摘要:

The last 5 years have witnessed an explosion in the use of genes and cells as biomedicines. While primarily aimed at cancer, gene engineering and cell therapy strategies have additionally been used for Mendelian, neurodegenerative and metabolic disorders. The main focus of gene and cell therapy strategies in metabolism has been diabetes mellitus. This disease is a disorder of glucose homeostasis, either due to the immune-mediated eradication of pancreatic β cells in the islets of Langerhans (type 1 diabetes) or resulting from insulin resistance and obesity syndromes where the insulin-producing capability of the β cell is ultimately exhausted in the face of insensitivity to the effects of insulin in the peripheral glucose-utilising tissues (type 2 diabetes). A significant number of animal studies have demonstrated the potential in restoring normoglycaemia by islet transplantation in the context of immunoregulation achieved by gene transfer of immunoregulatory genes to allo- and xenogeneic isletsex vivo. Additionally, gene and cell therapy has also been used to induce tolerance to auto- and alloantigens and to generate the tolerant state in autoimmune rodent animal models of type 1 diabetes or rodent recipients of allogeneic/xenogeneic islet transplants. The achievements of gene and cell therapy in type 2 diabetes are less evident, but seminal studies promise that this modality can be relevant to treat and perhaps prevent the underlying causes of the disease. Here we present an overview of the current status of gene and cell therapy for type 1 and 2 diabetes and we propose potential therapeutic options that could be clinically useful.For type 1 diabetes, transplantation of islets engineered to evade or suppress the recipient immune response is the most readily-available technology today. A number of gene delivery vectors encoding proteins that impair a variety of immune cells have already been examined and proven versatile. More challenging but, nonetheless, just over the horizon are attempts to promote tolerance to islet allografts. Type 2 diabetes will likely require a better understanding of the processes that determine insulin sensitivity in the periphery. Targeting tissues such as muscle and fat with vectors encoding genes whose products promote insulin sensitivity and glucose uptake is an approach that does not carry with it the side-effects often associated with pharmacologic agents currently in use. In the end, progress in vector design, elucidation of antigen-specific immunity and insulin sensitivity will provide the framework for gene drug use in the treatment of type 1 and type 2 diabetes.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Gastric inhibitory polypeptide (GIP, also called glucose-dependent insulinotropic polypeptide) and glucagon-like peptide-1 (GLP-1) are peptide hormones from the gut that enhance nutrient-stimulated insulin secretion (the ‘incretin’ effect). Judging from experiments in mice with targeted deletions of GIP and GLP-1 receptors, the incretin effect is essential for normal glucose tolerance. In patients with type 2 diabetes mellitus it turns out that the incretin effect is severely impaired or abolished. The explanation seems to be that both the secretion of GLP-1 and the effect of GIP are impaired (whereas both the secretion of GIP and the effect of GLP-1 are near normal). The impaired GLP-1 secretion is probably a consequence of diabetic metabolic disturbances. The known genetic variations in the GIP receptor sequence are not associated with type 2 diabetes mellitus, but a defective insulinotropic effect of GIP may be found in first degree relatives of the patients, suggesting a genetic background for the defect. The molecular nature of the defect is not known and given the close similarity of the two receptors and their signalling, the dissociation of their effects is remarkable. Whereas GLP-1 and its analogues are attractive as therapeutic agents for type 2 diabetes mellitus, analogues of GIP are unlikely to be effective. On the other hand, GIP seems to play an important role in lipid metabolism, promoting the disposal of ingested lipids, and mice with a targeted deletion of the GIP receptor do not become obese when exposed to a high-fat diet. Therefore, antagonistic analogues of GIP may be speculated to have a role in the pharmaceutical management of obesity.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The therapy for multiple sclerosis (MS) has changed dramatically over the past decade. Recent immunobiological findings and current pathophysiological concepts together with advances in biotechnology, improvements in clinical trial design and development of magnetic resonance imaging have led to a variety of evaluable therapeutic approaches in MS. However, in contrast to the successfully introduced and established immunomodulatory therapies (e.g. interferon-β and glatiramer acetate), there have been a remarkable number of therapeutic failures as well. Despite convincing immunological concepts, impressive data from animal models and promising results from phase I/II studies, the drugs and strategies investigated showed no benefit or even turned out to have unexpectedly severe adverse effects.Although to date there is no uniformly accepted model for MS, there is agreement on the significance of inflammatory events mediated by autoreactive T cells in the CNS. These can be modified therapeutically at the individual steps of a hypothetical pathogenetic cascade. Crucial corners like:the prevalence and peripheral activation of CNS-autoreactive T cells in the periphery;adhesion and penetration of T cells into the CNS;local activation and proliferation and;de- and remyelination processes can be targeted through their putative mediators.Like a ‘specificity pyramid’, therapeutic approaches therefore cover from general immunosuppression up to specific targeting of T-cell receptor peptide major histocompatibility (MHC) complex.We discuss in detail clinical MS trials that failed or were discontinued for other reasons. These trials include cytokine modulators [tumour necrosis factor (TNF)-α antagonists, interleukin-10, interleukin-4, transforming growth factor-β2], immunosuppressive agents (roquinimex, gusperimus, sulfasalazine, cladribine), inducers of remyelination [intravenous immunoglobulins (IVIg)], antigen-derived therapies [oral tolerance, altered peptide ligands (APL), MHC-Peptide blockade], T cell and T-cell receptor directed therapies (T cell vaccination, T-cell receptor peptide vaccination), monoclonal antibodies against leucocyte differentiation molecules (anti-CD3, anti-CD4), and inactivation of circulating T cells (extracorporeal photopheresis).The main conclusions that can be drawn from these ‘negative’ experiences are as follows. Theoretically promising agents may paradoxically increase disease activity (lenercept, infliximab), be associated with unforeseen adverse effects (e.g. roquinimex) or short-term favourable trends may reverse with prolonged follow-up (e.g. sulfasalzine). One should not be too enthusiastic about successful trials in animal models (TNFα blockers; oral tolerance; remyelinating effect of IVIg) nor be irritated by non-scientific media hype (deoxyspergualine; bone marrow transplantation). More selectivity can imply less efficacy (APL, superselective interventions like T-cell receptor vaccination) and antigen-related therapies can stimulate rather than inhibit encephalitogenic cells. Failed strategies are of high importance for a critical revision of assumed immunopathological mechanisms, their neuroimaging correlates, and for future trial design. Since failed trials add to our growing understanding of multiple sclerosis, ‘misses’ are nearly as important to the scientific process as the ‘hits’.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Waldenström's macroglobulinaemia is a rare B-cell malignancy. It is prevalent in the sixth and seventh decades, the median age at diagnosis being 63 years. Conventional treatment has involved alkylator therapy, especially chlorambucil given daily at a low dose or intermittently at a higher dose. Purine analogues, used initially as salvage therapy in refractory disease, are increasingly used for initial therapy. However, purine analogue therapy entails significant complications, including immunosuppression, pancytopenia and autoimmune haemolysis. Moreover, it is unclear whether purine analogues extend survival. All of these need to be considered before initiation of therapy. More recently, anti-CD20 monoclonal antibody and thalidomide have been used with a 30% response in treated patients. High-dose therapy with stem cell support achieves a partial response in a majority of patients receiving this modality of therapy. The median survival of 5 years has not improved considerably since the introduction of purine analogues. Complete response is still uncommon; using all available modalities of therapy may increase the complete response rate and improve survival. Great strides in understanding the malignant cell, the microenvironment and the potential interactions have identified potential targets for therapy in multiple myeloma. These agents may also be useful in Waldenström's macroglobulinaemia. Since this is a rare malignancy, all patients should be treated with well-designed clinical protocols to achieve improvement in outcome.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

BioDrugs Company Profilesprovide brief overviews of emerging and established companies in the biotechnology industry, featuring information on strategies, product development and R&D partnering.CellControl is a biotech company specialising in the fusion of tumour diagnostics and therapeutics, with the goal of achieving breakthroughs for cancer patients.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Peginterferon-α-2a (40KD) is a new ‘pegylated’ subcutaneous formulation of interferon-α-2a that has been developed to improve on the pharmacokinetic profile and therapeutic efficacy of interferon-α-2a. Peginterferon-α−2a (40KD) is produced by the covalent attachment of recombinant interferon-α-2a to a branched mobile 40KD polyethylene glycol moiety, which shields the interferon-α-2a molecule from enzymatic degradation, reduces systemic clearance and enables once-weekly administration.Peginterferon-α-2a (40KD) was significantly more effective than interferon-α-2a in interferon-α therapy-naive adults with chronic hepatitis C in three nonblind, randomised, multicentre trials. Virological responses (intention-to-treat results) were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-α-2a (40KD) 180 µg/week; sustained virological responses 24 weeks after the end of treatment occurred in 30 to 39% of patients. Virological responses at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-α-2a. Peginterferon-α-2a (40KD) was significantly more effective than interferon-α in patients with or without cirrhosis infected with HCV genotype 1.Sustained biochemical responses achieved with peginterferon-α-2a (40KD) 180 µg/week ranged from 34 to 45% and were significantly higher than with interferon-α-2a. Recipients of peginterferon-α-2a (40KD) also experienced histological improvements; 24 weeks after discontinuation of treatment with peginterferon-α-2a (40KD) 180 µg/week, 54% to 63% of patients had a ≥2-point improvement in histological activity index score. Peginterferon-α-2a (40KD) produced histological responses in patients (with or without cirrhosis) with or without a sustained virological response.Peginterferon-α-2a (40KD) produced better results than interferon-α-2a alone or interferon-α-2b plus oral ribavirin on various measures of quality of life in patients with chronic hepatitis C.The tolerability profile of peginterferon-α-2a (40KD) is broadly similar to that of interferon-α-2a in patients with chronic hepatitis C with or without cirrhosis. Headache, fatigue and myalgia are among the most common adverse events.In conclusion, peginterferon-α-2a (40KD) administered once weekly produces significantly higher sustained responses, without compromising tolerability, than interferon-α-2a administered thrice weekly in noncirrhotic or cirrhotic patients with chronic hepatitis C, including those infected with HCV genotype 1 - a group in whom interferon-α treatment has usually been unsuccessful. Peginterferon-α-2a (40KD) is a valuable new treatment option and appears poised to play an important role in the first-line treatment of patients with chronic hepatitis C, including difficult-to-treat patients such as those with compensated cirrhosis and/or those infected with HCV genotype 1.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

All drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D Insight™1, a proprietary product of Adis International. The information in the profiles is gathered from the world's medical and scientific literature, at international conferences and symposia, and directly from the developing companies themselves. The emphasis of this section inBioDrugsis on the clinical potential of new drugs, and selection of agents for inclusion is based on products in late phase clinical development that have recently had a significant change in status.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Exendin 4 and exendin 3 are 39-amino acid peptides isolated from Heloderma lizard venom.1The two molecules differ at amino acids 2 and 3, are agonists of glucagon-like peptide 1, and exhibit glucose-lowering effects in animal models of diabetes. Amylin Pharmaceuticals has acquired exclusive patent rights for two exendin compounds from the originator, Dr John Eng (Bronx, New York, USA). Exendins have demonstrated stimulation of secretion of insulin in response to rising blood glucose levels, and modulation of gastric emptying to slow the entry of ingested sugars into the bloodstream. Due to these effects, exendins provided a glucose-lowering ability in animal models of diabetes. Synthetic exendin 4 (AC 2993) has potential as a therapy for type 2 diabetes mellitus.Amylin Pharmaceutical has chosen synthetic exendin 4 as a clinical candidate for further development. Three phase II clinical studies have been completed in patients with type 2 diabetes mellitus in the UK and the USA. On 24 June 2001 Amylin announced the results of a phase II trial of AC 2993 that determined the effect on glucose control in patients with type 2 diabetes not responding adequately to current oral therapies. The 28-day, placebo-controlled trial in over 100 patients at multiple centres demonstrated that exendin 4 significantly lowered glycosylated haemoglobin level compared with controls. Amylin's pivotal phase III clinical studies development programme ‘AC 2993: Diabetes Management for Improving Glucose Outcomes (AMIGO)’ comprises three studies: a first phase III trial of AC 2993 in approximately 400 patients with type 2 diabetes has been initiated on 10 December 2001. A randomised, three-group study (two on AC 2993 and one on placebo) will evaluate an introductory 5μg dose of AC 2993 (SC injection twice daily for 1 month), which will be followed by doses of either 5μg or 10μg (twice daily for 6 months) in combination with metformin. Patients completing the study will be offered entry into an open-label extension study. The second phase III clinical study has begun in January 2002. This study will evaluate effects of AC 2993 in combination with sulfonylureas. The third study has been initiated in March 2002, and will investigate the effects of AC 2993 in combination with metformin and sulfonylureas. This randomised study will enrol approximately 800 patients with type 2 diabetes. All patients will continue to receive metformin and sulfonylureas during the study. Patients completing the study will be offered entry into an open-label extension study.Amylin and Alkermes have signed an agreement to cooperate on the development, manufacture and commercialisation of AC 2993 for type 2 diabetes mellitus. Under the agreement, Amylin is getting an exclusive worldwide license to Alkermes' Medisorb®formulation technology of injectable sustained-release AC 2993 as well as other exendins and related compounds. The microsphere-based technology incorporates drug molecules into a matrix of poly-(DL-lactide-co-glycolide), a common, biodegradable medical polymer PLG.Under the terms of agreement, Alkermes will receive research and development funding and milestone payments, and also a combination of royalty payments and manufacturing fees based on product sales. Alkermes undertakes the responsibility for the development of several initial formulations of the long-acting drug and manufacturing the final product, while Amylin will be responsible for clinical trials, regulatory filings and worldwide marketing. The goal of the AC 2993 LAR development programme is a once a month injectable formulation of AC 2993. A phase I study of the long-acting release formulation, AC 2993 LAR, began in Europe in March 2001 and was completed in Q3 2001. A long-acting, sustained-release formulation of AC 2993 lowered both pre-meal and post-meal glucose concentrations during a 24-h period in patients with type 2 diabetes. This result, along with the previous phase I studies with AC 2993 LAR formulation that demonstrated a sustained-release of AC 2993 over 30 days, will provide for the incoming, dose-ascending, phase II study in patients with type 2 diabetes that is scheduled for Q1 2002.In March 2001, it was announced that Amylin has signed a license agreement with the US National Institutes of Health (NIH), under the terms of which Amylin obtained exclusive worldwide rights to patent applications for use of AC 2993 for conversion of non−insulin-producing cells into insulin-producing cells. Amylin will pay license fees to the NIH and will perform research with regard to this use of AC 2993.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Hemolink™ is a highly purified human haemoglobin-based oxygen carrier that has been developed by Hemosol.1It combines both polymerised and non-polymerised haemoglobin components of varying molecular weights. Hemolink™ is designed to facilitate delivery of oxygen to vital organs and tissues in patients undergoing cardiac, orthopaedic and other surgery, as well as in patients undergoing chemotherapy.Hemolink™ is under review in Canada for use in coronary artery bypass grafting (CABG) surgery to reduce or avoid the use of donor red cells. In August 2000, Hemosol announced that the Canadian New Drug Submission for Hemolink™ had received Priority Review status from Health Canada. In their Q2 2001 results, Hemosol stated that it has responded in full to requests for more information from Canada’s Biologics and Genetic Therapies Directorate. In March 2002, Health Canada advised Hemosol™ that Hemolink™ would not be approved at this time and that additional data would be required for a refiled New Drug Submission. Hemosol has been conducting continuing dialogue with the US Food and Drug Administration (FDA) over amendments of its phase III Hemolink™ programme in cardiac surgery. In November 2001, Hemosol announced that it has received approval from the US FDA to begin a key phase III clinical trial of Hemolink™ in primary CABG. This trial will be conducted in the USA and the UK. The modified clinical programme also includes a ‘re-do’ CABG trial. The ‘re-do’ trial, which was approved by the FDA in January 2002, will enrol approximately 140 patients in more than 40 centres in the USA. It is anticipated that results from these studies will be reported towards the end of 2002. Following analysis of the results, Hemosol will work with the FDA to design and initiate a third phase III study. Phase III trials in the UK have been completed, and a marketing authorisation application (MAA) has been submitted to European authorities. The UK will act as the reference member state for the Mutual Recognition Procedure. Hemosol has received a comprehensive set of questions from the UK Medicines Control Agency (MCA) regarding the MAA. Hemosol plans to strengthen its regulatory filing in the UK in mid-2002 with results from the CABG and ‘re-do’ trials so that the MCA can complete its review by the end of 2002. Several other clinical trials of Hemolink™ have also been conducted. Phase II clinical trials have been completed in Canada for use as a blood substitute in patients undergoing orthopaedic surgery and in patients with chronic anaemia associated with renal failure. Hemosol is to begin a phase I/II Canadian/US study of Hemolink™ in patients with non-small cell lung cancer experiencing chemotherapy-associated anaemia. Hemosol has also completed a phase II trial of Hemolink™ in elective orthopaedic surgery in the UK, and in patients with anaemia in the USA. An extended trial in orthopaedic surgery patients has been completed in the UK and the USA. A phase IIb trial in patients undergoing orthopaedic surgery was expected to start in Canada/USA in the first half of 2001. In March 2002, the US FDA approved the start of a phase II trial of Hemolink™ as a treatment for chemotherapy-induced anaemia. The single-blind study will enrol 50 patients with lung or ovarian cancer who are being treated with erythropoietin for chemotherapy-induced anaemia. The study will be conducted at Duke University and is due to begin enrolment in June 2002.Other potential indications for Hemolink™ include trauma, oxygen delivery for cancer patients, ischaemic rescue in patients with stroke or myocardial infarction, and tissue perfusion in angioplasty and organ transplants.On 31 October 2000, Hemosol announced that it intended to form a strategic alliance with Dompé Farmaceutici for marketing of Hemolink™ in Austria, Greece, Hungary, Italy, Poland, Portugal, Russia, Spain and Switzerland. Under the terms of this memorandum of understanding and depending on regulatory approval of the product, Dompé will purchase $Can5 million of Hemosol common shares at $Can15 per share. In addition, Dompé has a 16-month option to make a further $Can5 million equity investment at $Can22.50 per share. The formation of the strategic alliance is subject to negotiation and execution of definitive agreements, after which Dompé will hold exclusive marketing rights to Hemolink™ in the aforementioned Southern and Eastern European countries.In September 1999, Hemosol announced that it had regained all rights to Hemolink™ from Fresenius AG. Previously, in June 1995, Hemosol had formed an alliance with Fresenius that gave the latter company exclusive marketing rights for Hemolink™ in Europe, including countries of the former Soviet Union, the Middle East and Africa. In April 1999, Hemosol received a $Can2.12 million milestone payment from Fresenius. The payment was made on the basis of the regulatory approval for phase III trials to begin in the USA, UK and Canada. The reason given for the termination of the agreement between the two companies was strategic differences concerning marketing of Hemolink™. Hemosol intends to develop Hemolink™ as an oxygen therapeutic in elective surgery and other therapeutic applications, whereas Fresenius viewed it strictly as a blood replacement product. In April 2000, Hemosol signed a 5-year renewable agreement with Pennyslvania Plama, a division of Sera-tec Biologics Limited Partnership in the USA to source human red blood cells used in the production of Hemolink™. In June 1998, Hemosol received a US patent for Hemolink™.A reduced but more stable form of Hemolink™, Deoxy-Hemolink™, has also been prepared for investigation by Hemosol.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Northwest Biotherapeutics is developing a prostate cancer vaccine based on its proprietary dendritic-cell based vaccine technology (DCVax™).1The vaccine (DCVax™-Prostate, CaPVax, DC1/HRPC) consists of prostate-specific membrane antigen (PSMA)-pulsed autologous dendritic cells and is in phase III development in the USA.On 15 February 2000, Northwest Biotherapeutics announced that a phase I/Il trial of the vaccine had begun at the MD Anderson Cancer Center in Houston and the University of California at Los Angeles. The study is enrolling 60 patients (30 at each site) with hormone-refractory, metastatic prostate cancer who are receiving four intradermal vaccinations at 4-week intervals of autologous dendritic cells pulsed with full-length PSMA, granulocyte-macrophage colony-stimulating factor, interleukin-4 and Bacille-Calmette-Guerin. In March 2002, Northwest Biotherapeutics announced that it had recently initiated a 495 patient phase III clinical trial in patients with late-stage prostate cancer. The trial will be conducted at 20 to 25 sites in the USA.Northwest Biotherapeutics has sublicensed the use of PSMA forex vivoimmunotherapy of prostate cancer from Cytogen Corporation. Cytogen licensed worldwide rights to use of PSMA for immunotherapy from the Memorial Sloan-Kettering Cancer Center in New York, USA, where the antigen was discovered. Cytogen has retained the rights for use of PSMA for all other indications, includingin vivoimmunotherapy for prostate cancer. In exchange for the sublicensing agreement, Northwest Biotherapeutics will make milestone and royalty payments to Cytogen. Previously, in January 1997, Cytogen had licensed PSMA to Prostagen, which initiated a collaboration with Northwest Biotherapeutics for development of the vaccine. However, in June 1999, Cytogen acquired Prostagen, thus regaining rights to PSMA. As part of this deal, Cytogen received a minority ownership in Northwest Biotherapeutics.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS