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CLINICAL DEVELOPMENT OF NEXT GENERATION BIOLOGICS Ms. Emily Tan Corporate Vice President, Portfolio Management, Asia Pacific, PAREXEL International February 17th, 2017 PAREXEL India Symposium 2017 ©2017 PAREXEL INTERNATIONAL CORP. ALL RIGHTS RESERVED. AGENDA CLINICAL DEVELOPMENT OF NEXT GENERATION BIOLOGICS • Growing Interest in Next Generation Biologics market • Key Considerations for Development • Challenges in ADC development • Conclusion © 2017 PAREXEL INTERNATIONAL CORP. / 2 BALANCING COST, RISKS AND REWARD Innovative biologics Next Generation Biologics Biosimilars New targets Already established target Improvement over existing therapy (safety, efficacy or administration) Advanced technologies (protein engineering, novel formulation, delivery e.g. affinity maturation, effector function enhancement, half life extension, bispecific & antibodydrug conjugate technology Already validated target Validating target mechanism for disease intervention Advanced technologies (recombinant DNA, Mammalian expression techniques) Complex manufacturing facilities Portfolio Risk Investment Reward © 2017 PAREXEL INTERNATIONAL CORP. / 3 Low risk to pipeline portfolio Unique manufacturing process Complex manufacturing facilities DUBLIN, IRELAND GROWING INTEREST IN NEXT GENERATION BIOLOGICS MARKET ANTIBODY DRUG CONJUGATES (ADC) © 2017 PAREXEL INTERNATIONAL CORP. / 4 DEFINITION OF ANTIBODY DRUG CONJUGATES A class of therapeutics that combine the selective targeting properties of mAbs with potent cell killing activities of cytotoxic agents Facilitate delivery of highly potent cytotoxic molecules directly to tumor cells expressing unique antigens that are specific to the mAb 3 main components • mAb: Specificity bind to cells expressing a specific target antigen with high affinity and potentially decrease off-target toxic effects • Linker: Molecular bridge which conjugates cytotoxin to mAb Potential to increase the therapeutic window of non-selective cytotoxic agents.. • Warhead (cytotoxic): Potent cell killing activity, significant toxicity • Payload = linker + Warhead Source: THE CLINICAL LANDSCAPE OF ANTIBODY-DRUG CONJUGATES, August 1, 2014 | Sohayla Rostami, Ibrahim Qazi, PharmD, Robert Sikorski, doi: 10.14229/jadc.2014.8.1.001 © 2017 PAREXEL INTERNATIONAL CORP. / 5 MECHANISM OF ACTION The ADC complex is engineered to remain stable after administration until the cellular target is reached Initial step in the mechanism of action is the binding of the mAb to the target antigen on the cancer cell. Once the ADC is localized to the cell surface, the entire complex (mAb+payload) is internalized through receptor-mediated endocytosis. Upon internalization, the ADC is trafficked to intracellular organelles where the linker is degraded, causing the warhead to be released inside the cell Subsequently, the warhead disrupts cell division via a cytotoxin-specific mechanism, which causes cell cycle arrest and apoptosis. Two mechanisms of cell cycle arrest are utilized 1) inhibition of tubulin polymerization (eg auristatins and maytansines) 2) based on direct binding to DNA and subsequent inhibition of replication (eg calicheamicins, duocarmycins, and pyrrolobenzodiazepines) © 2017 PAREXEL INTERNATIONAL CORP. / 6 INDUSTRY OVERVIEW OF ADC 59 ADCs in active clinical development by 24 companies. In 2015, there are almost 332 unique 80 trials, with a total of different ADCs (active and discontinued), with majority 85% targeting solid of tumors Source: Antibody Drug Conjugates Clinical Insights EBook, 2016, Hansonwade © 2017 PAREXEL INTERNATIONAL CORP. / 7 INDUSTRY OVERVIEW OF ADC HOW MANY ADCS HAVE BEGAN CLINICAL TRIALS IN 2015? Source: Antibody Drug Conjugates Clinical Insights E-Book, 2016, Hansonwade © 2017 PAREXEL INTERNATIONAL CORP. / 8 TYPES OF ADC TRIALS WHAT IS THE RATIO OF SOLID VS LIQUID CANCERS TARGETING ADCS IN THE CLINIC? Source: Antibody Drug Conjugates Clinical Insights E-Book, 2016, Hansonwade © 2017 PAREXEL INTERNATIONAL CORP. / 9 DUBLIN, IRELAND KEY CONSIDERATIONS FOR DEVELOPMENT © 2017 PAREXEL INTERNATIONAL CORP. / 10 T-DM1 (KADCYLA, ROCHE, GENENTECH) ADO-TRASTUZUMABEMTANSINE The only ADC licensed in non-haematological malignancies Trastuzumab: humanised IgG1 anti-HER-2 Ab linked with a stable non-cleavable linker to Maytansinoid DM1 Approved in 2nd line setting by FDA in 2013 for HER-2 positive patients who had previously received treatment with trastuzumab and taxane chemotherapy. Also being investigated as a single agent compared to docetaxel in previously treated gastric cancer with results Overall tolerable toxicity profile with most common adverse events being fatigue, transaminitis, nausea, thrombocytopenia and rash. In USA, T-DM1 carries black box warnings for hepatotoxicity, embryo-fetal and cardiac toxicity © 2017 PAREXEL INTERNATIONAL CORP. / 11 BRENTUXIMAB VEDOTIN (BV, ADCETRIS, SEATTLE GENETICS) Anti-CD30 mAb connected with a cleavable peptide to the highly potent tubulin inhibitor MMAE Gained accelerated approval for treatment of patients with relapsed or refractory CD30þ HL following autologous stem cell transplant (ASCT) or patients not legible for ASCT who have failed at least two other chemotherapy treatments. Also approved for patients with anaplastic large cell lymphoma (ALCL) as a second line – Approval for Hodgkin’s lymphoma was based on a single-arm phase II clinical trial (73% response rate, 32% complete remission, median duration 20.5 months) (Younes et al, 2012). – Indication for ALCL established based on results of the phase II study (86% overall response rate, 54% complete responses) (Pro et al, 2012). Most common adverse reactions were peripheral sensory neuropathy, neutropenia, fatigue, nausea and thrombocytopenia. In USA, Carries a black box warning for progressive multifocal leukoencephalopathy (Younes et al, 2012) © 2017 PAREXEL INTERNATIONAL CORP. / 12 GEMTUZUMAB OZOOGAMICIN (GO, MYLOTARG, PFIZER) First ADC to be approved by FDA in 2000 – positive results were from the first single-agent phase II studies achieving 30% remissions (Tsimberidou et al, 2006). Consisted of a humanised IgG4 mAb directed against CD33 (a surface antigen present in 85–90% of AML) linked to a calicheamicin cytotoxin Licensed as a monotherapy in patients over 60 years old with acute myelogenous leukemia (AML) who were not candidates for cytotoxic chemotherapy In 2010, results of a post-approval phase III study showed no clinical benefit. In fact, patients in the GO arm had a higher risk of fatal AEs – This trial led to the retraction of its FDA licence approval (Petersdorf et al, 2013). – The failures were attributed to an unstable linker allowing premature release of the cytotoxic payload and to the notso-selective antibody target (ten Cate et al, 2009). – More recent trials such as the ALFA-0701 using intermittent dosing regimens have showed good results, improving event-free survival and overall survival in patients with AML, reigniting discussions about the future of GO (Castaigne et al, 2012). © 2017 PAREXEL INTERNATIONAL CORP. / 13 DUBLIN, IRELAND CHALLENGES IN ADC DEVELOPMENT 1 © 2017 PAREXEL INTERNATIONAL CORP. / 14 TARGET ANTIGENS FOR ADC IN SOLID TUMOR Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis1 and Udai Banerji*. British Journal of Cancer (2016) 114, 362–367 | doi: 10.1038/bjc.2015.435 © 2017 PAREXEL INTERNATIONAL CORP. / 15 CHALLENGES OF ADC DEVELOPMENT Bystander effect • • Helps with problem of non-homogeneous expression of the target antigen in solid tumors from the linker However, can increase off-target systemic toxicity Rate of internalization (receptor mediated endocytosis) of the ADC in the cancer cell poorly understood Delivery efficiency Drug Antibody Ratio • Optimal DAR is undetermined and highly dependent on other ADC variables; More commonly the ADCs aim to attain a DAR close to 4 Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis and Udai Banerji. British Journal of Cancer (2016) 114, 362–367 | doi: 10.1038/bjc.2015.435 © 2017 PAREXEL INTERNATIONAL CORP. / 16 CHALLENGES OF ADC DEVELOPMENT 1. Antigen related 2. Antibody selection • Tumor Antigen density • Target antigens expressed in normal cells • Heterogeneity of target antigen expression in the tumor • Antigen shedding in circulation • Down-regulation after treatment with ADC • Humanized & fully human e.g. human IgG isotypes • Early generation ADCs used murine Ab causing significant immunogenicity and reducing efficacy • Multi mode of action: receptor inhibitors/ signal modulators, activate immune functions or complement-dependent cytotoxicity. can lead to increased toxicity, reduced tumor localization and internalization of the ADC Source: Antibody-drug conjugates—an emerging class of cancer treatment. Nikolaos Diamantis1 and Udai Banerji*. British Journal of Cancer (2016) 114, 362–367 | doi: 10.1038/bjc.2015.435 © 2017 PAREXEL INTERNATIONAL CORP. / 17 CHALLENGES OF ADC DEVELOPMENT 3. Linkers 4. Conjugation © 2017 PAREXEL INTERNATIONAL CORP. / 18 • • Influence the ADC’s PK, therapeutic index and efficacy The ideal linker should be: • Stable so that the ADC does not release the cytotoxic drug before reaching its target, causing off-target toxicity. • Able to release the drug efficiently once internalized • Non-cleavable and cleavable: • Noncleavable: following lysosomal degradation the cytotoxic payload remains active while still being attached to the linker and an amino acid residue. - Cleavable: acid/ lysosomal protease/ gluthathione sensitive linkers, release of cytotoxic drug, increasing the possibility of bystander effect • Nonspecific conjugation to lysine residues – undesirable heterogeneous mixture of ADCs, with high DAR. • Ongoing efforts for more homogeneous ADCs with increased number of drug molecules stably linked to the Ab. • Site-specific conjugation has enabled the production of homogeneous ADCs with the desired and prespecified DAR DRUG RESISTANCE ISSUES Mechanism of resistance is complex and variable: confronts different components • The cytotoxic drug - subject to the same multidrug resistance mechanisms • The monoclonal antibody • By activating survival signaling pathways • Mechanisms that will limit the intracellular concentration of the ADC. • e.g. -DM1 - down regulation of the target antigen, reduced internalization of ADC, diminished lysosomal degradation or increased ADC recycling to the cell surface and masking of the antigen epitope. Potential combinations with small molecule inhibitor to overcome resistance • Evidence that activation of PI3K/AKT, MEK/ERK and JAK/STAT pathways leads to increased ADC resistance © 2017 PAREXEL INTERNATIONAL CORP. / 19 Source: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates MABS 2016, VOL. 8, NO. 4, 659–671 © 2017 PAREXEL INTERNATIONAL CORP. / 20 DRUG TOXICITY ISSUES • The payload often drives the toxic effects. However, the target and linker may determine the organ specificity of the toxicity • Different toxicities in different disease types with the same drug • During the dose escalation of polatuzumab vedotin, DLTs were observed in patients with CLL at much lower doses than NHL. Analysis of the PK profile revealed lower exposure and faster clearance in patients with CLL compared to NHL, consistent with target-mediated clearance due to higher numbers of circulating B cells in CLL.4 • Ocular toxicities • Commonly reported: Blurred vision, keratitis, dry eye and microcystic epithelial damage • Payload association, with ocular toxicity typically induced by ADCs that include DM4 and MMAF. Both tend to utilize a stable linker: • Unclear why the eye is particularly sensitive to toxicities with these payloads, but, for MMAF-conjugated ADC, the toxicity may be related to accumulation of the drug within cells • Therapeutic window of ADCs can be increased by dose modifications to optimize the plasma concentration. • Good monitoring of PK profiles in patients beyond Phase 1 Source: Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates MABS 2016, VOL. 8, NO. 4, 659–671 © 2017 PAREXEL INTERNATIONAL CORP. / 21 FUTURE PROSPECTS More stable and effective ADCs due to combination of new linker technologies and more powerful cytotoxic payloads More rationally designed ADCs with specific DARs Use high-affinity molecules as cytotoxic payload carriers Combination strategies, for example with TKIs . Predictive biomarkers © 2017 PAREXEL INTERNATIONAL CORP. / 22 HAVE WE FINALLY FOUND THE ANSWER TO RATIONAL TARGETED STRATEGY? © 2017 PAREXEL INTERNATIONAL CORP. / 23 THANK YOU © 2017 2016 PAREXEL INTERNATIONAL CORP. / 24 CONFIDENTIAL