4E10 495 HA-1A Nebacumab Centoxin 595 496 BIIB037; BART 596 497 PAT-SC1 597 498 PAT-SM6 598 499 KBSA301 599 500 TCN-202 600 501 AVP-21D9; Thravixa 601 502 LFB-R593 Roledumab 602 503 SAR-279656; mAb F598 603 504 KBPA101 Panobacumab 604 505 TCN-032 605 506 FlumAb 606 507 CV-18C3; MABp1 607

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Antibody Technologies and Attrition Rates

2 Introduction

Therapeutic monoclonal antibodies have become a clinically relevant and commercially successful treatment modality. At present, a number of technologies are available to generate antibodies, but it is not yet described whether there exist differences between the various antibody generation technologies regarding the success rate of development (or failure rate = attrition rate). One important difference between “in vitro” and “in vivo” antibody generation technologies is the presence of a selection pressure by B-cells in vivo, either in wild-type animals, transgenic animals or in human B-cells, whereas such a selection pressure is missing in phage or yeast based display technologies. This study aimed at finding out whether there is any difference in clinical attrition rates between in vitro generated antibodies and in vivo generated antibodies and between the various technologies within each category.

The main in vitro antibody generation technologies identified and evaluated in this study were display libraries from Cambridge Antibody Technology (CAT), Dyax, Morphosys, Genentech, Domantis and a number of various smaller technologies.

The main in vivo technologies studied here were chimeric antibodies, humanized antibodies by various technologies, transgenic mouse technologies from Abgenix, Medarex/Genmab, Medarex/Kirin and Regeneron Pharmaceuticals; and human B-cell derived antibodies.

Attrition rate was defined as the number of failed antibodies divided by the total number of active and discontinued antibodies. Attrition rate was limited to the clinical stage of development including the market stage. Active antibodies were those during the study periof of January and February 2013, whereas discontinued antibodies were included as early as the 1990ies.

Information for each antibody was retrieved from publicly available sources and documented for each antibody in a Antibody Data Sheet with references for the source of information (literature reference of a hyperlink leading to the website of information).

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Antibody Technologies and Attrition Rates

By definition, this analysis has limitations as it 1) only considers naked antibodies, i.e. a number of other antibody-based constructs (e.g. antibody-drug conjugates, Fc-fusion proteins) were excluded and 2) only those naked antibodies were included for which the underlying antibody generation technology has been disclosed in any publicly available document. Furthermore, the analysis only considered clinical stage antibodies and does not address the preclinical antibody discovery and development efforts. Excluded were also smaller antibody technology companies although they might have fulfilled the criteria of at least eight antibodies in clinical development. Licensed out, in house-developed and co- developed antibodies were considered for each company separately, i.e. a given antibody may have been considered twice. A total of 17 pharma and biotech companies were included in this analysis and their naked antibody profile was summarized for each company separately in Tables 24-40.

The analysis shows that the number one antibody development company is the Roche Group including former Genentech and the Japanese participation Chugai as well as Roche in house antibody R&D capabilities (Table 24). The Roche group has advanced 53 naked antibodies with disclosed antibody generation technology into development of which 21 had dropped out of development and 32 (60%) are in development in the period of January- February 2013. Roche has a clear preference for in vivo antibody technologies and especially for humanized antibodies. Humanized antibodies counted for 74% of all antibodies which ever entered development and for 78% for currently active antibodies. Considering the enourmous commercial success of marketed Roche antibodies, the overall attrition rate of 40% is an insufficient, only quantitative parameter. It also might reflect a more rigorous approach to early sort out antibody projects not promising enough for the company. It is noteworthy, that the only Genentech/Roche in house technology (i.e. in vitro Fab display) has not contributed to a higher number of development projects. Furthermore, the transgenic mouse technologies were only used occasionally with little success. Roche rather relied on the generic antibody humanization technology. This strategy is supported by the finding of the present analysis that safety was a minor reason for failure of in vitro and in vivo generated antibodies, and that none of the 20 antibodies terminated for safety ______March 2013 Page: 44 / 606

Antibody Technologies and Attrition Rates

Table 15d Targets vs. in vitro and in vivo antibody generation technologies

Target / Drug Code (reason for failure) In vitro antibody EGF-R BAFF-R BAFF (BlyS) IL-23(p19) technology CAT phage display Benlysta Dyax phage display IMC-11F8 HuCAL phage display VAY736 CNTO-1959 Genentech Fab library n-CoDeR library dAb library Various in vitro MM-151 In vivo antibody technology Chimeric SYM004 Erbitux Primatized Nanobodies Deimmunized Human engineered Humaneered Humanized Matuzumab Anti-Br3 MK-3222 (efficacy) GA201 Nimotuzumab Mixed tech bispec mAbs Transgenic precursor tech XenoMouse Abgenix Vectibix HuMAb Medarex LY2127399 HuMAb Genmab Zalutumumab (business) KM mouse Medarex KM mouse Kirin VelocImmune mouse Human B-cell derived Failed antibodies marked by shadow

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Antibody Technologies and Attrition Rates

Antibody Data Sheet Id No 011

Trade Name INN Drug Codes BI-836845 Target IGF-1 and IGF-2 Technology Fully human by HuCAL phage display technology (Morphosys) Species of parent antibody IgG Isotype IgG1 Binding affinity KD of 0.07 nM and 0.8 nM for human IGF-1 and IGF-2, respectively Mutations Glycosylation Effector function Other Therapeutic Area Oncology Indications Solid tumors Status Active Reason for failure - Year of failure - Highest phase I Company Boehringer Ingelheim URL http://clinicaltrials.gov/ct2/show/NCT01317420?term=BI- 836845&rank=1

References:

 Adam PR, Friedbichler K, Hofmann MH et al. BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation J Clin Oncol 30, 2012 (suppl; abstr 3092)

 Adam PJ, Ostermann E, Lamche HR et al. Abstract A208: Pharmacodynamic properties and antitumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody Molecular Cancer Therapeutics: November 2011; Volume 10, Issue 11, Supplement 1doi: 10.1158/1535-7163.TARG-11-A208

 http://www.morphosys.com/pressrelease/morphosys-announces-clinical-milestone- within-boehringer-ingelheim-alliance

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