American Home Products Research Articles

Bazedoxifene

Bazedoxifene is a third-generation selective estrogen receptor modulator (SERM) that is being developed by Ligand Pharmaceuticals in collaboration with Wyeth. The agent has effects on bone and cardiovascular tissue, but does not affect breast or uterine tissue. Bazedoxifene is in clinical development as a monotherapy for the prevention and treatment of postmenopausal osteoperosis, and in combination with conjugated estrogens for the treatment of menopausal symptoms and prevention of postmenopausal osteoporosis. American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth Lederle to Wyeth in March 2002. Wyeth and Ligand entered into a discovery research collaboration for bazedoxifene in September 1994. Under the agreement, Wyeth has worldwide development rights to the compound and is solely responsible for its clinical development. In exchange, Ligand is entitled to milestone and royalty payments associated with development and commercialization achievements. Ligand entered into an agreement with Royalty Pharma in March 2002 whereby Royalty Pharma purchased the rights to a share of Ligand's entitlement to milestone and royalty payments. Under the agreement, Ligand received $US6 million from Royalty Pharma in exchange for a 0.25% stake in net sales of three SERM products (lasofoxifene, bazedoxifene and bazedoxifene/Premarin) for a period of 10 years. Subsequently, Ligand and Royalty Pharma further amended their existing royalty agreement for three SERM products in November 2004. Under the revised agreement, Royalty Pharma would purchase an additional 1.625% of the SERM products' net sales for $US32.5 million, which represents an acceleration of the previous option timetable and an increase in the royalty amount as well as aggregate purchase price. Consequently, Royalty Pharma increased its rights to a total of 3.0125% of net sales of each SERM product for 10 years following first commercial sale of each product and has no further options. Ligand retains an approximately equal portion of lasofoxifene and other SERM's net sales going forward and for periods that could exceed 10 years. The royalty rates owed to Royalty Pharma for the royalties just purchased could be reduced by one-third if product sales exceed certain thresholds. Payments from the royalty purchase are non-refundable, regardless of whether the products ever become successfully launched or not. Milestone payments owed by Ligand's partners as products achieve development and regulatory targets would be paid to Ligand as earned, and are not included in this amended agreement. The US FDA issued a second approvable for bazedoxifene in December 2007, after Wyeth submitted additional study reports from two completed clinical studies for the prevention of postmenopausal osteoporosis. The study reports provided data from two studies conducted in Asia and will form part of a complete response to safety and efficacy issues raised in an initial approvable letter issued by the FDA in April 2007. Prior to approval of the NDA, the FDA must also analyse final safety and efficacy data from a completed phase III trial, and complete an acceptable establishment evaluation on the manufacturing facilities for bazedoxifene. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene. While the second approvable letter issued by the FDA expressed concerns about the incidence of stroke and venous thrombotic events, Wyeth has reported that no additional studies would be needed. Initial filing of the NDA in June 2006 triggered a milestone payment from Wyeth to Ligand.A 2-year, randomized, phase III trial (study 300) has been conducted to compare bazedoxifene (10, 20 and 40 mg) and raloxifene (60 mg) in 1583 patients for the prevention of osteoporosis. Data presented in September 2007 demonstrated that bazedoxifene treatment prevented bone loss, reduced bone turnover, and was generally well tolerated in postmenopausal women with normal or low bone mineral density. Wyeth submitted an NDA to the FDA in July 2007 to gain marketing approval for bazedoxifene as a treatment for postmenopausal osteoporosis. In January 2008, Wyeth stated that the FDA expects to convene an Advisory Committee meeting in July 2008 to review both the treatment and prevention of osteoporosis indications for bazedoxifene. Wyeth has completed a phase III trial comparing bazedoxifene with raloxifene and placebo in 7492 patients with moderate-to-severe postmenopausal osteoporosis. The three-year, randomized, double-blind study commenced in October 2001, and was conducted at sites in the US. Data presented in September 2007 indicated that bazedoxifene showed significant risk reduction for new vertebral fractures, compared with placebo. In addition, Wyeth conducted a phase II trial in Japan to investigate bazedoxifene dose-response in 375 patients with postmenopausal osteoporosis. The randomized, double-blind, placebo-controlled, parallel assignment study commenced in August 2003 and is no longer recruiting patients. The patent covering bazedoxifene will expire in 2017 with the potential for extension.

Temsirolimus

Wyeth (formerly American Home Products) is developing temsirolimus [Cell cycle inhibitor-779, CCI 779], an ester analogue of sirolimus, for the treatment of cancer, multiple sclerosis and rheumatoid arthritis. Temsirolimus binds to the cytosolic protein, FKBP, which subsequently inhibits mTOR (mammalian target of rapamycin). Inhibition of mTOR blocks a number of signal transduction pathways that suppress translation of several key proteins regulating the cell cycle. These effects lead to a cell cycle block at the G1 phase. In animal models of human cancers, temsirolimus inhibited the growth of a diverse range of cancer types even when an intermittent dosing schedule was used. The compound also appears to have potential for the blockade of inflammatory responses associated with autoimmune and rheumatic diseases by inhibiting T-cell proliferation. On 11 March 2002, American Home Products changed its name and the name of its subsidiary Wyeth-Ayerst to Wyeth. During the first half of 2004, Wyeth initiated ongoing recruitment into a US phase III trial comparing orally administered temsirolimus plus letrozole versus letrozole alone as first-line treatment among approximately 1200 postmenopausal women with advanced breast cancer. The multicentre, randomised, double-blind, placebo-controlled trial is estimated to last 34 months. All subjects will have the option of participating in the long-term follow-up phase of the trial that involves follow-up every 3 months until disease progression; the primary endpoint is overall progression-free survival. In August 2004, the US FDA granted temsirolimus fast-track status for the first-line treatment of poor-prognosis patients with advanced renal cell carcinoma. Previously in March 2002, temsirolimus received fast-track status from the FDA for the treatment of renal cell carcinoma in patients who failed to respond to interleukin-2 treatment. Wyeth intends to file a NDA for temsirolimus for this indication by 2006. Researchers from Wyeth presented the findings from a preclinical study of temsirolimus at the 67th Annual Scientific Meeting of the American College of Rheumatology and the 38th Annual Meeting Association of Rheumatology Health Professionals (ACR/ARHP-2003) [Orlando, FL, USA; October 2003]. The aim of this study was to determine the effect of temsirolimus on lymphocyte proliferation and cytokine production. Since lymphocytes and cytokines are significantly involved in the pathogenesis of rheumatoid arthritis, temsirolimus could have disease-modifying antirheumatic drug (DMARD) activity against rheumatoid arthritis via the inhibition of these factors. According to Wyeth's investor presentation in June 2004, the patent covering temsirolimus is due for expiry in 2014.

Pralmorelin

Pralmorelin [GPA 748, GHRP 2, growth hormone-releasing peptide 2, KP-102 D, KP 102 LN] is an orally active, synthetic growth hormone-releasing peptide from a series of compounds that were developed by Polygen in Germany and Tulane University in the US. Researchers at Tulane University led by Dr Cyril Bowers synthesised a series of small highly active peptides ranging in size from 3-5 amino acids or partial peptides that were suitable for a variety of administration formats (subcutaneous, buccal, oral, depot). These peptides mimic the actions of ghrelin, a 28 amino acid octanoyl peptide that regulates the release of growth hormone (GH), and may play an important role in bone and muscle growth, food intake and possibly improve recovery from injury. The use of pralmorelin as a diagnostic agent for GH deficiency is based on its ability to markedly increase plasma levels of GH in healthy subjects irrespectively of gender, obesity or age. However, in patients with GH deficiency, the effect of pralmorelin on GH levels is significantly lower compared with healthy controls. Analysis of the receiver-operating characteristics curve provided the cut-off threshold value for the GH peak of 15.0 micro g/L for the identification of patients with GH deficiency from those of healthy controls. Kaken acquired worldwide manufacturing and marketing rights to pralmorelin, and then sublicensed it to Wyeth (formerly American Home Products) for the US and Canada. Kaken retains rights to pralmorelin in Japan. On 11 March 2002 American Home Products changed its name and the names of its subsidiaries Wyeth-Ayerst and Wyeth Lederle to Wyeth. Kaken also granted exclusive sublicense options in Africa, Australia, Europe, Latin America and New Zealand to unspecified partners. Pralmorelin as KP-102 D [KP-102D] is currently awaiting approval in Japan as a diagnostic agent for hypothalamo-pituitary function. It is planned to be launched in Japan for this indication in 2004. Pralmorelin is also undergoing phase II clinical trials with Kaken in Japan for short stature (pituitary dwarfism) as KP-102 LN [KP-102LN]. Its launch for the treatment of short stature is planned for 2009 (Kaken, Annual Report 2003). The agent was undergoing phase II trials in the US for the treatment of GH deficiency with Wyeth; however, it appears that its development was discontinued. Tulane University was granted a US Patent (6,468,974 issued in October 2002), as well as patent protection in Europe and other countries for a series of synthesised GH-releasing peptides.

The menopausal vampire: arabella kenealy and the boundaries of true womanhood

This article examines the work of the late-Victorian writer and physician, Arabella Kenealy, whom Bram Dijkstra says is “still a bedrock of our own sense of sexual identity.” Kenealy preached the dangers of excessive exercise and education to woman's true vocation of motherhood. Although motherhood is at the core of nearly every piece – fictional or medico-social – that Kenealy wrote, she was also concerned with the figures who defined the boundaries of motherhood – the pubescent teenager, the “neuter,” and the menopausal woman. In her 1896 story, “A Beautiful Vampire,” published in Ludgate Magazine, Kenealy makes a rare foray into the genre of Gothic fiction in order to highlight the eugenic monstrosity of one such “other,” the ageing woman. “What are you supposed to do? Shrivel up and die?” (in Frueh, 1999) We are proud of the ability of our people, during a quarter marked by major strategic developments, to … deliver strong double digit sales and earnings per share growth. … Global sales of the Premarin family of products grew 8% to $542 million. (Jack Stafford, CEO of American Home Products, 19 April 2000)[1]

Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

Influenza virus vaccine live intranasal--MedImmune vaccines: CAIV-T, influenza vaccine live intranasal.

AN1792 vaccination immunotherapy in Alzheimer’s disease: the case of a therapy before its time

Due to increasing incidents of cerebral inflammation, Elan Corporation and American Home Products Corporation have recently announced the decision to terminate the clinical trial of AN1792 vaccine for Alzheimer’s disease (AD). Descriptive reports of the complications experienced in the Phase IIA trial of AN1792, following as little as one dose, have not been released. However, it has been reported that affected patients are recovering following anti-inflammatory drug treatment. Proponents of vaccination therapy attest that the unexpected events of the Phase IIA trial of AN1792 were part of the perceived risk in employing a novel therapeutic treatment. And in the case of treating a disorder as devastating as AD inevitably is, it may be that taking the “chance” with AN1792 was merited. This first open peer commentary to discuss vaccination therapy in AD reemphasizes the need for concerted efforts in approaching the design and initiation of AD therapeutics, and encouragingly, demonstrates the shared viewpoint that promise may lie in future therapeutic trials aimed at manipulating amyloid load in AD. However, there is evidence throughout the commentaries presented here (and in other forums), that there are many aspects of AD vaccination immunotherapy suggesting that we are not yet prepared to move forward with this therapeutic approach in humans. For example, it has been proposed that, although inflammation may be a component of AD vaccination immunotherapy, it is a short-lived phenomena and potentially integral to the eventual benefit of vaccination treatment. This theory is supported by experimental data [12], and human disease indicating, for example, that suppression of certain features of inflammation may unfavorably influence the progression of multiple sclerosis [1] (see Dr. Schenk’ commentary). This is very interesting, however, the role of inflammation associated with AD and with the vaccination-based clearance of amyloid from the

Low-dose HRT is effective

Low doses of estrogen and progesterone can be as effective at treating the symptoms of the menopause as are higher doses, and create fewer side effects. Two reports on the Women's HOPE (health, osteoporosis, progesterone and estrogen) study are published in the June issue of Fertility and Sterility. The HOPE study was conducted on 57 sites and has involved 2673 healthy, postmenopausal woman who still had their uterus. The research, funded by Wyeth-Ayerst Research [part of American Home Products (AHP)], has shown that low-dose combinations of progesterone and estrogen worked about as well as higher doses in reducing hot flushes, maintaining the thickness of the vaginal lining and preventing ‘breakthrough’ bleeding. By the end of the year, AHP hopes to sell a low-dose version of its Pempro, containing 0.45 mg of estrogen and 1.5 mg of progesterone. HN

FDA extends patent protection for drug giants

The US Food and Drug Administration (FDA) has extended patent protection, for paediatric studies, to several of the largest drug companies for an extra six months. The FDA's paediatric exclusivity provision was established in 1997 to provide marketing incentives to manufacturers who conduct studies of drugs in children. Pharmaceutical giants GlaxoSmithKline will benefit from this six-month exclusivity extension for three of their products, Ziagen (abacavir), Epivir (lamivudine) and Zantac (ranitidine). Abbott Laboratories received protection for Calcijex (calcitriol), Ultiva (remifentanil) and Ultane (sevoflurane). Other companies that will do well by this ruling are Johnson & Johnson, American Home Products, Eli Lilley and Merck. This has generated criticism from companies producing generic drugs that account for ∼40% of the US prescription-market, who feel that the FDA's ruling gives the brand companies an unfair advantage. HN

Erratum: Public biotech 2000—the numbers

On page 410 of the May 2001 issue, the Feature article entitled “Public biotech 2000—the numbers” by Riku Lähteenmäki and Liz Fletcher contains the incorrect statement that Monsanto was acquired by American Home Products last year. Monsanto was actually acquired by Pharmacia & Upjohn last year.

'Molecular Break Lights' Detect DNA-Cleaving Agents

The first continuous assay for DNA cleavage by small molecules such as the enediyne compound calicheamicin has been developed by an academic research group and biotech and pharmaceutical industry collaborators. The technique is based on break lights—hairpin-shaped DNAs from which a fragment breaks off and lights up in the presence of a DNA-cleaving agent. The work was carried out by assistant professor of molecular pharmacology and therapeutics Jon S. Thorson and a coworker at Memorial Sloan-Kettering Cancer Center, New York City, and scientists from EraGen Biosciences, Madison, Wis., and the Wyeth-Ayerst Research Division of American Home Products, Pearl River, N.Y. [ Proc. Natl Acad. Sci. USA , 97, 13537 (2000)]. Enediynes are small organic compounds that exhibit antibiotic and anticancer effects and have a mechanism of action involving cleavage of singlestranded or double-stranded DNA Although the mechanism by which enediynes cleave DNA has been studied extensively by numerous groups, a con...

Sales, Earnings Still Rising For Drug Firms

Sales and earnings continued to rise for pharmaceutical producers in the third quarter and first nine months of this year. A dozen major global drug companies reporting had combined sales growth of 11% for the quarter, to $54.8 billion, and net earnings up 20%, to $10.7 billion, compared with the same period last year. Similar changes were seen over nine months, with overall sales up 10% to $161 billion and net earnings up 18% to $30.9 billion. The trend also continues to be positive for biopharmaceutical and small drug discovery firms. Combined third-quarter revenues for 30 leading companies rose 19% to $3.72 billion, and net earnings jumped 35% to $820 million. For the ninemonth period, the group's revenues were up 20% to $10.7 billion and net earnings hit $2.05 billion, an increase of 33%. Sales growth among pharmaceutical producers was driven largely by just a few companies. American Home Products (a), Merck, and Pharmacia had ...

Bayer Keeps Pace In Agrochemicals

Signaling its serious intention to stay in the top ranks of the agrochemical industry, Bayer has agreed to acquire Novartis' Flint fungicide business for $760 million. The planned purchase, which has been cleared by the European Commission (EC) but is still subject to U.S. Federal Trade Commission (FTC) approval, marks Bayer's second recent stab at a major acquisition in the crop protection arena. Bayer executives acknowledge being in the running to purchase American Home Products' Cyanamid agrochemical unit earlier this year, but they were outbid by BASF, which paid $3.8 billion. Although it's not Cyanamid, Flint—known genetically as trifloxystrobin—will provide Bayer entry into the new and fast-growing strobilurin class of fungicide chemistry. Launched last November, Flint will see sales of about $40 million this year, but Bayer expects it to turn into a blockbuster agrochemical by 2003, with sales of about $300 million annually. Trifloxystrobin is a potent inhibitor of fungal spore germination and my...

BASF Buys American Cyanamid Crop Unit

BASF has taken another significant step to boost its agricultural products portfolio. Two weeks ago, BASF committed $700 million to ag biotech R&D over the next 10 years. Last week, the company said it would spend five times as much, or $3.8 billion, to boost its traditional crop protection business through the purchase of American Home Products' (AHP) American Cyanamid unit. The purchase, expected to close July 1 following regulatory approvals, will engender a business with $3.6 billion in annual sales of herbicides, fungicides, and insecticides, almost doubling the size of BASFs annual crop protection sales of $1.9 billion. It will make BASF the fourth largest crop protection company worldwide after number-one Syngenta—the proposed combination of Novartis' and AstraZeneca's crop protection portfolios—Monsanto, and Aventis. We plan to take a leading role in the new agro-market through this acquisition and through our planned R&D investments in plant biotechnology, says Eggert Voscherau ...

And the winner is...Pfizer

Warner-Lambert has capitulated, giving to Pfizer's unrelenting pursuit of a merger. Pfizer will pay just more than $90 billion stock, up from the $82 billion hostile bid it first offered three months ago when it interrupted Warner- Lambert's plans to merge with American Home Products (AHP) (C&EN, Nov. 8, 1999, page 6). The new company—to be called Pfizer—will be created in a spirit of partnership and mutual respect, says Pfizer Chairman and Chief Executive Officer William C. Steere, 63. Pfizer's current stockholders will own about 61% and Warner-Lambert's will own 39% of the merged company. Steere and Pfizer President and Chief Operating Officer Henry McKinnell, 56, will keep their jobs. Warner-Lambert Chairman, President, and CEO Lodewijk J. R. de Vink, 54, has decided not to join Pfizer. The new Pfizer will have about $29 billion annual sales, with about 76% of that pharmaceuticals. Although its overall sales will surpass those of the ...

MERGER MANIA CONTINUES

The pharmaceutical industry's spate of mergers continues as Glaxo Wellcome and SmithKline Beecham agreed to a megamerger, and Warner-Lambert conceded that Pfizer's hostile bid may be better for shareholders than its proposed merger with American Home Products (AHP). Glaxo Chairman Sykes and SmithKline Chief Executive Officer Jan Leschly appeared willing to let bygones be bygones as they announced a $76 billion stock deal that would create the world's largest pharmaceutical company. Two years earlier, the men had tried and failed to pull off a merger, largely because of a power struggle over who would run the company. Richard has done a hell of a job to make sure this happened, Leschly says. I am delighted we're together to realize the vision we've talked about for years. Glaxo SmithKline—as the combined companies will be called—will have annual sales of more than $25 billion, a market capitalization of $189 billion, and a dominant 7.3% share ...

AMERICAN HOME PRODUCTS CORP. V. NOVARTIS PHARMACEUTICALS U.K. LTD

Journal Article AMERICAN HOME PRODUCTS CORP. V. NOVARTIS PHARMACEUTICALS U.K. LTD Get access Reports of Patent, Design and Trade Mark Cases, Volume 117, Issue 15, 2000, Pages 547–571, https://doi.org/10.1093/rpc/2000rpc547 Published: 01 August 2000

Battling on: Warner-Lambert sues Pfizer

has asked a Delaware court to allow it to terminate comarketing agreements with Pfizer and reclaim all rights to the blockbuster cholesterollowering drug Lipitor. At stake for Pfizer is a share in revenues estimated to exceed $3.6 billion in 1999 and nearly $6 billion by 2002. Warner-Lambert's countersuit is the latest step in an ongoing battle over creation of die world's largest drug producer. Early last month, as announced a friendly $67 billion merger with American Home Products (AHP), Pfizer stepped in with a higher offer for Warner-Lambert. When that offer was not accepted, Pfizer, seeking to stop the merger, sued and AHP in Delaware Chancery Court, and separately charged the companies with breaching the comarketing agreements. Pfizer believes that Warner-Lambert has engaged in a series of desperate defensive measures designed to deny its shareholders the opportunity to consider an offer . . . that represents a premium. At recent stock prices, ...

AHP, Warner-Lambert try to create drug giant, but Pfizer moves in

American Home Products (AHP) and Warner-Lambert have announced they want to merge to create the world's largest pharmaceutical firm in a $72 billion stock deal. AmericanWarner—as the combined New Jersey-based companies would be called—would have annual sales of about $26 billion, market capitalization of $145 billion, 95,000 employees, and net income of $4 billion. Such a combination would surpass Merck, Novartis, Glaxo Wellcome, and AstraZeneca in drug sales and be among the top in industry R&D spending with an annual budget of about $3 billion. But just as the deal was being made public, Pfizer launched a competing $82.4 billion offer for Warner-Lambert. Pfizer says it has been in contact with Warner-Lambert for several weeks and is now unhindered by a prior antitakeover agreement. Pfizer's stock offer, worth $96.40 per share, is a 30% premium over Warner-Lambert's average October stock price. In the AHP and Warner-Lambert deal, stockholders would share ...

Sales And Earnings Perk Along For Drug Producers

The first half of 1999 got off to a strong start for major pharmaceutical producers. Overall sales and earnings growth was in the double digits for 12 major drug and 30 leading biopharmaceutical firms surveyed by C&EN. Still, a great deal of change started to emerge in the second quarter as several major mergers and acquisitions were completed or announced. Combined sales for 12 leading drug producers in the second quarter increased 13%, compared with the same period last year, to $45.1 billion. For the first half of 1999, combined sales rose 14% to $89.1 billion. Similar increases occurred in overall net earnings that rose 14% in both the quarter and half to $7.89 billion and $15.9 billion, respectively. Although individual company results were mixed, strong product sales generally contributed to the gains. American Home Products was the exception, with sales and earnings falling because of the poor performance of its agricultural products business. To ...

Drug Producers Have Strong Start For 1999

If the first quarter of 1999 sets the pace for the rest of this year, then pharmaceutical producers have much prosperity ahead. The trend of overall double-digit sales and earnings growth has continued in yet another quarter. However, not all companies are equally prosperous. Individual drug and biopharmaceutical producers have been showing increasingly mixed results. Combined first-quarter 1999 sales for 15 global pharmaceutical companies rose 12% from last year's first quarter to nearly $54 billion. Net earnings, reported by 13 of those companies, rose an overall 16% to $8.13 billion. Profitability—measured as aftertax earnings as a percentage of sales—remained healthy, inching up to 18.3% from 18.0% in the first quarter of 1998. Most gains were based on volume, and not price, increases. Looking more closely at company results shows that two—Madison, N.J.-based American Home Products (AHP) and Switzerland's Novartis—had decreases of 1% in sales. For both companies, a downturn in their agricultural produ...