DOCSLIB.ORG

Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab Published OnlineFirst July 2, 2010; DOI: 10.1158/1078-0432.CCR-10-0570 Published OnlineFirst on August 24, 2010 as 10.1158/1078-0432.CCR-10-0570 Report from the FDA Clinical Cancer Research U.S. Food and Drug Administration Approval: Ofatumumab for the Treatment of Patients with Chronic Lymphocytic Leukemia Refractory to Fludarabine and Alemtuzumab Steven J. Lemery1, Jenny Zhang2, Mark D. Rothmann2, Jun Yang3, Justin Earp3, Hong Zhao3, Andrew McDougal1, Anne Pilaro1, Raymond Chiang1, Joseph E. Gootenberg1, Patricia Keegan1, and Richard Pazdur1 Abstract Purpose: To describe the data and analyses that led to the U.S. Food and Drug Administration (FDA) approval of ofatumumab (Arzerra, GlaxoSmithKline) for the treatment of patients with chronic lympho- cytic leukemia (CLL) refractory to fludarabine and alemtuzumab. Experimental Design: The FDA reviewed the results of a planned interim analysis of a single-arm trial, enrolling 154 patients with CLL refractory to fludarabine, and a supportive dose-finding, activity-estimat- ing trial in 33 patients with CLL. Patients in the primary efficacy study received ofatumumab weekly for eight doses, then every 4 weeks for an additional four doses; patients in the supportive trial received four weekly doses. In the primary efficacy study, endpoints were objective response rate and response duration. Results: For regulatory purposes, the primary efficacy population consisted of 59 patients with CLL refractory to fludarabine and alemtuzumab. In this subgroup, the investigator-determined objective response rate was 42% [99% confidence interval (CI), 26–60], with a median duration of response of 6.5 months (95% CI, 5.8–8.3); all were partial responses. The most common adverse reactions in the primary efficacy study were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. Infusion reactions occurred in 44% of patients with the first infusion (300 mg) and 29% with the second infusion (2,000 mg). The most com- mon serious adverse reactions were infections, neutropenia, and pyrexia. Conclusions: On October 26, 2009, the FDA granted accelerated approval to ofatumumab for the treatment of patients with CLL refractory to fludarabine and alemtuzumab, on the basis of demonstration of durable tumor shrinkage. Clin Cancer Res; 16(17); 4331–8. ©2010 AACR. Chronic lymphocytic leukemia (CLL) is a clonal disor- patients with CLL has been based on a clinically mean- der of B cells with a variable clinical course. Median sur- ingful prolongation of progression-free survival (PFS) ac- vival is longer than 10 years4; however, reported median companied by an acceptable safety profile; whereas survival is only 2 to 3 years for patients with high-risk accelerated approval has been granted on the basis of disease (Rai category III or IV or Binet stage 3; ref. 1). Re- durable overall response rates (ORR) in patients with ported survival in CLL patients whose disease is refractory CLL, which has progressed following available therapy. to multiple drugs is shorter; in one report, median survival In order to be considered for accelerated approval, a was 8 months in patients with CLL refractory to fludara- drug that shows an effect on a surrogate endpoint that bine and alemtuzumab (2). is reasonably likely to predict clinical benefit must treat In the past decade, regular U.S. Food and Drug a serious or life-threatening disease or condition and Administration (FDA) approval for the treatment of show an advantage over available therapy (3). Addition- ally, the commercial manufacturer must commit to study the drug further to verify and characterize the pre- Authors' Affiliations: 1Office of Oncology Drug Products, Office of New dicted clinical benefit (3). Drugs; 2Office of Biostatistics; and 3Office of Clinical Pharmacology, Alemtuzumab received accelerated approval in 2001 Center for Drug Evaluation and Research, U.S. Food and Drug and regular approval in 2007. Accelerated approval was Administration, Silver Spring, Maryland based on the results of three single-arm studies enrolling Corresponding Author: Steven Lemery, Division of Biological Oncology Products, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Building 22, Room 2374, Silver Spring, MD 20993. Phone: 301-796-2276; Fax: 301-796-9849; E-mail: [email protected]. 4 Horner MJ, Ries LAG, Krapcho M, et al., editors. SEER Stat Fact Sheets, doi: 10.1158/1078-0432.CCR-10-0570 1975-2006. Bethesda (MD): National Cancer Institute; [cited 2007 Jul ©2010 American Association for Cancer Research. 27]. Available from: http://seer.cancer.gov/. www.aacrjournals.org 4331 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst July 2, 2010; DOI: 10.1158/1078-0432.CCR-10-0570 Lemery et al. 149 patients with CLL and progressive disease following Nonclinical Pharmacology and Toxicology alkylating agents and fludarabine. The rates of durable objective responses (ORR) in the three studies ranged Ofatumumab binds specifically to the CD20 molecule, from 21 to 33% (4). Regular approval was based on supe- which is expressed on normal B lymphocytes (pre-B– to rior PFS [HR 0.58 (95% confidence interval [CI], 0.43– mature B–lymphocyte) and on B-cell CLL tumor cells. 0.77), P < 0.0001 stratified log-rank test] in a randomized The CD20 molecule is not shed from the cell surface active-controlled study comparing alemtuzumab to chlor- and is not internalized following antibody binding (6). ambucil in previously untreated patients with CLL (4). The Fab domain of ofatumumab binds to the CD20 Alemtuzumab also showed an improvement in ORR molecule, and the Fc domain mediates immune effector (83% versus 55%) and complete response rates (24% functions to result in B-cell lysis in vitro (6). Possible me- versus 2%) compared with chlorambucil (4). chanisms of action for ofatumumab include complement- The FDA approved bendamustine in 2008 on the basis dependent cytotoxicity and antibody-dependent cell- of superior PFS [HR 0.27 (95% CI, 0.17-0.43), P < 0.0001] mediated cytotoxicity. in a randomized active-controlled study comparing bend- Nonclinical data submitted in support of the applica- amustine to chlorambucil in previously untreated patients tion included tissue-binding studies in human and cyno- with CLL. In the study, bendamustine also showed an molgus monkey tissue panels, evaluation of in vitro improvement in ORR (59% versus 26%) and complete pharmacologic activity (receptor binding, lysis of CD20- response rates (8% versus <1%) compared with chloram- expressing cells), in vivo pharmacologic activity (antitumor bucil (5). activity in severe combined immunodeficient mice bearing In addition to bendamustine and alemtuzumab, the fol- human tumor xenografts, characterization of B-cell deple- lowing drugs are approved for the treatment of patients tion in treated monkeys), pharmacokinetic studies in cy- with CLL: fludarabine, cyclophosphamide, and chloram- nomolgus monkeys, and subacute (4-week) and chronic bucil. These drugs were approved on the basis of durable (7-month) toxicology studies in cynomolgus monkeys. objective tumor responses prior to the codification of the The major ofatumumab toxicities observed in nonclinical accelerated approval regulations. studies were extensions of its expected pharmacologic The Biologics License Application (BLA) for ofatumu- activity, that is, the severe and prolonged depletion of mab was submitted on January 30, 2009. The application B lymphocytes both in the circulation and in the major contained the interim results of a single-arm, fixed-dose, lymphoid organs (follicular germ centers of the spleen, multicenter trial (Hx-CD20-406), and the final results cortical lymph nodes, and Peyer's patches in the gastroin- of a multicenter, sequential dose-escalating cohort and testinal tract). Other toxicities observed in the 7-month re- activity-estimating trial (Hx-CD20-402), which used a peat-dose cynomolgus monkey toxicity study included shorter treatment duration (4 doses versus 12 doses) than sporadic, nonsevere infusion reactions, hematologic the primary efficacy study. Both trials enrolled adults with changes including B-cell depletion, mild hemolytic ane- CLL who had relapsed following, or were refractory to, mia, and changes in neo- and recall-antigen responses. one or more standard treatments. The BLA was supported by safety information from several trials enrolling 151 patients with follicular lymphoma or diffuse large B-cell Clinical Pharmacology lymphoma, 282 patients with rheumatoid arthritis or chronic obstructive pulmonary disease, and 28 patients Pharmacokinetic data were obtained from 146 patients with CLL who received ofatumumab in combination with with refractory CLL who received a 300-mg initial dose chemotherapy. The primary efficacy trial used the highest followed by seven weekly and four monthly infusions of dose and longest duration of ofatumumab in the clinical 2,000 mg (6). The Cmax and AUC(0−∞) after the eighth safety database. infusion in study Hx-CD20-406 were approximately 40% and 60% higher than after the fourth infusion in study Hx-CD20-402 (6). The mean volume of distribution Chemistry, Manufacturing, and Controls at steady-state (Vss) values ranged from 1.7 to 5.1 L (6). Ofatumumab is eliminated through both a target- Ofatumumab is an immunoglobulin G1 (IgG1) kappa independent route and a B-cell–mediated route (6). Ofa- human monoclonal
Load more

Recommended publications
  • Activity of Rituximab and Ofatumumab Against Mantle
    ACTIVITY OF RITUXIMAB AND OFATUMUMAB AGAINST MANTLE CELL LYMPHOMA(MCL) IN VITRO IN MCL CELL LINES BY COMPLEMENT DEPENDENT CYTOTOXICITY (CDC)AND ANTIBODY-DEPENDENT CELL MEDIATED CYTOTOXICITY ASSAYS(ADCC) Dr. Gopichand Pendurti M.B.B.S Mentor: Dr. Francisco J. Hernandez-Ilizaliturri MD Overview of presentation •Introduction to mantle cell lymphoma. •Concept of minimal residual disease. •Anti CD 20 antibodies. •51Cr release assays. •Flow cytometry on cell lines. •Results. •Future. MANTLE CELL LYMPHOMA •Mantle cell lymphoma is characterized by abnormal proliferation of mature B lymphocytes derived from naïve B cells. •Constitutes about 5% of all patients with Non Hodgkin's lymphoma. •Predominantly in males with M:F ratio 2.7:1 with onset at advanced age (median age 60yrs). •It is an aggressive lymphoma with median survival of patients being 3-4 years. •Often presents as stage III-IV with lymphadenopathy, hepatosplenomegaly, gastrointestinal involvement, peripheral blood involvement. Pedro Jares, Dolors Colomer and Elias Campo Genetic and molecular pathogenesis of mantle cell lymphoma: perspectives for new targeted therapeutics Nature revision of cancer 2007 October:7(10):750-62 •Genetic hallmark is t(11:14)(q13:q32) translocation leading to over expression of cyclin D1 which has one of the important pathogenetic role in deregulating the cell cycle. •Other pathogentic mechanisms include molecular and chromosomal alterations that Target proteins that regulate the cell cycle and senecense (BMI1,INK4a,ARF,CDK4 AND RB1). Interfere with cellular
    [Show full text]
  • Refreshing the Biologic Pipeline 2020
    news feature Credit: Science Lab / Alamy Stock Photo Refreshing the biologic pipeline 2020 In the absence of face-to-face meetings, FDA and industry implemented regulatory workarounds to maintain drug and biologics approvals. These could be here to stay. John Hodgson OVID-19 might have been expected since 1996) — a small miracle in itself “COVID-19 confronted us with the need to severely impair drug approvals (Fig. 1 and Table 1). to better triage sponsors’ questions,” says Cin 2020. In the event, however, To the usual crop of rare disease and Peter Marks, the director of the Center for industry and regulators delivered a small genetic-niche cancer treatments, 2020 Biologics Evaluation and Research (CBER) miracle. They found workarounds and also added a chimeric antigen receptor at the FDA. “That was perhaps the single surrogate methods of engagement. Starting (CAR)-T cell therapy with a cleaner biggest takeaway from the pandemic related in January 2020, when the outbreak veered manufacturing process and the first to product applications.” Marks says that it westward, the number of face-to face approved blockbuster indication for a became very apparent with some COVID- meetings declined rapidly; by March, small-interfering RNA (siRNA) — the 19-related files that resolving a single they were replaced by Webex and Teams. European Medicines Agency’s (EMA) issue can help a sponsor enormously and (Secure Zoom meeting are to be added registration of the RNA interference accelerate the development cycle. Before this year.) And remarkably, by 31 December, (RNAi) therapy Leqvio (inclisiran) for COVID-19, it was conceivable that a small the US Food and Drug Administration cardiovascular disease.
    [Show full text]
  • Whither Radioimmunotherapy: to Be Or Not to Be? Damian J
    Published OnlineFirst April 20, 2017; DOI: 10.1158/0008-5472.CAN-16-2523 Cancer Perspective Research Whither Radioimmunotherapy: To Be or Not To Be? Damian J. Green1,2 and Oliver W. Press1,2,3 Abstract Therapy of cancer with radiolabeled monoclonal antibodies employing multistep "pretargeting" methods, particularly those has produced impressive results in preclinical experiments and in utilizing bispecific antibodies, have greatly enhanced the thera- clinical trials conducted in radiosensitive malignancies, particu- peutic efficacy of radioimmunotherapy and diminished its toxi- larly B-cell lymphomas. Two "first-generation," directly radiola- cities. The dramatically improved therapeutic index of bispecific beled anti-CD20 antibodies, 131iodine-tositumomab and 90yttri- antibody pretargeting appears to be sufficiently compelling to um-ibritumomab tiuxetan, were FDA-approved more than a justify human clinical trials and reinvigorate enthusiasm for decade ago but have been little utilized because of a variety of radioimmunotherapy in the treatment of malignancies, particu- medical, financial, and logistic obstacles. Newer technologies larly lymphomas. Cancer Res; 77(9); 1–6. Ó2017 AACR. "To be, or not to be, that is the question: Whether 'tis nobler in the pembrolizumab (anti-PD-1), which are not directly cytotoxic mind to suffer the slings and arrows of outrageous fortune, or to take for cancer cells but "release the brakes" on the immune system, arms against a sea of troubles, And by opposing end them." Hamlet. allowing cytotoxic T cells to be more effective at recognizing –William Shakespeare. and killing cancer cells. Outstanding results have already been demonstrated with checkpoint inhibiting antibodies even in far Introduction advanced refractory solid tumors including melanoma, lung cancer, Hodgkin lymphoma and are under study for a multi- Impact of monoclonal antibodies on the field of clinical tude of other malignancies (4–6).
    [Show full text]
  • B-Cell Targets to Treat Antibody-Mediated Rejection In
    Muro et al. Int J Transplant Res Med 2016, 2:023 Volume 2 | Issue 2 International Journal of Transplantation Research and Medicine Commentary: Open Access B-Cell Targets to Treat Antibody-Mediated Rejection in Transplantation Manuel Muro1*, Santiago Llorente2, Jose A Galian1, Francisco Boix1, Jorge Eguia1, Gema Gonzalez-Martinez1, Maria R Moya-Quiles1 and Alfredo Minguela1 1Immunology Service, University Clinic Hospital Virgen de la Arrixaca, Spain 2Nephrology Service, University Clinic Hospital Virgen de la Arrixaca, Spain *Corresponding author: Manuel Muro, PhD, Immunology Service, University Clinic Hospital “Virgen de la Arrixaca”, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain, Tel: 34-968-369599, E-mail: [email protected] Antibody-mediated rejection (AMR) in allograft transplantation APRIL (a proliferation-inducing ligand). These co-activation signals can be defined with a rapid increase in the levels of specific are required for B-cell differentiation into plasma cell and enhancing serological parameters after organ transplantation, presence of donor their posterior survival and are a key determinant of whether specific antibodies (DSAs) against human leukocyte antigen (HLA) developing B-cells will survive or die during the establishment molecules, blood group (ABO) antigens and/or endothelial cell of immuno-tolerance [5,6]. Important used agents commercially antigens (e.g. MICA, ECA, Vimentin, or ETAR) and also particular available are Tocilizumab (anti-IL6R) and Belimumab (BAFF). histological parameters [1,2]. If the AMR persists or progresses, the The receptors of BAFF and APRIL could also be important as treatment to eliminate the humoral component of acute rejection eventual targets, for example BAFF-R, TACI (transmembrane include three sequential steps: (a) steroid pulses, antibody removal activator and calcium modulator and cyclophyllin ligand interactor) (plasma exchange or immuno-adsorption) and high doses of and BCMA (B-cell maturation antigen).
    [Show full text]
  • Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with Zirconium 89 In
    Journal of Nuclear Medicine, published on January 18, 2018 as doi:10.2967/jnumed.117.203299 Evaluation of Next-Generation Anti-CD20 Antibodies Labeled with Zirconium 89 in Human Lymphoma Xenografts Jason T. Yoon†,1, Mark S. Longtine†,1, Bernadette V. Marquez-Nostra1,2, and Richard L. Wahl1 †Contributed equally. 1Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110. 2Current address: Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, PO Box 208048, New Haven, CT, 056520. First author (Jason Yoon) address: as noted above. Phone, 714-364-7560; E-mail, [email protected] For correspondence or reprints contact: Richard Wahl, MD Washington University School of Medicine, Department of Radiology, Campus Box 8131, 660 S. Euclid Ave, St. Louis, MO 63110 Telephone: (314) 362-7100, Fax: (314)747-4189 Email: [email protected] Financial Support: This study was funded, in part, by Radiological Society of North America Education and Research Foundation Medical Student research award, RMS1646, to JTY and RLW. BVMN is supported by the National Institutes of Health (grant 1K99CA201601). Word Count of Manuscript: 4,994 Running Title: Next-Generation 89Zr-Anti-CD20 mAbs ABSTRACT Radioimmunotherapies with monoclonal antibodies (mAbs) to the B-lymphocyte antigen 20 (CD20) are effective treatments for B-cell lymphomas, but United States Food and Drug Administration (FDA)-approved radioimmunotherapies exclusively use radiolabeled murine antibodies, potentially limiting re-dosing. The FDA recently approved two unlabeled anti-CD20 monoclonal antibodies, obinutizumab and ofatumumab, termed "next generation" as they are humanized (obinituzumab) or fully human (ofatumumab), thus potentially allowing a greater potential for re-dosing than with previous generation anti-CD20 antibodies, including rituximab (chimeric) and tositumumab (murine) which contain more murine peptide sequences.
    [Show full text]
  • One Target, Different Effects: a Comparison of Distinct Therapeutic Antibodies Against the Same Targets
    EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 43, No. 10, 539-549, October 2011 One target, different effects: a comparison of distinct therapeutic antibodies against the same targets Hyunbo Shim ple, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and Department of Life Science certolizumab pegol -- with many more in clinical and Division of Life and Pharmaceutical Sciences preclinical development. The situation is similar for Ewha Womans University HER2, CD20, EGFR, and VEGF, each having one or Seoul 120-750, Korea more approved antibodies and many more under Correspondence: Tel, 82-2-3277-4240; development. This review discusses the different bind- Fax, 82-2-3277-3760; E-mail, [email protected] ing characteristics, mechanisms of action, and bio- http://dx.doi.org/10.3858/emm.2011.43.10.063 logical and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and Accepted 2 August 2011 provides insights into the development of therapeutic Available Online 3 August 2011 antibodies. Abbreviations: ADC, antibody-drug conjugate; ADCC, antibody- dependent cellular cytotoxicity; CD20, cluster of differentiation Keywords: antibodies, monoclonal; antigens, CD20; 20; CDC, complement dependent cytotoxicity; CLL, chronic pharmacology; receptor, epidermal growth factor; re- lymphocytic leukemia; ECD, extracellular domain; EGFR, epi- ceptor, erbB-2; tumor necrosis factor-α dermal growth factor receptor; EpCAM, epithelial cell adhe- sion molecule; FcγR, Fc gamma receptor;
    [Show full text]
  • Hodgkin's Lymphoma Unresponsive to Rituximab Or a Rituximab
    Clinical Development GSK1841157 Protocol OMB110918 / NCT01077518 A Randomized, Open Label Study of Ofatumumab and Bendamustine Combination Therapy Compared with Bendamustine Monotherapy in Indolent B-cell Non- Hodgkin’s Lymphoma Unresponsive to Rituximab or a Rituximab-Containing Regimen During or Within Six Months of Treatment Authors Document type Amended Protocol Version EUDRACT number 2008-004177-17 Version number 11 Development phase III Document status Final Release date 13-Apr-2017 Novartis internal reference number COMB157E2301 Property of Novartis Confidential May not be used, divulged, published, or otherwise disclosed without the consent of Novartis Novartis Confidential Page 2 Amended Protocol Version 11 Clean Protocol No. COMB157E2301/OMB110918 Amendment 9 (13-Apr-2017) Amendment rationale The purpose of amendment 9 is to revise the total number of events required for the primary analysis of the primary end point PFS. The primary analysis was planned after reaching 259 PFS events as determined by an Independent Review Committee (IRC). Based on the current status of the study and PFS event count by IRC, it is highly unlikely that the 259 PFS events will be achieved. The study has been ongoing since September 2010 when the first patient was enrolled and the study sponsorship changed in February 2016 from GSK to Novartis (Amendment 8 , dated 18Mar2016). Per protocol, Interim Analysis for efficacy and futility and IDMC review occurred (22Feb2016) after 180 PFS events by IRC were reached (31Oct2015). IDMC recommended to continue the study without changes. The interim analysis of PFS was performed by an independent Statistical Data Analysis Centre. As per IDMC charter, unblinded results were not communicated to the sponsor in order to maintain the integrity of the trial.
    [Show full text]
  • Antibodies for the Treatment of Brain Metastases, a Dream Or a Reality?
    pharmaceutics Review Antibodies for the Treatment of Brain Metastases, a Dream or a Reality? Marco Cavaco, Diana Gaspar, Miguel ARB Castanho * and Vera Neves * Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal * Correspondence: [email protected] (M.A.R.B.C.); [email protected] (V.N.) Received: 19 November 2019; Accepted: 28 December 2019; Published: 13 January 2020 Abstract: The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.
    [Show full text]
  • Ofatumumab in RMS • BTD for Janssen’S JNJ-61186372 (Amivantamab) • Anthony Pagano Appointed to CFO and Anthony Mancini Appointed to Newly Created Position of COO
    Quarter End Results Period Ended March 31, 2020 Forward Looking Statement This presentation contains forward looking statements. The words “believe”, “expect”, “anticipate”, “intend” and “plan” and similar expressions identify forward looking statements. All statements other than statements of historical facts included in this presentation, including, without limitation, those regarding our financial position, business strategy, plans and objectives of management for future operations (including development plans and objectives relating to our products), are forward looking statements. Such forward looking statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by such forward looking statements. Such forward looking statements are based on numerous assumptions regarding our present and future business strategies and the environment in which we will operate in the future. The important factors that could cause our actual results, performance or achievements to differ materially from those in the forward looking statements include, among others, risks associated with product discovery and development, uncertainties related to the outcome of clinical trials, slower than expected rates of patient recruitment, unforeseen safety issues resulting from the administration of our products in patients, uncertainties related to product manufacturing, the lack of market acceptance of our products, our inability to manage growth, the competitive environment in relation to our business area and markets, our inability to attract and retain suitably qualified personnel, the unenforceability or lack of protection of our patents and proprietary rights, our relationships with affiliated entities, changes and developments in technology which may render our products obsolete, and other factors.
    [Show full text]
  • The Role of Monoclonal Antibodies in the Management of Leukemia
    Pharmaceuticals 2010, 3, 3258-3274; doi:10.3390/ph3103258 OPEN ACCESS pharmaceuticals ISSN 1424-8247 www.mdpi.com/journal/pharmaceuticals Review The Role of Monoclonal Antibodies in the Management of Leukemia Ali Al-Ameri 1, Mohamad Cherry 2, Aref Al-Kali 1 and Alessandra Ferrajoli 1,* 1 Department of Leukemia, the University of Texas MD Anderson Cancer Center, Houston, TX 77005, USA 2 Department of Internal Medicine, Hematology Oncology section, Oklahoma University Health Sciences Center, 700 N.E. 13th Street, Oklahoma City, OK 74103, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-713-792-2063. Received: 20 September 2010 / Accepted: 18 October 2010 / Published: 18 October 2010 Abstract: This article will review the monoclonal antibodies more commonly used in leukemias. In the last three decades, scientists have made considerable progress understanding the structure and the functions of various surface antigens, such as CD20, CD33. The introduction of rituximab, an anti CD20 monoclonal antibody, had a great impact in the treatment of lymphoproliferative disorders. Gemtuzumab, an anti CD 33 conjugated monoclonal antibody has activity in acute mylegenous leukemia (AML). As this field is undergoing a rapid growth, the years will see an increasing use of monoclonal antibodies in hematological malignancies. Keywords: monoclonal Abs; leukemia; CLL; AML; ALL 1. Introduction In 1900, speaking of monoclonal antibodies (MAbs), Paul Ehrlich proposed that “immunizations such as these which are of great theoretic interest may come to be available for clinical application attacking epithelium new formations, particularly carcinoma by means of specific anti-epithelial sera”[1]. Erlich’s dream came true with the first report of the manufacturing of MAb in 1975 by Kohler and Milstein [2,3].
    [Show full text]
  • 2.03.502 Monoclonal Antibodies for the Treatment of Lymphoma
    MEDICAL POLICY – 2.03.502 Monoclonal Antibodies for the Treatment of Lymphoma BCBSA Ref. Policy: 2.03.05 Effective Date: Sept. 1, 2021 RELATED MEDICAL POLICIES: Last Revised: Aug. 3, 2021 5.01.549 Off-Label Use of Drugs and Biologic Agents Replaces: N/A 5.01.550 Pharmacotherapy of Arthropathies 5.01.556 Rituximab: Non-oncologic and Miscellaneous Uses 8.01.533 Radioimmunotherapy in the Treatment of Non-Hodgkin Lymphoma Select a hyperlink below to be directed to that section. POLICY CRITERIA | DOCUMENTATION REQUIREMENTS | CODING RELATED INFORMATION | EVIDENCE REVIEW | REFERENCES | HISTORY ∞ Clicking this icon returns you to the hyperlinks menu above. Introduction An antibody is a blood protein. When the immune system detects an unhealthy cell, antibodies attach themselves to a molecule known as an antigen on that unhealthy cell. The antibody then acts as flag for other immune system cells, causing those other immune system cells to swarm to the area and fight the unhealthy cell. Cancer cells can evade the immune system by reproducing very quickly, avoiding detection, or completely blocking the immune system. Monoclonal antibodies are drugs that work with the body’s natural immune response. Monoclonal antibodies are produced in a laboratory and made to specifically attach to the antigens which are typically found in high numbers on cancer cells. This policy describes when treatment with monoclonal antibodies may be approved to treat lymphoma. Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals.
    [Show full text]
  • Lemtrada (Alemtuzumab)
    UnitedHealthcare® Value & Balance Exchange Medical Benefit Drug Policy Lemtrada (Alemtuzumab) Policy Number: IEXD0023.02 Effective Date: May 1, 2021 Instructions for Use Table of Contents Page Related Policies Applicable States ........................................................................... 1 None Coverage Rationale ....................................................................... 1 Applicable Codes .......................................................................... 2 Background.................................................................................... 2 Benefit Considerations .................................................................. 3 Clinical Evidence ........................................................................... 3 U.S. Food and Drug Administration ............................................. 4 References ..................................................................................... 5 Policy History/Revision Information ............................................. 5 Instructions for Use ....................................................................... 6 Applicable States This Medical Benefit Drug Policy only applies to the states of Arizona, Maryland, North Carolina, Oklahoma, Tennessee, Virginia, and Washington. Coverage Rationale See Benefit Considerations Lemtrada (alemtuzumab) is proven and medically necessary for treatment of relapsing forms of multiple sclerosis when all of the following criteria are met:1 Diagnosis of relapsing forms of multiple sclerosis
    [Show full text]