Roflumilast: APTA 2217, B9302-107, BY 217, BYK 20869

Roflumilast [APTA 2217, B9302-107, BY 217, BYK 20869] is a selective phosphodiesterase IV inhibitor. It is being developed by Altana Pharma (formerly Byk Gulden), a subsidiary of Altana Group, as an orally administered therapy for asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and psoriasis. The drug is awaiting regulatory approval in Europe for the treatment of asthma and COPD. Byk Gulden has stated that roflumilast relieves asthma symptoms through both an anti-inflammatory effect and a muscle relaxant effect. Roflumilast has potential as first-line long-term therapy in mild-to-moderate COPD and as additive long-term therapy in moderate-to-severe COPD. Altana has stated that roflumilast is to be marketed under the brand name Daxas. Altana Group and Pharmacia Corporation (now Pfizer) signed an agreement on 22 April 2002 to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory disorders, including asthma and COPD. The companies will jointly develop the drug for the US, Europe and other markets. Pharmacia will co-ordinate development in the US and Altana will co-ordinate development in Europe. After approval of the drug, Pharmacia and Altana will jointly launch and promote roflumilast in the US, Europe and elsewhere. Altana will receive an upfront payment and additional milestone payments. Altana additionally has the option to co-promote Pharmacia products in the US and elsewhere. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. In November 2002, Altana and Tanabe Seiyaku signed an agreement to collaborate on the development and commercialisation of roflumilast for the treatment of respiratory diseases, including asthma and COPD. Tanabe Seiyaku and Altana will develop roflumilast for asthma and COPD in Japan, and will jointly launch and co-promote roflumilast in Japan following regulatory approval. Roflumilast has been in multinational phase III clinical studies in Europe for the treatment of asthma and COPD. In September 2003, Altana announced the completion of a phase III trial in COPD in more than 1400 patients; the trial showed positive results. In the US, roflumilast is in phase III trials for the treatment of asthma and phase II trials for the treatment of COPD. Phase I clinical trials of roflumilast were begun in Japan by Tanabe Seiyaku in the fourth quarter of 2003. Altana has stated that roflumilast has shown significant superiority over placebo in the treatment of asthma in phase II trials. The efficacy of the drug appears to be comparable to low-dose inhaled corticosteroids in the treatment of asthma and at least equal to inhaled corticosteroids in the treatment of COPD. Altana Group presented data from phase II trials in 516 patients with COPD at an analyst meeting [August 2001, Bad Homburg, Germany] that showed that roflumilast 500 microg/day significantly improved FEV(1) at 24 weeks compared with placebo. In March 2004, Altana Pharma presented pharmacokinetic data from a phase I trial of roflumilast at the 60th Annual Meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI-2004) [San Francisco, CA, USA]. This open-label, randomised, two-period crossover study investigated the pharmacokinetics of oral roflumilast and its active metabolite, roflumilast N-oxide, among 12 healthy male subjects. Participants received single doses of oral roflumilast 500 microg and intravenous (i.v) roflumilast 150 microg as a 15-min short-term infusion. In November 2002, the combined global market for asthma and COPD products was estimated to be worth >11 billion US dollars. In Japan, products in this market segment reached sales of approximately 1.5 billion US dollars in 2001. Roflumilast has patent protection in Europe and Japan until 2014 and in the US until 2015. The Financial Times in April 2002 claimed that roflumilast is an 'important' product for Altana, due to be listed on the New York Stock Exchange later in the same month. The Altana chairman confirmed that the company had been in talks with Pfizer, Bristol-Myers Squibb and Novartis with regard to future development and commercialisation of roflumilast. In September 2002, Dow Jones Newswires stated that Altana is to file for European approval of roflumilast 1 year later than initially was expected; however, this has not changed the company's outlook for the product, which was said to remain at at 1 billion Euros. In August 2001, the Financial Times reported that roflumilast, for the indication of smoker's cough alone, has the potential to reach sales of more than 500 million US dollars a year. A future co-marketing deal for roflumilast in the US was said to be "a key step towards expanding Altana's presence in the US".     

Eszopiclone: esopiclone, estorra, S-zopiclone, zopiclone--Sepracor

Eszopiclone [Lunesta, Estorra] is a short-acting hypnotic agent that is a stereoselective isomer of the agent zopiclone, which has been available in Europe since 1992. Eszopiclone is structurally unrelated to the benzodiazepines, and Sepracor (the originator of eszopiclone) has stated that the drug acts rapidly, with the duration of effect lasting up to 6 hours. This may result in improved sleep maintenance, with less nocturnal awakening.Originally, racemic zopiclone was developed and marketed by Rhone-Poulenc Rorer, which merged with Hoechst Marion Roussel to form Aventis. Sepracor anticipates that eszopiclone will have equivalent efficacy to the racemic version with potential for an improved side effect profile. In October 1999, Sepracor exclusively licensed Aventis Pharma's preclinical, clinical and postmarketing surveillance data package for zopiclone, its isomers and metabolites. The company intends to use this information in addition to data from Sepracor's own studies as part of the regulatory package to gain approval of eszopiclone in the US. In July 2004, Sepracor announced terms of an additional agreement with Aventis under which it would have the right to read and reference Aventis' regulatory filings related to zopiclone outside the US for the purpose of development and regulatory registration of eszopiclone outside the US. Additionally, Aventis would assign Sepracor the foreign counterparts to the US patent covering eszopiclone and its therapeutic use. In August 2004, Paul Royalty Fund II, an affiliate of Paul Capital Partners, purchased from Sanofi-Aventis the royalty rights on US sales of eszopiclone. In exchange for the rights, Sanofi-Aventis will receive fixed and milestone payments totalling up to US$115 million. In December 2004 the US FDA approved eszopiclone (Lunesta) for the treatment of insomnia. It is indicated for patients who experience difficulty falling asleep as well as for patients who have sleep maintenance difficulty, and is approved for long-term treatment. The recommended dosing to improve sleep onset and/or maintenance is 2mg or 3mg for adult patients (aged 18-64 years) and 2mg for older adult patients (aged > or =65 years). The 1mg dose is for sleep onset in older adult patients whose primary complaint is difficulty falling asleep. The launch of eszopiclone in the US is expected to take place in the first quarter of 2005. The approval follows an NDA submission in January 2003, an approvable letter in February 2004, and a resubmission of the NDA in June 2004. The NDA contained data from 24 clinical trials that included >2700 adult and elderly subjects, as well as data from >60 preclinical studies. Six phase III trials in adult and elderly patients with chronic or transient insomnias were also included in the data submission. Preliminary results from a completed phase IIIB/IV trial report that eszopiclone in combination with fluoxetine significantly improved sleep parameters among patients with insomnia and co-existing major depressive disorder. Furthermore the combination of eszopiclone and fluoxetine resulted in greater improvement in HAM-D17 scores in patients than the fluoxetine-placebo group. This trial and three other phase IIIB/IV were initiated in late 2003 to evaluate the efficacy of eszopiclone in the treatment of insomnia in patients with depression, rheumatoid arthritis, chronic insomnia, and in women who experience symptoms of perimenopause. Sepracor has been granted a US patent for eszopiclone [S-zopiclone, (+)-zopiclone, Lunesta, Estorra], a single isomer of zopiclone.US patents (Nos. 6,319,926 and 6,444,673) have been issued covering the use of eszopiclone for the treatment of insomnia, eszopiclone and pharmaceutical compositions comprising eszopiclone.     

(S)-Zopiclone Sepracor

(S)-Zopiclone, a cyclopyrrolone sharing activity with benzodiazepines in the CNS, is a short-acting sedative being developed by Sepracorfor the potential treatment of sleeping disorders. In August 2000, the company had completed phase II trials of (S)-zopiclone for insomnia [380377]; by September 2000, patient enrollmentfor phase III studies for insomnia was completed and the trial initiation was planned for October 2000 [381361]. Merrill Lynch expects US filing to take place in the second half of 2001 [383230]. Sepracor was granted US-05786357 in August 1998 covering methods and compositions of (S)-zopiclone in the treatment of sleeping disorders [342938]. In August 2000, Merrill Lynch predicted (S)-zopiclone sales of US $30 million in 2002, rising to US $150 million in 2004 [383230].     

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].     

AN-1792 (Elan)

Elan is developing AN-1792 as a potential immunotherapy for Alzheimer's disease (AD). It is currently in phase I trials [350904]. Phase II/III trials, running in parallel in the US and UK, are expected to start by the end of 2001 [375061], [383226], [401966]. American Home Products (AHP) are collaborating with Elan on research and development of an immunotherapy directed towards the beta-amyloid peptide, including AN-1792 and other potential products [361702]. In September 2000, an agreement was established between Elan, AHP and Cambridge Antibody Technology (CAT), whereby CAT are investigating anti-beta-amyloid human antibodies [394844]. In July 2000, Merrill Lynch predicted a possible late-2001 entry into pivotal trials with a potential NDA filing in 2004 [375966]. The clinical program is expected to take approximately four years [339630]. In April 2001, ABN Amro Hoare Govett stated that, if data from the large phase II trial expected to start late in 2001 satisfied FDA requirements, then Elan might be able to file an NDA in 2003, with a potential launch in 2005 [407412].     

MethyPatch Noven

Noven Pharmaceuticals is developing a transdermal patch formulation of methylphenidate for the treatment of attention deficit hyperactivity disorder (ADHD) [325808]. Phase III trials were completed in February 2002 [438893]; at this time, the company predicted a 2003 launch for the product [441478]. In April 2002, based on pivotal phase III trial results, Noven expected to file an NDA with the FDA in mid-2002 and to launch the product in the second half of 2003 [445181]. In June 2002, the NDA was filed [456552]. The original phase III trials were completed in the first quarter of 2001 [407254]. However, preliminary analysis of the phase III trial, reported in April 2001, suggested that a supplemental study would be required to support the filing [403771]. At this time, an NDA filing, originally planned for the second quarter of 2001, was rescheduled for the first half of 2002 [400122], [407640], [410285], [441478]. As of August 2001, the supplemental study was expected to begin in autumn of that year [417877]. In October 2001, enrolment was initiated in Noven's pivotal, double-blind, placebo-controlled, multicenter phase III study of MethyPatch [427321], and it was completed in February 2002 [438893]. In May 2001, the company was issued patent US-06210705 relating to the transdermal delivery of methylphenidate for the treatment of ADHD [410285]. In June 2001, ABN AMRO predicted sales of US $61 million in 2002, rising to US $74 million in 2005 [422762]. Analysts at Morgan Stanley predicted in May 2002 that the product would make US sales of US $9.1 million in 2003, rising to US $22.5 million in 2006 [454573].     

Cinacalcet: AMG 073, Calcimimetics--Amgen/NPS Pharmaceuticals, KRN 1493, NPS 1493

Cinacalcet [AMG 073, KRN 1493, NPS 1493] is an orally active, second-generation calcimimetic compound licensed by NPS Pharmaceuticals to Amgen in the US for potential treatment of hyperparathyroidism (HPT). Cinacalcet modulates (increases the sensitivity of) calcium receptors on the surface of parathyroid cells thereby inhibiting the oversecretion of parathyroid hormone, which characterises HPT. It also represents a potentially significant advance for chronic kidney disease patients diagnosed with secondary HPT, a common yet serious metabolic disorder where parathyroid hormone levels are elevated. Patients with this disease can suffer from bone disease, bone pain and fractures, soft tissue calcification, vascular calcification and cardiovascular complications. Amgen has rights to develop and sell cinacalcet throughout the world except in Japan, Taiwan and China, where the compound was licensed to Kirin Brewery. Kirin is developing it as KRN 1493 in phase II clinical studies in Japan. In December 2001, commencement of a phase III clinical trial with cinacalcet for the treatment of secondary HPT, triggered a 3 million US dollars milestone payment to NPS Pharmaceuticals. In September 2003, submission of an NDA to the US FDA for cinacalcet for secondary HPT will be followed by a milestone payment of 6 million US dollars to NPS. NPS, Kirin and Amgen were also developing another compound, tecalcet, for HPT, but that project has been discontinued in favour of cinacalcet. In September 2003, Amgen submitted an NDA to the US FDA for secondary HPT in patients with chronic kidney disease. In April 2003, Amgen announced positive results from a phase III clinical trial with cinacalcet in patients with secondary HPT. In a clinical study in patients on dialysis suffering from the effects of chronically elevated levels parathyroid hormone, cinacalcet appeared to be safe and well tolerated and was significantly more effective than placebo. Two more additional efficacy studies with cinacalcet have also been completed. Phase II trials of cinacalcet in dialysis patients with secondary HPT and in patients with primary HPT were successfully completed.     

Rubitecan: 9-NC, 9-Nitro-20(S)-camptothecin, 9-nitro-camptothecin, 9-nitrocamptothecin, RFS 2000, RFS2000

Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for rubitecan in the treatment of pancreatic cancer and fast-track status for rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.     

Histrelin Hydrogel Implant--Valera: Histrelin implant, LHRH-Hydrogel implant, RL 0903, SPD 424

Valera Pharmaceuticals, formerly Hydro Med Sciences, is developing a once-yearly Histrelin Hydrogel Implant [Histrelin implant, LHRH-Hydrogel implant, RL 0903, SPD 424, Vantas], a subcutaneous (s.c.) reservoir device capable of long-term delivery of histrelin at constant release rates for the treatment of prostate cancer. Histrelin is a luteinising hormone-releasing hormone agonist (LHRH). A different formulation of the LHRH implant is currently in development for the treatment of central precocious puberty (CPP). On 4 September 2003, Hydro Med Sciences announced that it had changed its name to Valera Pharmaceuticals. Shire Pharmaceuticals had an option to market and distribute the histrelin implant outside the US, but in a realigned agreement announced in January 2002, Shire stated that HydroMed (now Valera) would be responsible for concluding the phase III studies, filing for regulatory approval and producing the implant, while also gaining marketing rights in the US. Shire has no further involvement in development, but retains an option to market and distribute the product outside the US. The product is available for rest-of-the-world licensing through Valera Pharmaceuticals' business development division. Paladin Labs has received the exclusive rights for the sale and marketing of histrelin hydrogel implant in Canada. Valera Pharmaceuticals will have the responsibility for manufacturing and completing development of the product. In July 2004, Paladin announced it had filed for regulatory approval with Health Canada for the treatment of prostate cancer. Phase III trials have been conducted and initially involved two open-labelled, randomised, parallel studies that compared the hydrogel implant with the active comparators, leuprorelin acetate 22.5 mg depot (TAP Pharmaceutical's Lupron Depot) and a 3-month implant of goserelin acetate (Astra Zeneca's Zoladex). However, because of financial constraints, HydroMed discontinued recruitment in a phase II European study and could not rationalise keeping the comparator arm of the phase III study. The US FDA then gave permission to continue the US part of the programme without the comparator arm, but with appropriate increases in the patient sample size. Patient enrolment in the phase III trial (US and Canada) was completed in July 2002. Valera Pharmaceuticals believes the product may have advantages over standard prostate cancer treatments including reduced costly surgical procedures, lower dosing, increased patient compliance and peace-of-mind, as well as potentially less cost to the patient. The phase III studies were completed in the second half of 2003.CPP arises from the increased release by the pituitary gland hormone gonadotropins and is characterised by an early onset of sexual development in pre-adolescents. Currently, the treatment of CPP involves injections of synthetic gonadotropic hormone-releasing factor agonists such as Supprelin (histrelin acetate) and TAP Pharmaceutical's Lupron Depot-Red (leuprolide acetate) every 28 days, a potentially painful procedure. This treatment inhibits pituitary release of gonadotropins. Valera's histrelin implant is a compact, removable subcutaneous implant that can be applied under a local anaesthetic in doctor's surgery.     

ONO-6818 Cortech/Ono

ONO-6818 (CP-955) is the lead compound in a series of orally bioavailable neutrophil elastase inhibitors licensed from Cortech and under investigation by Ono for the potential treatment of inflammatory conditions, such as rheumatoid arthritis, inflammatory bowel disease and chronic obstructive pulmonary disease (COPD) [174095]. ONO-6818 was in phase I studies for COPD in Japan as of December 1999 [366431]. Phase I trials for this indication in Japan and the US were ongoing in September 2001 [368565], [422782], [446138]. As of June 2002, however, a number of unconfirmed reports stated that the compound had moved into phase II trials in Japan and was in preparation for phase II trials in the US [456596], [456597].     

Oxipurinol: alloxanthine, Oxyprim, oxypurinol

Oxipurinol [alloxanthine, Oxyprim, oxypurinol] is the active metabolite of the only commercially available xanthine oxidase inhibitor, allopurinol. Oxipurinol is also a xanthine oxidase inhibitor. Oxipurinol is currently being developed by Cardiome Pharma. It is waiting for approval in the US for the treatment of allopurinol-intolerant hyperuricaemia (gout) and is in phase III trials for the treatment of congestive heart failure. Allopurinol is indicated for the treatment of symptomatic hyperuricaemia, or gout. Approximately 3-5% of patients receiving allopurinol develop intolerance to the drug. Oxipurinol was originally developed by Burroughs Wellcome (later GlaxoSmithKline), and has been available on a compassionate-use basis since 1967 for use in allopurinol-intolerant patients. The licensee company ILEX Oncology has stated that oxipurinol does not have patent protection. Oxipurinol's potential for treatment of congestive heart failure is based on the possibility that xanthine oxidase inhibitors may improve myocardial work efficiency by sensitising cardiac muscle cells to calcium ions, which are a key determinant of cardiac muscle function. This results in more efficient contraction of cardiac muscle cells, without the same increase in oxygen demand. At the second annual BioPartnering North America conference (BPN-2004) [February 2004, Vancouver, Canada], Cardiome Pharma stated that it was seeking a commercialisation partner to market and distribute oxipurinol in the US for the treatment of allopurinol-intolerant hyperuricaemia. In 1995, ILEX Oncology obtained an exclusive licence to oxipurinol from Burroughs Wellcome. Burroughs Wellcome later became part of Glaxo Wellcome, which merged with SmithKline Beecham in December 2000 to form GlaxoSmithKline. ILEX's licence agreement is now with GlaxoSmithKline and The Wellcome Foundation. In December 2001, ILEX granted Paralex, a privately held New York-based company, an exclusive sublicence to all of ILEX's rights to oxipurinol for the treatment of hyperuricaemia in allopurinol-intolerant patients. Paralex additionally gained the right to develop and commercialise oxipurinol in all fields, under data and technology owned by ILEX. Furthermore, Paralex had licensed certain intellectual property rights from The John Hopkins University relating to cardiovascular applications of xanthine oxidase inhibitors. Paralex was acquired by Cardiome Pharma in March 2002. Cardiome Pharma announced early in May 2002 that it had exercised its option to acquire from ILEX Oncology Inc. rights to clinical trial data for oxypurinol for the treatment of gout in allopurinol-intolerant patients. ILEX completed its open-label phase II clinical study of Oxyprim in allopurinol-intolerant gout patients, and the trial data were transferred to Cardiome. Cardiome stated in May 2002 that it intended to commence a further phase II trial of oxypurinol in gout. Phase III trials were in progress in 2003 in this indication. In 1995, ILEX Oncology continued the compassionate use distribution of oxipurinol while establishing a US FDA-approved registration plan for the agent. In November 1998, ILEX received Orphan Drug status for the use of oxipurinol in patients with symptomatic hyperuricaemia. ILEX Oncology's Development Pipeline for 1998 stated that oxipurinol had entered phase II clinical trials for the treatment of hyperuricaemia. In 2001, the clinical trials listing service CenterWatch stated that oxipurinol was in a phase II clinical trial with ILEX Oncology for the treatment of symptomatic hyperuricaemia in patients who are intolerant to allopurinol. The trial appeared to be taking place in the US, and was a multicentre, open-label, 14-week study in 90 patients. In February 2003, Cardiome confirmed beginning patient enrollment in three smaller phase II studies, with the first trial (EXOTIC) now completed. These three smaller proof-of-concept studies will observe surrogate endpoints such as cardiac output and exercise tolerance. The second proof-of-concept study in patients with CHF of ischemic aetiology (IV), known as EXOTIC-EF (Evaluation of XanThine Oxidase Inhibition on Cardiac Ejection Fraction), will assess the effects of oxypurinol on left ventricular performance. The EXOTIC-EF trial will start in the first quarter of 2004 and be completed by the second quarter of 2004. The third, LA PLATA, proof-of-concept study will explore the effects of 1 month of oral oxypurinol therapy on exercise capacity and left ventricular performance. It is projected that the LA PLATA study will start in the first quarter of 2004 and be completed by the third quarter of 2004. During the Heart Failure Society of America's meeting on 21 September 2003, Cardiome presented clinical data from its first proof-of-concept EXOTIC (European Xanthine Oxidase Inhibitors Trial In Cardiac Disease) study. Cardiome intends to conduct a second trial, at the Eppendorf Clinic at the University of Hamburg, to determine the effect of oxypurinol on left ventricular performance in patients with CHF of ischaemic aetiology. This study will be an extension of the original proof-of-concept study. According to the 1st Annual BioPartnering conference held in Vancouver, Canada, in February 2003, Cardiome is seeking co-development partners for oxipurinol in the treatment of congestive heart failure. In July 2003, the US Patent and Trademark Office issued a new patent providing additional protection to Cardiome's programme focused on treatment of congestive heart failure with oxypurinol. The patent, No. 6,569,862, was the second issued to the Johns Hopkins University (JHU) in this field. The key claims in the new patent cover use of the entire family of drugs known as xanthine oxidase inhibitors applied to contractile disorders of the heart, including congestive heart failure. An earlier patent issued to JHU contained provisions relating to a specific mechanism of action and to specific forms of heart disease. Both patents and related intellectual property are licensed exclusively to Cardiome.     

Motexafin gadolinium: gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser for the treatment of brain metastases. The trial was conducted at 35 centres in Europe, Canada and the US. Full results from this initial phase III trial were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida, USA, held in May 2002. Pharmacyclics also announced in October 2002, at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO), that motexafin gadolinium significantly prolonged time to neurological progression when added to whole brain radiation therapy and reduced the number of deaths in patients with brain tumour. Pharmacyclics announced in September 2000 that it has initiated two NCI-sponsored phase I trials conducted under a Cooperative Research and Development Agreement (CRADA) between Pharmacyclics and the NCI. The first trial, conducted in patients with stage IIIA non-small cell lung cancer, was designed to determine the safety of two different dosing regimens of motexafin gadolinium during preoperative radiotherapy after induction chemotherapy. The second study was designed to examine the use of motexafin gadolinium in combination with stereotactic Gamma Knife radiosurgery in patients with primary glioblastoma mutiforme. Two phase I clinical trials have also been conducted for the treatment of newly diagnosed glioblastoma multiforme at the UCLA Jonsson Comprehensive Cancer Center, USA. These phase I studies were sponsored by the NCI and were conducted under a CRADA with the NCI. Pharmacyclics has also completed multicentre US phase II clinical trials of motexafin gadolinium fin gadolinium in patients with metastatic tumours of the brain who require whole brain radiotherapy. Motexafin gadolinium is in a phase II trial in patients with lymphomas and multiple myeloma in the US.     

Formoterol dry-powder inhalation--Novartis/SkyePharma: Foradil MDDPI, Foradil MDPI, Foradil SkyeHaler, formoterol fumarate dry-powder inhalation

In November 1998, Novartis Pharma of Switzerland and SkyePharma PLC of the UK signed an agreement to jointly develop a new formulation of the beta(2)-adrenoceptor agonist formoterol (Foradil). The new product, Foradil Certihaler, utilises a multidose dry-powder inhaler (MDPI or MDDPI) device, SkyeHaler, developed by SkyePharma. It also utilises SkyePharma's SkyeProtect powder formulation technology, which protects the drug from moisture. The product is waiting for approval for the treatment of asthma. Foradil MDPI may also have potential for the treatment of chronic obstructive pulmonary disease (COPD). Novartis has stated that Foradil Certihaler offers certainty of dosing and dose confirmation, and will also contain a dose counter that indicates the number of doses left. SkyePharma is responsible for development of the product in its finished form; this includes the supply of both the powder and the inhalation device as a product to Novartis. The product is manufactured at SkyePharma's Lyon facility in France. SkyePharma is receiving fees, development costs and milestone payments from Novartis. SkyePharma will also receive royalty income on worldwide sales. SkyePharma has granted Novartis an exclusive worldwide licence to market Foradil MDPI.Foradil Certihaler was approved in Switzerland in March 2004. This is the first approval in Europe, and will trigger an undisclosed milestone payment by Novartis to SkyePharma. Submissions for regulatory approval in the asthma indication were filed in the EU (on a country-by-country basis) and the US in December 2002. On 22 October 2003, SkyePharma announced that the US FDA had issued an 'approvable' letter for Foradil Certihaler. Launch of the product is anticipated for 2004. Clinical trials of Foradil MDPI for the treatment of asthma began in October 1999. In December 2000, phase III trials commenced in Europe. SkyePharma stated in April 2001 that phase III trials had commenced recently in the US. SkyePharma estimated in April 2001 that the worldwide sales potential of Foradil MDPI could be as much as 600 million US dollars. SkyePharma anticipates receiving royalties and manufacturing revenues of more than 10%.     

ISA 247: trans-ISA 247, trans-R 1524, ISA(TX)247, ISAtx 247, ISATx247, LX 211, LX211, R 1524, R-1524

Isotechnika is developing the immunosuppressive drug ISA 247, a calcineurin inhibitor that is undergoing clinical development for the treatment of psoriasis (phase III) and prevention of organ rejection after transplantation (phase II). Preclinical development for uveitis is also underway. Other autoimmune disease indications that could be explored include arthritis, type I diabetes and Crohn's disease. ISA 247 was being co-developed as R 1524 by Isotechnika and Roche. However, Roche is no longer involved in the development of this compound. Based on analysis of previously collected data, the trans-ISA 247 isomer was found to be more bioavailable and it is expected that this isomer can be administered at a lower dose compared with the previous formulation that consisted of an equivalent mixture of the two geometric isomers (cis and trans). Preclinical observations indicate that ISA 247 has the potential to be more potent and less toxic than other marketed immunosuppressants in its class used for the prevention of transplant rejection. Experiments to date suggest that ISA 247 is about three times as potent as ciclosporin, while genotoxicity studies in animals have shown that the compound has a significantly reduced tendency to cause renal toxicity. The combination of reduced toxicity and improved potency would give ISA 247 a therapeutic benefit over existing calcineurin-based treatments. Isotechnika and Roche entered into a co-development and commercialisation agreement in April 2002, with Roche gaining the exclusive worldwide marketing rights for ISA 247; Isotechnika received milestone payments of $US4 million and $CAN21.9 million in September 2002 and May 2003, respectively. The agreement was restructured in April 2004, under which Isotechnika will now solely manage and fund the clinical development of trans-ISA 247. Upon successful completion of these trials, Isotechnika will conduct at its own expense a phase IIb study in renal transplantation and phase III studies in psoriasis. Roche will have the right to opt-in to the development and commercialisation of trans-ISA 247 for transplant indications up to the end of the phase IIb renal transplantation trial. Isotechnika retains all rights to develop and commercialise the product outside of transplant indications. Under an agreement signed with Cellgate Inc. on 25 April 2006, Isotechnika has the option to obtain an exclusive licence to develop and commercialise conjugates consisting of Cellgate's patented transporter technology, for the topical delivery of ISA 247 in patients with mild-to-moderate psoriasis. Cellgate will perform studies to evaluate the feasibility of using their technology to topically deliver ISA 247. In return, Isotechnika will pay Cellgate Inc. a total of $US500 000, with $US100 000 paid upfront, and the remainder at predetermined time points. Upon successful completion of the studies, Isotechnika has the option to further develop and commercialise conjugates for topical delivery of ISA 247. Isotechnika and Atrium Medical Corporation announced an exclusive worldwide licensing agreement for ISA 247 alone and in combination with TAFA 93 with respect to drug-eluting devices, in September 2005. Atrium's implantable products include those for the local, non-systemic treatment of vascular and cardiovascular disorders, soft tissue repair and other disorders. In May 2006, Isotechnika licensed ISA 247 to Lux Biosciences for ophthalmic indications. Under terms of the agreement, Lux Biosciences obtains the exclusive worldwide marketing rights to ISA 247 for treatment and prophylaxis of all ophthalmic indications. The company will be responsible for development, registration and marketing of the drug for ophthalmic indications and will make upfront and milestone payments to Isotechnika in addition to royalties on any sales. Isotechnika formalised a manufacturing agreement with Swiss-based Lonza Ltd in June 2004. Under the terms of the agreement, Lonza will manufacture sufficient quantities of trans-ISA 247 in a GMP environment for use in the company's upcoming clinical trials. Isotechnika completed the phase III SPIRIT trial of ISA 247 for psoriasis in Canada. The randomised, double-blind trial compared the efficacy of three doses of ISA 247 (0.2 mg/kg [low dose], 0.3 mg/kg [mid dose] and 0.4 mg/kg [high dose] twice daily) with placebo, with equal numbers of patients assigned to each of the four groups. Subsequent to the first 12 weeks, those patients who received placebo moved into the mid-dose group for the remaining 12 weeks of the study. Patients already receiving ISA 247 remained in their respective dosing groups for the final 12 weeks of the trial. Patients completing the 24-week SPIRIT trial were given the opportunity to continue therapy for an addditonal 36 weeks or to discontinue therapy. Those patients who chose to enrol in the extension trial were moved from the 0.2 mg/kg bid (low-dose) or 0.4 mg/kg bid (high-dose) groups into the the 0.3 bid mg/kg bid (mid dose) group. Patients who commenced the SPIRIT trial in the mid-dose group remained on the same dosage regimen for the duration of the extension trial. The goal of the extension trial is to demonstrate continued therapeutic benefit to psoriasis patients while gathering long-term safety data. So far, data has been received on 193 patients receiving treatment for a total of 48 weeks. A phase IIa trial investigating the safety and efficacy of ISA 247 in renal transplantation was completed in the US and Canada in January 2003. The trial compared ISA 247 with ciclosporin (Neoral in approximately 130 stable renal transplant patients who underwent transplantation at least 6 months prior to enrolment; patient recruitment was completed in October 2002. Half of the patients were treated with ciclosporin and the other half received ISA 247 over a 90-day period. An extension trial was then initiated in which another 200 patients were treated with ISA 247 for up to 6 months from the time of transplantation. Results from the trial were reported. All endpoints were achieved in a multiple ascending dose study of trans-ISA 247 in November 2004. The study, initiated in June 2004, was conducted by SFBC Anapharm in Montreal, Canada and involved 43 healthy volunteers. Final dosing recommendations are to be determined in phase III trials in patients with psoriasis. Interim results reported in September 2004, of a double-blind, parallel-group, placebo and moxifloxacin controlled, randomised single-dose QTc trial in healthy volunteers, showed no evidence of QTc prolongation when trans-ISA 247 was administered at therapeutic doses. A single ascending dose (SAD) trial for trans-ISA 247 was completed in July 2004. The SAD trial was conducted among healthy volunteers to assess the appropriate dosage of trans-ISA 247 for further clinical evaluations. The trial commenced in March 2004 with approximately 46 subjects enrolled under the supervision of MDS Pharma Services in Phoenix, Arizona, USA. Isotechnika received US FDA approval for the SAD trial in February 2004. A European patent (No. EP 0 991 660) entitled 'Deuterated and Undeuterated Cyclosporine Analgoues and Their Use as Immunomodulating Agents' was issued to Isotechnika for ISA 247, in October 2006. A US patent entitled 'Novel Cyclosporin Analogue Formulations' was issued to Isotechnika (No. 7 060 672) for ISA 247 in June 2006. The patent claims have been filed in 36 countries, and in the US it is the first patent to be issued in this patent family. Isotechnika was issued a US patent (No. 6 998 385, entitled 'Cyclosporine Analogue Mixtures and their use as Immunomodulating Agents') in February 2006 covering mixtures of cis- and trans- isomers of ISA 257. This patent is the first US patent to be issued in this family of patents. These patent claims have been filed in 36 countries. Three patents relating to this claim were previously issued in the following countries; Morocco (No. 26337 issued 1 October 2004); Pakistan (No. 138338 issued 30 September 2004) and South Africa (No. 2004/2270 issued 25 May 2005). A US patent (No 6 686 454) was issued in February 2004 entitled 'Antibodies to Specific Regions of Cyclosporine Related Compounds'. This patent covers a novel, simple and cost-effective assay used in the use and management of ISA 247. It also received another US patent entitled 'Deuterated Cyclosporine Analogs and their Use as Immunomodulating Agents'. Isotechnika has received patents for chemical composition of ISA 247 in New Zealand (November 2001; New Zealand Patent No. 502362), Canada (December 2001; Canadian Patent No. 2 298 572), South Korea (June 2006; South Korean Patent No. 585348) and Australia (November 2002; Australian Patent No. 750245). In addition, Isotechnika announced in August 2003 that it had been granted US patent No. 6 605 593, entitled 'Deuterated Ciclosporine Analogs and their use as Immunomodulating Agents'. An additional US patent covering ISA 247 was granted in September 2003.     

Retigabine (ASTA Medica)

ASTA Medica is developing retigabine, a carbamic acid ethyl ester and a selective potassium channel opener, for the treatment of complex partial seizures. Phase II trials have commenced [249117], and a multicenter placebo-controlled dosage-finding study has begun in Europe and Australia [392702]. Retigabine is also undergoing phase II testing in Germany, Switzerland, Russia and the US for the potential treatment of epilepsy [323383]. Phase II trials have shown >50% reduction in seizure frequency in 12 of 35 patients with refractory epilepsy [373379]. Phase I clinical trials for epilepsy were successfully completed in Germany in 1995 [180371]. Single and multiple dose trials demonstrated the tolerability and favorable pharmacokinetic behavior of the compound [264306]. The compound showed good compatibility and exhibits an antisense anticonvulsive effect in various preclinical epilepsy models [250565,299344]. Side effects of mild to moderate tiredness, fatigue and nausea were observed [276123]. The spectrum of activity of retigabine resembles that of valproate, but its potency is greater and toxicity is reduced [373379]. The mechanism of action of retigabine is probably multifactorial. Research has shown that retigabine acts as a selective K+ channel opener in neuronal cells and this can be expected to contribute to its anticonvulsant effect [273670]. In addition it demonstrates potentiation of GABA transmission and possibly also weak modulation of sodium and calcium channels [299344]. Retigabine also has neuroprotective activity with potential for the treatment of stroke and neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease and multiple sclerosis [249381]. In February 2000, Lehman Brothers predicted product launch could be as early as 2002 for epilepsy in the US [357788]. In February 1999, Lehman Brothers predicted that the first major launch date of the drug would be 2003, and the year of peak sales to be 2011 [319225].     

TRX-4 (TolerRx Inc)

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.     

Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

ABSTRACT

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis.

Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies.

Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.

Trial registration: ClinicalTrials.gov identifier: NCT03937479.     

ALX 111: ALX1-11, parathyroid hormone (1-84) - NPS Allelix,PREOS, PTH,recombinant human parathyroid hormone,rhPTH (1-84)

ALX 111 [parathyroid hormone (1-84) - NPS Allelix, recombinant human parathyroid hormone, rhPTH (1-84), PREOS] is a full-length, recombinant human parathyroid hormone. It has potential as an anti-osteoporotic agent, due to its properties as a bone formation stimulant. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It has been recommended that ALX 111 should be given for 1 to 2 years and may be given in combination with an antiresorptive agent, such as estrogen or a bisphosphonate. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. NPS harmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. Until 1994, Allelix Biopharmaceuticals and Glaxo in Canada were involved in a joint venture to investigate the efficacy of ALX 111 in osteoporosis. Allelix was subsequently, until September 1998, collaborating with Astra of Sweden in developing ALX 111. Astra had acquired exclusive worldwide rights to ALX 111 and was responsible for development of the agent. However, Astra returned all rights to ALX 111 to Allelix as a result of its merger with Zeneca to form AstraZeneca. In December 1999, Allelix Biopharmaceuticals merged with NPS Pharmaceuticals. This combined company is operating as NPS Pharmaceuticals in the US and as NPS Allelix in Canada. The merger has enabled a phase III study of ALX 111 to begin in the US, Europe and South America. The phase III trial of ALX 111 for the treatment of osteoporosis has completed patient enrolment, and phase II trials have been completed in Canada and the Netherlands. The 18-month, phase III, multicentre, placebo-controlled trial (Treatment of Osteoporosis with Parathyroid Hormone; TOP) has been designed to assess the bone-building and fracture-reducing potential of the drug, and over 2600 postmenopausal women with osteoporosis who have not received previous drug therapy for osteoporosis have been enrolled. Treatment will be completed in September 2003, but more than 75% of patients enrolled in the TOP study have chosen to enrol in an Open Label Extension Study (OLES), which allows for a total treatment period of up to 24 months. NPS Pharmaceuticals has signed an agreement with Bio-Imaging Technologies, which will provide all image handling and analysis for this trial. In September 2002, NPS Pharmaceuticals announced that it has met its patient enrolment target (n > 150) for its POWER (PTH for Osteoporotic Women on Estrogen Replacement) study; a 24-month phase III trial initiated in Europe in November 2001. In this trial, women with osteoporosis receive SC injections of ALX 111 or placebo, in combination with their existing hormone replacement therapies, to test the bone building potential of the drug. In addition to the POWER study, a clinical trial sponsored by the National Institutes of Health (NIH) is being conducted to evaluate the potential of ALX 111 to build bone in combination with another osteoporosis medication. The 'PaTH' study (PTH/alendronate) is designed to assess the effect of various combinations and sequential uses of ALX 111 and Merck's Fosamax, a drug for slowing the loss of bone due to osteoporosis. The PaTH study, initiated in May 2000 and scheduled to conclude in September 2003, involved 238 patients with postmenopausal osteoporosis. It is thought that alendronic acid and ALX 111, when administered in combination, may act in an additive manner to treat osteoporosis because they act in different ways; alendronic acid acts to inhibit resorption and ALX 111 speeds up bone formation and resorption, with a net increase in formation. Results of this study are still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures underare still being analysed but preliminary results appear to be positive. The effect of ALX 111 on bone cell cultures under conditions of microgravity was tested in orbit on the Space Shuttle Columbia, which was launched on 16 January 2003 but did not survive re-entry. This study was one in a series of studies known as 'OSTEO' and had been prepared by researchers from NPS Pharmaceuticals using Millenium Biologix' OSTEO Mini-Lab System. Under space flight conditions, astronauts experience a loss in bone density at a rate up to ten times faster than that of earth-bound patients with osteoporosis, and it was hoped that this study would indicate the mechanism of action of ALX 111 at cellular and genetic levels. The results of these studies were represented by the samples of human bone cells, which were lost during the re-entry tragedy.     

ZD-1839 (AstraZeneca)

AstraZeneca is developing ZD-1839, an inhibitor of epidermal growth factor receptor 1 (EGFR1) tyrosine kinase, for potential treatment of cancers which overexpress EGF receptors, including non-small cell lung cancer (NSCLC) and pancreatic cancer [196279], [270898]. Phase III studies had started by August 2000 [349551], [350295], [353050], [377656], with first results being expected at the 2001 meetings of the American Association for Cancer Research (AACR) and the American Society for Clinical Oncology (ASCO). The US FDA has issued ZD-1839 with Fast Track status [350295], [353050]. In September 2000, the company expected global NDA filing to take place at the end of 2001, with launch in the next four to five years [383469]. In January 1999, ABN Amro predicted sales of US $25 million in 2004 rising to $82 million in 2005 [316250]. In March 1999, Lehman Brothers predicted a 30% probability that the drug would reach worldwide markets and be launched onto the market in 2004 [336599]. In June 2000, Deutsche Bank predicted sales of US $8 million in 2002, rising to $100 million in 2003 [374500]. In September 2000, analysts Merrill Lynch predicted a launch in 2002 with sales estimated at UK 50 million pounds, rising to 360 million pounds in 2004, while in December 2000, the analysts predicted a filing date in the fourth quarter of 2001 [383742], [396280]. Also in December 2000, Lehman Brothers predicted a filing date late in 2001, and a possible Fast Track review. They also estimated peak sales of US $1 billion [394606].     

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.