MK-0991 (Merck & Co)

Merck is developing the echinocandin-type antifungal, MK-0991 (L-743872), a beta-1,3-glucan synthesis inhibitor. It is currently undergoing phase III trials for the potential treatment of systemic fungal infections. The compound entered phase II clinical trials in late 1996. It was administered iv once daily and showed antifungal activity in vitro and in vivo against Candida (including azole-resistant Candida), Aspergillus and certain other fungi. The in vitro activity of MK-0991 has been confirmed by several studies. In November 1998, Morgan Stanley Dean Witter predicted worldwide sales of 40 million USD in 2000, rising to 275 million USD in 2005. In February 1999, Credit Suisse Dean Witter predicted sales of 65 million USD in 2001, rising to 330 million USD in 2002. In February 1999, Lehman Brothers predicted 60% probabilities of US and ex-US market penetrations and launch onto these markets by 2000. Expected sales are predicted to be 15 million USD (in the US) and 10 million USD (ex-US) in 2000, rising to 200 USD million and 175 million USD respectively in 2002. Peak annual sales of 500 million USD (US) and 500 million USD (ex-US) are predicted in 2008.     

Lemildipine Merck and Co Inc

Lemildipine is a 1,4-dihydropyridine calcium channel blocker which is under phase III development by Banyu (Merck and Co), in Japan, for its potential to treat hypertension and cerebrovascular ischemia. In one study, involving five patients with essential hypertension accompanied by cerebrovascular disorder, lemildipine, administered orally at doses of 5 to 20 mg/day, significantly lowered blood pressure and increased cerebral blood flow [256721]. Another study in 31 patients with essential hypertension demonstrated that lemildipine has significant pressure lowering effects without affecting serum lipids [256722]. Worldwide rights to market the drug have been assigned to Kowa in Japan.     

MK-431 (Merck)

Merck & Co is developing MK-431, the lead from a series of dipeptidyl peptidase IV inhibitors that enhance endogenous glucagon-like peptide-1 levels, for the potential treatment of type 2 diabetes. Phase III studies were initiated in the second quarter of 2004.     

Tomoxetine (Eli Lilly & Co)

Eli Lilly is developing tomoxetine, a norepinephrine reuptake inhibitor, for the potential treatment of attention deficit hyperactivity disorder (ADHD) and depression. As of May 2000, tomoxetine was undergoing phase III trials in the US [368128]. An NDA was filed with the FDA in October 2001, with a launch expected in the second half of 2002 [426786]. Tomoxetine was first investigated by Lilly in the 1980s as a potential treatment for depressive illness. The compound was selected from a series of potent inhibitors of norepinephrine reuptake, and reached large-scale phase II clinical trials for depression in 1990. Development for this indication appeared to stop at that time, despite some evidence that tomoxetine wasfairly effective [273943]. In 1996, Lilly apparently restarted preclinical development of tomoxetine as a potential therapyfor ADHD, and submitted EP-00721777 claiming tomoxetine's utility for this disorder in July of that year [273956]. In June 2001, ABN AMRO predicted sales of $121 million in 2002, rising to $4,064 million in 2012 [422762]. In October 2001, analysts at Salomon Smith Barney predicted that the product would make sales of $24 million in 2002, rising to $305 million in 2005 [427501].     

PD-140248 (Parke-Davis & Co)

PD-140248 is an isomerase inhibitor and topoisomerase II inhibitor under development by Parke-Davis and Co as a potential treatment for bacterial infection. Although no details of active development have been published in the scientific literature since 1996, in September 1999, the company confirmed that PD-140248 is still in active development [338530]. The compound is one of two new pyrrolidinyl naphthyridines (the other compound being PD-131628) with a broad spectrum of antibacterial activity, including activity against quinolone-resistant bacteria. PD-140248 demonstrates strong in vitro activity, particularly against Gram-positive bacteria, such as quinolone-susceptible Staphylococcus aureus (S aureus), Staphylococcus epidermidis (S epidermidis), Staphylococcus haemolyticus (S haemolyticus), methicillin- and ciprofloxacin-resistant S aureus, Streptococcus species, Streptococcus pneumoniae (S pneumoniae) and Enterococcus faecalis (E faecalis). An MIC90 value of 0.015 microg/ml was obtained against Haemophilus influenzae (H influenzae) and Moraxella catarrhalis [160129]. The (3R,1S) enantiomer, PD-140248, demonstrated a 1- to 10-fold enhanced activity against Gram-positive and Gram-negative organisms in vitro and in vivo compared to its stereoisomers, and has thus been targeted for further preclinical studies [133377].     

Anidulafungin (Eli Lilly & Co)

The pentyloxyterphenyl side chain derivative of echinocandin B, anidulafungin, is a 1,3-alpha-glucan synthesis inhibitor undergoing phase II clinical trials by Versicor and Eli Lilly, in various formulations, for the potential treatment of fungal and protozoal infections. Eli Lilly has retained options to the oral formulation of the compound, but development, clinical registration and marketing rights were licensed to Versicor in June 1999. The primary target of this compound is Candida, but Eli Lilly also intends to develop the drug for Aspergillus infections. No activity has been shown against Cryptococcus. The oral activity of anidulafungin is compromised by a low bioavailability, a decreased absorption when taken with food, and gastrointestinal side effects at higher doses. The development of a phosphorylated prodrug, LY-307853, which is converted in the body to anidulafungin by tissue and serum phosphatases, was discontinued in favor of an oral formulation, which uses anidulafungin directly. In February 1999, Deutsche Bank predicted sales of $100 million in 2001, rising to $300 million in 2003.     

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.     

Liquid-chromatographic profiling of Saponinum album (Merck)

Saponinum album (Merck) is a complex composite of triterpene saponins. It was shown that Saponinum album (Merck) dramatically enhances the toxicity of the N-glycosylase saporin from the seeds of Saponaria officinalis L. as well as the toxicity of a saporin based anti-tumor toxin. This study was intended to chromatographically profile the saponins present in Saponinum album (Merck) in order to identify saponins that determine the cytotoxicity enhancing properties of Saponinum album (Merck) on saporin. For this purpose a liquid-chromatographic profiling (HPLC) followed by ESI-TOF-MS analysis and evaluation of cytotoxicity enhancer effects of saponins from Saponinum album (Merck) was performed. This is the first study describing a liquid-chromatographic profiling of saponins from Saponinum album (Merck). Ten different saponins were isolated. There was a lot of variation observed in the cytotoxicity enhancing properties of different isolated saponins, 8 out of 10 isolated saponins showed an enhancer effect on the toxicity of saporin. Based on these results it was concluded that the cytotoxicity enhancer effect of Saponinum album (Merck) is not attributable to a single, activity determining saponin.     

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.     

Zoster vaccine live (Oka/Merck)

A subcutaneously administered, live, high-titre (18,700-60,000 plaque-forming units per dose) varicella zoster virus (VZV) vaccine (zoster vaccine) of the Oka/Merck strain has been evaluated for the prevention of herpes zoster and the reduction of zoster-associated pain in adults aged > or =60 years. Zoster vaccine, when compared with placebo, reduced the burden of herpes zoster illness by 61%, the incidence of herpes zoster by 51% and the incidence of postherpetic neuralgia by 67% during more than 3 years of surveillance. The zoster vaccine caused an initial 1.7-fold rise in VZV antibody titre after 6 weeks that declined progressively over 3 years. Increases in gamma-interferon-secreting peripheral blood mononuclear cells were 2.2-fold greater with the zoster vaccine than with placebo 6 weeks after vaccination. Zoster vaccine was generally well tolerated. The most frequently reported adverse reactions following vaccination were injection-site reactions; the only systemic adverse event with zoster vaccine that differed significantly in incidence from that with placebo was headache.     

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].     

Cilengitide Merck

Merck KGaA is developing cilengitide, the lead in a series of integrin antagonists with anti-angiogenic activities, for the potential treatment of a variety of cancer types. The National Cancer Institute is conducting clinical trials of cilengitide. In October 1999, phase II trials in non-small-cell lung cancer (as a monotherapy) and pancreatic cancer (in combination with gemcitabine) were initiated. These were ongoing in February 2002, by which time, a phase I trial and a phase I/II trial in glioblastoma were underway.     

Cinoxacin (Cinobac, Eli Lilly & Co.)

Cinoxacin, a synthetic organic acid antibacterial agent, related structurally to nalidixic and oxolinic acid, has been approved for the treatment of initial and recurrent urinary tract infections (UTIs) caused by susceptible gram-negative microorganisms. The role of cinoxacin in the treatment of UTIs, compared with the usual first-line agents, is uncertain at this time. The efficacy of cinoxacin in the treatment of pyelonephritis, compared with these proven agents, has been examined in only small numbers of patients, and cinoxacin is more expensive than these agents. Cinoxacin may prove valuable in the treatment of prostatitis and in the prophylaxis of recurrent UTIs; further study in these areas is warranted. In the routine treatment of acute UTIs, cinoxacin perhaps should be reserved only for those patients with organisms resistant to usual first-line agents or those who fail to respond to therapy with these agents. In this respect, cinoxacin may, in the future, replace nalidixic acid.     

Merck & Co., Inc.: analysis of patenting 1998 – 2002

This article complements an earlier (1997) review of the patenting policy of Merck and indicates how the company continues to file extensively. It compares the patenting activity across each major therapeutic area with the company’s 2001 revenues from these therapeutic areas.     

Tödliche Vergiftung mit Mevinphos (PD 5 „Merck“)

Zusammenfassung Es wird über einen Suicid mit dem Sch?dlingsbek?mpfungsmittel PD 5 „Merck“, welches als Wirkstoff Mevinphos enth?lt, berichtet. Die durchgeführten chemischen Untersuchungen führten zur qualitativen und quantitativen Bestimmung des Wirkstoffes im Mageninhalt.     

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.     

Aripiprazole (Otsuka Pharmaceutical Co)

Otsuka Pharmaceuticals in collaboration with Bristol-Myers Squibb is developing aripiprazole, a dual dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist, for the potential treatment of psychoses including schizophrenia [281327], [340364]. A regulatory filing for schizophrenia in the US was submitted at the end of 2001 [340364]. The compound entered phase III trials in Japan in 1995 [192966]. Although presynaptic dopamine autoreceptor agonists may be efficacious in the treatment of schizophrenia, they may also potentially increase the risk for exacerbation of psychosis through stimulation of postsynaptic dopaminergic receptors [245791], [350478], [350479]. However, earlier neuropharmacology studies have shown that aripiprazole can act as a presynaptic D2 agonist while displaying an antagonistic effect at the postsynaptic D2 receptors [281327], [337126], [350479], [424587], [424588]. In animal models, aripiprazole inhibits the apomorphine-induced stereotypy, without causing catalepsy [281327], [337126]. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in expression of the c-fos mRNA in the striatum, in agreement with the low risk for extrapyramidal side effects (EPS) during aripiprazole treatment [245781], [262096], [350481], [350483]. Collectively, aripiprazole is an important atypical antipsychotic candidate with a favorable safety profile. Moreover, the mechanism of action of aripiprazole differentiates it from both typical and atypical antipsychotics and hence, may provide important leads for pharmacotherapy of schizophrenia and other psychotic disorders. In January 2000, Lehman Brothers predicted peak sales of aripiprazole could reach US $500 million [357788]. In February 2001, Credit Suisse First Boston predicted sales of US $403 million in 2005 [399484].     

HIV integrase inhibitors: from diketoacids to heterocyclic templates: a history of HIV integrase medicinal chemistry at Merck West Point and Merck Rome (IRBM)

Replication of the human immunodeficiency virus (HIV) is dependent upon the enzyme HIV integrase (IN), one of three essential enzymes encoded in the viral genome. HIV-1 IN catalyzes the insertion of the proviral DNA into the host genome (strand transfer). HIV-1 IN therefore presents an attractive chemotherapeutic target for the treatment of HIV infection and AIDS that could provide patients and physicians with an additional option for treatment. Assays were developed to identify inhibitors of IN strand transfer. Diketoacid lead compounds were explored and developed into a variety of heterocyclic templates that are potent inhibitors of integrase strand transfer with suitable medicinal chemical properties for treating HIV infection and AIDS. The 1,6-naphthyridine L-870810 (Antiviral activity in cells IC(95) NHS = 102 nM, n=237), was shown to be efficacious in reducing viral RNA by 1.7 log units after doses of 400mg BID to HIV infected patients. Optimization of physical properties led to L-900564, an inhibitor of HIV IN that has excellent cell potency in the presence of protein (Antiviral activity in cells IC(95) NHS = 16 nM, n=15), excellent activity against mutants raised to HIV integrase inhibitors, and a very good pharmacokinetic profile.