Servier’s pipeline in oncology






1Jean-Pierre ABASTADO, PhD
Oncology Therapeutic Innovation
Center, IRIS (Institut de Recherches Internationales Servier)
Suresnes, FRANCE

1,2Emmanuel CANET, MD, PhD
President, Research and Development, IRIS
Suresnes, FRANCE

Servier’s pipeline in oncology


by J. P. Abastado and E. Canet, France



Decades of basic research aimed at understanding the processes of carcinogenesis, cancer progression, and metastasis have fueled the development of novel therapeutic approaches in oncology. A new generation of anticancer drugs, including targeted therapies and immunotherapies, are reaching a stage where they are becoming available for cancer patients. Servier is determined to play a significant role in this therapeutic revolution. The current review summarizes ongoing studies and future areas of development of Servier’s armamentum to fight cancer.

Medicographia. 2015;37:319-324 (see French abstract on page 324)



The field of oncology is set for dramatic changes in the next 10 years. With the aging of populations and better management of other diseases, the incidence of cancer and the corresponding medical need are expected to rise. The arrival of innovative therapies is also expected to modify the management of cancer, prolonging survival and improving quality of life. Many targeted therapies have become available to cancer patients in the past five years. Cancer immunotherapy (the mobilization of the patient’s own immune system to fight his or her cancer) is now a reality. Servier is committed to becoming an important player in this field. We believe that only innovative products that are based on strong scientific knowledge and improved understanding of carcinogenesis will be able to make a significant contribution to therapeutic progress in oncology.

Cancer is a complex multifactorial disease. In order to understand the diversity of neoplastic diseases, Hanahan and Weinberg have proposed a logical framework of ten biological capabilities—referred to as hallmarks—acquired by tumor cells during their multistep transformation. These include sustained proliferative signaling, induction of angiogenesis, resistance to apoptosis (programmed cell death), and hijacking of the immune system for survival and metastasis.1 This improved knowledge is allowing us to fight cancer by targeting the molecular pathways responsible for these acquired capabilities. Unfortunately, however, when targeted therapies are directed toward a single one of these hallmarks of cancer, a few cancer cells will often manage to survive and eventually the tumor adapts and escapes treatment. Indeed, this explains why, even though targeted therapies often report dramatic rates of tumor response, the majority of cancers eventually progress and become refractory to treatment. Servier is therefore convinced that durable clinical benefit can only be achieved by using either drugs targeting multiple pathways or combined therapies.

Starting from these considerations, Servier’s International Research Institute (IRIS) has built a diversified pipeline of innovative products targeting multiple and complementary cancer hallmarks. Servier’s research and development activity is organized around three axes: molecules targeting receptors with tyrosine kinase (TK) activity, molecules able to restore apoptosis in cancer cells, and molecules harnessing the immune system to fight cancer. In addition, Servier currently commercializes two cytotoxic products: Muphoran® (fotemustine) and Pixuvri® (pixantrone). To optimize drug combination and accelerate clinical development, Servier has leveraged an extensive network of biotechnology and industrial partners with recognized track records in oncology. To maximize the efficiency of its discovery programs, Servier has also developed scientific collaborations with many of the most prestigious research institutes in oncology.

Pixantrone

Pixantrone (Pixuvri®) is a novel aza-anthracenedione, and was initially developed by CTI BioPharma.2 This new treatment partially inhibits topoisomerase II and forms stable, covalently bound DNA adducts, thereby preventing DNA replication and transcription that ultimately induces mitotic infidelity and catastrophe. Unlike classical anthracyclines, pixantrone has little cardiotoxicity: no contraindication is stipulated within the summary of product characteristics; there is no exclusion for prior cumulative anthracycline use; and, unlike other in-class drugs, no cumulative dose restrictions apply. This means that it can be administered to patients who have had near maximal lifetime exposure to anthracyclines. CTI BioPharma and Servier have recently signed an exclusive license and collaboration agreement for the commercialization and further development of pixantrone.

In 2012, pixantrone obtained a conditional marketing authorization in the European Union as a monotherapy to treat patients with multiply relapsed or refractory aggressive non- Hodgkin B-cell lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL). This authorization was granted following a phase 3, multicenter, open-label, randomized trial in 140 patients with aggressive NHL.3 In this trial, patients were randomly allocated to up to six cycles of pixantrone (50 mg/m2 base intravenously on days 1, 8, and 15 of a 28-day cycle) or physician’s choice of treatment (administered according to the manufacturer’s instructions on dosage and schedule). Significantly more patients in the pixantrone group achieved complete or unconfirmed complete response by the end of the treatment period: 14 patients (20%) vs 4 patients (6%) of the comparator group (P=0.021). The median duration of these responses was 9.6 months in patients given pixantrone compared with 4 months in the comparator group. There was also a significantly better rate of overall response with pixantrone (37% vs 14%; P=0.003), which translated into a prolongation of progression- free survival (5 months vs 2.6 months; P=0.0035). These highly promising results in relapsed or refractory patients were obtained against an acceptable safety profile, supporting the use of pixantrone as a single-agent therapy for the care of these difficult patients.





CTI BioPharma and Servier are currently conducting a confirmatory phase 3 trial in patients with aggressive NHL to compare pixantrone versus gemcitabine when both drugs are used in combination with rituximab. Further studies will determine whether pixantrone could also be applied as a second-line therapy or in combination with various novel and targeted therapies. Pixantrone is currently commercialized in various European countries, including Germany, France, and the United Kingdom.

Tyrosine kinase inhibitors

Lucitanib
Lucitanib (S80881) is an orally bioavailable TK inhibitor currently being codeveloped worldwide by Servier and a US-based company Clovis Oncology, and in China with the Shanghai Institute of Materia Medica (SIMM).4 Lucitanib is a potent and selective inhibitor of the fibroblast growth factor receptors (FGFR) 1, 2, and 3, the vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and the platelet-derived growth factor receptor (PDGFR) &lapha;and β. At the present time, it is being developed in hormone-sensitive breast cancer and advanced squamous cell lung cancer patients. The activity of lucitanib in other solid tumors is currently evaluated in phase 1 studies. Preclinical and clinical studies have established that lucitanib inhibits tumor angiogenesis.4 Angiogenesis is the process by which new blood vessels are produced, and is essential for growth once a tumor reaches a certain diameter. Indeed, in the absence of new blood vessels, tumor cells die from nutrient starvation, metabolite poisoning, and hypoxia, thereby constituting a potential target for anticancer therapy. VEGF is the main driver of angiogenesis in human tumors. However, it has been shown in clinical studies that when cancer patients were treated with bevacizumab (an anti-VEGF antibody), other proangiogenic factors, such as FGF and PDGF remained active or even became upregulated; high serum levels of FGF or PDGF in bevacizumab-treated patients were associated with a poorer prognosis. In this context, it has been suggested that the FGF/FGFR and PDGF/PDGFR pathways underly the mechanisms of resistance to VEGF inhibitors.5,6 As lucitanib inhibits VEGFR, FGFR, and PDGFR, it is a particularly promising candidate to counteract resistance to therapies targeted uniquely to VEGF/VEGFR. Tumor-infiltrating myeloid cells also regulate angiogenesis. Inhibition of the colony-stimulating factor 1 receptor (CFS1R, another target of lucitanib that is also known as macrophage colony-stimulating factor receptor [M-CFSR]), prevents hypoxia-induced infiltration of macrophages and may reinforce the antiangiogenic properties of lucitanib.

In addition to its effect on tumor vasculature, lucitanib may also act directly on cancer cells via the inhibition of FGFR. Indeed, FGFR is frequently amplified in human tumors, especially from breast or lung. In these tumors, FGF secretion by either the cancer cells or the surrounding stroma contributes to tumor growth through an autocrine or paracrine loop. The direct activity of lucitanib on FGFR expressed by cancer cells has been observed in in vitro experiments and in animal models.

Lucitanib has been tested for the first time in humans in a phase 1/2a study,7 which demonstrated clinical benefit in both FGF-aberrant and angiogenesis-sensitive populations. Between June 2010 and September 2012, this open-label study included 76 patients with solid tumors (17 in the dose-escalation and 59 in the expansion phase). Nineteen patients had breast cancer (25%), 11 had colon cancer (14%), 9 had thyroid cancer (12%), and 7 had lung cancer (9%); 42% had greater than three lines of previous chemotherapy. Lucitanib has shown clinical activity in a variety of tumor types, with an objective RECIST (Response Evaluation Criteria In Solid Tumors) response rate of 28%, a disease control rate of 80%, and several durable responses and long-lasting stabilizations, with all patients having previously received at least three lines of chemotherapy. Notably, half of patients with FGF-aberrant breast cancer (ie, 6 patients out of 12) achieved partial response during the study with a median progression-free survival close to 10 months. Toxicity was mainly related to its antiangiogenic properties, with hypertension and proteinuria, which are well-known side effects of angiogenesis inhibition. Whether direct inhibition of FGFR expressed on cancer cells contributes to tumor regression in breast cancer patients is currently being investigated in a phase 2 trial (FINESSE).

S49076
S49076 is another TK inhibitor currently in development for the treatment of glioblastoma and non–small cell lung cancer. S49076 is an orally bioavailable inhibitor of the hepatocyte growth factor receptor cMET, the growth arrest-specific 6 (GAS6) receptor AXL, as well as FGFR 1 and 2.8 It appears to be particularly suitable for the management of patients who are resistant to specific targeted therapies or chemotherapies. The enthusiasm for targeted therapies has been tempered by the observation of frequent and rapid relapses following good initial response in the designated subpopulation of patients. For example, lung cancer patients treated with inhibitors of epidermal growth factor receptor (EGFR), such as gefitinib or erlotinib, experience clinical response that rarely lasts more than 2 years. These relapses are often due to the selection of cancer cells that overexpress other TK, thereby short-circuiting the effects of EGFR inhibition. In this context, we note that the most commonly upregulated TK receptors include cMET, AXL, and FGFR.9 Insofar as S49076 targets exactly these three TK receptors, we expect this agent to have the potential to address this important medical need. Similar mechanisms have been described for the onset of resistance to VEGFR inhibition or various chemotherapies.

More generally, the activation of cMET, AXL, and FGFR pathways is associated with epithelial to mesenchymal transition, cancer cell dissemination, and metastasis. We should recall that some chemotherapy drugs appear to induce objective responses, but fail to confer any survival benefit. This has been shown to be due to the selection of cell variants that have undergone epithelial to mesenchymal transition and display a more aggressive phenotype.10 Combination of chemotherapy with S49076 may have a substantial preventive effect on this phenomenon.

The first study of S49076 in humans demonstrated that it has a remarkable safety profile, which is essential for a product whose principal benefit is expected to be found in combination with other anticancer agents. In summary, S49076 will allow us to target a number of critical steps for cancer progression, and is an agent with great promise.

S81694
S81694 is a member of the pyrazoloquinazoline family and is a specific inhibitor of the cell cycle checkpoint kinase TTK, also known as MPS1 (monopolar spindle 1).11 TTK plays a critical role in the control of mitosis regulating the spindle assembly checkpoint (SAC) through proper kinetocore recruitment of other essential SAC proteins. The SAC complex regulates a mitotic mechanism required for proper chromosome alignment, influencing the stability of the kinetochore–microtubule interaction and ensuring that cells do not divide until all sister chromatids correctly align to the metaphase plate. Failure to assemble the SAC complex results in unbalanced chromosome separation, leading to aneuploidy and cell death. TTK is highly expressed in fast-dividing cells, including virtually all cancer cells. Triple-negative breast cancer and acute myelocytic leukemia are among the tumor types that are the most dependent on the activity of TTK.12 Unlike mitotic inhibitors, such as taxanes and vinca alkaloids, TTK inhibitors accelerate cell division and therefore represent a novel mechanism to target fast-dividing cells.

The new agent, S81694, is a specific ATP-competitive inhibitor of TTK. It was initially discovered by Nerviano Medical Science (as a follow-up of NMS-P71513) from whom Servier acquired the patent in 2014. S81694 will enter clinical development in solid tumors the second quarter of 2015.

Inducers of apoptosis in cancer cells

S55746
Evasion from apoptosis (programmed cell death) is one of the hallmarks of cancer, ie, one of the most frequent alterations of cancer cells responsible for carcinogenesis.1 Apoptosis is also one of the most frequent mechanisms of escape from chemotherapy or targeted therapies. Proteins of the B-cell lymphoma 2 (Bcl-2) family are crucial inhibitors of apoptosis, and are therefore regarded as prosurvival factors.14 They act by sequestering and antagonizing the inducers of apoptosis BAX and BAK. Inhibiting the prosurvival members of the Bcl-2 family is expected to restore the competence of cancer cells for apoptosis. On the other hand, apoptosis is also a physiological process and, until recently, the clinical application of such inhibitors was hindered by the difficulties in designing molecules that could prevent specific interactions between BAX, BAK, and antiapoptosis proteins. The strong homology within the Bcl-2 family of proteins initially led only to the development of drugs that blocked several members of the protein family, which gave rise to undesirable side effects, mostly platelet toxicity due to Bcl-xL inhibition, and limited clinical application.15

A new collaboration between Servier and Vernalis was set up in 2007 with the aim of discovering new specific inhibitors of the main members of the Bcl-2 family of proteins. In 2014, the first of these molecules, S55746, a Bcl-2–specific inhibitor, entered clinical development. A month later, Servier and Novartis signed a global collaboration agreement for the development and commercialization of S55746.

Other inducers of apoptosis
Further inhibitors of the prosurvival members of the Bcl-2 family of proteins are currently in preclinical development at Servier. Notably, Servier has discovered an inhibitor of Mcl-1, one of the most important members of this family that is not yet targeted.16 Consistent preclinical data show that Mcl-1 inhibitors are highly active against models of hematological and solid tumors, either as single agents or in combination with approved targeted therapies.

Immunotherapy

Cancer cells develop complex interactions with mesenchymal cells, as has been observed in in vivo models in both patients and animals.17 In solid tumors (including lymphomas), these mesenchymal cells are organized and are collectively referred to as the tumor stroma.18 The tumor stroma, which contains activated fibroblasts, endothelial cells, and immune leukocytes, is essential for tumor growth, cancer dissemination, colonization of distant organs (ie, metastasis), and resistance to treatment. Importantly, solid tumors contain many types of immune cells, including macrophages, neutrophils, lymphocytes, and various myeloid-derived suppressor cells, whose number, localization, polarization, and activation status are some of the best predictors of patient survival. In recent years, targeting the interactions between cancer cells and tumor-infiltrating leukocytes (TILs) was recognized as a promising strategy to fight cancer. In the recent years, the US Food and Drug Administration (FDA) approved two novel drugs, sipuleucel-T (Provenge® in 2010) and ipilimumab (Yervoy® in 2011), which directly harness the immune system against cancer,19 and are being applied in advanced prostate cancer and unresectable or metastatic melanoma, respectively.

More recently, adoptive therapies using genetically modified autologous T lymphocytes have shown impressive results in acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL).20 Immunotherapy via agents such as these is one of Servier’s priorities in oncology.

Engineered antibodies

In collaboration with the US-based biotech MacroGenics, Servier is developing a number of engineered antibodies, including a humanized, B7-H3–specific IgG1 (immunoglobulin G 1) with an Fc domain optimized for enhanced immune effector functions like antibody-dependent cell cytotoxicity and several Dual-Affinity Re-Targeting (DART) antibodies.21 All these antibodies are first in class. The most advanced DART antibody recognizes both CD3 expressed on T lymphocytes and CD123 expressed on acute myelocytic leukemia and myelodysplastic syndrome cells. When this dual binding occurs on T lymphocytes and cancer cells, it stabilizes the formation of conjugates between cancer cells and lymphocytes, and leads to T-cell receptor aggregation and lymphocyte activation. This results in tumor cell lysis.

The power of this approach is that any lymphocyte, irrespective of its original antigen specificity, can be mobilized against tumor cells, leading to a very strong immune reaction. Servier also has an option on a number of other DART antibodies discovered by MacroGenics, including a gpA33 x CD3 bispecific one for the treatment of colorectal cancers.

Cell therapy

Servier is currently collaborating with the French biotech Cellectis to develop and commercialize a UCART19 product candidate. The use of autologous T cells engineered to express chimeric antigen receptors (CARs, a genetic fusion between a tumor antigen binder, an intracellular T-cell activation domain, and a costimulation signal) has recently emerged as a powerful approach to treat patients with advanced CLL and ALL.22 The production of autologous CAR-expressing T cells requires a long and tedious process that starts with the purification of a patient’s own T cells.

Following this, the cells are genetically modified to express the tumor-specific CAR. The transduced cells are then purified and amplified, and finally transferred back to the patient. This process has to be repeated for each patient, therefore making this a true personalized medicine.

The goal of the UCART19 (universal CAR T) program, developed by Cellectis and for which Servier has an exclusive option to license, is to modify this process so that T cells from healthy donors, instead of those derived from the patient, can be used as the starting material for this treatment. Consequently, a single preparation of modified lymphocytes (universal CAR T cells or UCART cells) could be used for several, and possibly hundreds of, patients. The hope is that UCART cells could become an “off-the-shelf” drug, with great promise for patients. The novelty here is the use of Cellectis proprietary gene editing technology TALEN®23 to inactivate the endogenous T-cell receptor gene expressed by the starting lymphocytes, thereby preventing the induction of graft-vs-host disease. This will also require proper conditioning of the patients to allow for sufficient UCART lymphocyte persistence in an allogeneic patient. The development of the UCART technology represents significant manufacturing and clinical challenges, but it would also be a game-changer making this promising approach available for large cohorts of patients.

Cellectis is currently developing UCART19 cells targetingCD19, an antigen expressed by CLL and ALL cells, which was successfully targeted in the previously conducted autologous CAR trials. Cellectis has also started to construct new CARs targeting different receptors expressed in various types of cancer, including solid tumors.

Conclusion

Servier’s portfolio in oncology is growing rapidly. The most advanced products comprise novel cytotoxics and thymidine kinase inhibitors targeting some of the most dramatic cancers: glioblastoma, non-Hodgkin lymphomas, melanoma, and breast and lung cancers. In the future, Servier will further develop its efforts on inducers of apoptosis and immunotherapies, which we believe carry potential in a large set of indications and could efficiently complement current standards of care. This activity is leveraged by a network of partnerships that includes some of the big names of global oncology and also a number of smaller partners from the field of biotechnology. Servier’s ambition is to bring new products and new therapeutic options to the many who suffer from cancer. ■

Acknowledgments. The authors wish to thank Renata Robert, Gordon Tucker, Michael Burbridge, Thierry Wurch, and Olivier Geneste for critical reading of the manuscript and Sarah Novack for help in its editing.


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Keywords: apoptosis; breast cancer; cell therapy; glioblastoma; immunotherapy; leukemia; non-Hodgkin lymphoma; targeted therapy