Haemoglobin-based oxygen carriers

Haemoglobin-based oxygen carriers are being developed for use in blood replacement therapies, either for perioperative haemodilution or for resuscitation from haemorrhagic blood loss. There is a high demand for these products because of risks associated with blood transfusions and pending worldwide blood shortages. Development of these products has required new technologies in protein engineering; since the haemoglobin is cell-free in solution, the molecule must be modified to be retained within blood circulation. Three classes of haemoglobin are under development: intramolecular cross-linked, intermolecular polymerised and surface conjugated with polyethylene glycol. Two products based on cross-linking chemistry have been discontinued because of serious adverse events and/or increased mortality rate in Phase III clinical trials. Three products based on polymerisation chemistry are in ongoing Phase III clinical trials. A new product based on surface conjugation is in preclinical evaluation. Although cross-linked and polymerised products have shown to be safe in preclinical and early Phase I/II clinical trials, they have had difficulty in proving efficacy. The primary adverse effect for the majority of cross-linked or polymerised products is a haemodynamic response, leading to increased vascular resistance to blood flow. The physiological mechanisms are still incompletely understood, so that safety and efficacy cannot be completely dissociated. New understandings on the mode of action of these products will help to define their utility and application. New products are under development, designed specifically to maximise blood flow and tissue perfusion and therefore, oxygenation.     

Vinflunine: drug safety evaluation of this novel synthetic vinca alkaloid

INTRODUCTION: Vinca alkaloid agents have been widely used in several different types of malignancies. However, cancer cells, ultimately, develop resistance to these agents. Therefore, the development of new agents with improved efficacy is warranted. Recently, a new synthetic vinca alkaloid, vinflunine, was developed through the addition of two fluor molecules by superacidic chemistry. AREAS COVERED: The authors describe the development of the new vinca alkaloid vinflunine from preclinical studies to the late-stage clinical trials, highlighting the most important clinical and safety data of vinflunine. In vitro and in vivo studies have shown a superior efficacy of vinflunine over other vinca alkaloids and with an improved safety profile. Early clinical trials have demonstrated a significant activity of vinflunine against different malignancies. Phase III trials showed that vinflunine increases survival in patients with advanced transitional cell carcinoma of the urothelium (TCCU) tract treated in the second-line and is as effective as docetaxel in second-line NSCLC. EXPERT OPINION: Vinflunine is currently approved in Europe for the treatment of second-line TCCU and is currently being developed in other malignancies. It has been shown to have predictable and manageable adverse effects, such as neutropenia, anemia, constipation and fatigue.     

Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs

Introduction: IL-6 is a key cytokine in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of tocilizumab (TCZ), a humanized anti-IL6-receptor mAb, confirmed the value of IL-6 blockade in this disease. A number of new anti-IL-6 biologics are currently in Phase I – III of clinical development for RA.

Areas covered: This article reviews the available results from Phase II trials of investigational anti-IL-6 agents in RA. The authors discuss the potential relevance of alternative IL-6-blocking agents, with regard to their specific molecular targets in IL-6 signaling pathways and to the main open questions in the clinical research agenda for anti-IL-6 biologics.

Expert opinion: The results of Phase II trials of new anti-IL-6 biologics show promising results in terms of efficacy. The most frequently reported adverse events were not unexpected based on previous experience with TCZ. Further evidence is needed to appraise whether the difference in molecular structure or in the specific target of new anti-IL-6 biologics might result in added therapeutic value over TCZ. New data from Phase III trials that provides a head-to-head comparison against TCZ and anti-TNF agents with or without methotrexate background treatment are expected in the future.     

Leflunomide and malononitriloamides

Leflunomide is a new immunomodulatory drug effective in experimental models of autoimmune diseases and allo- or xenotransplantation. In a Phase II clinical trial leflunomide has shown high tolerability and efficacy in patients with advanced rheumatoid arthritis. The immunomodulatory activity of leflunomide is attributed to its primary metabolite, A77 1726, a malononitriloamide. The in vitro and in vivo mechanisms of action of this class of compounds remain to be completely defined. A77 1726 and several malononitriloamide analogues inhibit T- and B-cell proliferation, suppress immunoglobulin production, and interfere with cell adhesion. While no one central molecular mechanism of action has been proposed to explain all the effects of the malononitriloamides, inhibition of de novo pyrimidine biosynthesis and inhibition of cytokine- and growth factor-receptor associated tyrosine kinase activity are leading hypotheses for the effects of A77 1726 on T- and B-cell proliferation and function. Leflunomide is effective when administered at daily doses of 10 and 25 mg to patients with active rheumatoid arthritis. The improved efficacy at the 25 mg dose is associated with a higher incidence of adverse effects (gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia). Due to the long plasma half-life of A77 1726 (11-16 days), loading doses are required to achieve steady-state concentrations. Phase III randomised, placebo-controlled trials using daily doses of 10 or 20 mg are underway in the US and Europe to confirm and extend the results of the Phase II study. Malononitriloamide analogues of A77 1726 are being evaluated for immunosuppressive efficacy in preclinical models of transplantation, because these compounds have a shorter half-life in animals than A77 1726. If these analogues show efficacies similar to leflunomide in these models and have shorter half-lives than A77 1726 in Phase I trials, the preclinical and Phase I data will be used to select the analogues for Phase II trials in organ transplant recipients.     

Vinflunine: a novel antitubulin agent in solid malignancies

Vinflunine is the first bi-fluorinated, tubulin-targeted agent that was obtained by semisynthesis using super-acidic chemistry, which allowed the selective introduction of two fluorine atoms at the C20′ position of vinorelbine. This compound has been selected for clinical development on the basis of promising preclinical activity that warranted a study in patients with a wide spectrum of solid tumours. Clinically significant activity was seen in the Phase II studies for the treatment of bladder, non-small cell lung and breast cancers, thus prompting the initiation of the Phase III trials that are currently ongoing.     

Vinflunine: a novel antitubulin agent in solid malignancies

Vinflunine is the first bi-fluorinated, tubulin-targeted agent that was obtained by semisynthesis using super-acidic chemistry, which allowed the selective introduction of two fluorine atoms at the C20' position of vinorelbine. This compound has been selected for clinical development on the basis of promising preclinical activity that warranted a study in patients with a wide spectrum of solid tumours. Clinically significant activity was seen in the Phase II studies for the treatment of bladder, non-small cell lung and breast cancers, thus prompting the initiation of the Phase III trials that are currently ongoing.     

Recent advances in the development of haemoglobin-based blood substitutes

The term 'blood substitute' is commonly used to describe products which can carry and deliver oxygen. These products are also referred to as 'oxygen carriers' or 'oxygen therapeutics'. Blood substitutes are a new generation of oxygen therapeutics and their introduction will redefine treatment approaches in a wide range of medical and surgical practices. There are two major classes of this new generation of oxygen therapeutics (1) modified haemoglobin solutions, referred to as haemoglobin-based blood substitutes (HBBS) and (2) perfluorocarbon emulsions. Tremendous progress has been made in the past four years with the development of HBBS. In comparison, not much progress has been made in the development of perfluorocarbons as oxygen carriers. In the present review we have limited our discussion to the development of HBBS. Several types of HBBS have been developed and are in different phases of clinical trials. Free haemoglobin has been crosslinked, conjugated, polymerised or encapsulated to prevent its dissociation into dimers. The stability and purity of HBBS are extremely important in overcoming most of the significant toxicities of these products. Commercial manufacturers have utilised better proprietary formulations and purification technologies, and HBBS developed by these organisations have demonstrated safety in both preclinical and clinical studies. Recent research activities suggest a broad range of therapeutic applications for these new generation of oxygen therapeutics, 'blood substitutes'. The introduction of HBBS in critical care medicine will introduce a new approach of not only improving perfusion, but delivering oxygen to tissues.     

Optimal dose selection accounting for patient subpopulations in a randomized Phase II trial to maximize the success probability of a subsequent Phase III trial

Phase II clinical trials are conducted to determine the optimal dose of the study drug for use in Phase III clinical trials while also balancing efficacy and safety. In conducting these trials, it may be important to consider subpopulations of patients grouped by background factors such as drug metabolism and kidney and liver function. Determining the optimal dose, as well as maximizing the e?ectiveness of the study drug by analyzing patient subpopulations, requires a complex decision-making process. In extreme cases, drug development has to be terminated due to inadequate efficacy or severe toxicity. Such a decision may be based on a particular subpopulation. We propose a Bayesian utility approach (BUART) to randomized Phase II clinical trials which uses a first-order bivariate normal dynamic linear model for efficacy and safety in order to determine the optimal dose and study population in a subsequent Phase III clinical trial. We carried out a simulation study under a wide range of clinical scenarios to evaluate the performance of the proposed method in comparison with a conventional method separately analyzing efficacy and safety in each patient population. The proposed method showed more favorable operating characteristics in determining the optimal population and dose.     

Novel therapeutic targets for the treatment of heart failure

Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin-angiotensin-aldosterone system activation, defects in Ca(2+) cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials.     

Artificial O2 carriers: status in 2005

Donor blood is a limited resource and its transfusion is associated with significant adverse effects. Therefore, alternatives have been searched, the ultimate being artificial oxygen (O2) carriers. There are two main groups of artificial O2 carriers: hemoglobin based and perfluorocarbon emulsions. The hemoglobin molecule in hemoglobin based artificial O2 carriers needs to be stabilized to prevent dissociation of the alpha2beta2-hemoglobin tetramer into alphabeta-dimers in order to prolong intravascular retention and to eliminate nephrotoxicity. Other modifications serve to decrease O2 affinity in order to improve O2 off-loading to tissues. In addition, polyethylene glycol may be surface conjugated to increase molecular size. Finally, certain products are polymerized to increase the hemoglobin concentration at physiologic colloid oncotic pressure. Perfluorocarbons are carbon-fluorine compounds characterized by a high gas dissolving capacity for O2 and CO2 and chemical and biologic inertness. Perfluorocarbons are not miscible with water and therefore need to be brought into emulsion for intravenous application. Development, product specification, physiologic effects, efficacy to decrease the need for donor blood in surgery and side effects of the following products are described: Diaspirin cross-linked hemoglobin (HemAssist), human recombinant hemoglobin (rHb1.1 and rHb2.0), polymerized bovine hemoglobin-based O2 carrier (HBOC-201), human polymerized hemoglobin (PolyHeme), hemoglobin raffimer (Hemolink), maleimide-activated polyethylene glycol-modified hemoglobin (MP4) and perflubron emulsion (Oxygent). In addition, enzyme cross-linked poly-hemoglobin, hemoglobin containing vesicles (nano-dimension artificial red blood cells) and an allosteric modifier (RSR13) are discussed. The most advanced products are in clinical phase III trials but no product has achieved market approval yet in the US, Europe or Canada.     

Effectiveness and safety of eribulin mesylate: a new therapeutic option in the treatment of metastatic breast cancer

INTRODUCTION: There is no standard third-line chemotherapy treatment option for patients with metastatic breast cancer who have received an anthracycline and/or a taxane. A recent Phase III randomized controlled trial compared a new agent, eribulin mesylate with physician's treatment of choice in heavily pretreated patients with metastatic breast cancer, and a survival advantage was observed. Eribulin is a non-taxane microtubule dynamics inhibitor, approved by the US Food and Drug Administration (FDA) in November 2010 for use in patients who previously received at least two prior lines of chemotherapy for metastatic breast cancer. AREAS COVERED: The mechanism of action, pharmacokinetics and the efficacy and safety data from preclinical and clinical trials of this new agent are presented in this paper. EXPERT OPINION: Phase II and a recent Phase III trial indicate that eribulin is well tolerated with a predictable safety profile. The most frequent adverse events observed in patients receiving eribulin were asthenia/fatigue, neutropenia, alopecia, peripheral neuropathy and nausea. It represents a new treatment option in the setting of anthracycline and taxane-refractory metastatic breast cancer.     

Pharmacokinetic evaluation of vadimezan (ASA404, 5,6-dimethylxanthenone-4-acetic acid, DMXAA)

INTRODUCTION: Understanding the pharmacokinetics (PK) and pharmacodynamics of a drug is important to optimizing its use. Vadimezan is a tumor vascular-disrupting agent that acutely disrupts blood flow within tumors and induces innate tumor immunity. It has enhanced the activity of anticancer treatments in preclinical models and early phase trials, although one Phase III trial result was negative and another is yet to be reported. AREAS COVERED: Areas covered in this review are the preclinical and human PK and the inter-relationship among PK, toxicity and efficacy of vadimezan as a single agent and in combination with other therapies. These data are derived from a literature search on Medline and also from conference proceedings, abstracts and trial reports available up to June 2011. EXPERT OPINION: The disappointing results of one Phase III trial, despite the promising randomized Phase II trial data, highlight the challenges in translational research, especially in selecting the optimal development strategy. This paper discusses how different scheduling of vadimezan could significantly enhance the anticancer efficacy of this drug in combination with other therapies, especially those that do not require concurrent corticosteroid administration.     

Characteristics of clinical trials in oncology: pharmacist's implication

French hospital pharmacists have been officially involved in the organization of clinical trials since 1988. New responsibilities included reception of clinical treatment units and nominative dispensation of these drugs. For quality assurance, they organized all the procedures to secure drugs utilization according to good clinical practices and ICH guidelines. The pharmacists can be participate in ethical counselling and training in methodology. For oncology trials, only a few pharmacies are involved because clinical trials for evaluation of cytotoxic drugs have been regulated by very strict standardized procedures since 1960 in accordance with international rules. Using these rules, Phase I studies determine the useful dose for human administration with tolerable toxicities. Phase II studies determine the efficacy in specific cancer localizations. Good response in a particular indication is usually followed by drug approval for Phase III. New clinical and biological end points are arising especially for new non-cytotoxic therapeutic agents. This activity is at the present time limited to inpatient treatments, but with the growing development of outpatient care networks, dispensary pharmacists will come to be more involved in the necessary research and development of new anticancer agents.     

Ximelagatran: an orally active direct thrombin inhibitor.

PURPOSE: The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, contraindications, and adverse effects of ximelagatran are reviewed. SUMMARY: Ximelagatran is the first orally active direct thrombin inhibitor to be tested in Phase III clinical trials. After oral administration, ximelagatran is rapidly converted to its active metabolite, melagatran. Melagatran (after oral ximelagatran administration) predictably inhibits thrombin function without need for routine anticoagulation monitoring. Melagatran effectively inhibits both free and clot-bound thrombin-a potential pharmacodynamic advantage over heparin products. Melagatran has a half-life of 2.4-4.6 hours, necessitating twice-daily administration. Melagatran is primarily eliminated by the kidneys and has not been studied clinically in patients with severe renal failure. Ximelagatran has undergone 10 Phase III trials (6 for prophylaxis of venous thromboembolism [VTE] due to orthopedic surgery, 1 for initial treatment of VTE, 1 for long-term prevention of VTE recurrence, and 2 for stroke prophylaxis due to atrial fibrillation). Results were generally positive. AstraZeneca applied in December 2003 for marketing approval of ximelagatran for prevention of VTE after total knee replacement surgery, long-term prevention of VTE recurrence after standard therapy, and stroke prevention due to atrial fibrillation. FDA denied approval of ximelagatran for all indications, mainly because of increased rates of coronary artery disease events in ximelagatran recipients in some studies and the possibility of hepatic failure when the medication is used for long-term therapy. CONCLUSION: Ximelagatran has shown promise as a possible alternative to warfarin and other anticoagulants but will require further study to ensure its safety.     

Red blood cell substitutes: fluorocarbon emulsions and haemoglobin solutions

The problems posed by transfusion of homologous blood have led to the development of substances able to replace the gas transporting properties of blood. Perfluorocarbons (PFCs) emulsions and modified haemoglobin (Hb) solutions have been developed for this goal and are now tested in clinical assays. PFCs are synthetic fluorinated hydrocarbons, capable of dissolving large quantities of oxygen (O2; without binding) at high inspired concentrations of O2, and of delivering this O2 to the tissues. They are administered as emulsions containing particles with a diameter of approximately 0.2 micron, capable of entering the microcirculation. They are eliminated unchanged by the lungs within several days. Fluosol-DA 20% was the first PFC emulsion used in clinical practice. Currently, Oxygent, a second generation PFC emulsion, is being evaluated in clinical studies. The PFCs are not blood substitutes, but rather a means to ensure tissue oxygenation during extreme haemodilution. Solutions of free Hb do not have the antigenic characteristics of the blood groups, and do not require compatibility testing. They are fully saturated with O2 at ambient FiO2. The Hbs used are derived from either human or bovine sources, or via recombinant DNA technology. In order to maintain satisfactory intravascular half-life and O2 affinity, the Hb molecules are modified by adding internal crosslinks, by polymerization, and/or by encapsulation. After promising animal studies, several of these modified Hb solutions are now being studied in Phase III clinical trials. Among them, diaspirin cross-linked haemoglobin (DCLHb) has been used in cardiac and orthopaedic surgery, and for resuscitation of traffic accident victims. The initial results of multicentre trials are now being analysed.     

Platelet substitutes and novel platelet products

Despite many advances in the safety, processing and storage of conventional 22ºC liquid-stored allogeneic platelet concentrates, there are still significant drawbacks to standard platelet concentrates used in transfusions for patients with thrombocytopenia. Efforts to overcome these shortcomings have been undertaken in both academic and commercial settings, resulting in an array of novel platelet products and substitutes that are currently at various stages of development. This review summarises the recent developments in lyophilised platelets, infusible platelet membranes (IPM), red cells bearing arginine-glycine-aspartic acid (RGD) ligands, fibrinogen-coated albumin microcapsules and liposome-based agents as putative alternatives to conventional transfusions involving allogeneic platelet concentrates. These various products are designed to replace the use of allogeneic donor platelets with modified or artificial platelets, to augment the function of existing platelets and/or provide a procoagulant material capable of achieving primary haemostasis in patients with thrombocytopenia. Preclinical studies have been encouraging for several of these platelet substitutes and novel platelet products, however, to date, only a few of these products have entered human trials. With the ongoing development of these diverse products, properties necessary for haemostatic effectiveness will become apparent. Safety and efficacy, however, must be demonstrated in preclinical and Phase I - III clinical trials, before these novel agents can be used clinically for patients with thrombocytopenia.     

Ambrisentan, a non-peptide endothelin receptor antagonist

Increasing numbers of experimental investigations and recently also of clinical trials strongly suggest an integral involvement of the endothelin (ET)-system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Ambrisentan (LU 208075), a selective ET(A)-receptor antagonist, is an orally active diphenyl propionic acid derivative. It has been shown to have a very promising efficacy to safety ratio in the initial clinical trials. Phase II and Phase III trials with ambrisentan in pulmonary arterial hypertension have been performed. The pharmacological properties and data from the experimental investigations suggest additional possible uses of ambrisentan in the prevention of reperfusion injury after organ transplantation and in restenosis following coronary artery dilatation. Furthermore, the pharmacological profile of ambrisentan indicates that this drug may also be suitable in the treatment of cerebrovascular disorders. In the present article basic investigations, animal studies and clinical trials with ambrisentan are reviewed. This review may help to define pathophysiological conditions, in which ambrisentan could be indicated and further evaluated in appropriate preclinical and clinical trials.     

Obeticholic acid for the treatment of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy.     

Emerging neuroprotective drugs for the treatment of acute ischaemic stroke

Introduction: Neuroprotection aims to restrict the ischaemic damage following stroke by preventing salvageable neurons from dying. Despite successes in experimental stroke studies, neuroprotective strategies have failed in clinical trials so far. Nevertheless, promising neuroprotective drugs are currently being investigated in clinical trials.

Areas covered: This review provides an overview of the existing treatment of acute ischaemic stroke, discusses current research goals and puts special emphasis on emerging neuroprotective drugs. The authors systematically searched the database Clinicaltrials.gov for ongoing Phase II and Phase III clinical trials of neuroprotective drugs for acute ischaemic stroke. Mechanisms of action of these candidate neuroprotectants and the results of preceding preclinical studies and clinical pilot trials are described.

Expert opinion: In order to facilitate a successful translation from bench to bedside, future experimental studies should follow rigorous quality standards. Recent concepts to overcome the translation roadblock include the implementation of multicentre preclinical Phase III studies, the use of stroke models in non-human primates and the introduction of a preclinical trial registration.     

ASA404: update on drug development

Background: Interrupting tumour blood flow and delivery of nutrients to cause tumour death is the aim of antiangiogenic and vascular disrupting agents (VDAs). ASA404 is the first VDA to enter Phase III trials. Objective: We review the preclinical and clinical data on this interesting agent and consider its place in modern therapeutics. Methods: PubMed database was searched for ‘ASA404’, ‘AS1404’, ‘DMXAA’, ‘vascular disrupting agents’, ‘ASA404 clinical trials’, ‘AS1404 clinical trials’, ‘DMXAA clinical trials’. Results/conclusions: ASA404 is a tumour VDA that is well tolerated and has shown promise in the treatment of NSCLC in combination with paclitaxel and carboplatin. A confirmatory Phase III trial is currently ongoing.