Charles River Biotech Symposium| Biotechnology-Derived Therapeutics Perspectives on Nonclinical Development

Detailed Agenda:

  • Closed  Closed
  • Optional  Optional
  • Fee  Fee
  • September 8, 2019
    8:00 AM  -  4:30 PM
    Sunday Biotech Workshop - Sept. 8, 2019  (Biotech Symposium)
    Demystifying the Late Stages of Nonclinical Development of Biotherapeutics The workshop will focus on late stage nonclinical scientific and regulatory strategies necessary for a successful BLA filing and marketing authorization. How to plan for and execute a US and worldwide nonclinical toxicology registration strategy based on specific requirements for biologics and share insight around regulatory procedures and the FDA review processes will be discussed. The different late-stage studies and sections of a BLA including reproductive toxicity, juvenile toxicity, carcinogenicity, and comparability assessment will be discussed in more detail also. The use of a gap analysis to assess for potential scientific and regulatory issues mid-development as well as tips for drafting appropriate supportive late-stage program documents (e.g. briefing documents, annual updates, PPSR/PIP, labels, RMP) will be shared.
    Fee  Optional 
  • September 9, 2019
    7:00 AM  -  8:00 AM
    Breakfast & Registration
    8:05 AM  -  8:30 AM
    Welcome & Opening Remarks
    8:30 AM  -  9:00 AM
    Anatomic Distribution of Immune-Related Lesions in Cynomolgus Monkeys
    Inflammatory cell infiltrates, vasculitis, and glomerulopathy may be encountered as lesions attributed to Type III hypersensitivity reactions in toxicity studies in cynomolgus monkeys administered biotherapeutics. Ultimately, the determination of these findings as immune-related depends on multiple factors, including characteristics and anatomic location(s) of the lesions, pharmacology of the test article, anti-drug antibody status, and results from additional investigative work that may be conducted. Anatomic location is an important piece factoring into this determination. As such, we conducted a retrospective analysis of internal pathology data to quantify the anatomic distribution of presumptive Type III hypersensitivity reactions related to biotherapeutic administration. 18 programs were identified in which tissue lesions that were observed during routine toxicity studies were attributed by the study team to be due to a likely immune-related mechanism. Descriptively, these lesions fell into 3 general categories, including immune cell infiltrates with or without inflammation, vasculitis and/or perivasculitis, and glomerulopathy. Evaluation of incidence data revealed that inflammatory cell infiltrates occurred without other immune-related lesions in half of the programs where they occurred, and these regions were variably positive for immune complexes by immunohistochemistry when orthogonal analysis was conducted. Most programs had between 1-3 organs affected and the most commonly affected sites were previously recognized as predilection sites for immune complex deposition in published literature (choroid plexus, joint, eye, heart). Vascular lesions were typically multi-systemic, with gall bladder, gastrointestinal tract, heart, kidney, and seminal vesicles among the most common sites affected across programs. Vasculitis/perivasculitis or glomerulopathy rarely occurred as the only immune-related lesion in a study; these were usually observed in combination with other lesion types. The incidence data provided in this retrospective analysis is intended to support pathologists and study teams in determining whether specific lesions that may be encountered in routine GLP or exploratory toxicity studies may be attributed to an immune-related mechanism.
    9:00 AM  -  9:40 AM
    Risk Assessment for a CD3 Redirector
    In her talk on risk assessment with CD3 bispecifics, Shoba will share an overview of the regulatory development and investigative assessments conducted for the development of CD3 bispecific antibodies.
    9:40 AM  -  10:20 AM
    Genetically Modified Oncolytic New Castle Disease Virus Encoding GM-CSF: Nonclinical Safety Consider
    Oncolytic viruses represent an important emerging class of anticancer agents. Historically, viruses were used to treat cancer beginning over 100 years ago. The evolution of oncolytic viruses has advanced to genetically engineered viruses designed to have enhanced tumor selectivity and more recently, to “armed” oncolytic viruses encoding transgenes intended to improve selectivity or immune stimulation. Significant advances include the milestone first approval of an oncolytic virus to treat cancer with the FDA approval of talimogene laherparepvec (T Vec), an engineered herpes simplex virus. Various oncolytic viruses from diverse viral families have advanced into clinical studies. The promise of OVs is that they offer direct tumor cell killing as well as immune stimulation, making them ideal combination partners for immuno-oncology agents such as checkpoint inhibitors. Newcastle disease virus (NDV) is a negative-strand RNA virus from the family paramyxoviridae that causes disease in avian species (the natural host). The anticancer potential of a mesogenic strain of NDV has been investigated in several clinical studies with mixed success. Since it was classified as a select agent because of its pathogenicity in chickens, the clinical development of NDV as an oncolytic agent has been challenging. MEDI5395 is a recombinant strain of NDV constructed using reverse genetics and manufactured in HeLa cells. MEDI5395 has reduced viral gene expression and replication in avian cells due to a modification at the fusion protein (F) cleavage site and an insertion of a 198-nucleotide sequence into the HN-L intergenic region. In order to enhance immune modulatory effects, MEDI5395 has been engineered to express granulocyte/ macrophage colony-stimulating factor (GM-CSF). In vitro and in vivo results demonstrated that MEDI5395 selectively replicates in tumor cells and shows potent anti-tumor activity in a range of syngeneic and xenograft mouse tumor models following intratumoral or intravenous administration. Furthermore, MEDI5395 infection of cancer cells results in increased pro-inflammatory cytokines and chemokines, which in turn are able to recruit mediators of both innate and adaptive immune responses. Immunomodulation with MEDI5395 can be an effective strategy to drive systemic efficacy of immune checkpoint blockade. Nonclinical study design challenges including regulatory requirements and safety endpoints will be discussed in this presentation.
    10:20 AM  -  10:40 AM
    10:40 AM  -  11:20 AM
    Adenoviral Vaccination Model to Assess T-Cell Function in NHP
    The development of new cancer immunotherapies requires monitoring of the immune response as the major driver of efficacy as well as for safety. Although CD8+ T cells play an important role in this process, no equivalent of the classic T-cell-dependent antibody response (TDAR) assay, which evaluates the humoral and T-helper immune response, is currently available in nonhuman primates, the typical non-clinical safety species of choice. We evaluated a vaccination model in cynomolgous monkeys using replication-defective adenovirus encoding for SIV antigens (Ad5-SIV) and compared the effects on T cells after dosing with a marketed check-point inhibitor (Atezolizumab) to a check-point inhibitor in early development. Interestingly, a slight immune enhancement of the SIV-specific CD8+ T cell response was demonstrated with both check-point inhibitors, whilst earlier TDAR data using KLH were not able to do so. Immune enhancement was seen when using different techniques including a novel cytotoxic T cell assay. In addition, Ad5-SIV-based vaccination led to an overall stimulation of T cells with a transient upregulation of checkpoint inhibitory and co-stimulatory receptors on total CD4+ and CD8 +T cells. This transient upregulation may be relevant when assessing for potential exaggerated pharmacology of cancer immunotherapies whose target molecules are not induced in healthy non-tumor bearing animals. Our data indicate that the Ad5-SIV vaccination procedure is well tolerated, produces strong CD8+ T cell responses after only one injection and could be used to characterize pharmacological effects of immune modulators in standard toxicity studies.
    11:20 AM  -  12:00 PM
    Slow Release/Long Activing Intravitreal Strategies for Age-Related Macular Degeneration
    Age-related macular degeneration (AMD), in particular neovascular AMD (nAMD), is the leading cause of blindness in people ≥ 65 years of age. Intravitreal (IVT) administration of anti-vascular endothelial growth factor (anti-VEGF) biotherapeutics has revolutionized treatment and has become the standard of care. However, anti-VEGF therapeutics that are approved for injection every 1-3 months leads to high treatment burden and risk of ocular complications due to repeated injections. In lieu of fixed-dosing schedules, alternative treatment regimens, such as treat-and-extend and pro re nata (PRN-as needed), have been utilized to reduce treatment burden and improve patient compliance, but real-world visual acuity outcomes are not always optimum. Thus, a high-unmet medical need exists for developing slow release/long-acting anti-VEGF therapies that could reduce treatment burden, improve patient compliance, and visual outcome. To this aim, implanted devices and novel formulations have been employed to extend the residence time of IVT biotherapeutics. This presentation will highlight the successes, failures, and limitations of these various anti-VEGF approaches.
    12:00 PM  -  1:00 PM
    1:05 PM  -  1:10 PM
    Case Studies Opening Remarks
    1:15 PM  -  1:45 PM
    Nonclinical Safety Strategy for a Therapeutic Cancer Vaccine
    2:15 PM  -  2:30 PM
    2:30 PM  -  3:15 PM
    Nonclinical Strategy of Novel MOA-based Bispecific Antibody in Early Development
    3:15 PM  -  4:00 PM
    Nonclinical Strategy Considerations for Bispecific Targeting Modalities
    4:00 PM  -  4:20 PM
    4:20 PM  -  5:15 PM
    WoE Approaches to Support Not Doing Repro, Carci, Juv, Chronic for Bx Moving from Oncology to Others
    5:30 PM  -  6:30 PM
    Cocktail Reception
  • September 10, 2019
    6:30 AM  -  7:20 AM
    Rise & Shine Yoga
    Limited capacity: 25
     Optional  Closed 
    7:00 AM  -  8:00 AM
    8:05 AM  -  8:10 AM
    Welcome & Announcements
    8:10 AM  -  8:15 AM
    Species Selection: The foundation of your toxicology program
    8:15 AM  -  8:25 AM
    Species Selection in a New Era of Biologics Drug Development
    Approaches to species selection have become more routine for traditional protein biotherapeutics (ie monoclonal antibodies and recombinant proteins). Standard approaches include sequence homology assessment, binding/binding affinity, flow cytometry, and development of in vitro cell-based assays or in vivo biomarkers to assess the pharmacologic relevance of animals species that will be used in the nonclinical toxicology program. In the last several years there has been explosive growth in new types of modalities, including multi-specific molecules and conjugates, other complex molecules including nanoparticles, cell and gene therapies, and engineered viruses to name a few. These complex modalities bring new challenges to species selection. Many of them only bind human cells/targets or work only in the context of human disease. Others that modulate the immune system, or due to their inherent structural attributes, may increase immunogenicity and/or immunogenicity-related findings in animals making longer duration toxicity studies less feasible. This means that new ways to assess nonclinical safety beyond general toxicity studies in normal animals need to be explored by industry and accepted by world-wide health authorities. Other approaches to species selection that can be considered include the use of surrogate molecules, and other animal models including animal models of disease, transgenic and knock-out models, and “humanized” mouse models. In some cases, there is no pharmacologically-relevant animal model system, and an in vitro only approach may be necessary.
    8:25 AM  -  8:40 AM
    Beyond Homology: Not as Straight Forward As You Think
    Species selection for protein therapeutics is target driven. ICH S6 (R1) states that a relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope. Understanding species relevance begins at target identification/target validation with an assessment of amino acid sequence identity between the human target and the orthologs in nonclinical species in conjunction with an assessment of target expression across species. Once there are candidate therapeutics, additional parameters can be compared between human and a short list of nonclinical species including candidate therapeutic binding/binding affinity and bioactivity (potency) in cell-based assays. We developed a monoclonal antibody designed to bind tau for the treatment of Alzheimer’s disease. The initial evaluation of tau amino acid sequence identity showed a high percent identity between cynomolgus monkey and human tau as well as rat and human tau leading to an accelerated program with a tolerability and toxicokinetic study in both animal species before the additional species selection data were available. Despite the fact that the antibody binds to an epitope on tau that is highly conserved between species, the antibody was later demonstrated to not bind to cynomolgus monkey tau. Binding was then tested against tau protein from additional large animal species leading to the identification of the mini-pig as the second species for the toxicology program. This confirms the importance of data beyond sequence identity in selecting toxicology species.
    8:40 AM  -  8:55 AM
    Binding vs. Pharmacologically Relevant Nonclinical species: 1 Fab Her2 T Cell Bispecific Case Study
    1Fab HER2 TDB is a new T cell engaging bispecific molecule engineered to specifically recruit T cells and kill, via cytotoxicity, HER2 overexpressing tumors while sparing cells that express low levels of HER2 on the cell surface (i.e. normal tissues). The molecule consists of a bispecific antibody with two low affinity anti-HER2 Fabs, linked in tandem, on one arm and one anti-CD3 Fab on the other arm. Due to the low monovalent affinity of the HER2 Fab to human and cynomolgus HER2, the 1Fab HER2 TDB is unable to bind to and kill tissues that express low levels of HER2, whereas the avidity effect of the bivalent HER2 Fabs is introduced in the cellular context of high HER2 density, which provides the basis for selective killing of HER2 overexpressing cancer cells. The cynomolgus monkey is the only relevant binding nonclinical species to test the safety of the 1Fab HER2 TDB. Because the affinity of the HER2 Fabs was intentionally lowered to minimize target-dependent killing of normal tissues, a single dose IV infusion study was conducted in female cynomolgus monkeys to evaluate the tolerability, pharmacodynamics and pharmacokinetics of the 1Fab HER2 TDB. Results of the study demonstrated that the 1Fab HER2 TDB was not pharmacologically active in cynomolgus monkeys up to 20 mg/kg when administered as a single IV infusion. This conclusion was based on the observation that the 1Fab HER2 TDB did not induce any of the expected TDB-associated pharmacological effects such as elevations in CRP, ALT/AST, and cytokines as well as transient decreases in lymphocyte populations. This is in contrast to a 1:1 format HER2 TDB where the HNSTD was defined as 4 mg/kg due to the acute inflammatory/cytokine response and histopathology findings. These data demonstrate that binding may not directly translate to pharmacological relevance in nonclinical species and may affect the nonclinical safety strategy used to support clinical development.
    8:55 AM  -  9:05 AM
    Protein Therapuetic Q&A
    9:05 AM  -  9:15 AM
    Introduction to Species Selection for Oligo Therapeutics
    In the early days of development of oligonucleotide (ON) therapeutics (1990s), a strong bias towards using nonhuman primates (mainly cynomolgus monkeys) developed because of findings that appeared to be unique to that species, specifically acute activation of the alternative complement pathway. Although this effect was seen only with those ONs that were chemically modified with sulfur replacing one of the non-bonding oxygens in each phosphate internucleotide linkage (phosphorothioate [PS]chemistry) and only with systemic administration (IV or SC) at dose levels sufficient to exceed a threshold blood level, the use of PS ONs was so ubiquitous for many years that the majority of regulatory reviewers adopted a vague belief that all ONs had the potential to produce that effect, regardless of their chemical modifications and/or whether they were administered systemically. In fact, it was not unusual for the FDA to expect that a repeat-dose toxicity study in monkeys should be conducted for ONs given by dermal, pulmonary and other routes that result in plasma levels of the ON far below the range that had been documented to produce complement activation, despite publications to the contrary. Interestingly, complement activation induced by PS ONs has been demonstrated for other nonrodent species, and the sensitivity of monkeys for this effect has been shown to be greater than that of humans, yet monkey remains the nonrodent species of choice for most ON programs. Likewise, the selection of the rodent species for ON programs has been influenced over the years by study findings, the details of which will be briefly presented.
    9:15 AM  -  9:35 AM
    Serendipitous identification of novel genotypes in Cynomolgus macaque:
    Angelman syndrome is a devastating neurodevelopmental disorder caused by loss of the maternally inherited UBE3A allele. In neurons of the CNS, the UBE3A gene is subject to genomic imprinting, a phenomenon in which the maternal allele is expressed and the paternal allele is turned off by the expression of the UBE3A antisense transcript (UBE3A-AS). Studies in a mouse model of Angelman syndrome indicate that ASOs targeting UBE3A-AS reactivate expression of the paternal UBE3A allele in the CNS, which improves some of the core symptoms associated with the condition. The genetic sequence of UBE3A-AS is not conserved between human and mouse, which impedes investigation of clinical ASO candidates in an animal model. ASOs were thus designed to target a region in UBE3A-AS that is conserved between human and non-human primates. Additionally, a single nucleotide polymorphism was discovered in the Cynomolgus UBE3A gene. As such, preclinical studies in Cynomolgus macaques are being used to assess the safety and efficacy of lead ASOs, including inhibition of UBE3A-AS and reactivation of the paternal UBE3A allele in the CNS.
    9:35 AM  -  9:50 AM
    Species Selection for 2’MOE Antisense Oligonucleotides: Considerations for Safety & Pharmacology
    The toxicology evaluation for single-stranded antisense oligonucleotides (ASO) follows the traditional path of evaluating a range of doses in both a rodent and non-rodent species. The difference in class effects and mRNA sequence heterogeneity between animals and human complicates the choice of optimal species. For the 2’- methoxyethyl (2' MOE) modified ASOs, the general repeat-dose toxicity studies have typically been performed in the mouse and non-human primate (NHP). The overriding considerations in the choice of species are 1) consistency in response between animal and human and 2) ability to assess the tolerability of expected pharmacology. There is little debate that the NHP is the most representative species for the general toxicology assessment. Due to the similarity in the target mRNA sequence between humans and NHPs, the clinical candidate ASO is often pharmacologically active in the NHP. This may support the evaluation of target-related toxicities (exaggerated pharmacology) using the same molecule in the NHP study, however, homology alone does not guarantee equal potency. Thus a surrogate mouse-active ASO is useful in the assessment of on-target toxicity. A mouse-active ASO also supports the assessment of exaggerated pharmacology in the reproductive, juvenile and carcinogenicity studies.
    9:50 AM  -  10:05 AM
    The Nonclinical Safety Assessment of ONPATTRO: Challenges in the Utilization of Standard Species
    Short interfering RNA (siRNA) are a new class of human therapeutics that selectively target the endogenous RNA interference mechanism controlling the translation of RNA to protein. Through this mechanism, siRNA therapeutics can be designed to specifically target mRNA and silence the production of disease-associated proteins. This presentation will describe the unique characteristics of RNAi therapeutics and how this influenced the selection of the nonclinical test species in the development program for patisiran, the first FDA approved siRNA therapeutic, for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. Examples will be provided where the properties of an RNAi-based therapeutic impacted study design in the nonclinical safety package for patisiran. Specifically, considerations of the species utilized in both reproductive and carcinogenicity studies will be discussed.
    10:05 AM  -  10:15 AM
    Oligo Therapeutics Q&A
    10:15 AM  -  10:30 AM
    10:30 AM  -  10:40 AM
    Introduction to Species Selection for Gene Therapy
    This presentation will provide an overview of biologic attributes of viral vectors used for gene therapy that influence species and cell tropism with a focus on adeno associated viral (AAV) vectors. Points to consider from regulatory guidance will be reviewed as well as experimental data that should be considered in formulating a plan to select species for nonclinical safety and efficacy studies. Examples of the impact of species selection on dose extrapolation to the clinic and safety evaluation will be discussed.
    10:40 AM  -  10:55 AM
    Translatability of Gene Therapy Promotors from Rodents to Large Animals to Humans
    Viral based gene therapy has historically used naturally occurring viral serotypes and constitutive promoters to achieve widespread infection and expression to maximize exposure to the gene product. However, on occasion, such breadth and levels of expression are not ideal for both efficacy and safety reasons. As the field of gene therapy evolves to move into spaces where particular cell types are both transduced and express the therapeutic gene, highly specialized viral serotypes and gene promoters are starting to be used in candidate constructs to drive activity only in these places. Some recent communications in the field have identified situations where constructs in early preclinical development showing promise in rodent models have not translated their expression characteristics in larger species possibly owing to a variety of evolutionary differences in viral receptors and transcriptional machinery. We have implemented a workstream to test construct expression early in candidate selection to optimize the chances for translatability to higher species, and hopefully humans as well. Examples will be shared where constructs were progressed or stopped at this stage.
    10:55 AM  -  11:10 AM
    Species Selection and Translation to the Clinic for ZFN-based Genome Editing Therapies
    Sangamo is a clinical stage biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for various monogenic and infectious diseases with unmet medical needs. Sangamo’s therapeutic products are based on our engineered zinc finger DNA-binding protein (ZFP) genome editing and adeno-associated virus (AAV) gene therapy platforms. We are leaders in the fields of gene therapy and genome editing. Our AAV-based gene therapy platform uses our proprietary vector constructs to enable the delivery and potent expression of any therapeutic gene. Our proprietary ZFP technology platform enables highly specific genome modification and gene regulation. ZFPs are a naturally occurring class of transcription factors, which we can engineer to bind to any DNA sequence with singular specificity and drive desired therapeutic outcomes. Our ZFPs can be linked to functional domains that normally activate or repress gene expression to create ZFP transcription factors (ZFP TFs) capable of turning genes on or off. We can also link ZFPs to endonuclease domains to create zinc finger nucleases (ZFNs) which enable precise genome editing in cells. Sangamo's engineered ZFNs can modify a cell's DNA at a precise location, thereby facilitating the correction or disruption of a specific gene or the targeted addition of a new DNA sequence, without the unwanted consequences of off-target DNA binding activity. Our ZFP technology can be broadly applied to the development of novel human therapeutics. We have proprietary programs in monogenic diseases that we are developing in the first ever in vivo human clinical trials. We also have a preclinical pipeline that is focused on monogenic and rare diseases, as well as diseases of the CNS. Today’s presentation will describe the nonclinical safety evaluation program supporting Sangamo’s first clinical study using genome editing technology for treating patients with Mucopolysaccharidosis (MPS) II and early clinical study results.
    11:10 AM  -  11:20 AM
    Introduction to Species Selection for Vaccines
    Selection of the toxicity species for prophylactic vaccine development is generally straightforward in that the primary requirement is that the test species exhibit an immune response to the vaccine antigen(s). However, with the development of new technologies (e.g. lipid nanoparticle delivery), vaccine modalities (e.g. nucleic acid-based vaccines, self-amplifying RNA), adjuvants (eg, CpG oligonucleotides), and indications (e.g. cancer vaccines), species selection may be much more challenging. This presentation will cover various factors to consider when choosing the toxicity species for any vaccine study and will provide a couple of case examples--one prophylactic vaccine and one cancer vaccine.
    11:20 AM  -  11:35 AM
    A Case Study for Lipid-Nanoparticle-Based Cancer Vaccine Species Selection and Regulatory Acceptance
    The most frequently mutated oncogene is KRAS, which is mutated in roughly 30% of epithelial cancers, primarily pancreatic, lung, and colorectal cancers (Pylayeva-Gupta et al 2011). The presence of a KRAS mutation confers a worse prognosis, and specifically in colorectal cancer, mediates primary resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, such that they are not indicated in this patient population. Moderna Therapeutics and Merck are co-developing mRNA-5671, a novel messenger RNA (mRNA)-based vaccine, to treat patients with various forms of advanced cancer harboring KRAS mutations. mRNA-5671 consists of 2 Drug Substances, one encoding the antigens for 4 KRAS mutations and a second encoding a constitutively active form of STING (stimulator of interferon [IFN] genes). This brief presentation will focus on the rationale for the nonclinical species selection for safety assessment with consideration for the vaccine-adjuvant, STING.
    11:35 AM  -  11:45 AM
    Gene Therapy & Vaccine Q&A
    11:45 AM  -  12:00 PM
    Session 3 Q&A
    12:00 PM  -  1:00 PM
    1:00 PM  -  1:45 PM
    A Novel Antibody Antibiotic Conjugate for Treating Invasive S. Aureus: A window into the Nonclinical
    Staphylococcus aureus (S. aureus) is a leading cause of serious bacterial infections worldwide, resulting in significant morbidity and mortality. There is a high unmet need for difficult-to-treat S. aureus infections such as bacteremia and endocarditis. THIOMAB™ Antibody-Antibiotic Conjugate (TAC) is a novel therapeutic option for treating invasive S. aureus infections that are not adequately eliminated by current Standard of Care Antibiotics. TAC is composed of a human monoclonal THIOMABTM IgG1 antibody that recognizes S. aureus and is linked to a novel rifamycin-class antibiotic (dmDNA31) via a protease-cleavable linker. Phagocytic cells ingest TAC-bound S. aureus and intracellular cathepsins cleave the linker, releasing dmDNA31 to kill intracellular S. aureus. The toxicology program was designed to evaluate the nonclinical safety profile of TAC and the unconjugated antibiotic payload, dmDNA31, to support the proposed Phase I trials. Both TAC and dmDNA31 were well tolerated in a series of single and repeat dose intravenous studies in rats and/or cynomolgous monkeys. In addition, there was no evidence of genotoxicity, cardiovascular toxicity, or neurotoxicity. TAC was well tolerated in a phase 1, randomized single ascending dose study in healthy volunteers with observations of a moderate infusion-related reaction in one patient and non-adverse blue discoloration (also seen in nonclinical studies). A Phase 1b multiple ascending dose study in patients is ongoing. To support the ongoing clinical development of TAC, developmental and reproductive toxicology studies in rat and rabbit and a longer term (6 month) repeat dose toxicology study in rat will be conducted.
    1:45 PM  -  2:30 PM
    Nonclinical Safety Assessment of Trastuzumab Deruxtecan, a HER2 Targeting Antibody-Drug Conjugate
    Trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a HER2-targeting antibody-drug conjugate composed of a humanized anti-HER2 antibody and an exatecan derivative (DXd), a topoisomerase I inhibitor, which are bound together by a cleavable peptide-based linker. Before clinical trials, a 6-week intravenous dosing (every 3 weeks totaling 3 doses) toxicity study was conducted in cynomolgus monkeys, the cross-reactive species for trastuzumab, and in rats (antigen non-binding species). In the rat study, no deaths or life-threatening toxicities were found at dose levels up to 197 mg/kg, the maximum dose. In the monkey study, one animal became moribund at the highest dose of 78.8 mg/kg, but trastuzumab was well tolerated at doses up to 30 mg/kg in monkeys. Microscopic examinations in rats and monkeys revealed that the major target organs/tissues were the intestines and bone marrow. The intestinal and bone marrow toxicities caused by trastuzumab also occurred in toxicity studies with DXd in rats and monkeys. This effect seemed to be attributable to the cytotoxic mechanism of action of DXd, as gastrointestinal toxicity and bone marrow toxicity are typical dose-limiting factors in the clinical use of topoisomerase I inhibitors. Toxicokinetic analysis in the monkey study demonstrated low plasma concentrations of DXd when administered trastuzumab, which correlated with its high tolerability. Most common adverse events related to trastuzumab in cancer patients included nausea, vomiting, diarrhea, constipation, anemia, decreases in neutrophil count and platelet count. However, most of these adverse events were not serious and were manageable. Trastuzumab caused pulmonary toxicity in monkeys at <30 mg/kg (every 3 weeks totaling 3 doses), although it was not observed in rats. In a 3-month monkey toxicity study (every 3 weeks totaling 5 doses) with trastuzumab, slight aggregation of foamy alveolar macrophages and focal alveolar and/or interstitial inflammation in the lungs were observed in the 30 mg/kg group (the highest dose) at the end of dosing period. An extended dosing period did not increase the severity of lesions, and the pulmonary finding in monkeys observed at 30 mg/kg showed reversibility after the 3-month recovery period. While comprehensive mechanisms of the pulmonary toxicity remain unclear, this finding in monkeys could be related to the interstitial lung disease that was observed in patients treated with trastuzumab.ILD is considered an identified risk.
    2:30 PM  -  2:50 PM
    2:50 PM  -  3:35 PM
    Nonclinical Development of Probody Drug Conjugates
    Probody™ therapeutics are prodrug forms of mAb-based therapeutics that are designed to be locally activated by proteolytic cleavage within a disease compartment, such as the tumor microenvironment (TME). The premise of the Probody therapeutic platform is to create antibody prodrugs that have significantly reduced ability to bind to the cognate antigen in the intact state. By reducing target engagement in normal tissues, Probody therapeutics have the potential to create or widen a therapeutic window where on-target toxicity is dose limiting. This technology is designed to enable the targeting of antigens that may have desirable properties but may not be amenable to a traditional ADC approach, such as CD166 (ALCAM) and the transferrin receptor, CD71. This presentation will review the pharmacology and IND-enabling safety studies of CX-2009, a DM4-containing Probody drug conjugate (PDC) targeting CD166, and provide a brief introduction to CX-2029, a CD71-targeting PDC. Both PDCs show potent anti-tumor activity in mouse xenograft tumor models whilst demonstrating an absence, or a substantial amelioration, of on-target toxicity in non-human primate studies. Bioanalytical approaches to the assessment of Probody therapeutics activation, both in animal studies and human cancer patients, will be discussed. CX-2009 and CX-2029 are currently in ongoing first-in-human Phase 1/2 studies in cancer patients. PROBODY is a trademark of CytomX Therapeutics, Inc. All other brands and trademarks referenced herein are the property of their respective owners.
    3:35 PM  -  4:30 PM
    ABBV-155 A first In-Class BCL-XL Inhibitor ADC
    BCL-XL plays an important role in the survival of many solid tumors making development of therapeutics targeting this protein an attractive strategy. We developed ABBV-155 an ADC comprised of an anti B7H3 antibody conjugated to a potent and specific BCL-XL inhibitor via a novel protease cleavable linker, which specifically inhibits BCL-XL function in cells expressing high levels of B7H3. Whilst some tumors are sensitive to BCL-XL inhibition alone, many solid tumors require inhibition of both BCL-XL and the related MCL1 to trigger apoptosis. We demonstrate that ABBV-155 is effective as a single agent and in combination with docetaxel in xenograft models. In non-clinical toxicity studies three toxicities were noted. Renal toxicity characterized by an increase in glomerular matrix was observed only with the ADC in cynomolgus monkey. Hematological toxicities comprised of decreased RBC mass and decreased platelets were noted both with the ADC and the small molecule BCL-XL inhibitor in cynomolgus monkey and rats, respectively. Cardiovascular (CV) toxicity characterized by a decrease in mean arterial pressure was noted only with the small molecule BCL-XL inhibitor in dog safety pharmacology studies. The toxicities were either partially to completely reversible or had a significant safety margin. ABBV-155 is currently under clinical investigation in patients with solid tumors both as monotherapy and in combination with taxanes.
    5:15 PM  -  6:45 PM
  • September 11, 2019
    7:00 AM  -  8:00 AM
    8:10 AM  -  8:25 AM
    Welcome & Announcements
    8:25 AM  -  8:40 AM
    Introduction: Overcoming Immunogenicity Associated with the Use of Biopharmaceuticals
    8:40 AM  -  9:15 AM
    Managing Immunogenicity in the Absence of an ADA Assay Is No Monkey Business (Case Study)
    Immunogenicity in nonclinical species is common; however, the management of immunogenicity in addition to loss of exposure, and infusion reactions in sub chronic and chronic studies can be more than challenging. In pilot and 4-week repeat dose toxicology studies of a mAb to a soluble immunomodulatory target, there was evidence of immunogenicity based on increased drug clearance on Day 28 compared to Day 1, especially at lower dose levels. This information was used to select higher dose levels for the 26-week chronic study. When infusion reactions occurred at all dose levels in the 26-week chronic study after repeat dosing, interim analyses (TK) and additional endpoints (complement activation and cytokines) were added to the study design to determine if immunogenicity or a direct test article-effect was causing the observed adverse toxicity. An ADA assay was being developed but was not readily available. The study then proceeded with an immunogenicity management plan for animals with infusion reactions, appropriate representation of animals in terminal and recovery groups, the terminal necropsy date was adjusted, and immunohistochemistry for the detection of immune complexes was added as a study endpoint. A weight of evidence approach, in the absence of ADA data, was then used to define the NOAEL to support the ongoing clinical program.
    9:15 AM  -  9:50 AM
    Immunogenicity Testing of Biologics: Thinking from Preclinical Assessment to Clinical Monitoring
    Immunogenicity monitoring is a regulatory requirement in preclinical and clinical studies and immunogenicity endpoints are included in preclinical repeated dose toxicity studies as they may aid data interpretation. Anti-drug antibodies, including those with neutralising activity have the potential to influence safety and/or efficacy in patients (and animals) as they may alter drug clearance, exposure or bio-distribution or cause diverse adverse events. This presentation will explore how the available toolbox of in vitro and in vivo assays and approaches has been applied in industry. Case studies outlining current strategies, applied both preclinically and clinically to proactively manage, mitigate and minimize the potential impact of immunogenicity on the clinical tolerability and activity of therapeutic antibodies, will be addressed.
    9:50 AM  -  10:15 AM
    10:15 AM  -  10:50 AM
    When ADA alter or exacerbate pharmacology – the death of a project?
    Anti-Drug Antibodies (ADA) can have different consequences for the treatment with biotherapeutics, ranging from no consequences at all to alterations in pharmacokinetic which may decrease or under certain circumstances also increase exposure. Further, ADA may induce adverse reactions such as local inflammation, hypersensitivity, anaphylaxis, complement activation or immune complex disease and in case the biotherapeutic protein has an endogenous counterpart that exerts a unique non-redundant biological function, ADA may lead to deficiency syndromes if the ADA neutralize the function of that protein. Although the adverse reactions are often independent of the biotherapeutic’s pharmacology, ADA may also directly interfere with the pharmacology. If ADA are boosting the effect of the drug, then the therapeutic window may be a shifted resulting in a lower maximum tolerated dose. If ADA reverse the function of the biotherapeutic, then the pathway that should be inhibited is actually being triggered, i.e. an antagonist is turned into an agonist. This presentation will cover a few case examples where the development of ADA resulted in altered or exacerbated pharmacology and to the termination of the respective programs.
    10:50 AM  -  11:30 AM
    Case Studies of Immunogenicity in Biotherapeutic Development
    Every biotherapeutic has the potential to elicit unwanted immune responses, leading to development of anti-drug antibodies (ADA) in treated patients. ADA responses may influence drug exposure, drug safety and/or therapeutic efficacy. This talk will review experimental data from immunogenicity risk assessment methods in the context of results from clinical studies.
    11:30 AM  -  11:50 AM
    Closing Remarks