BMS-310705 Bristol-Myers Squibb/GBF

Bristol-Myers Squibb, in collaboration with the German Research Centre for Biotechnology, is developing BMS-310705, an epothilone analog, for the potential treatment of cancer. By April 2002, phase I trials of BMS-310705 were underway.     

BMS-184476 Bristol-Myers Squibb

BMS-184476 is a taxane analog under development by Bristol-Myers Squibb for the potential treatment of solid tumors. By February 2001, it had entered phase II trials and, as of May 2002, phase II studies had been carried out in patients with a number of tumor types, including breast, ovarian and non-small-cell lung cancer.     

BMS-275291. Bristol-Myers Squibb

Bristol-Myers Squibb (BMS) is developing BMS-275291, which is a matrix metalloproteinase (MMP) inhibitor, for the potential treatment of cancer. It was originally developed by Chiroscience R&D (now known as Celltech Group plc), and it inhibits a broad range of MMPs known to be associated with the growth and spread of tumors. Advantageously, it does not inhibit MMP-mediated shedding events, which may be involved in the side effects associated withfirst-generation MMP inhibitors. ByMarch 2001, BMS-275291 was undergoing phase II/III trials, as an adjunct to standard chemotherapy, involving non-small cell lung cancer patients. In March 1999, Lehman Brothers predicted that the compound had a 25% chance of reaching the market, with a possible launch anticipated in 2005 and potential peak sales of $500 million in 2010. In November 2000, Lehman Brothers revised their predictions estimating a 2004 launch with a 20% chance of reaching the market; predicted peak sales were unchanged. In January 2002, Morgan Stanley Dean Witter expressed the view that release of positive phase II/III trials data would surprise stock markets.     

BMS-561392. Bristol-Myers Squibb

Bristol-Myers Squibb Pharma Co is developing the tumor necrosis factor-alpha (TNF alpha) converting enzyme inhibitor BMS-561392 (DPC-333) for the potential treatment of diseases characterized by overproduction of TNF alpha, such as rheumatoid arthritis (RA). A phase IIa trial in RA patients had commenced by April 2001, and by October 2002, BMS-561392 was also under investigation for the potential treatment of inflammatory bowel disease.     

BMS-193884 and BMS-207940 Bristol-Myers Squibb

Bristol-Myers Squibb is developing BMS-193884, an oral endothelin antagonist, for the potential treatment of congestive heart failure (CHF) and pulmonary hypertension [206604]. The compound entered phase I trials in November 1996 [242721] and had progressed to phase II trials [399460], [441398]. Structural modifications led to the development of a second-generation analog, BMS-207940, a biphenylsulfonamide endothelin A receptor-selective antagonist, and the probable discontinuation of the first clinical candidate, BMS-193884 [446511]. By April 2002, BMS-207940 was in phase I trials [446511]. By March 2002, filing for NDA was expected to take place in 2004 at the earliest [452734].     

BMS-232632 (Novartis/Bristol-Myers Squibb)

BMS-232632, an azapeptide HIV protease inhibitor, is in development by Bristol-Myers Squibb (BMS), under license from Novartis, as a potential treatment for HIV/AIDS [248556]. Early preclinical work was carried out by Novartis [248556]. BMS-232632 was developed as part of a series of compounds (as CGP-73547) and evaluated against drug-resistant strains of HIV; the compounds in this series belong to a series of azadipeptide analogs and are bis(L-tert-leucine) derivatives that exhibit good antiviral activity and satisfactory pharmacokinetic profiles [297907]. Novartis subsequently discontinued evaluation of the compound in November 1999 [347827]. Phase II trials had already begun by July 1999 [334335] and BMS expects NDA filing to take place in 2001 [358937]. Use of BMS-232632 in combination with other antiretroviral agents has demonstrated that it may be used in combination with a variety of nucleoside analogs and protease inhibitors [298464]. It is thought to have a genotypic resistance profile that differs from that of other protease inhibitors [302157]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2001. The analysts predicted peak sales would occur in 2007, with sales of $500 million in the US and $300 million in the rest of the world at that time [319225].     

BMS-214662 (Bristol-Myers Squibb)

Bristol-Myers Squibb is developing BMS-214662, a farnesyl transferase inhibitor, for the potential treatment of cancer. By October 2000, preclinical investigations were ongoing in Japan. By February 2001, the drug was in phase II trials in the US for pancreatic, head and neck, lung and colorectal cancers.     

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.     

Ravuconazole Eisai/Bristol-Myers Squibb

Eisai and Bristol-Myers Squibb (BMS) are developing the triazole, ravuconazole, as a potential treatment for fungal infection [187888]. Eisai selected the compound for further development on the basis of its good safety profile and well-balanced antifungal activity [187888]. Ravuconazole has a broader antifungal spectrum than fluconazole and itraconazole, particularly against strains of Candida krusei and Cryptococcus neoformans [271854], [342757], [370312]. By June 1999, the compound was undergoing phase II trials [327113]. In November 2001, it was reported that BMS was seeking a co-development partner for the compound [430011]. In October 2001, analysts at ABN Amro predicted sales of US $50 million in 2003 [444020].     

Omapatrilat. Bristol-Myers Squibb

Bristol-Myers Squibb (BMS) is developing the vasopeptidase inihibitor, omapatrilat, a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), for the potential treatment of cardiovascular diseases such as hypertension and heart failure [306287]. An NDA for the use of omapatrilat in hypertension was filed with the FDA and the regulatory authorities in the EU in December 1999 [351207], [353287]. In April 2000, BMS voluntarily withdrew the NDA in response to questions raised by the FDA regarding the comparative incidence and severity of an infrequent side effect (angioedema) reported within the NDA database. Prospective controlled clinical studies in patients with hypertension and heart failure were to continue. In May 2001, BMS reported that its blinded omapatrilat hypertension study was continuing and, pending supportive results from a data analysis anticipated in late summer/early autumn 2001, the company expected to refile an NDA with the FDA [409203]. In July 2000, BMS reported that it planned to conduct a multinational, 25,000 patient study (OCTAVE - Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) to compare the efficacy and safety of omapatrilat against enalapril in the treatment of hypertension [374909]. The OCTAVE trial was expected to generate data by mid-2001, which could allow for a launch by early 2002 [380280]. Phase III trials for hypertension had commenced by January 1998 [273646]. In January 2001, Merrill Lynch expected BMS to refile its NDA with the FDA in the second half of 2001 [395423]. In February 2001, Credit Suisse First Boston made a similar prediction, adding that it believed BMS would launch the drug in late 2002 or early 2003. The analysts also predicted peak sales for the drug of $585 million in 2005 [399484]. In May 2001, Merrill Lynch estimated sales of $1.8 billion in 2005 [411811].     

Anti-MRSA cephalosporins Bristol-Myers Squibb

BMS is investigating a series of cephalosporins for potential use in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection [274213]. In vitro activity tests resulted in a minimum inhibitory concentration (MIC) of 1 to 8 microg/ml against MRSA 1274213]. A series of C(3) benzoyloxymethyl cephalosporins exhibited in vitro activity against MRSA and methicillin-susceptible Staphylococcus aureus (MSSA), with MIC values ranging from 0.007 to 2 microM, and improved in vivo stability in human plasma [258890].     

T-3811. Toyama/Bristol-Myers Squibb

Toyama and Bristol-Myers Squibb (BMS) are developing the des-F(6)-quinolone T-3811 (BMS-284756) as a potential treatment for bacterial infections, including respiratory and urinary tract infections, and skin and soft tissue infections. The drug is in phase II trials in the US and Europe, and an injectable formulation began phase I trials in the US in April 2000. Phase I trials commenced in Japan in September 1999. Phase III trials were expected to begin outside Japan in 2000. T-3811 is expected to be administered as an oral or injectable once-a-day formulation. Preclinical studies suggests it has a better side-effect profile than commonly associated with other quinolones on the market. Bristol-Myers Squibb has acquired worldwide development and marketing rights, with the exception of Japan, South Korea, Taiwan and China. In December 2001, Morgan Stanley predicted that T-3811 could have peak sales potential exceeding $500 million if the positive clinical data released at this year's ICAAC continued, and that BMS was on track for filing in 3Q02.     

DPC-423 Bristol-Myers Squibb

DPC-423 is a biphenylamine-containing amide which is under development by Bristol-Myers Squibb (formerly DuPont Pharmaceuticals) as a Factor Xa inhibitor for the potential treatment of thrombotic disorders [372092]. As of August 2000, DPC-423 was in phase I trials [380880]. DPC-423 was discovered as a result of SAR modifications of DuPont's SN-429, including replacement of the benzamidine moiety with a less basic benzylamine [398701]. Its 2-aminomethylphenyl analog DPC-602 is also under investigation for thrombotic disorders [402714].     

Muraglitazar (Bristol-Myers Squibb/Merck)

Bristol-Myers Squibb and Merck & Co are co-developing muraglitazar, a dual peroxisome proliferator-activated receptor-alpha/gamma agonist, for the potential treatment of type 2 diabetes and other metabolic disorders. In November 2004, approval was anticipated as early as mid-2005.     

Cetuximab (Imclone/Merck/Bristol-Myers Squibb)

ImClone, in collaboration with licensees, Merck KGaA and Bristol-Myers Squibb (BMS), are developing cetuximab, a chimeric monoclonal antibody that blocks the epidermal growth factor receptor, for the potential treatment of various cancers, including colorectal, and head and neck tumors [179103]. The companies are evaluating the product both as a single agent, and in combination with radiation and a variety of chemotherapeutic agents. By January 2002, phase III trials had been initiated in head and neck cancer, and phase II trials were ongoing for colorectal and other cancers [427710], [437833]. In November 2001, ImClone completed the filing of a rolling BLA with the FDA for cetuximab in combination with irinotecan to treat irinotecan-refractory colorectal cancer. In December 2001, however, the FDA advised ImClone that its BLA was not acceptable for filing. In January 2002, it was reported that resubmission of the BLA was expected within 3 months [434999], and by February 2002, ImClone was expecting to use data from an ongoing phase II study in colorectal cancer patients conducted by Merck KGaA. In March 2002, Merck had anticipated European launch in 2003 [444653]; however, in April 2002, Merck reported that it was delaying its application to the European Agency for the Evaluation of Medicinal Products from the last half of 2002 to the first half of 2003, so that it could primarily include its own colorectal cancer data rather than ImClone's data. European launch was thus expected in 2004 [449226]. In May 2002, Lehman Brothers predicted global peak sales of US $2 billion [454652], while in the same month, Bear Stearns estimated that sales for Merck KGaA would reach 285 million Euros in 2007 [453500].     

Entecavir (Bristol-Myers Squibb)

Bristol-Myers Squibb (BMS) is developing entecavir, a viral replication inhibitor, for the potential treatment of hepatitis B virus (HBV) infection [220240]. The compound is a cyclopentyl guanosine analog and is in phase II trials in the US [383065]. Entecavir was originally developed as SQ-34676 for the treatment of herpes simplex virus infections [221992], but displayed only moderate activity which eventually led to discontinuation of development for this indication. However, Bristol-Myers Squibb later discovered that entecavir was extremely potent against HBV (ED50 = 3.0 nM, compared with 200 nM for lamivudine) with relatively low toxicity (CC50 = 30,000 nM) [221986] and acted through inhibition of DNA polymerase [220240]. The triphosphate form is a potent HBV polymerase inhibitor in both woodchuck and duck models [306056]. By September 2000, a large-scale clinical trial was underway in China for HBV infection [400209] and by October 2000 phase I trials were ongoing in Japan [384751]. In March 2001 SG Cowen predicted sales of US$25 million in 2002, US$50 million in 2003 and US$75 million in 2004 [403751].     

Bucindolol (Bristol-Myers Squibb Co)

Bucindolol is a beta1 and beta2 adrenoceptor antagonist under development by Intercardia as a potential treatment for hypertension and congestive heart failure (CHF). Intercardia, Knoll AG and the NIH are conducting phase III trials for these indications. Intercardia is a subsidiary of Interneuron formed to acquire 80% of Cardiovascular Pharmacology and Engineering Consultants (CPEC) which includes the rights to bucindolol. CPEC was founded by researchers who had studied bucindolol in CHF for Bristol-Myers Squibb which ceased development of the compound in 1989 and licensed it to CPEC.     

Bristol-Myers Squibb drug information department services

The pharmaceutical industry has become a leading source of information on pharmaceutical products. Recent data from Bristol-Myers Squibb Primary Care Division indicate that pharmacists are leading users of drug information services. This article was written with the intent to augment the journal's annual feature of the Pharmaceutical Manufacturer's Directory.     

BMS-204352 (Bristol Myers Squibb)

BMS-204352 is a fluoro-oxindole potassium channel opener being developed by Bristol-Myers Squibb as a potential neuroprotectant for the treatment of acute ischemic stroke. Phase I trials were underway in Japan in 1998 [288541]. By July 1999, it was in phase II trials in the US [331682] and by October 2000, phase II trials had also begun in Japan [384751]. At the 219th American Chemical Society meeting in March 2000, it was reported that BMS-204352 had entered worldwide phase III trials involving patients with suspected acute stroke [362077], [361291]. In February 2001, Credit Suisse First Boston predicted sales of $111 million in 2005 [399484]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2004. The analysts predicted peak sales would occur in 2008, with sales of $500 million in the US at that time [319225].