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Duragesic 2.08 J & J

Duragesic 2.08 J & J

r NMEs - New Medical Entities (Novel) (e.g., kinase inhibition in cancer)

k Second generation molecule (e.g., Neulasta® vs Neupogen®)

Ist-in-Class versus 2nd-in-Class products (e.g., Prevacid® vs Crestor®)

k Molecular manipulation (e.g., TNKase® vs Activase®) r Route of use additions (Oral vs injectible) k Formulation improvements (XL) k Product delivery systems (Insulin pen) k Manufacturing process improvements

Fig. 3.8. Molecule & Product Opportunities a large patient population with the disease that are addressable patients for such a new product, an unmet medical need being addressed wherein the product offers novel therapy for a disease not controlled significantly enough, and a chronic disease that is treated with the product for months to years. The product profile for a blockbuster usually requires sufficiently strong data demonstrating superiority in efficacy or toxicity. With the above-noted sufficiently positive societal and product attributes, a company can charge a premium in the price that will be paid by the health care systems, adding to its profitability. Process issues for company operations that contribute to blockbuster achievement are suggested to be threefold now: global approvals in a timely fashion across the world, a sufficiently high marketing budget at launch to reach the providers, the information and education to warrant a high prescription volume (good market penetration), and execution of a plan to perform further research expanding the approved labeling with new indications, or formulations, or new doses. Finally, the protected patent life needs to be as long as possible after marketing, ideally at least 5 years, in order to recoup all R&D and operational costs, as well as pay for the product failures [31-33].

Blockbuster products with sales over $1 billion numbered 94 in 2004 worldwide (Fig. 3.7). They accounted for $186 billion in sales out of total worldwide sales of $550 billion (34%). Cardiovascular products with 14 (e.g., Lipitor®, Zocor®, Plavix®, Norvasc®) and central nervous system products with 17 (e.g., Zyprexa®, Effexor®, Zoloft®, Neurontin®) were the leading blockbuster categories. The top single product was Lipitor® for hyperlipidemia at $12 billion in 2004, the first time a product exceeded $10 billion in worldwide sales. Two gastrointestinal products and two respiratory products hit the top products in 2004 ($2 billion plus), Prevacid® and Nexium®, and Advair® and Singulair®, respectively. For the first time, oncology products moved strongly into the top used products with eight blockbusters (e.g., Rituxan®, Taxotere®, Gemzar®, Cozaar/Hyzaar®, and Gleevec®). Biotechnology products as blockbusters expanded significantly to 20 in 2004, led by erythropoiesis products around the world (all forms of epoietin alfa, Procrit®, Epogen®, Eprex®, Neorecormon®, and Epogin®, and Aranesp®), the insulins (Humulin/Humalog®, Novolins/Novolog®, and Lantus®), the Neupogen® and Neulasta® franchise in oncology supportive care, oncology therapy products Rituxan®/MabThera® and Herceptin®, the inflammation products Enbrel® and Remicade®, and the multiple sclerosis products Avonex® and Rebif®. Collectively, the erythropoietin products became the first $10.3 billion product franchise in 2004. The top companies with blockbuster products were GlaxoSmithKline with 12, Pfizer with 10, Sanofi-Aventis with 9, Johnson & Johnson companies with 8, Merck with 6, Astra-Zeneca with 6, Amgen with 5, and Novartis with 5 [3, 9, 12, 13, 18].

In addition to new product approvals, a variety of other product-related outcomes can be accomplished by R&D (Fig. 3.8). New products ideally need to be new molecular entities, which the regulatory authorities consider as major advances in treatment of a previously untreated or already treated disease. A product candidate may be a second-generation molecule with some patient care advantage being established, for example, pegylation of proteins to stretch out the injectible dosing of these products from daily to weekly with Neulasta® or from thrice weekly to weekly for interferons (Pegasys®). Some products may be approved for use as the second or third or later product within an existing therapeutic category with already approved products, but their success is based on the R&D organization doing the research to show best-in-class properties of the product (e.g., better cholesterol reduction with Crestor® vs. Pravachol®). Manipulation of molecules can be done to change their properties and possibly improve their efficacy or toxicity or utility. For example, Genentech created Activase® first for clot lysis in acute myocardial infarction (AMI), and then several years later created a follow-up molecule, TNKase®. Protein changes allowed intravenous bolus versus slow infusion, a major advantage in the acute setting of AMI. Other product changes (improvements) are goals and outcomes for an R&D operation, such as a new route of administration for treatment flexibility, formulation improvements for extended release and less frequent daily doses, more stability for a better shelf-life, or a new product delivery system with convenience for health care delivery, such as self-injector pens for insulins given by injection once or more per day. A new formulation is a patentable new product, which continues a company's dominance in patient care and the related product sales. For example, the calcium channel blocker Diltiazem® for hypertension originally from Marion Laboratories was a major therapeutic advance for hypertension (new mechanism of action) at its time of marketing 20 years ago but was given multiple times a day. The extended release form with once-daily dosing offered much better patient convenience and compliance especially for a silent killer like hypertension and gave them continued market exclusivity for several years further. R&D or the manufacturing division has a unit called process engineering that does research on improved manufacturing processes to improve the yield, remove contaminants, or reduce cost of operations, using less manpower, fewer steps in the process, faster process, more automation, or less ingredient costs [17, 33-36].

A very undesirable outcome of the R & D organization is product failures at various stages in a product's life cycle (Fig. 3.9). A company wants to kill a product at the earliest possible stage if it eventually believes that it will become a failure, thus not wasting research dollars and better utilizing resources for faster product approvals with more likely better products. The kill decision is by far one of the most difficult ones for a company. A significant number of scientists devoted time, energy, creativity, and emotions into their work, which is very hard to turn off and redirect sometimes into whole new therapeutic or disease areas, where the scientists may not be as comfortable or as capable. Too often the company will try to do one more study to tease out some benefit, but it may be only marginal. On the other side of coin, you do not want to abandon a molecule completely if it may have other indications. One of the best examples is etanercept (Enbrel®), which was first studied for sepsis, based on the major inflammatory problems in sepsis and the significant role tumor necrosis factor (TNF) plays in sepsis. However, it was a complete failure in phase 3 trials with marginal benefit being observed at best. The Immunex company continued to look for other applications for its molecule, other inflammatory conditions where TNF is a major mediator, because they knew their molecule favorably lessened TNF effects in several disease models. Rheumatoid arthritis was studied, and about 5 years later it was not only approved for use, but etanercept is a major advance to control arthritis and slow

Biotech drugs in 1980s & 1990s, Success Rates = about 30-35% (P.1 to Approval)

Products (Company) Indication

Products (Company) Indication

Ad5FGF4 (Schering) Astenose (Glycomed) Antril (Synergen)

Angina

Restenosis

Sepsis

GDNF (Amgen) Hirulog (Biogen) Lamin gel (ProCyte)

Parkinsonism Angioplasty Diabetic ulcers

Arasine (Gensia)

AMI (bypass)

NS2330 (Neurosearch)

Alzheimers

Argidene (Telios)

Diabetic ulcers

Pactimibe (Daiichi)

Atherosclerosis

Glitazone (NovoNord)

Diabetes

Repinostan (Bayer)

Ischemic stroke

Betakine (Celtrix) CB001 (Viacell) CEP-1347 (Cephalon) CD-5 (Xoma)

Macular holes

REN-850 (Renovis)

Multiple sclerosis

Cell Transplant

Sumanirole (Pfizer)

Restless legs

Parkinson's Transplant

T-88 (Chiron) Tezosentan (Actelion)

Sepsis Heart failure

Centoxin (Centocor)

Sepsis

Therafectin (Greenwich)

Arthritis

CNTF (Regeneron)

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