Recombinant human antithrombin III: rhATIII

GTC Biotherapeutics (formerly Genzyme Transgenics Corporation) is developing a transgenic form of antithrombin III known as recombinant human antithrombin III [rhATIII]. It is produced by inserting human DNA into the cells of goats so that the targeted protein is excreted in the milk of the female offspring. The transgenic goats have been cloned in collaboration with the Louisiana State University Agriculture Center. GTC Biotherapeutics is conducting clinical trials of rhATIII in coagulation disorders. rhATIII is believed to be both safer and more cost-effective than the currently available plasma-derived product. rhATIII is also being investigated in cancer and acute lung injury. Genzyme Transgenics Corporation, originally a subsidiary of Genzyme Corporation, changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. GTC Biotherapeutics is seeking partners for the commercialisation of rhATIII. Restructuring of GTC Biotherapeutics to support its commercialisation programmes was announced in February 2004. Genzyme Transgenics Corporation was developing rhATIII in association with Genzyme General (Genzyme Corporation) in the ATIII LLC joint venture, but in November 2000 a letter of intent was signed for the reacquisition of the rights by Genzyme Transgenics Corporation. It was announced in February 2001 that this reacquisition was not going to be completed and that the development of rhATIII was to continue with ATIII LLC. However, in July 2001, Genzyme Transgenics Corporation reacquired all the rights in the transgenic antithrombin III programme. SMI Genzyme Ltd, a joint venture between Sumitomo Metal Industries, Japan, and Genzyme Transgenics Corporation, USA, was set up to fund development of transgenic antithrombin III in Asia. However, in October 2000, Genzyme Transgenics Corporation reacquired, from Sumitomo Metal Industries, the rights to its technology for production of medicines from milk in 18 Asian countries, including Japan. The 10-year-old joint venture, SMI Genzyme Ltd, was dissolved. In June 2002, GTC Biotherapeutics estimated the current market size for plasma ATIII products to be approximately $US250 million - of which sales in Europe amounted to $US110 million, Japan $US130 million and the US $US10 million.     

Clofarabine

Clofarabine (Clolar; Genzyme), a purine nucleoside antimetabolite, was granted accelerated approval by the US FDA for the treatment of paediatric patients with relapsed or refractory acute lymphoblastic leukaemia in December 2004. It is the first new drug for paediatric leukaemia to be approved in more than a decade, and the only one to receive approval for paediatric use before adult use.     

BMS-188667 (Bristol-Myers Squibb)

Bristol-Myers Squibb is developing CTLA4-Ig, an immunosuppressant immunoglobulin, for the potential treatment of various immunological disorders, including graft versus host disease, lupus erythematosus and psoriasis. A phase II trial has commenced for psoriasis. The compound is also in development for inflammation, rheumatoid arthritis and allergy. A collaboration with Genzyme Transgenics covers the following indications: psoriasis; organ transplant rejection; and several autoimmune disorders.     

Ecallantide (Dyax/Genzyme)

Ecallantide is one of a series of small-protein kallikrein inhibitors, identified through Dyax Corp's phage display technology, that is being developed by Dyax and Genzyme as a potential subcutaneous treatment for hereditary angioedema (HAE). Dyax is also independently developing ecallantide for the reduction of peri-operative blood loss during cardiopulmonary bypass surgery. The company had expected to begin phase II clinical studies in coronary bypass graft patients in the first half of 2005; however, by October 2005, these trials had been delayed until partnership negotiations for the program were completed. A pivotal, phase III clinical trial of ecallantide in HAE began in December 2005.     

Transgenic antithrombin III (Genzyme)

ATIII LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB). GTC has a license from Behringwerke (Hoechst Marion Roussel; now Aventis Pharma) to develop transgenic AT-III. Behringwerke retains exclusive worldwide marketing rights to the product, but has to purchase its entire supply of transgenic AT-III from GTC [156364]. In March 1997, GTC signed an agreement with SMIG, a joint venture formed by GTC and Sumitomo Metals, under which SMIG has the rights to develop rhAT-III in Asia in return for US dollar 4.4 million in additional funding for the continued transgenic development of rhAT-III. The dollar 4.4 million will be paid upon reaching certain milestones, which GTC expected to complete in 1997 [240202]. In December 1998, US-05843705 was issued covering rhAT-III production in transgenic goats [302263]. In January 2000, the results of the European phase III trial, which were significant in meeting the trial's primary endpoint of reduction in the use of fresh frozen plasma were reported. The trial was also significant in two of three secondary endpoints, maintenance of normal AT-III levels and changes in D-dimer and fibrin monomer [352041,353372]. Three phase III trials were initiated in the second quarter of 1998. Two identical trials, one in Europe and one in the US, evaluated the safety and efficacy of rhAT-III compared to placebo in restoring heparin sensitivity to heparin-resistant patients scheduled for elective cardiac surgery requiring CPB. The third trial, in both the US and Europe, will determine whether rhAT-III matches, at equivalent doses, the ability of plasma-derived AT-III to restore heparin sensitivity among heparin-resistant patients undergoing CPB [292235,292861]. Full enrollment onto the US trial was complete by the end of first quarter 2000 [363589], and the companies aim to complete trials and submit a filing by the end of 2000 [353372]. Clinical trials of the proteins in Japan were expected to begin in 1998 [286086].     

Genzyme: success through diversity

Genzyme, the US biotechnology company, has a remarkably broad product base in contrast to similar corporations which have more focused portfolios. In biotechnology, a company’s value is based largely upon its patent portfolio. In the case of Genzyme, the Company’s leading product Ceredase (recombinant glucocerebrosidase), is manufactured under licence. Substantial income streams are produced from the manufacture of pharmaceuticals and diagnostic reagents. Of particular note are Genzyme’s tissue repair products which combine membrane and recombinant DNA technologies.     

Drug evaluation: deferitrin (GT-56-252; NaHBED) for iron overload disorders

Deferitrin (GT-56-252) is the first drug in a class of desferrithiocin-derived hexadentate iron chelators. Genzyme Corp is developing this compound as an oral drug for the treatment of severe iron overload in people who require repeated erythrocyte transfusion for management of chronic anemia such as beta-thalassemia major. In phase I trials in adults with beta-thalassemia, deferitrin promoted iron excretion in a dose-related manner and was well tolerated as both a liquid and capsule in fed and fasted states. There were no serious adverse events or significant laboratory abnormalities. The author concludes that deferitrin may be useful as chelation monotherapy or as part of combination or doublet chelation therapy for the treatment of severe iron overload in patients with beta-thalassemia major if its favorable pharmacokinetic profile, efficacy, safety and tolerability are confirmed in more extensive clinical trials. A phase I/II trial that began in September 2003 has reportedly completed recruitment.     

Neutralization of beta-lactam antibiotics in an environmental monitoring medium

The neutralizing ability of Difco Bacto Penase, BBL Penicillinase, and Genzyme beta-lactamase for penicillin G, oxacillin, cephalothin, cefazolin, ceftazidime, ceftriaxone, cefotaxime, imipenem, and meropenem was determined in an agar medium. Trypticase soy agar plates (20 mL) containing 200 MU/L Difco Penase, 200 MU/L BBL Penicillinase, or 2 vials/L of Genzyme beta-lactamase were dosed with 20, 50, and 100 micrograms of each antibiotic and then inoculated (50-100 CFU/plate) with a susceptible microorganism. Percentage recoveries of the organism were calculated after incubation. Genzyme beta-lactamase effectively neutralized 100 micrograms of all the antibiotics except ceftazidime (32% recovery with 20 micrograms). The two penicillinases effectively neutralized 100 micrograms of penicillin G, oxacillin, cephalothin, and cefazolin; were slightly effective against ceftriaxone and cefotaxime (20-57% recovery with 20 micrograms); and totally ineffective against ceftazidime, imipenem, and meropenem. This investigation resulted in a useful procedure for qualifying and/or selecting a beta-lactamase for use in environmental monitoring medium to neutralize a particular beta-lactam.     

Gadofosveset (EPIX/Schering)

EPIX Medical and Schering are developing gadofosveset, an albumin-binding gadolinium-based intravascular magnetic resonance imaging contrast agent, for the potential imaging of blood vessels and blood flow, particularly in patients with peripheral vascular disease (PVD). By February 2004, US approval of the agent was anticipated in October 2004, and in June 2004, Schering filed an MAA in the EU for PVD.     

Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody

Natalizumab [AN 100226, anti-alpha4 integrin monoclonal antibody, Antegren] is a humanised monoclonal antibody that blocks alpha4beta1 integrin-mediated leukocyte migration. Natalizumab is in phase III trials for the treatment of multiple sclerosis in North America and the UK, and for the treatment of Crohn's disease also in the UK. It may have potential in the treatment of other immune-related inflammatory disease. Elan Corporation intends to examine the potential of natalizumab in rheumatoid arthritis and ulcerative colitis. 4beta1 integrin on circulating leukocytes binds to vascular cell adhesion molecule-1, which is expressed at high levels in the blood vessels in the CNS during exacerbations of multiple sclerosis. This allows leukocytes expressing alpha4beta1 integrin (very late antigen-4) to move from the peripheral blood into the CNS. Inflammatory proteins and other factors released from lymphocytes in the brain lead to the progression of symptoms. A limitation of natalizumab is that it must be injected and cannot be administered orally. Scientists have transformed the large anti-alpha4 monoclonal antibody into much smaller, drug-like molecules suitable for oral administration. Protein Design Labs has granted a worldwide nonexclusive licence under its antibody humanisation patents to Elan Pharmaceuticals for natalizumab. Biogen Inc. has entered into an agreement with Elan for a worldwide exclusive collaboration to develop, manufacture and commercialise natalizumab for multiple sclerosis and Crohn's disease and rheumatoid arthritis. Development of natalizumab is also being funded, in part, by Axogen (acquired by Elan in 1999). In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Elan repurchased royalty rights on a package of products, including natalizumab, from Autoimmune Disease Research Company. Elan and Genzyme Transgenics Corporation signed an agreement to produce natalizumab in GTC's genetically engineered goats, which will express the compound in their milk. Genzyme Transgenics Corporation changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. Following discussions with the US FDA, Elan completed enrolment in a second phase III trial, involving approximately 420 patients with Crohn's disease. This Evaluation of Natalizumab as Continuous Therapy-2 (ENACT-2) trial evaluated the effect of natalizumab on duration of response and remission in patients with Crohn's disease. In January 2004, Elan Corporation and Biogen Idec announced that the phase III, ENACT-2 maintenance trial of natalizumab in Crohn's disease met the primary endpoint of maintenance of response. Elan and Biogen Idec will discuss these data with regulatory authorities in both the US and Europe and determine the appropriate path forward for natalizumab in Crohn's disease. An NDA for Antegren in Crohn's disease was expected to be filed at the end of 2003; however, due to failing to meet the primary endpoint in the induction trial, Elan is unable to predict when and if a regulatory filing will be made. Earlier, on 23 January 2001, the Wall Street Journal reported that the Biogen CEO expects Antegren to become a blockbuster drug, with sales of at least $US1 billion. He also predicted that Antegren could be on the market as early as 2003 for the indication of Crohn's disease and in 2004 for multiple sclerosis. The Journal stated that Biogen is under pressure to develop new drugs since its flagship product Avonex will be losing its US Orphan Drug Act protection in 2003. Antegren has a different mechanism to that of Avonex and could be used either alone or as a combination therapy.     

Ezetimibe + simvastatin (Merck/Schering-Plough)

Merck/Schering-Plough Pharmaceuticals has developed and launched ezetimibe + simvastatin (Vytorin), a fixed combination tablet of Schering-Plough's cholesterol absorption inhibitor ezetimebe (Zetia), and Merck's HMG CoA reductase inhibitor simvastatin (Zocor), for the treatment of hypercholesterolemia. The drug had been launched in Germany and Mexico by April 2004, and, in July 2004, was approved in the US, with expected launch late in 2004.     

Clofarabine

Clofarabine [Clofarex] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute. In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine. Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute. Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003. In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio. Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license. Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing. The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML). In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL. A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported. In May 2004, Bioenvision announced that it had decided to stop enrollment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enroll approximately 65 patients with AML considered unsuitable for intensive chemotherapy. Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe. In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2-6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia. In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment. As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002. Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers. A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.     

Tegaserod (Novartis)

Novartis has developed and launched tegaserod, an aminoguanidine indole 5-HT(4) receptor partial agonist, for the potential treatment of constipation-predominant irritable bowel syndrome (IBS) [286804], [311514] and other functional GI disorders, such as gastroesophageal reflux disease (GERD), chronic constipation and functional dyspepsia [342937], [362853]. It was launched in Mexico for IBS in July 2001 [416879] and in the Czech Republic, Venezuela and Colombia by October 2001. By this time, the product had also been approved in Switzerland [427419]. In September 2001, launch of the product for GERD, chronic constipation and functional dyspepsia was expected after 2003 [422828]; later in October 2001, the launch dates for the latter two indications were anticipated for 2004 [427419], [431614]. In December 2000, Merrill Lynch predicted sales of SFr 150 million in 2001, rising to SFr 612 million in 2004, larger than the September 2000 predictions of SFr 120 million in 2001 rising to SFr 378 million in 2004 [394812], [383742]. Later in February 2001, Merrill Lynch predicted sales of SFr 150 million in 2001 rising to SFr 785 million per annum in 2005, assuming a US launch during the third quarter of 2001 [411704]. Following the withdrawal of the MAA and then the rejection of tegaserod's NDA by the FDA, in June 2001, Merrill Lynch progressively revised its 2005 sales forecasts from SFr 1.1 billion to SFr 950 million and then to SFr 375 million [422783]. In June 2001, Merrill Lynch also suggested that there was a significant possibility that tegaserod would never reach the market. In August 2001, Deutsche Bank estimated sales of SFr 200 million in 2004 and SFr 550 million in 2005 [422674]. Analysts at Credit Suisse predicted in October 2001, that there was only a three in ten chance that tegaserod would ever reach a major market following the issuance of a 'non-approvable' letter by the FDA in June 2001. They predicted sales of SFr 5 million in 2001, rising to SFr 325 million in 2005 [426409].     

Ciclesonide ( Byk Gulden)

Ciclesonide, a non-halogenated inhaled corticosteroid with anti-inflammatory activity, is under development by Byk Gulden, Aventis and Teijin as a potential treatment for asthma [213439]. It was also being developed by Byk Gulden for chronic obstructive pulmonary disease (COPD), but no development had been reported for this indication since 1999; however, Teijin was carrying out clinical trials in this indication at the end of 2000. During 2000, Byk Gulden was carrying out phase III trials in the US and Europe and in March 2001, results were expected in the third quarter of 2001 [312399], [383726], [423659]. Two inhalant formulations (multidose powder and propellant filled) and a nasal formulation of ciclesonide are being developed by Byk Gulden for the treatment of asthma and seasonal allergic rhinitis, respectively [337147]. The compound is formulated for once-daily dosing and demonstrated good efficacy without corticosteroid-associated systemic side effects [409257]. In January 2001, Byk Gulden expected launch of a CFC-free multidose inhaler formulation in 2003 [395596]; in March 1999, launch of a nasal formulation was expected in 2004 and a multidose powder inhaler in 2005 [337147]. By September 2001, the compound was in phase III trials in the US for asthma, with a potential US launch anticipated by Aventis in 2004 [423465]. In November 2001, Aventis expected to submit an NDA to the FDA in 2003 [428057]. Teijin, which has a development and licensing agreement with Byk Gulden for the treatment of asthma and COPD in Japan, commenced phase I trials of ciclesonide in Japan in spring 1999, had completed these during 2000, and began phase II trials by September of that year [383726]. An NDA is expected to befiled in Japan in 2003. In October 2000 and April 2001, Merrill Lynch predicted peak sales of Euro400 million in 2007, with sales of Euro5 million in 2002, rising to Euro150 million in 2004 [395562], [420574]. Deutsche Bank predicted in August 2001, that sales of the product would reach Euro70 million in 2004, rising to Euro150 million in 2005 [420814].     

Use of Identical INN “Imiglucerase” for Different Drug Products: Impact Analysis of Adverse Events in a Proprietary Global Safety Database

Drug Safety - Approved in 1994 and assigned the International Nonproprietary Name (INN) imiglucerase by the World Health Organization, Cerezyme® (Sanofi Genzyme) is an enzyme replacement...     

Maribavir (ViroPharma)

ViroPharma, under license from GlaxoSmithKline, is developing maribavir, a DNA synthesis inhibitor for the potential prevention and treatment of human cytomegalovirus infections related to transplants (including solid organ and hematopoietic stem cells), congenital transmission, and in patients with HIV infection. In July 2004, a phase II trial was initiated.     

SPK-843 (Aparts/Kaken)

SPK-843 is a water-soluble antibiotic under co-development by Aparts and Kaken for the potential treatment of systemic fungal infections. By November 2004, SPK-843 was in phase II trials for systemic mycosis.     

Tolevamer, an orally administered, toxin-binding polymer for Clostridium difficile-associated diarrhea

Genzyme Corp is developing tolevamer, an anionic toxin-binding polymer that binds and neutralizes the Clostridium difficile A and B toxins, for the potential treatment of C difficile-associated diarrhea (CDAD). Two phase III clinical trials of tolevamer in patients with CDAD have been completed and results from the second trial are expected to be released imminently.     

Telavancin (Theravance)

Theravance is developing telavancin, an injectable peptidoglycan inhibitor antibiotic for potential use in the treatment of Gram-positive bacterial infection. Phase III trials in complicated skin and skin structure infections commenced in September 2004.     

Valdecoxib (Pharmacia)

Pharmacia (formerly Searle), in collaboration with Pfizer and Yamanouchi, has developed valdecoxib, a second-generation cyclooxygenase (COX)-2 inhibitor as a follow-up to celecoxib, for the treatment of arthritis. Pharmacia filed an NDA with the FDA in March 2001 for the treatment of acute pain, dysmenorrhea, osteoarthritis (OA) and rheumatoid arthritis (RA). At this time, Pharmacia anticipated a 12-month review [402883]. In June 2001, launch was anticipated in 2002 [412616], and in November 2001, valdecoxib was granted FDA approval [429715]. The company claims that valdecoxib has improved potency and broader therapeutic range than other COX-2 inhibitors including celecoxib, and has the potential for once-daily dosing [287279], [313957]. By 1999, due to the poor water solubility of valdecoxib, Searle was also developing the prodrug parecoxib [324667]. Valdecoxib has been described by Searle as almost superimposable at the site critical for COX-2 inhibition, a structural side pocket in the enzyme which coincides with the sulfonamide group of the drug [324667]. In April 2000, Morgan Stanley Dean Witter estimated sales would be US $400 million in 2003, rising to US $750 million in 2004 [375906]. In April 2001, Merrill Lynch predicted world sales of US $460 million in 2002, rising to $1,065 million in 2005 [420574]. In September 2000, Merrill Lynch reported that additional pain data were being accumulated for this drug, the possible inclusion of which could push filing back to later in the first half of 2001 [382577]. In May 2001, Merrill Lynch expected launch in 2002 [411811]. In August 2001, Lehman Brothers predicted that launch would take place in thefirst half of 2002 and the product would make peak sales of US $1,500 million [420809]. Credit Suisse predicted in this month that total sales would reach US $330 million in 2002, rising to US $1832 million in 2004 [422318]. In September 2001, Morgan Stanley expected launch in the first half of 2002 [427113]. By October 2001, Credit Suisse had revised its sales predictions to US $180 million in 2002, US $790 million in 2003 and US $1,430 in 2004 [427185].