Showing papers in "BioDrugs in 2011"
TL;DR: Data is reviewed on new anti-CD20 mAbs that are potentially useful in the treatment of lymphoid malignancies and a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs.
Abstract: Over the last few years, new generations of anti-CD20 monoclonal antibodies (mAbs) have been developed for potential benefits over the classical, first-generation mAb rituximab. Compared with rituximab, new mAbs have enhanced antitumor activity resulting from increased complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC) and increased Fc binding affinity for the low-affinity variants of the FcγRIIIa receptor (CD16) on immune effector cells. The second-generation mAbs, which include ofatumumab, veltuzumab, and ocrelizumab, are humanized or fully human to reduce immunogenicity, but with an unmodified Fc region. Ofatumumab is a fully human anti-CD20 IgG1 mAb in clinical development for hematological malignancies and autoimmune diseases. Ofatumumab specifically recognizes an epitope encompassing both the small and large extracellular loops of CD20 molecule, and is more effective than rituximab at CDC induction and killing target cells. Veltuzumab (IMMU-106, hA20) is a humanized anti-CD20 mAb with complementarity-determining regions similar to rituximab. This antibody has enhanced binding avidities and a stronger effect on CDC compared with rituximab. Ocrelizumab is a humanized mAb with the potential for enhanced efficacy in lymphoid malignancies compared with rituximab due to increased binding affinity for the low-affinity variants of the FcγRIIIa receptor. The third-generation mAbs are also humanized mAbs, but in addition they have an engineered Fc to increase their binding affinity for the FcγRIIIa receptor. The third-generation mAbs include AME-133v, PRO131921 and GA-101. AME-133v (LY2469298) is a type I, humanized IgG1 mAb with enhanced affinity for FcγRIIIa receptor and an enhanced ADCC activity compared with rituximab. PRO131921 is a humanized anti-CD20 mAb engineered to have improved binding to FcγRIIIa and better ADCC compared with rituximab. GA-101 (RO5072759) is a fully humanized, type II, IgG1 mAb derived from humanization of the parental B-Ly1 mouse antibody and subsequent glycoengineering using GlycoMab® technology. GA-101 was designed for enhanced ADCC and superior direct cell-killing properties, in comparison with currently available type I antibodies. TRU-015 is a small modular immunopharmaceutical (SMIP) derived from key domains of an anti-CD20 antibody. TRU-015 represents a novel biological compound that retains Fc-mediated effector functions and is smaller than mAbs. In this article we review data on new anti-CD20 mAbs that are potentially useful in the treatment of lymphoid malignancies.
111 citations
TL;DR: How the results of GlaxoSmithKline’s clinical studies on immunogenicity, protection, and reactogenicity with the AS04-adjuvanted HPV vaccine are supported by the observed mechanism of action for the adjuvant is discussed.
Abstract: A novel human papillomavirus (HPV) vaccine has been formulated with virus-like particles of the L1 protein of HPV-16 and HPV-18, and the Adjuvant System 04 (AS04). AS04 is a combination of the toll-like receptor 4 agonist monophosphoryl lipid A (MPL) and aluminum hydroxide. The AS04-adjuvanted HPV vaccine induces a high and sustained immune response against HPV, including high levels of neutralizing antibodies at the cervical mucosa in women aged 15–55 years. Recently, the mechanism of action of AS04 has been evaluated in vitro in human cells and in vivo in mice and the data provide evidence for the molecular and cellular basis of the observed immunogenicity, efficacy, and safety profile of this formulation.
97 citations
TL;DR: Treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general, and it has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure.
Abstract: Bevacizumab, a recombinant humanized monoclonal antibody targeting the vascular endothelial growth factor (VEGF), has been approved in the US as first- and second-line treatment of colorectal cancer and in the first-line treatment of advanced non-small cell lung cancer. The US FDA has also granted approval for the use of bevacizumab for the treatment of patients with metastatic renal cell carcinoma and glioblastoma, and in Europe, it is also approved in metastatic breast cancer in combination with paclitaxel. Bevacizumab is under investigation in the first-line and adjuvant setting of almost all types of solid tumors. However, anti-VEGF therapy is associated with significant toxicity. The incidence of grade 3-4 hypertension differs among the various malignancies in which bevacizumab is administered, possibly because of drug interactions with co-administered chemotherapy drugs. Hypertension appears to be dose dependent, and it is under investigation as a biomarker for VEGF inhibition efficacy. There are three main theories concerning the underlying pathophysiology: (i) the nitric oxide theory; (ii) the renal impairment theory; and (iii) the pre-eclampsia-like theory. The correct evaluation of the levels of hypertension is of critical importance and home blood pressure monitoring seems to be the most effective technique. A baseline assessment and follow-up monitoring of blood pressure is considered necessary for all patients receiving bevacizumab. There are no evidence-based recommendations regarding which antihypertensives are more appropriate for the management of bevacizumab-related hypertension. It has been suggested that the benefits from antihypertensive treatment are largely independent of the drugs used, as long as they adequately lower blood pressure. Randomized prospective studies are necessary to provide data that will be useful for the development of specific guidelines for the management of bevacizumab-related hypertension. In the meantime, treatment of anti-VEGF-induced hypertension should follow current guidelines for diagnosis and management of hypertension in general.
88 citations
TL;DR: The rationale behind the shift from conventional to current treatment options is described and investigational, most notably biopharmaceutical, drugs that are in clinical trials are discussed, specifically regarding their delivery.
Abstract: Age-related macular degeneration (AMD) is a condition that may cause blindness. The prevalence of the disease in the Western world is estimated at 1–2% of the population. Over the past decade, treatment of neovascular AMD has been shifting from destruction of newly formed blood vessels towards inhibitors that silence the vascular endothelial growth factor (VEGF) pathway. Such agents are often first-in-class biopharmaceuticals that benefit from the fact that they can be locally administered in an immune-privileged environment with slow clearance. These new VEGF pathway inhibitors have improved therapeutic effects over conventional treatment and have promoted the identification of novel targets for inhibition of AMD angiogenesis. This review describes the rationale behind the shift from conventional to current treatment options and discusses investigational, most notably biopharmaceutical, drugs that are in clinical trials. It also provides possible points for improvement of these treatments, specifically regarding their delivery.
72 citations
TL;DR: The present review focuses on the recent progress in the development of ‘Fc engineering,’ which dramatically improves (and sometimes silences) Fc-mediated functions.
Abstract: Since the establishment of monoclonal antibody production using hybridoma technology in the mid-1970s, there has been expanding progress and continuous technological improvement in the development of therapeutic antibodies. The initial technological breakthroughs involved reduction of immunogenicity and thus enabled repeated administration. The establishment of chimeric, humanized, and fully human antibodies has led to the great success of several ‘second-generation’ therapeutic antibodies, such as rituximab, trastuzumab, cetuximab, and bevacizumab. However, there still exists an urgent demand for improvement in the efficacy of the current antibody therapeutics, which is not yet fully satisfactory for patients. Based on the current understanding of the clinical mechanisms of several therapeutic antibodies, many now believe that Fc-mediated functions (e.g. antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and neonatal Fc receptor [FcRn]-mediated storage) will improve the clinical outcomes of therapeutic antibodies. The present review focuses on the recent progress in the development of ‘Fc engineering,’ which dramatically improves (and sometimes silences) Fc-mediated functions. These achievements can be classified into two technological approaches: (i) introducing amino acid mutations and (ii) modifying Fc-linked oligosaccharide structures. The effectiveness of multiple third-generation therapeutic antibodies armed with various engineered Fcs is now ready to be tested in clinical trials.
68 citations
TL;DR: Tacrolimus (FK506) has been used successfully as a systemic immunomodulator for more than 2 decades, and numerous studies have investigated its mechanisms of action.
Abstract: Tacrolimus (FK506) has been used successfully as a systemic immunomodulator for more than 2 decades, and numerous studies have investigated its mechanisms of action. Systemic and topical tacrolimus have been investigated as treatments for ocular surface disorders that may have an immune-based inflammatory component. In these studies, tacrolimus has shown efficacy in corneal graft rejection, inflammatory conjunctival and corneal diseases, uveitis, and graft-versus-host disease. As these disorders are often refractory to other available treatments, ophthalmic or systemic tacrolimus is a welcome nontoxic adjunct or replacement to potentially toxic topical or systemic immunosuppressive therapies.
64 citations
TL;DR: GPC3 and mesothelin are attractive candidates for liver cancer therapy given that they show high expression in HCC and CCA, respectively, and fully human monoclonal antibodies against these antigens have been isolated by antibody phage display technology.
Abstract: Liver cancer is one of the most common malignancies worldwide. Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common primary liver cancers, yet there have been no significant advances in effective therapeutics. There is an urgent need to identify molecular targets for the development of novel therapeutic approaches. In this review, glypican-3 (GPC3) and mesothelin are discussed, with a focus on their potential as targets for antibody therapy in liver cancer. GPC3 and mesothelin are glycosylphosphatidylinositol-anchored proteins present on the cell surface. They are attractive candidates for liver cancer therapy given that GPC3 and mesothelin show high expression in HCC and CCA, respectively. Antibody drugs targeting GPC3 or mesothelin have shown anti-cancer activity in mice. Humanized or chimeric IgG molecules based on first-generation murine monoclonal antibodies against these antigens are being evaluated in clinical studies. Recently, fully human monoclonal antibodies against GPC3 and mesothelin have been isolated by antibody phage display technology that may provide opportunities for novel cancer therapy.
55 citations
TL;DR: This review focuses on arming T cells with BiAbs to create the ‘poor man’s cytotoxic lymphocyte’.
Abstract: Bispecific antibodies (BiAbs) offer a unique opportunity to redirect immune effector cells to kill cancer cells. BiAbs combine the benefits of different binding specificities of two monoclonal antibodies (mAbs) into a single construct. This unique feature of BiAbs enables approaches that are not possible with single mAbs. Advances in antibody engineering and antigen profiling of malignant cells have led to the development of a number of BiAb formats and their combinations for redirecting effector cells to tumor targets. There have been significant advances in the design and application of BiAbs for intravenous and local injection.The initial barrier of cytokine storm has been partially overcome by more recent constructs that have improved clinical effectiveness without dose-limiting toxicities. Since the recent revival of BiAbs, there has been multiple, ongoing, phase I/II and III trials, and some promising clinical outcomes have been reported in completed clinical studies. This review focuses on arming T cells with BiAbs to create the 'poor man's cytotoxic lymphocyte'.
44 citations
TL;DR: A review of gene therapy for CF lung disease can be found in this article, where the authors discuss recent developments with viral and non-viral vectors and cell therapy, and provide an update on clinical gene therapy studies.
Abstract: Although the development of gene therapy for cystic fibrosis (CF) was high priority for many groups in academia and industry in the first 10-15 years after cloning the cystic fibrosis transmembrane conductance regulator (CFTR) gene, more recently active research into CF gene therapy is only being performed by a small number of committed groups. However, despite the waning enthusiasm, which is largely due to the realization that gene transfer into lungs is more difficult than originally thought, and the fact that meaningful clinical trials are expensive and difficult to perform, gene therapy continues to hold promise for the treatment of CF lung disease. Problems related to repeat administration of adenovirus and adeno-associated virus-based vectors led to a focus on non-viral vectors in clinical trials. However, the recent evidence that lentiviral vectors may be able to evade the immune system and, thereby, allow for repeat administration and long-lasting expression opens new doors for the use of viral vectors in the context of CF gene therapy. In addition, early pre-clinical studies have recently been initiated to address cell therapy-based approaches for CF. In this review, we discuss recent developments with viral and non-viral vectors and cell therapy, and provide an update on clinical gene therapy studies.
43 citations
TL;DR: Experimental data show that both phages and lysins could be effective in the treatment of MRSA, one of today’s most dangerous pathogens.
Abstract: Bacteriophages (phages) are viruses that specifically infect and kill bacteria. Lysins are enzymes of bacteriophage origin that cleave covalent bonds in peptidoglycan, thereby inducing rapid lysis of a bacterial cell. As potential antibacterial agents, phages and lysins have some important features in common, especially the capacity to kill antibiotic-resistant bacteria, a narrow antibacterial range, and lack of toxic effects on mammalian cells. In this article we present the staphylococcal phages and their lysins that can be used to combat methicillin-resistant Staphylococcus aureus (MRSA), one of today's most dangerous pathogens. We also discuss the use of phages as vectors specifically delivering different antibacterial agents to bacterial cells. Experimental data show that both phages and lysins could be effective in the treatment of MRSA.
33 citations
TL;DR: Overall, recent advances in experimental vaccines and in vaccine production processes provide the potential to lower mortality and morbidity resulting from influenza infection.
Abstract: The emergence and spread of highly pathogenic avian influenza (H5N1) viruses among poultry in Asia, the Middle East, and Africa have fueled concerns of a possible human pandemic, and spurred efforts towards developing vaccines against H5N1 influenza viruses, as well as improving vaccine production methods In recent years, promising experimental reverse genetics-derived H5N1 live attenuated vaccines have been generated and characterized, including vaccines that are attenuated through temperature-sensitive mutation, modulation of the interferon antagonist protein, or disruption of the M2 protein Live attenuated influenza virus vaccines based on each of these modalities have conferred protection against homologous and heterologous challenge in animal models of influenza virus infection Alternative vaccine strategies that do not require the use of live virus, such as virus-like particle (VLP) and DNA-based vaccines, have also been vigorously pursued in recent years Studies have demonstrated that influenza VLP vaccination can confer homologous and heterologous protection from lethal challenge in a mouse model of infection There have also been improvements in the formulation and production of vaccines following concerns over the threat of H5N1 influenza viruses The use of novel substrates for the growth of vaccine virus stocks has been intensively researched in recent years, and several candidate cell culture-based systems for vaccine amplification have emerged, including production systems based on Madin-Darby canine kidney, Vero, and PerC6 cell lines Such systems promise increased scalability of product, and reduced reliance on embryonated chicken eggs as a growth substrate Studies into the use of adjuvants have shown that oil-in-water-based adjuvants can improve the immunogenicity of inactivated influenza vaccines and conserve antigen in such formulations Finally, efforts to develop more broadly cross-protective immunization strategies through the inclusion of conserved influenza virus antigens in vaccines have led to experimental vaccines based on the influenza hemagglutinin (HA) stem domain Such vaccines have been shown to confer protection from lethal challenge in mouse models of influenza virus infection Through further development, vaccines based on the HA stem have the potential to protect vaccinated individuals against unanticipated pandemic and epidemic influenza virus strains Overall, recent advances in experimental vaccines and in vaccine production processes provide the potential to lower mortality and morbidity resulting from influenza infection
TL;DR: A growing body of evidence appears to indicate that overexpression of HER2 in gastric cancer is also correlated with poor carcinoma-specific survival, and improvements in patient survival are encouraging.
Abstract: Withmore than 900 000 new cases annually, gastric cancer is the fourth most prevalent cancer worldwide and, with 700 000 deaths annually, it is the second most common cause of cancerrelated death. There is a large geographical variation in its incidence (almost two-thirds of cases occur in developing countries) and 5-year survival rates (27% in Western Europe vs 6% in sub-Saharan Africa). Typically, up to 80% of patients present with advanced disease and the majority of these are elderly (aged >65 years). Patients with advanced gastric cancer have a poor prognosis, with median survival times ranging from 6 to 9 months. For patients with early stages of gastric cancer, surgical resection is the primary curative treatment option even though 5-year survival rates are relatively low (typically <50% for stage II disease). Curative resection in patients with advanced disease is unlikely, although preoperative therapy does enable downsizing of the tumormass. However, significant advances in the treatment of gastric cancer have been made following the introduction of perioperative chemotherapy as an adjuvant treatment for patients undergoing curative resection. Optimization of chemotherapy regimens for the treatment of gastric cancer is ongoing; consequently, no one agent or combination regimen has been accepted as standard therapy. However, the combination of cisplatin with fluorouracil or capecitabine appears to be one of the more active two-drug regimens, with response rates of approximately 30–40% and median overall survival times of approximately 10 months. Although these improvements in patient survival are encouraging, there is clearly a need for therapeutic regimens of more durable efficacy. Targeted therapies that are directed to signaling pathways that play a key role in deregulated tumor cell proliferation are increasingly recognized as an effective addition to the range of pharmacotherapies for treating cancer. Overexpression of human epidermal growth factor receptor 2 (HER2) as a result of amplification of the HER2 gene (ERBB2; also known as HER2/neu) appears to mediate the initiation, progression, and metastasis of many types of cancer. Approximately 20–30% of primary breast cancers areHER2-positive and this is associated with a more aggressive form of the disease and a poorer prognosis for the patient. A wider variation in the overexpression of HER2 has been reported in gastric cancer (9–38%), possibly as result of smaller sample sizes, greater histologic variation of gastric tissue and differences in immunohistochemistry (IHC) scoring technique. Nevertheless, a growing body of evidence appears to indicate that overexpression of HER2 in gastric cancer is also correlated with poor carcinoma-specific survival. Trastuzumab (Herceptin ), a recombinant humanized IgG1 monoclonal antibody directed against the extracellular domain of HER2, is a well established adjuvant to chemotherapy that has demonstrated survival benefits for patients with early and metastatic HER2-positive breast cancer. In the EU and the US, trastuzumab, in combination with cisplatin and either capecitabine or fluorouracil, has recently received approval for the treatment of HER2-positive (IHC 2+ and fluorescence in situ hybridization [FISH]or silver-enhanced in situ hybridization [SISH]-positive or IHC 3+) metastatic adenocarcinoma of the stomach or oesophagogastric junction in patients without prior anti-cancer treatment for metastatic disease. The features and properties of trastuzumab in patients with HER2-positive metastatic gastric cancer are presented in table I. HER2-positive expression (defined as IHC 3+ or FISHpositive) was observed in 22.1% of almost 4000 metastatic gastric cancers in patients who were screened for randomization in the
TL;DR: The evidence for miRNA regulation of inflammation, angiogenesis, fibroblast function, keratinocyte function, and apoptosis, which are essential components for effective wound repair are reviewed.
Abstract: A group of small non-coding RNA molecules, termed microRNAs (miRNAs), have generated considerable interest in recent years due to their central role in a growing number of biologic processes. Serving as post-transcriptional regulators of gene expression, miRNAs have also emerged as critical factors in the pathogenesis of many diseases. As a result, they show great potential as accurate diagnostic and prognostic markers, as well as viable therapeutic targets for treating disease. It has been proposed that miRNAs play a significant role in cutaneous wound repair and that aberrant miRNA expression may result in disorganized or poor healing. Specific patterns of miRNA expression have been identified in wound healing models. miRNAs are important regulators of leucocyte function and the cytokine network, and are necessary for endothelial cell migration and capillary formation. These molecules also control proliferation and differentiation of wound-specific cells and can determine extracellular matrix composition. This article reviews the evidence for miRNA regulation of inflammation, angiogenesis, fibroblast function, keratinocyte function, and apoptosis, which are essential components for effective wound repair. The future potential for improving wound healing outcomes using miRNA-based therapies is also discussed.
TL;DR: Sipuleucel-T: Current Status.
Abstract: Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days.
TL;DR: The quadrivalent HPV vaccine offers an effective means, in combination with screening programs, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts.
Abstract: Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil®; Silgard®) is composed of virus-like particles (VLPs) formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16, and 18. The VLPs are noninfectious, containing no DNA, and are highly immunogenic, inducing high levels of neutralizing antibodies against the particular HPV types when administered to animals or humans. Quadrivalent HPV vaccine is indicated for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar, and vaginal), cervical cancer, and external genital warts (condyloma acuminata) causally related to certain oncogenic or specific HPV types. In placebo-controlled clinical trials, quadrivalent HPV vaccine administered as three doses over 6 months provided high-level protection against infection or disease caused by the vaccine HPV types over 2-4 years of follow-up in females aged 15-45 years who were naive to the vaccine HPV types. A degree of cross-protection against certain other non-vaccine high-risk HPV types was also observed. The vaccine is not effective against current infection with a vaccine HPV type. Girls or women with current infection with one or more of the vaccine HPV types gained protection from infection or disease caused by the remaining vaccine HPV types and they were also protected against reinfection with the same HPV type after clearance of an infection caused by a vaccine HPV type. High seroconversion rates and high levels of anti-HPV antibodies were observed in all vaccinated individuals of all age ranges from 9 to 45 years. No correlation was found between antibody levels and protective efficacy of the vaccine. Rechallenge with quadrivalent HPV vaccine produced a potent anamnestic humoral immune response. The vaccine is generally well tolerated and is projected to be cost effective in most pharmacoeconomic models. Therefore, quadrivalent HPV vaccine offers an effective means, in combination with screening programs, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts.
TL;DR: A shorter duration of illness and a lower age at the start of treatment were significantly associated with a greater productivity gain after 50 weeks of treatment with natalizumab, which indicates that it is more beneficial to initiate efficient therapy early in patients with MS.
Abstract: Background: Sweden is a high endemic region for multiple sclerosis (MS), a neurologic disorder characterized by repeated inflammatory episodes affecting the CNS The disease has its peak age of ons
TL;DR: A single subcutaneous injection of corifollitropin alfa provides sustained multifollicular stimulation for up to a week in women undergoing controlled ovarian stimulation and provides a well tolerated and more convenient treatment option to induce multiple follicular growth prior to assisted reproduction.
Abstract: Corifollitropin alfa (Elonva®) is a fusion product of human follicle-stimulating hormone (FSH) and the C-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) produced by recombinant DNA technology. It has the same pharmacologic activity as FSH and recombinant FSH (rFSH; follitropin alfa; follitropin beta), but with a slower absorption and a longer half-life. Corifollitropin alfa is indicated as a multifollicular stimulant for women undergoing controlled ovarian stimulation using gonadotropin-releasing hormone (GnRH) antagonist-assisted reproduction protocols. In two large, randomized, double-blind, phase III trials, a single subcutaneous injection of corifollitropin alfa was no less effective as a multifollicular stimulant than seven once-daily injections of rFSH when used as part of a GnRH antagonist-assisted controlled ovarian stimulation cycle. With regard to primary endpoints, the mean number of retrieved oocytes per started cycle demonstrated that the two treatments were equivalent, and the ongoing pregnancy rate in recipients of corifollitropin alfa was noninferior to that in recipients of rFSH. The median duration of stimulation with FSH was 9 days in both treatment arms of both trials, which means that, on average, recipients of corifollitropin alfa required only 2 further days of stimulation with rFSH prior to triggering oocyte maturation with the administration of hCG. Fertilization rates were high, ranging from 66% to 68%, in recipients of corifollitropin alfa or rFSH in both trials. When used as part of a GnRH antagonist-assisted reproduction protocol, corifollitropin alfa was generally well tolerated, with a tolerability profile similar to that of rFSH. In large, pooled analyses of clinical trials, the incidence of ovarian hyperstimulation syndrome in both the corifollitropin alfa and rFSH treatment arms was consistent with that expected in the relatively young patient population. Furthermore, there were no clinically relevant differences in pregnancy complications and the incidence of infant adverse events between treatment arms. In conclusion, a single subcutaneous injection of corifollitropin alfa provides sustained multifollicular stimulation for up to a week in women undergoing controlled ovarian stimulation. Compared with seven once-daily injections of rFSH, a single injection of corifollitropin alfa achieves equivalent efficacy, and provides a well tolerated and more convenient treatment option to induce multiple follicular growth prior to assisted reproduction.
TL;DR: This review focuses on the current limitations of existing demethylating agents and highlights possible approaches using recent developments in drug delivery systems to improve the clinical potential of these drugs.
Abstract: DNA methylation, which often occurs at the cytosine residue of cytosine-guanine dinucleotides, is critical for the control of gene expression and mitotic inheritance in eukaryotes. DNA methylation silences gene expression either by directly hindering the access of transcription factors to the target DNA, or through recruitment of histone deacetylases to remodel the chromatin structure to an inactive state. Aberrant hypermethylation of tumor suppressor genes is commonly associated with the development of cancer. A number of anti-cancer agents have been developed that function through demethylation, reversing regional hypermethylation to restore the expression of tumor suppressor genes. Azacitidine and decitabine are used in the clinic, but their applications are limited to myelodysplastic syndrome and other blood-related diseases. Despite the potency of these drugs, their broader clinical application is restricted by cytotoxicity, nonspecific targeting, structural instability, catabolism, and poor bioavailability. Further improvements in the delivery systems for these drugs could overcome the issues associated with inefficient bioavailability, whilst facilitating the administration of combinations of demethylating agents and histone deacetylase inhibitors to enhance efficacy. This review focuses on the current limitations of existing demethylating agents and highlights possible approaches using recent developments in drug delivery systems to improve the clinical potential of these drugs.
TL;DR: This review discusses gene therapeutic approaches that have been attempted for patients with RA, and novel strategies that are in development for delivery into patients, and analyzes the advantages and disadvantages of the various approaches.
Abstract: Rheumatoid arthritis (RA) was one of the earliest targets for gene therapy. Since the first clinical trial involving gene therapy in RA was initiated in 1996, eight clinical trials have been conducted assessing gene therapy in RA. Gene therapy has benefited from advances in biologics in terms of the increasing choice of novel, efficient targets to treat RA and also from the optimization of the delivery systems. Several strategies are possible; one of particular interest is local gene therapy directed to rheumatic joints, which avoids systemic vector diffusion. In this review, we discuss (i) gene therapeutic approaches that have been attempted for patients with RA, and (ii) novel strategies that are in development for delivery into patients. We analyze the advantages and disadvantages of the various approaches and how best to optimize them with regard to choosing the most promising vectors and strategies to allow for efficient, long-term, safe delivery of gene therapy in RA.
TL;DR: The AS04-adjuvanted HPV 16/18 vaccine prevents cervical disease associated with certain oncogenic HPV types, thereby reducing the burden of premalignant cervical lesions and, very likely, cervical cancer.
Abstract: The AS04-adjuvanted human papillomavirus (HPV) 16/18 vaccine (Cervarix®) is a noninfectious recombinant vaccine produced using purified virus-like particles (VLPs) that induce a strong immunogenic response eliciting high levels of anti-L1 VLP antibodies that persist at levels markedly greater than those observed with natural infection. The vaccine adjuvant (AS04) is composed of monophosphoryl-lipid A, which enhances cellular and humoral immune response, adsorbed to aluminum hydroxide. The vaccine is indicated for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in females aged ≥10 years.
TL;DR: In conclusion, rituximab remains a valuable therapy in patients with CLL, low-grade or follicular lymphoma, and diffuse large B-cell lymphoma and, in a variety of treatment settings, represents the standard of care.
Abstract: Rituximab (MabThera®, Rituxan®) is a chimeric mouse anti-human CD20 monoclonal antibody. This article reviews the use of intravenous rituximab in the treatment of chronic lymphocytic leukemia (CLL), low-grade or follicular lymphoma, and diffuse large B-cell lymphoma. The addition of rituximab to fludarabine plus cyclophosphamide significantly prolonged progression-free survival both in previously untreated patients with CLL and in those with relapsed or refractory CLL, according to the results of two randomized, open-label, multicenter trials. In patients with previously untreated advanced follicular lymphoma, the addition of rituximab to chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]; cyclophosphamide, vincristine, and prednisone [CVP]; mitoxantrone, chlorambucil, and prednisolone; or cyclophosphamide, doxorubicin, etoposide, and prednisolone) was generally associated with better outcomes than chemotherapy alone in randomized, multicenter trials. In a similarly designed trial, progression-free survival was significantly longer in previously untreated patients with follicular lymphoma, other indolent lymphomas, or mantle-cell lymphoma who received rituximab plus bendamustine than in those receiving rituximab plus CHOP. Monotherapy with rituximab also demonstrated efficacy in patients with relapsed or refractory low-grade or follicular lymphoma, according to the results of noncomparative trials. In terms of maintenance therapy, progression-free survival was significantly prolonged with rituximab maintenance therapy versus observation alone in patients with advanced indolent lymphoma who had not progressed following first-line therapy with CVP and in patients with relapsed or refractory follicular lymphoma who had responded to CHOP (with or without rituximab), according to the results of randomized, open-label, multicenter trials. In four randomized, open-label, multicenter trials in younger or elderly patients with previously untreated diffuse large B-cell lymphoma, event-free survival, failure-free survival, progression-free survival, and overall survival were generally improved to a significant extent by the addition of rituximab to CHOP or CHOP-like chemotherapy. Intravenous rituximab was generally well tolerated in patients with CLL, low-grade or follicular lymphoma, or diffuse large B-cell lymphoma, both as monotherapy and when administered in combination with chemotherapy. Infusion reactions were one of the most commonly occurring adverse events in patients receiving intravenous rituximab. The results of pharmacoeconomic modeling analyses demonstrated that rituximab appears to be cost effective in patients with previously untreated follicular lymphoma, in patients with follicular lymphoma receiving rituximab maintenance therapy following treatment for relapsed or refractory disease, and in patients with previously untreated diffuse large B-cell lymphoma. In conclusion, rituximab remains a valuable therapy in patients with CLL, low-grade or follicular lymphoma, and diffuse large B-cell lymphoma and, in a variety of treatment settings, represents the standard of care.
TL;DR: Therapeutic Efficacy, Dosage and Administration, Ecallantide: Current Status, and Tolerability.
Abstract: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1423 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1425 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1426 4. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1429 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430 6. Ecallantide: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1430
TL;DR: These antibodies bind to different targets using a single antigen-combining site while maintaining high affinity and specificity, thus challenging the ‘one antibody, one antigen’ dogma.
Abstract: Antibodies capable of targeting more than one antigen are envisioned to expand therapeutic efficacy in complex disease settings. Several strategies have been developed to achieve multiple targeting, including antibody mixtures and bispecific formats. In recent years, several dual- and pan-specific antibodies have been described and represent an alternative approach. These antibodies bind to different targets using a single antigen-combining site while maintaining high affinity and specificity, thus challenging the 'one antibody, one antigen' dogma. Despite certain drawbacks, the simple IgG format of this drug class enables rapid progression into the clinic.
TL;DR: Results of a phase III trial in newly diagnosed patients demonstrated that dasatinib 100 mg od has superiority in terms of confirmed cytogenetic and molecular responses, with faster responses and high activity in high Sokal risk patients compared with standard-dose imatinib.
Abstract: Dasatinib is an oral dual tyrosine kinase inhibitor active against ABL1 and SRC family kinases. The US FDA approved it for the treatment of chronic myeloid leukemia (CML) patients in chronic, accelerated, or blastic phase with resistance or intolerance to imatinib therapy. Dasatinib is also indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia who have become resistant to or intolerant of other treatments. The agent is now also approved for newly diagnosed chronic phase (CP) patients. This article reviews the pharmacokinetic and pharmacodynamic properties of dasatinib as well as clinical data limited to CP-CML patients. Four-year follow-up of a phase III dose-optimization trial confirmed that better progression-free survival (66%) and overall survival (82%) were obtained with a dose of 100 mg once daily (od) than with the standard 70 mg twice daily dosing (65% and 75%, respectively). The 100 mg od dosing schedule was also associated with the highest benefit-risk ratio for CP patients with resistant, intolerant, or suboptimal response. Recent results of a phase III trial in newly diagnosed patients demonstrated that dasatinib 100 mg od has superiority in terms of confirmed cytogenetic and molecular responses, with faster responses and high activity in high Sokal risk patients compared with standard-dose imatinib.
TL;DR: Biosimilars in the US are not likely to lead to aggressive pricing, but will more likely mirror current situations where several similar biologics are available, dampen the already soft outlook for biosimilars.
Abstract: In March 2010, the US passed the healthcare reform bill, including The Biologics Price Competition and Innovation Act of 2009, which established an abbreviated Biologic License Application (aBLA) pathway for the approval of biosimilars.
TL;DR: Recent advances in the development of novel therapeutic approaches to PAC are discussed, focusing in particular on recent developments in immune and vaccine therapy.
Abstract: The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential FOLFIRINOX (5-fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy The success of immune therapy with the anti-cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy
TL;DR: Intravenous crotalidae polyvalent immune Fab was generally well tolerated; acute hypersensitivity reactions were the most commonly occurring adverse event.
Abstract: Crotalidae polyvalent immune Fab is an antivenom comprising purified, sheep-derived, Fab IgG fragments and is indicated for use in patients with North American crotaline envenomation. Crotalidae polyvalent immune Fab is produced using four North American snake venoms: Crotalus atrox, Crotalus adamanteus, Crotalus scutulatus, and Agkistrodon piscivorus. Intravenous crotalidae polyvalent immune Fab was effective in patients aged ≥10 years who had minimal or moderate envenomation by a North American crotaline, who presented within 6 hours of the snakebite, and who had progression of the envenomation syndrome, according to the results of two prospective trials. One trial was a noncomparative, multicenter pilot study and the other trial was a randomized, open-label, multicenter trial in which patients received scheduled or 'as needed' administration of crotalidae polyvalent immune Fab after initial control had been achieved. A prospective, postmarketing trial demonstrated the efficacy of crotalidae polyvalent immune Fab in confirmed Crotalus viridis helleri envenomation (indicating cross-protection against a venom not used in its production). Results of these prospective trials are supported by the findings of additional (mainly retrospective) studies demonstrating the efficacy of crotalidae polyvalent immune Fab in patients with crotaline envenomation, including patients with severe envenomation, pediatric patients, and patients with symptoms of neurotoxicity. Despite treatment with crotalidae polyvalent immune Fab, patients may experience delayed-onset or recurrent venom effects (e.g. coagulopathy). Intravenous crotalidae polyvalent immune Fab was generally well tolerated; acute hypersensitivity reactions (e.g. urticaria, rash, pruritus) were the most commonly occurring adverse event.
TL;DR: Open-label intravenous C1-INH NF concentrate 1000 U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE.
Abstract: Intravenous nanofiltered human C1 inhibitor (C1-INH NF) concentrate (Cinryze®) is used as a direct replacement of deficient levels of plasma C1 inhibitor in patients with hereditary angioedema (HAE). In the EU, C1-INH NF concentrate 1000 U is indicated in the treatment, pre-procedural prevention, and routine prevention of angioedema attacks in adults and adolescents with HAE. Intravenous C1-INH NF concentrate 1000 U effectively relieved angioedema attacks in patients with HAE. In a randomized, double-blind trial in pediatric and adult patients, the median time to onset of unequivocal relief from an attack was significantly shorter with C1-INH NF concentrate than with placebo. In an open-label trial, both unequivocal relief and clinical relief were shown in the majority of attacks within 1 and 4 hours of infusion of C1-INH NF concentrate, regardless of the site (i.e. gastrointestinal, cutaneous, laryngeal, or genitourinary) of the defining symptom. When administered prior to a procedure, open-label intravenous C1-INH NF concentrate 1000 U reduced the incidence of angioedema attacks during and after a variety of dental, surgical, or interventional diagnostic procedures in pediatric and adult patients with HAE. Routine preventative treatment with intravenous C1-INH NF concentrate 1000 U every 3 or 4 days reduced the number of angioedema attacks. In a randomized, double-blind, crossover trial in pediatric and adult patients with HAE, the mean normalized number of attacks per 12-week period was significantly lower during routine prevention with C1-INH NF concentrate than with placebo. Routine prevention with C1-INH NF concentrate reduced the median monthly attack rate from baseline in an open-label trial. Intravenous C1-INH NF concentrate was well tolerated in clinical trials in patients with HAE. No cases of viral transmission were reported.
TL;DR: Temsirolimus: Current Status in Relapsed and/or Refractory Mantle Cell Lymphoma and Dosage and Administration.
Abstract: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1819 1. Pharmacological Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1820 2. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1822 3. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1826 4. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827 5. Temsirolimus: Current Status in Relapsed and/or Refractory Mantle Cell Lymphoma . . . . . . . . . . . . . 1828
TL;DR: Although the phase II safety data for ramucirumab appear better than the data for necitumumab, fewer phase III data are available, its phase II results are the most robust.
Abstract: Joining cetuximab, sorafenib, afatinib, intedanib, and crizotinib in phase III development for non-small cell lung cancer (NSCLC) are ramucirumab (developed by ImClone, a subsidiary of Lilly), necitumumab (developed by ImClone and Bristol-Myers Squibb), and tivantinib (ARQ 197, developed by ArQule and Daiichi Sankyo). Necitumumab is a second-generation anti-EGFR monoclonal antibody (mAb) similar to cetuximab. Enrollment has been stopped in one of two necitumumab phase III trials because of safety concerns. Ramucirumab is an anti-VEGFR2 mAb targeting the same pathway as bevacizumab. Although the phase II safety data for ramucirumab appear better than the data for necitumumab, fewer phase III data are available. Tivantinib is a highly selective, orally available MET tyrosine kinase inhibitor. MET is overexpressed in 61% of NSCLC cases. Although tivantinib is the last of the three agents discussed here to enter phase III, its phase II results are the most robust.