摘要:

Asthma is an inflammatory disease of the airways leading to significant morbidity and mortality. With advances in the understanding of the molecular and cellular mechanisms involved in the asthmatic response, researchers have identified specific mediators that may be targeted to control the inflammatory state of asthma. The Th2 hypothesis proposes that the inflammation in asthma arises from an imbalance between the two CD4+ T lymphocyte subsets, T helper (Th) type 1 and Th2. Th2 cells release many cytokines that have been shown to regulate the inflammatory response, while the Th1 cytokines counteract this response. The Th1 cytokine, interleukin (IL)-12, has been a target of intense study because it mediates the Th1 response and offers a means of modifying the asthmatic inflammatory response. Numerous murine studies have shown that this cytokine can potently inhibit allergic airway inflammation in asthma. Inhalation of IL-12 has been shown to increase its efficacy in inhibiting allergic inflammation in murine models while decreasing adverse effects seen with systemic administration of this cytokine. However, an initial study of inhaled IL-12 in humans with asthma was terminated because of adverse effects. The use of systemically administered IL-12 in patients with asthma has been limited due to cytokine toxicity. Another treatment option that has the potential of inducing a Th1 cytokine response is the use of IL-12 linked to polyethylene glycol (PEG) moieties. This mode of administration is likely to enhance cytokine delivery to the target organ, while decreasing its toxicity. IL-12 gene therapy has also been examined as a means of suppressing airway hyperreactivity in murine asthma, but its potential in human asthma has not been explored. Several recent studies have investigated the role of CpG DNA motifs as endogenous inducers of IL-12 with encouraging results in both mice and humans. These studies may result in novel Th1- inducing CpG-based immunotherapies for asthma.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Inhaled insulin first entered clinical human testing in the mid 1990s. Since then, the commercial potential and technical challenges of an inhaled insulin product have grown increasingly clear, with several pharmaceutical partnerships now targeting treatment of diabetes mellitus through inhalation products in clinical development. While clinical results to date show the therapy to be generally promising, recent data have raised questions related to human safety and slowed progress toward a commercial product. Answering these questions positively in the coming years will be critical to making inhalation therapy a practical diabetes-care reality.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The major functions of pituitary thyroid-stimulating hormone (TSH) are to maintain the biosynthesis and secretion of the thyroid hormones L-thyroxine (T4) and L-3,5,3′triidothyronine (T3). The TSH core contains two apoproteins, the α and β subunits. The α subunit is identical to that of pituitary follitropin, pituitary lutropin and placental chorionic gonadotropin, whereas the β subunit is unique. TSH is a glycoprotein; the glycoprotein components of the α and β subunits account for more than 10% of their mass and are essential for normal thyrotropic action and intravascular kinetics. The hypothalamic tripeptide, TSH-releasing hormone (TRH) is required for optimum TSH biosynthesis, particularly as far as addition of the glycoprotein components is concerned. TRH deficiency is associated with secretion of TSH molecules that are appropriately measured in most assays but have reduced bioactivity. In previous years the TSH used in clinical practice was obtained and purified from bovine pituitaries. Bovine TSH was used to test thyroid function and to augment the uptake of radioiodine in patients with thyroid cancer. Bovine TSH has been largely abandoned as a clinical agent because of adverse immune reactions.A recombinant human TSH (rhTSH; Thyrogen®1), has been approved by the US FDA for diagnostic use in patients with thyroid cancer. The α and β subunits of Thyrogen®are identical to those of human pituitary TSH. Thyrogen®has a specific activity of approximately 4 IU/mg and is a potent stimulator of T4, T3 and thyroglobulin (Tg) secretion in healthy volunteers. It also increases thyroid iodide uptake in patients with thyroid cancer or multinodular goitre and in volunteers, even those exposed to large amounts of stable iodide. Thyroid cancer patients who have been treated by thyroidectomy and radioiodine ablation but are at risk of harbouring residual thyroid cancer are candidates for Thyrogen®administration to prepare them for whole body iodide scans and serum Tg measurements. In thyroidectomised thyroid cancer patients who are unable to secrete pituitary TSH upon thyroid hormone withdrawal, Thyrogen®is the only acceptable method to prepare them for these procedures. Thyrogen®has been used on a compassionate basis to prepare patients for radioiodine ablation. rhTSH, in addition to being useful in the management of patients with thyroid cancer, is potentially useful to test thyroid reserve and to aid in thyroid-related nuclear medicine procedures. In the future, TSH analogues that have superagonist or antagonist properties may become available as therapeutic agents.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Type 1 diabetes mellitus affects about 1 in 300 people in North America and Europe. Epidemiological studies indicate that the incidence and thus prevalence of type 1 diabetes is rising worldwide. Intervention in autoimmune type 1a diabetes could occur at the time of diagnosis or, preferably, prior to clinical presentation during the ‘prediabetic’ period (e.g. prevention). Prediabetes is best recognised by the detection of islet autoantibodies in the serum. Promising intervention strategies include monoclonal antibody therapies (e.g. anti-CD3, anti-CD25, anti-CD52 or anti-CD20 monoclonal antibodies), immunosuppression (e.g. calcineurin inhibitors, B7 blockade, glucocorticoids, sirolimus (rapamycin), azathioprine or mycophenolate mofetil), immunomodulatory therapies (e.g. plasmapheresis, intravenous immunoglobulin, cytokine administration, adoptive cellular gene therapy) and tolerisation interventions (e.g. autoantigen administration or avoidance, altered peptide ligand or peptide-based therapies). To date, islet and pancreas transplantation have essentially been reserved for patients with long-standing diabetes who have complications and are also in need of a concurrent kidney transplant. None of the therapies attempted to date has produced long-term remissions in new-onset type 1 diabetes patients and no therapies have been shown to prevent the disease. Nevertheless, with advances in our understanding of basic immunology and the cellular and molecular mechanisms of tolerance induction and maintenance, successful intervention therapies will be developed. The balance between safety and efficacy is critical. Higher rates of adverse events might be more tolerable in new-onset type 1 diabetes patients if the therapy is extremely effective at inducing a permanent remission. However, therapies must not harm the β-cells themselves or any organ system that is a potential target of diabetes complications, such as the nervous system, retina, cardiovascular system or kidney. In the treatment of prediabetes, successful therapies should provide a level of safety similar to that of currently used vaccines and a high level of efficacy.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

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:2003

数据来源: ADIS

摘要:

Cerus Corporation is developing a variety of pathogen-inactivation systems, based on its Helinx®technology.1Three of the systems include amotosalen [S 59] as the inactivation compound. Amotosalen is a light-activated, DNA-, RNA-crosslinking psoralen compound, which is used to neutralise pathogens. The systems that utilise amotosalen are called the INTERCEPT™ Platelet System, the INTERCEPT™ Plasma System and the Allogeneic Cellular Immunotherapies (ACIT) system.The INTERCEPT™ Platelet System and INTERCEPT™ Plasma System are two of the systems that make up Cerus' INTERCEPT™ Blood Systems. The other system is the INTERCEPT™ Red Blood Cell System, which contains S 303 as the inactivation compound rather than amotosalen.Cerus' Helinx®technology is able to prevent replication of DNA or RNA that is present in pathogens but not in the blood components being treated (e.g. platelets and plasma). When added to the blood components, the inactivation agent (in this case amotosalen) crosses the membrane or cell wall of the pathogen. When activated by light, amotosalen binds to the nucleic acid of the pathogen and prevents replication. This process prevents infection.INTERCEPT™Platelet System: Cerus developed its INTERCEPT™ Platelet System, in collaboration with Baxter Healthcare, for use in blood centres. Platelets are an essential component of the coagulation process and may be required by patients undergoing surgery, cancer chemotherapy, transplantation or with bleeding disorders. The system is made up of an illuminator device, a compound absorption device and a processing kit containing amotosalen.In October 2002, the two companies announced that CE Mark approval had been received for the illuminator device for the INTERCEPT™ Blood System. Application of this technology to platelets is the first to be approved. As it is a new technology, the system is currently undergoing process validation in accordance with European Blood Bank GMP requirements. This validation process is currently being conducted in Denmark, France, Germany, Sweden and the UK.Marketing approval applications for the INTERCEPT™ Platelet System have also been submitted in Australia and Canada. In addition, the regulatory submission process has begun in the US.A phase III trial (EuroSPRITE) has been conducted in 103 patients in Europe with pooled random donor platelets. The platelets were collected using the buffy coat process. Another two 20-patient clinical trials have also been conducted in Europe, as well as a 40-patient trial using platelets collected by an apheresis collection system.Cerus has also conducted a phase III trial (SPRINT) in the US. The trial was conducted in 671 patients and used platelets collected by Baxter's apheresis collection system.INTERCEPT™ Plasma System: Cerus is also developing the INTERCEPT™ Plasma System in collaboration with Baxter Healthcare. The system also combines amotosalen, an illumination device and a compound absorption device. The two companies are currently preparing regulatory applications for the INTERCEPT™ Plasma System for the US. This application will be followed by a submission for CE Mark designation in Europe.Patients undergoing surgery, or transplantation, or with bleeding disorders, may require transfusions of plasma, often to control bleeding. The type of plasma is stored in frozen form and is called fresh frozen plasma (FFP).The INTERCEPT™ Plasma System is currently in phase IIIc development in the US. Patient enrolment in the trial is still ongoing. The trial is comparing INTERCEPT™ Plasma System treated versus untreated FFP in 30 patients with thrombotic thrombocytopenic purpura.Allogeneic Cellular Immunotherapies system:Cerus is also investigating the potential of its Helinx®technology to improve the outcome of bone marrow transplantation procedures (used to treat leukaemia and lymphoma) through the treatment of T cells.Bone marrow transplantation is a highly effective treatment for many forms of leukaemia and is most effective when the donor is very closely matched to the patient for the major human leucocyte antigen (HLA) groups. As part of the transplant procedure, patients receive donor T cells to improve engraftment of the bone marrow transplant and strengthen the patient's immune system. However, donor T cells expose the patient to a high risk of contracting graft-versus-host disease (GVHD) caused by the proliferation of donor T cells, which attack the patient's healthy tissue. GVHD has a high mortality rate.Cerus' ACIT system has been developed to decrease the stringency of matching donors to patients and to inhibit the ability of donor T cells to cause GVHD. Light-activated amotosalen binds and permanently crosslinks DNA, preventing replication and thus stopping proliferation of donor T cells.[1]Phase I development is currently being conducted in this area in the US using amotosalen as the neutralising agent. Cerus completed a phase I study investigating the safety and tolerability of its ACIT system in 2001. The study was conducted in patients receiving closely matched allogeneic bone marrow transplants for leukaemia. The company is currently collaborating with the National Marrow Donor Program in order to conduct further clinical studies in patients receiving bone marrow transplants from unmatched donors.Cerus has development, manufacturing and marketing agreements with Baxter covering the INTERCEPT™ Blood Systems, which includes the INTERCEPT™ Platelet system, the INTERCEPT™ Plasma System, and the INTERCEPT™ Red Blood Cell System. Under the terms of the agreements the two companies usually share the very early development activities. Cerus then conducts preclinical and clinical trials, while Baxter is responsible for the development of the systems disposables and devices. Following commercialisation Cerus will supply amotosalen and Baxter will supply the other components of the system and market, sell and distribute the systemIn January 2001, Cereus announced that it has entered into a collaborative agreement with the Pharmaceutical Division of Kirin Brewery in Japan to develop and market products for stem cell transplantation based on Cerus' proprietary Helinx®technology. Under terms of the agreement, Cerus and Kirin will jointly develop the products. Cerus has received an initial license fee of $US1 million. In addition it may receive up to $US11 million in future payments upon achievement of development milestones. Kirin will also fund all development expenses for the Asia-Pacific region and a portion of Cerus' development activities aimed at obtaining product approval in the US. Kirin will market the products in the Asia-Pacific region, including Japan, China, Korea and Australia, and Cerus will receive a specified share of product revenues. Cerus will retain marketing rights in the rest of the world, including the US and Europe.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

AVAX Technologies is developing a therapeutic melanoma vaccine [M-Vax™, DNP-VACC] consisting of autologous tumour cells conjugated to a highly immunogenic hapten, dinitrophenyl, which makes the cancer cells more easily recognised by the immune system.1AVAX licensed the autologous cell vaccine technology (AC Vaccine™) from Thomas Jefferson University in Philadelphia, USA, where it was originally developed.M-Vax™ was launched in Australia in the first half of 2000, but was withdrawn from this market in September 2002 due to financial constraints faced by the company and its need to focus its resources on initiatives that provide the greatest return. Although AVAX applied for Federal Government price reimbursement in Australia through the Medical Services Advisory Committee during 2001, the vaccine is not reimbursed in Australia. Obtaining Federal Government reimbursement was a step AVAX considered essential for the success of the M-Vax™. AVAX has not ruled out re-entering the Australian market again at a later date. AVAX will now concentrate on gaining approval in the US and Europe. M-Vax™ has received orphan drug designation from the US FDA.M-Vax™ is in preregistration in Germany, Japan and The Netherlands for treatment of stage III melanoma. In September 1999, the company announced that it expected to market M-Vax™ for treatment of stage III melanoma in Germany, Japan and the Netherlands. This announcement came after AVAX's continuing dialogue with senior regulatory authorities in several pharmaceutical markets. The commercial availability of M-Vax™ in Germany, Japan and The Netherlands will be subject to meeting certain requirements specified by the regulatory agency in each country. Phase II data have been submitted for regulatory approval in these countries; phase III data may not be required because the vaccine contains autologous tumour cells. This was the case with the Australian approval of M-Vax™, which was on the basis of data from phase II trials.Clinical development:M-Vax™ was in a pivotal phase III trial for treatment of stage III melanoma in the US, and a multicentre phase II trial in the US for treatment of patients with stage IV melanoma with lung metastases. However, in late March 2001, AVAX announced that the FDA had suspended these trials until the agency had further reviewed them.Subsequently, AVAX received written communication from the FDA indicating that the suspension is related to manufacturing issues. These events triggered the resignations of AVAX's executive Vice-President and Vice-President of operations, at the request of the company's board of directors. AVAX met with the FDA in October 2001 to discuss the clinical holds on M-Vax™ and O-Vax™. AVAX's proposed improvements involving a frozen vaccine were also discussed at the meeting.Following the meeting AVAX was told by the FDA that selected characterisation work would have to be carried out on the new products, and new INDs submitted. In December 2001 AVAX announced that the development of a frozen vaccine and changes to various policies and procedures would ensure that the company complied with the FDA regulations.A new IND was submitted to the FDA for M-Vax™ in September 2002. In August 2002, AVAX had been unsure whether following approval of its new IND it would re-initiate clinical development for both M-Vax™ and O-Vax™ in parallel, or advance one of the agents and wait for further funding for the other. However, in September it indicated that clinical trials of both vaccines would be conducted following approval of the IND. A total of 42 patients are to be enrolled in each trial. In October 2002, AVAX announced that the US FDA had no outstanding issues regarding the IND. AVAX can now proceed with clinical trials as planned.AVAX Technologies was enrolling patients with stage III melanoma in the pivotal US phase III trial for registration of M-Vax™. The company expected to enrol approximately 400 patients in this randomised, multicentre trial designed to compare the efficacy of the vaccine against high-dose interferon-α, the standard post-surgical treatment for stage III melanoma. The two end-points are rate of melanoma tumour recurrence and overall survival. The dosing regimen chosen for this study is that which was found from several clinical studies to be most effective at eliciting a positive delayed-type hypersensitivity skin response to autologous melanoma cells. The study was being conducted at more than 20 US sites.A low dose of M-Vax™ was also being evaluated in a phase II study at Thomas Jefferson University in the US. On 16 March 2000, AVAX announced promising interim results from this study, which revealed that 65% of 23 evaluated patients developed an immune response of the same magnitude as that observed with higher doses of M-Vax™ in previous studies. The study was to enrol a total of 46 patients, who were to receive seven doses of M-Vax™ over 7 weeks. The advantage of using a low dose of M-Vax™ is that it requires a smaller amount of the patient's tumour tissue to produce the vaccine (approximately half that required in previous studies) and therefore more patients would be eligible for treatment. On the basis of these results, AVAX modified the pivotal phase III trial to use the low dose of M-Vax™ to treat additional patients with smaller tumours.On 29 March 2000, AVAX announced that it had initiated a multicentre phase II study in the US in patients with stage IV melanoma and lung metastases. Patients were receiving seven doses of M-Vax™ at weekly intervals and a booster at 6 months. AVAX initiated the study because of promising results in a study of stage IV melanoma patients with lung metastases in which patients treated with M-Vax™ had tumour regression and prolonged survival.Commercial agreements:In June 1999, AVAX announced its first international commercialisation opportunity for M-Vax™, in Australia, where the company subsequently launched the vaccine (now withdrawn) in the first half of 2000. AVAX formed a subsidiary, AVAX Australia, which was co-marketing M-Vax™ in Australia together with Australian Vaccine Technologies (formerly Neptunus International Holdings). Under the terms of this agreement, Australian Vaccine Technologies purchased $A10 million in shares, a 50% interest, in AVAX Australia. The final $A3 million instalment was made in August 2000. AVAX had an option to purchase up to 5% of shares in Australian Vaccine Technologies.In August 2002, AVAX extended and expanded an existing production agreement with Medigene for approximately 1 year. Under the terms of the agreement, Genopoietic (Medigene) in France will process clinical samples of M-Vax™.In October 2002, AVAX signed a distribution agreement with Ferrer International, SA (Grupo Ferrer) for sales and distribution of the AC Vaccines™, including M-Vax™ and O-Vax™. The agreement covers Europe, Latin America and certain Asian territories. Under the terms of the agreement AVAX will retain manufacturing rights and will sell the vaccine to Ferrer. In return, Ferrer will make payments to AVAX for the product as well as certain milestone payments for marketing and registration goals.M-Vax™ was manufactured in Australia by Bioenterprises, a subsidiary of Biotech Australia. However, in 2002, the manufacturer underwent an acquisition with significant changes, which resulted in its decision to discontinue manufacturing M-Vax™.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Pramlintide [AC 0137, AC 137, tripro-amylin, Symlin™] is a synthetic human amylin analogue with proline substitutions at positions 25, 28 and 29, which limits the self-aggregation seen with native amylin. Pramlintide improves glycaemic control, and appears to reduce postprandial blood glucose peaks and flatten the glucose peaks and troughs observed in diabetic patients. The reduction of hypoglycaemia would be an immediate advantage, and the reduction of hyperglycaemia could potentially prevent diabetic complications.Development − US: Amylin has submitted an NDA in the US for pramlintide acetate (Symlin™) as an adjunctive therapy for the treatment of type 1 and type 2 diabetes mellitus. However, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee at their meeting on 26 July 2001, voted not to recommend approval of pramlintide for type 1 and type 2 diabetes. Although eight out of nine Committee members were convinced of the potential of pramlintide therapy, the Committee expressed concerns regarding safety issues and requested additional data addressing these concerns.[1] Finally, on 12 October 2001, Amylin received an ‘approvable letter’ for Symlin− for the treatment of diabetes.In April 2002, Amylin commenced a trial in 250 patients with type 1 diabetes to evaluate the safety issues regarding cases of severe hypoglycaemia with pramlintide in combination with insulin reported in this group of patients. The trial will investigate dose titration in the initial first month of the treatment period combined with insulin adjustment for the optimisation of glucose control. Patients are then treated for 6 months at a steady-state dose of pramlintide or placebo, accompanied by the additional insulin adjustments. Amylin has completed patient enrolment in September 2002.[2]Final approval is subject to satisfactory results from this safety and dose titration study and the four small pharmacology studies already completed or underway. Amylin plans to file an amendment to the pramlintide's NDA in the Q1 of 2003.[3]Development − non-USA:A wholly owned subsidiary of Amylin Pharmaceuticals, Amylin Europe, filed a regulatory submission with the European Agency for Evaluation of Medicinal Products (EMEA) and Switzerland for pramlintide for the treatment of both type 1 and type 2 diabetes under the centralised procedure.Amylin completed pivotal phase III clinical trials with pramlintide acetate (Symlin™) for the treatment of type 1 and type 2 diabetes mellitus in North America and Europe.However, in October 2002, Amylin announced that following consultation with the Committee for Proprietary Medicinal Products (CPMP) of the EMEA, it has found that additional information is necessary to proceed with review of the MAA for pramlintide for diabetes. Since, the centralised procedure does not allow the adding of new information to the application that is already under review, Amylin has decided to withdraw the MAA for pramlintide. The company will continue discussions with the EMEA to clarify the information required for a resubmission of the application.[3]The submission for pramlintide in Switzerland is currently under review.[3]In a separate phase II programme, Amylin is investigating the use of pramlintide in type 2 diabetes mellitus patients who are not achieving satisfactory results with oral hypoglycaemic agents but who have not progressed to using insulin.Collaborations:Pramlintide was under joint development with Amylin Pharmaceuticals and Johnson and Johnson, as an injectable partner hormone for insulin for the treatment of both type 1 and type 2 diabetes mellitus. The terms of the agreement between Amylin and Johnson and Johnson were that Amylin had primary responsibility for development and regulatory submissions, while Johnson and Johnson had primary responsibility for marketing; development costs and eventual profits were to be shared equally. Later, Johnson and Johnson decided to terminate the collaboration to commercialise pramlintide. An earlier development collaboration between Amylin and Glaxo Wellcome was also discontinued. However, Amylin is in new ongoing discussions with collaborative partners for pramlintide in Europe and Japan.Amylin has signed an agreement with CP Pharmaceuticals in the UK to manufacture pramlintide.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS