AG-636 for the Treatment of Adults with Advanced Lymphoma: Initiation of a Phase 1 Clinical Study

Background: Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines, key building blocks for RNA and DNA biosynthesis. Inhibitors of DHODH are currently in clinical use for the treatment of rheumatoid arthritis (leflunomide) and multiple sclerosis (teriflunomide). Brequinar, a more specific and potent DHODH inhibitor, was evaluated in several phase 1 trials in patients with advanced solid tumors in the 1990s and demonstrated little evidence of antitumor activity; however, patients with hematologic malignancies were not evaluated in those studies. More recent preclinical studies show that cell lines and in vivo models derived from hematologic malignancies are highly sensitive to inhibition of DHODH. AG-636, a novel small molecule DHODH inhibitor, demonstrated strong in vitro and in vivo anti-tumor activity across diverse models of lymphoma and acute leukemia, supporting the evaluation of AG-636 as a treatment for patients with lymphoma and other hematologic malignancies. A phase 1, multicenter, open-label study investigating AG-636 for the treatment of patients with advanced lymphoma began enrollment on May 24, 2019 (NCT03834584). Methods: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-636 and to characterize its dose-limiting toxicities (DLTs) when given to patients with advanced lymphoma. The study includes a dose escalation phase followed by an expansion phase. Approximately 54 adults (42 in the dose escalation phase and 12 in the expansion phase) with advanced lymphoma refractory to standard treatment, will be enrolled at up to 6 centers in the United States. Broad inclusion criteria enable patients with Hodgkin, Diffuse Large B-Cell (DLBCL), Follicular, Peripheral T-Cell, Cutaneous T-Cell, Mantle Cell, and less common subtypes of lymphoma as defined in 2017 by the World Health Organization to enroll. There are no limits on the number of prior lines of therapy and patients may have received prior stem cell transplant or chimeric antigen receptor T-cell therapy. Patients with active central nervous system disease are excluded. Patients must have an Eastern Cooperative Oncology Group performance status ≤2, an absolute neutrophil count ≥1.0×109/L, a platelet count ≥75×109/L, a serum total bilirubin level ≤1.5×upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase levels ≤3.0×ULN, and a creatinine clearance ≥30 mL/min (Cockcroft-Gault formula). AG-636 is given as an oral capsule once daily for 2-5 days each week, with 1 cycle of therapy defined as 4 consecutive weeks of treatment. During the dose escalation phase of the study, successive cohorts of patients will be treated with increasing doses of AG-636 to estimate the MTD. The study employs a 2-parameter adaptive Bayesian logistic regression model using escalation with overdose control to guide dose escalation and to estimate the MTD. The MTD is the highest dose that is unlikely (<25% posterior probability) to cause DLTs in ≥ 33% of participants in their first cycle of treatment. Secondary objectives include the safety and tolerability of AG-636, its pharmacokinetics and pharmacodynamics (via measurement of plasma dihydroorotate concentrations), and characterization of any anti-lymphoma activity that may be associated with AG-636 treatment. The dose-expansion phase of the study will treat approximately 12 additional patients at the MTD in order to better characterize the safety, pharmacokinetics, and pharmacodynamics of the dose that may be suggested for future studies. Further expansion may be undertaken if AG-636 shows high activity in specific subtypes of lymphoma, either in the clinic or in preclinical models. The experience in this study with the pharmacokinetics, pharmacodynamics, and safety of AG-636 will inform the optimal starting dose and regimen for evaluation in subsequent studies. Disclosures Huntington: Celgene: Consultancy, Research Funding; Pharmacyclics: Honoraria; DTRM Biopharm: Research Funding; Genentech: Consultancy; Bayer: Consultancy, Honoraria; AbbVie: Consultancy. Basile:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Ulanet:Agios: Employment, Equity Ownership. Xu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yin:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mobilia:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria. Leonard:Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Nordic Nanovector: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy; AstraZeneca: Consultancy. von Keudell:Bayer: Consultancy; Genentech: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Pharmacyclics: Consultancy; Bayer: Consultancy. Gopal:Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte.: Consultancy; Teva, Bristol-Myers Squibb, Merck, Takeda, Seattle Genetics, Pfizer, Janssen, Takeda, and Effector: Research Funding; Seattle Genetics, Pfizer, Janssen, Gilead, Sanofi, Spectrum, Amgen, Aptevo, BRIM bio, Acerta, I-Mab-pharma, Takeda, Compliment, Asana Bio, and Incyte: Honoraria.

Indolent Lymphoma and Vitamin D (ILyAD): A Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Supplemental Effect of Vitamin D on Event-Free Survival in Patients with Low Tumor Burden Indolent Non-Hodgkin Lymphoma Treated with Rituximab

Background: Indolent lymphomas, including follicular lymphoma (FL) and marginal zone lymphoma, are the most prevalent lymphomas in the United States. Though outcomes have improved substantially since the introduction of rituximab, with median overall survival now exceeding 20 yrs for FL, these diseases are characterized by an incurable clinical course (Tan et. al. Blood 2013). A subset of patients has substantially shorter survival and virtually all patients require intermittent or chronic, and often morbid therapy. Moreover, the financial cost of these therapies often exceeds $100,000 annually per patient. Therefore, lower intensity and better-tolerated, cost-effective treatments are needed. An analysis of newly diagnosed FL patients treated with standard chemotherapy plus anti-CD20 therapy in two clinical trials reported a significant association between low vitamin D levels and inferior clinical outcomes; this observation has been subsequently validated by other groups. The magnitude of this association is stronger than the individual clinical prognostic factors within the FL-IPI score and may be the strongest, and only modifiable, association reported to date of a pre-therapy prognostic factor in FL (Kelly et. al. J Clin Oncol 2015). Moreover, rituximab-mediated cytotoxicity is improved in vitro in the setting of sufficient vitamin D (Bittenbring et al. J Clin Oncol 2014). Based upon these observations, we designed a randomized trial to evaluate whether vitamin D supplementation improves outcomes in patients with indolent lymphoma treated with rituximab. Methods: This NIH-funded, multi-center, double-blind, randomized, placebo-controlled, phase III study is currently enrolling adults with biopsy-proven, indolent, low tumor burden FL, marginal zone, small lymphocytic lymphoma and mucosal associated lymphoid tissue histologies. Subjects are randomized, 2:1, to vitamin D, 2000IU daily or placebo daily for 3 years, or until disease progression. All patients receive standard treatment with rituximab in 4 weekly doses. The primary endpoint is 3-year event free survival (EFS), secondary endpoints include treatment response at week 13 and overall survival. Events are defined as lack of response at week 13, disease progression, initiation of new treatment and death. The study design provides 81% power to detect a HR of 0.55 at a 0.05 significance level, which corresponds to an increase in 3-year EFS from 40% to 60%. The primary analysis will include all treated subjects. Correlative studies of blood PTH and vitamin D will identify if baseline vitamin D levels can predict patients for whom supplementation is particularly effective or ineffective. Evidence suggests that response to vitamin D supplementation may be dependent upon specific genotypes of the vitamin D receptor and vitamin D binding protein, and we are performing whole exome sequencing of patients to determine whether vitamin D related germline variations are critical determinants of outcome in the context of supplementation. Implications: A positive finding of our study would have major implications on the treatment of follicular lymphoma and other indolent lymphomas, and given the low cost and low toxicity, the combination of vitamin D with rituximab would likely become standard of care for these patients. The cost of 3 years of vitamin D supplementation for all randomized patients in our trial is less than the commercial cost of two months of lenalidomide treatment for a single patient; lenalidomide has been approved in a similar patient population. Further implications of a positive study include support for subsequent studies of vitamin D supplementation in other lymphoma subtypes, and other malignancies treated with monoclonal antibodies relying on antibody dependent cellular cytotoxicity, such as the subset of breast cancer treated with trastuzumab, and solid tumors treated with cetuximab. Our study is currently open and accruing at 7 centers with an enrollment target of 210 subjects (NCT03078855). Disclosures Friedberg: Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Leonard:Celgene: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Nordic Nanovector: Consultancy; MorphoSys: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; Epizyme, Inc: Consultancy; Merck: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sandoz: Consultancy; Karyopharm Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Sandoz: Consultancy; Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; BeiGene: Consultancy; MorphoSys: Consultancy; Bayer Corporation: Consultancy; Sutro Biopharma: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Merck: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees. Flowers:Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Optimum Rx: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Karyopharm: Consultancy; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; TG Therapeutics: Research Funding; National Cancer Institute: Research Funding; Burroughs Wellcome Fund: Research Funding; Celgene: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Spectrum: Consultancy; Millenium/Takeda: Research Funding; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding. Cohen:Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; UNUM: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Spectrum: Honoraria.

Evaluation of the Functional Landscape of Systemic Immunity in Classical Hodgkin Using a Novel Single Cell Platform (Isolight)

Background: Classical Hodgkin lymphoma (HL) has a unique histopathology, with rare malignant Hodgkin/Reed Sternberg (HRS) cells surrounded by a strong inflammatory cellular component in the tumor microenvironment (TME). Although extensive studies describe the interdependence of the HRS cells and the TME, the impact of HL on systemic immunity has not been well described. Here, we develop a new approach, employing a recently commercialized single cell cytokine secretion platform (IsoLight) to assess, precisely and comprehensively, the function of peripheral blood mononuclear cells (PBMCs) in HL patients. Methods: Cells were selected from 4 HL patients: 2 newly diagnosed who had a complete response (CR) to therapy standard first line therapy, and 2 relapsed patients who progressed on second line chemotherapy (PD). Cryopreserved PBMCs from a pre-treatment and post-treatment time point for each patient were thawed, rested overnight, stimulated with PMA/ionomycin and loaded into the IsoLight single cell cytokine secretion system. IsoLight captures single cells in microwells; as cytokines are secreted, they are bound by antibodies lining the microwell cover. Bound cytokines are then revealed by fluorescent secondary antibodies and photos are taken at various time points to assess fluorescence intensity, which corresponds to the relative amount of each cytokine secreted. Twenty thousand cells can be assayed per sample simultaneously. Results: The percentage of cytokine-secreting cells varied dramatically by donor (12%-48%), with monofunctional cells making only TNFa, MIP1b, or IL-15 dominating the functional landscape. Polyfunctional cells, capable of making three or more cytokines simultaneously represented only 0.1-7% of the cells in each sample, but there were more of these cells, and each secreted higher levels of cytokines, in individuals who responded to therapy with a CR. Responders also secreted higher levels of IL2, Perforin, IL4, IL12, MIP1a, and TNFb (p values ranging from 0.005 to 0.03), and lower levels of IL9 and IL22 (p=0.0028 and 0.021, respectively), compared to non-responders at diagnosis. Responders lost expression of IL4, IL7, and MIP1a over the course of treatment (pre- vs post-treatment, p=0.01 to 0.05), while non-responders gained cells that expressed IL4, IL5, IL10, IL17, and TNFb from diagnosis to end of treatment (p=0.001 to 0.05). Conclusion: This work represents an important methodological advance in immune monitoring for hematologic malignancies. Single cell cytokine secretion technology measures more cytokines simultaneously than flow cytometry, providing a sample-sparing and comprehensive overview of the functional landscape of immune cells in a patient. Moreover, the technology provides cell-by-cell information about cytokine secretion, unlike Luminex. Our work represents the first application of this technology to HL, which we use to define, for the first time, the particular combinations of 32 cytokines that can be secreted by individual immune cells. We also identify candidate cytokines whose frequency at diagnosis may predict treatment outcome, and reveal changes in cytokine levels over treatment time that may distinguish patients destined to relapse. Immunotherapy may impact PBMC function differently, this may partially explain the high efficacy of this therapy in the relapsed population. The impact of immunotherapy on cytokine levels is currently under investigation by our group in a larger study. Other important questions which are under investigation include the impact of prior chemotherapy on cytokine profiles in relapsed patients, and whether certain cytokines which increase during treatment may be a surrogage for tumor bulk in patients with PD. Cytokines elevated in patients with poor responses to treatment include IL9, IL10, IL17, and IL22, which may present attractive drug targets if validated in our larger ongoing follow-up study. Disclosures Diefenbach: Bristol-Myers Squibb: Consultancy, Research Funding; MEI: Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding. Hymes:Celgene: Consultancy. Martin:Janssen: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy. Ruan:Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy. Leonard:Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; BeiGene: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; Nordic Nanovector: Consultancy; BeiGene: Consultancy; Merck: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy.

Microenvironmental Signatures Reveal Biological Subtypes of Diffuse Large B-Cell Lymphoma (DLBCL) Distinct from Tumor Cell Molecular Profiling

Research in DLBCL pathogenesis has largely focused on the lymphoma cells that defined molecular subtypes. To elucidate the role of the lymphoma microenvironment (LME) in this process, we developed and deconvoluted transcriptomics signatures of LME cells and pathways from 3,026 DLBCLs from 13 datasets including our new cohort of 127 pts. Mutations were available for 562 pts of the datasets and for 22 pts from our cohort (WES with matched normal). Applying density-based clustering we identified 4 LME signatures, independent of reported transcriptional and genetic classifications based on lymphoma cells: LME-1 DLBCLs (n=726, 24% - GCB/ABC: 35%/36%) were characterized by an "immunosuppressive" ME enriched for Tregs, myeloid-derived suppressor cells, CD8PD1high, natural killer and macrophages type 2 and prevalence of genetic mechanisms of immune escape in malignant cells such as mutations in B2M (33%) and CD70 (10%). Malignant cells in LME-1 DLBCL presented high activity of NF-kB and JAK/STAT signaling pathways, likely due to high frequency of co-occurring MYD88L265and CD79B mutations (40%) and the presence of a cytokine rich milieu including high expression of IL10, IL6 and TNFS13B. Good outcome genetic groups BN2 and EZB constituted 46% of pts LME-2 DLBCLs (n=484, 16% - GCB/ABC: 55%/30%) were characterized by an "anti-tumor immunity" ME enriched for T cells, follicular TH and follicular dendritic cells (FDC). Lymphoma cells presented the highest number of BCL2 translocations and EZH2 mutations (40%, p=0.001 vs. other LME groups) and activation of cell motility and chemotaxis pathways that likely account for the advance stage at presentation (70% were stages III/IV p=0.02 vs. 40-50% in the other LME groups). Lymphoma cells expressed higher levels of CCL20, CCR6 and CXCR5. Good outcome genetic groups BN2 and EZB constituted 74% of pts. Notably, ABC LME-2 DLBCLs had better prognosis that any other ABC DLBCL (p&lt;0.007 n=848) and similar to GCB DLBCLs LME-3 DLBCLs (n=847, 28% - GCB/ABC: 56%/25%) were characterized by a "mesenchymal" ME enriched for cancer-associated fibroblasts (CAFs), reticular DC, FDC and endothelial cells. Lymphoma cells showed higher mutations in BCR/Pi3K signaling intermediates SGK1 and GNA13 (20 and 13%) and activation of the TGFB signaling and matrix remodeling pathways. LME-3 DLBCLs expressed higher levels of MMP9, MMP2, TIMP1 and TIMP2. Good outcome genetic groups BN2 and EZB constituted 75% of pts, and were no patients harboring NOTCH1 mutations. LME-3 DLBCL also had the higher proportion of non-cellular LME component represented by the extracellular matrix (ECM). Patients with DLBCL with higher ECM proportion had better progression free survival (p=0.0004). We specifically tested the ECM effect in a murine DLBCL model by analyzing changes in ECM proteins associated with disease progression by serial proteomics. DLBCL progression was accompanied by increase in lymphoma cells in detriment of CAFs and ECM proteins. Among them, we identified the small proteoglycan decorin (DCN). Accordingly, parental administration of recombinant DCN to DLBCL mice (n=10 vs vehicle n=10) decreased tumor volume (p&lt;0.001) and lymphoma cell proliferation while improving the LME immune infiltrate LME-4 DLBCLs (n=969, 32% - GCB/ABC: 46%/38%) were characterized by a "depleted" ME with increased proportion of lymphoma cells with mutations in MYD88, PIM1 and HLA-C (36, 38 and 13%), higher genomic instability and epigenetic heterogeneity (by DNA methylation). Good outcome genetic groups BN2 and EZB constituted 68% of pts. Lymphoma cells showed activation of Pi3K signaling and hypermethylation and low expression of the TGFB mediator SMAD1 (p&lt;0.01 vs other LME groups). In agreement with our demonstration that pharmacologically reversible SMAD1 hypermethylation drives chemoresistance in DLBCL (Cancer Discovery 2013), patients with LME-4 DLBCL had less favorable outcomes in overall survival (HR=1.65 P&lt;0.005 n=1,980) and response to immunochemotherapy (p&lt;0.0001 n=810) than any other LME groups; likely reflecting the acquisition of ME-autonomous survival mechanisms by lymphoma cells. The bad outcome of LME-4 DLBCLs was not dependent on MYC/BCL2 or BCL6 double translocations, or the overall mutational load. In sum, ME signatures in DLBCL associate with clinical outcomes independently of existing molecular subtypes, contribute to explain DLBCL biology and provide potential novel therapies Disclosures Rutherford: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria. Martin:Celgene: Consultancy; Teneobio: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy. Leonard:Nordic Nanovector: Consultancy; Nordic Nanovector: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy; Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; MorphoSys: Consultancy; Sutro Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy.

Building national initiatives of compulsory licences

Purpose – The purpose of this paper is to examine the extent to which developing countries could build national initiatives of compulsory licences. Design/methodology/approach – The focus of this article is only on developing countries. The author reflects on the Indian patent jurisprudence regarding the operational relationship between the general principles applicable to working of patented inventions locally and the grant of compulsory licences. The discussion that follows is based on a review of the case: Bayer Corporation versus Natco Pharma with a view to presenting a model for developing countries to maintain that the public interest principle of patent law is well-founded in their domestic patent regimes. Findings – The analysis confirms that failure to work locally continues to be abusive of the patent right under the Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement, and remains a valid condition on which to grant a compulsory licence. Thus, this reverses the often-contrary misconception that has become almost a unanimous assumption that failure to work basis for granting compulsory licensing would violate Article 27(1) of TRIPS and its enforcement provisions on patent. Originality/value – The author argues that as no member state has challenged the legality of Indian’s decision in the World Trade Organisation, under the dispute settlement understanding (DSU) system is more supportive of the contention that failure to work locally continues to be permissible under TRIPS and remains valid conditions on which member states can grant compulsory licences. This further adds weight to the understanding that nothing in the light of TRIPS would, in fact, preclude any possibility of developing countries amending their patent laws accordingly to maintain that the public interest principle underlining patent law is well-founded in their domestic patent regimes.

Evaluation of Foliar-Applied Insecticides on Abundance of Parasitoids of Bemisia argentifolii (Homoptera: Aleyrodidae) in Vegetables2

The relative abundance of parasitoids of Bemisia argentifolii Bellows & Perring was studied in insecticide-treated and untreated field plots of cantaloupe, collard, cucumber, and tomato. Treatments were made using foliar-applied chlorpyrifos (Lorsban®, DowElanco, Indianapolis, IN) in 1994, and foliar-applied imidacloprid (Provado®, Bayer Corporation, Kansas City, MO) in 1995 and 1996. Yellow sticky cards were used to monitor parasitoids associated with B. argentifolii in plots untreated or treated weekly in 1994 and bi-weekly in 1995 and 1996 with insecticide over 10 wks. The abundance of parasitoids varied among fields and across years. Five species of parasitoids were captured: Eretmocerus sp., Encarsia nigricephala Dozier, E. pergandiella Howard, E. quaintancei Howard, and E. strenua (Silvestri). The first three species comprised approximately 95% of the captured parasitoids. Parasitoids persisted in all field locations and crops whether the vegetables were treated or not. Parasitoids were captured in the treated plots throughout the study, although in fewer numbers than in the untreated plots. Overall, about 60 to 70% of parasitoids captured were from plots without insecticide. Whitefly captures on the sticky traps were relatively high in collard compared with the other crops studied. In addition, more E. nigricephala and E. pergandiella were collected in collard than in the other vegetable crops.