Biomarkers: Opportunities and Challenges for Drug Development in the Current Regulatory Landscape.

Biomarkers are widely used at every stage of drug discovery and development. Utilisation of biomarkers has a potential to make drug discovery, development and approval processes more efficient. An overview of the current global regulatory landscape is presented in this article with particular emphasis on the validation and qualification of biomarkers, as well as legal framework for companion diagnostics. Furthermore, this article shows how the number of approved drugs with at least 1 biomarker used during development (biomarker acceptance) is affected by the recent advances in the biomarker regulations. More than half of analysed approvals were supported by biomarker data and there has been a slight increase in acceptance of biomarkers in recent years, even though the growth is not continuous. For certain pharmacotherapeutic groups, approvals with biomarkers are more common than without. Examples include immunosuppressants, immunostimulants, drugs used in diabetes, antithrombotic drugs, antineoplastic agents and antivirals. As a conclusion, potential benefits, challenges and opportunities of using biomarkers in drug discovery and development in the current regulatory landscape are summarised and discussed.

19th Annual Meeting of the Safety Pharmacology Society: regulatory and safety perspectives for advanced therapy medicinal products (cellular and gene therapy products).

This report summarizes and discusses talks delivered at an educational course offered during the 2019 Annual Meeting of the Safety Pharmacology Society on advanced therapy medicinal products (ATMPs) and cell gene therapeutic products (CGTPs). ATMPs and CGTPs comprise gene and cell therapy medicinal products, tissue-engineered products, or the incorporation of one of these products into a medical device. Cited examples of ATMPs are autologous CD34+ cells encoding for the ßA-T87Q-globin gene, CAR (chimeric antigen receptor)-T cell immunotherapy medicines, genome editing products, and engineered heart muscle patches constructed from induced human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for remuscularization of the failing human heart. The nonclinical assessment of efficacy and safety of ATMPs for undertaking human clinical trials requires innovative, product-specific strategies. In order to succeed in gaining marketing approval for these novel medicines, sponsors should establish well-defined collaborative relationships with the appropriate regulatory authorities.

From fiction to science: clinical potentials and regulatory considerations of gene editing.

Gene editing technologies such as CRISPR/Cas9 have emerged as an attractive tool not only for scientific research but also for the development of medicinal products. Their ability to induce precise double strand breaks into DNA enables targeted modifications of the genome including selective knockout of genes, correction of mutations or precise insertion of new genetic material into specific loci. Gene editing-based therapies hold a great potential for the treatment of numerous diseases and the first products are already being tested in clinical trials. The treatment indications include oncological malignancies, HIV, diseases of the hematopoietic system and metabolic disorders. This article reviews ongoing preclinical and clinical studies and discusses how gene editing technologies are altering the gene therapy landscape. In addition, it focusses on the regulatory challenges associated with such therapies and how they can be tackled during the drug development process.

Expediting Drug Development: FDA's New Regenerative Medicine Advanced Therapy Designation.

In March 2017, the US FDA introduced the new Regenerative Medicine Advanced Therapy (RMAT) designation thus recognizing the enormous potential of these medicines and the need for efficient regulatory tools to accelerate their development and their commercial availability. The development of regenerative medicines is very challenging because of their complex and unique nature, especially to the rather unexperienced small- and medium-sized developing enterprises. With the new RMAT designation, FDA aims at providing intensive support to companies developing cell- and tissue-based therapies, tissue-engineering products, and combination treatments. This may also include cell-based products where the genome has been edited by emerging technologies such as CRISPR-Cas9. This article presents the newly launched "Regenerative Medicine Advanced Therapy" (RMAT) designation, outlines existing FDA regulatory tools aiming at expediting approval, and discusses the overall value of these programs. Additionally, recommendations are provided for companies developing these very specific and complex therapies on how and when to consider these tools for an integrated development and regulatory strategy.

Approval of First CAR-Ts: Have we Solved all Hurdles for ATMPs?

T cells are known as the most potent killer cells of the immune system, designed by nature to prevent unwanted challenges. The first class of therapeutic products harnessing the power of T cells for target-specific treatment of oncological diseases was bispecific antibodies. The first T-cell engaging bispecific antibodies that obtained approval were catumaxomab and blinatumomab1,2. Eight years later, the first chimeric antigen receptor (CAR)-T cells received regulatory approval3. CAR-T cells are the cellular interpretation of T-cell engaging therapies and have shown remarkable clinical results. CAR-T cells belong to the regulatory group of advanced therapy medicinal products (ATMPs). Due to the cell-/gene-based complex nature, ATMPs are far more challenging to develop than other, more defined, medicinal products. Despite very encouraging clinical results, there have been many set-backs in the development of ATMPs during the past 20 years. Therefore, the approval of the first two CAR-Ts KYMRIAH and YESCARTA is highly encouraging for the field. In this article we review the current landscape of CAR-Ts as a special class of ATMPs. This comprises the pathway to approval including the use of dedicated regulatory tools and challenges that were faced during the procedure. Furthermore, we highlight important future trends in the field.

The role of relative lymphocyte count as a biomarker for the effect of catumaxomab on survival in malignant ascites patients: results from a phase II/III study.

PURPOSE: We report the role of relative lymphocyte count (RLC) as a potential biomarker with prognostic impact for catumaxomab efficacy and overall survival (OS) based on a post hoc analysis of the pivotal phase II/III study of intraperitoneal catumaxomab treatment of malignant ascites. EXPERIMENTAL DESIGN: The impact of treatment and RLC on OS was evaluated using multivariate Cox models. Kaplan-Meier and log-rank tests were used for group comparisons. Survival analyses were performed on the safety population [patients with paracentesis plus ≥ 1 dose of catumaxomab (n = 157) and paracentesis alone (n = 88)]. Determination of the optimal cutoff value for RLC was based on five optimality criteria. RESULTS: OS was significantly longer with catumaxomab versus paracentesis alone (P = 0.0219). The 6-month OS rate with catumaxomab was 28.9% versus 6.7% with paracentesis alone. RLC had a positive impact on OS and was an independent prognostic factor (P < 0.0001). In patients with RLC > 13% (n = 159: catumaxomab, 100 and control, 59), catumaxomab was associated with a favorable effect on OS versus paracentesis alone (P = 0.0072), with a median/mean OS benefit of 41/131 days and an increased 6-month survival rate of 37.0% versus 5.2%, respectively. In patients with RLC ≤ 13% at screening (n = 74: catumaxomab, 50 and control, 24), the median (mean) OS difference between the catumaxomab and the control group was 3 (16) days, respectively (P = 0.2561). CONCLUSIONS: OS was significantly improved after catumaxomab treatment in patients with malignant ascites. An RLC > 13% at baseline was a significant prognostic biomarker.

The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting.

BACKGROUND: Patients with gastric cancer benefit from perioperative chemotherapy, however, treatment is toxic and many patients will relapse. The trifunctional antibody catumaxomab targets EpCAM on tumor cells, CD3 on T cells, and the Fcγ-receptor of antigen-presenting cells. While in Europe catumaxomab is approved for treating malignant ascites, it has not been investigated in the perioperative setting and its exact immunological mode of action is unclear. METHODS: In our study, gastric cancer patients received neoadjuvant platinum-based chemotherapy, one intraoperative application of catumaxomab, and 4 postoperative doses of intraperitoneal catumaxomab. Immunomonitoring was performed in 6 patients before surgery, after completion of catumaxomab treatment, and one month later. RESULTS: Intraperitoneal application of catumaxomab caused an increased expression of activation markers on the patients' T cells. This was accompanied by a transient decrease in numbers of CXCR3(+) effector T cells with a T-helper (Th)-1 phenotype in the peripheral blood. All patients evidenced pre-existing EpCAM-specific CD4(+) and/or CD8(+) T cells. While these cells transiently disappeared from the blood stream after intraperitoneal application of catumaxomab, we detected increased numbers of peripheral EpCAM-specific cells and a modified EpCAM-specific T-cell repertoire 4 weeks after completion of treatment. Finally, catumaxomab also amplified humoral immunity to tumor antigens other than EpCAM. CONCLUSIONS: Our findings suggest that catumaxomab exerts its clinical effects by (1) activating peripheral T cells, (2) redistributing effector T cells from the blood into peripheral tissues, (3) expanding and shaping of the pre-existing EpCAM-specific T-cell repertoire, and (4) spreading of anti-tumor immunity to different tumor antigens.

Transient lymphocyte decrease due to adhesion and migration following catumaxomab (anti-EpCAM x anti-CD3) treatment in vivo.

INTRODUCTION: In patients, a transient decrease in peripheral blood lymphocyte counts was observed following intraperitoneal administration of the trifunctional monoclonal antibody catumaxomab (anti-human EpCAM x anti-human CD3). The aim of this study was to clarify the observed effect in a preclinical mouse model and to analyse the related mechanism of action in vitro. MATERIALS AND METHODS: A related antibody, BiLu (antihuman EpCAM x anti-mouse CD3), was administered to mice and blood leukocytes were analysed. In vitro studies measured activation and cytokine secretion from human peripheral blood mononuclear cells (PBMC). For the analysis of T cell adhesion, PBMC were preincubated with catumaxomab and then co-cultured with human endothelial cells (HUVEC); T cell adhesion was assessed in the presence or absence of endothelial cell preactivation by TNFα. Adherent T cells were determined by flow cytometry. RESULTS: Treatment of mice with BiLu resulted in a dosedependent transient decrease in CD3+ T cells (both CD4+ and CD8+) that returned to the normal range within 48 h. Catumaxomab physiologically activated T cells in vitro (increased CD69 expression) and induced cytokine release (TNFα, IFNγ). TNFα increased expression of adhesion molecules CD54 and CD62E on endothelial cells. Furthermore, catumaxomab dose-dependently enhanced adhesion of T cells to endothelial cells. Adhesion was further increased when endothelial cells were preactivated with TNFα. CONCLUSIONS: Catumaxomab increases adhesion of T cells to endothelial cells due to antibody-mediated activation of T cells and production of T cell cytokines that up-regulate endothelial cell adhesion molecules. These results provide a mechanistic rationale for the transient, reversible decrease in lymphocyte counts observed following catumaxomab administration in patients, which is likely to be due to redistribution of lymphocytes.

Humoral response to catumaxomab correlates with clinical outcome: results of the pivotal phase II/III study in patients with malignant ascites.

The trifunctional antibody catumaxomab is a targeted immunotherapy for the intraperitoneal treatment of malignant ascites. In a Phase II/III trial in cancer patients (n = 258) with malignant ascites, catumaxomab showed a clear clinical benefit vs. paracentesis and had an acceptable safety profile. Human antimouse antibodies (HAMAs), which could be associated with beneficial humoral effects and prolonged survival, may develop against catumaxomab as it is a mouse/rat antibody. This post hoc analysis investigated whether there was a correlation between the detection of HAMAs 8 days after the fourth catumaxomab infusion and clinical outcome. HAMA-positive and HAMA-negative patients in the catumaxomab group and patients in the control group were analyzed separately for all three clinical outcome measures (puncture-free survival, time to next puncture and overall survival) and compared to each other. There was a strong correlation between humoral response and clinical outcome: patients who developed HAMAs after catumaxomab showed significant improvement in all three clinical outcome measures vs. HAMA-negative patients. In the overall population in HAMA-positive vs. HAMA-negative patients, median puncture-free survival was 64 vs. 27 days (p < 0.0001; HR 0.330), median time to next therapeutic puncture was 104 vs. 46 days (p = 0.0002; HR 0.307) and median overall survival was 129 vs. 64 days (p = 0.0003; HR 0.433). Similar differences between HAMA-positive and HAMA-negative patients were seen in the ovarian, nonovarian and gastric cancer subgroups. In conclusion, HAMA development may be a biomarker for catumaxomab response and patients who developed HAMAs sooner derived greater benefit from catumaxomab treatment.

Novel monoclonal antibodies for cancer treatment: the trifunctional antibody catumaxomab (removab).

THE TRIFUNCTIONAL ANTIBODY (TRAB) CATUMAXOMAB IS CHARACTERIZED BY A UNIQUE ABILITY TO BIND THREE DIFFERENT CELL TYPES: tumor cells; T-cells; and accessory cells. It binds to epithelial cell adhesion molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and to type I, IIa, and III Fcγ receptors (FcγRs) on accessory cells (e.g. natural killer cells, dendritic cells, and macrophages). Catumaxomab exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent, cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Catumaxomab represents a self-supporting system, as no additional immune cell activation is required for tumor eradication. The efficacy and safety of catumaxomab have been demonstrated in a pivotal phase II/III study in malignant ascites (MA) and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions of 10, 20, 50, and 150 µg on days 0, 3, 7, and 10, respectively. Catumaxomab was approved for the i.p. treatment of MA in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible in the European Union in April 2009. It is the first trAb and the first drug in the world approved specifically for the treatment of MA. Catumaxomab was awarded the Galen of Pergamon Prize, which recognizes pharmacological research for developing new and innovative drugs and diagnostics, in the specialist care category in 2010. The use of catumaxomab in other indications and additional routes of administration are currently being investigated to further exploit its therapeutic potential in EpCAM-positive carcinomas.

Catumaxomab: clinical development and future directions.

Catumaxomab, a monoclonal bispecific trifunctional antibody, was approved in the European Union in April 2009 for the intraperitoneal treatment of patients with malignant ascites. The marketing authorization holder Fresenius Biotech GmbH developed catumaxomab (Removab(®)) together with its partner TRION Pharma GmbH, Germany. It is the first substance worldwide with a regulatory label for the treatment of malignant ascites due to epithelial carcinomas. Since the peritoneum is of mesothelial origin and therefore lacks EpCAM expression, the intraperitoneal administration of catumaxomab is an attractive targeted immunotherapeutic approach. Catumaxomab is able to destroy EpCAM positive tumor cells in the peritoneal cavity known as the main cause of malignant ascites. In addition, catumaxomab is a potential therapeutic option for several primary tumors since the EpCAM molecule is expressed on the majority of epithelial carcinomas. This review focuses on the clinical development of catumaxomab and indicates future directions.

Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3) as a targeted cancer immunotherapy.

Catumaxomab is a trifunctional antibody (trAb) characterized by its unique ability to bind three different cell types: tumor cells, T-cells, and accessory cells. It has two different antigen-binding specificities: one for epithelial cell adhesion molecule (EpCAM) on tumor cells and one for the CD3 antigen on T-cells. Catumaxomab also binds to type I, IIa, and III Fcγ receptors (FcγR) on accessory cells, e.g. macrophages, dendritic cells, and natural killer cells, via its intact Fc region. Its anti-tumor activity results from T-cell-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Importantly, no additional activation of immune cells is necessary for effective tumor eradication by catumaxomab, which represents a self-supporting system. Catumaxomab's efficacy and safety have been demonstrated in a pivotal phase II/III study and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions on days 0, 3, 7, and 10 at doses of 10, 20, 50, and 150µg, respectively. Catumaxomab has been approved in the European Union since April 2009 for the i.p. treatment of malignant ascites (MA) in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible. Catumaxomab is the first trAb and the first drug worldwide to be approved specifically for the treatment of MA. It is in clinical trials in a number of other indications including ovarian and gastric cancer. Alternative routes of administration are also under evaluation to further exploit the therapeutic potential of catumaxomab in EpCAM-positive carcinomas.