ADDING VALUE TO A PRODUCT S LIFE CYCLE MANAGEMENT: Product Enhancement Through Drug Delivery Systems

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1 ADDING VALUE TO A PRODUCT S LIFE CYCLE MANAGEMENT: Product Enhancement Through Drug Delivery Systems Anand Baichwal, Ph.D. Sr. VP of Research & New Technology Development, and Chief Scientific Officer Deborah Neville Director of Marketing Penwest Pharmaceuticals Company Faced with soaring R&D costs, an impending onslaught of patent expirations, mega-merger mania and increasing consumer demands for improved medications, pharmaceutical companies are relying more heavily on advanced drug-delivery technologies to help them sustain the high growth and profit margins they have been experiencing since the 90s. With more than 300 products coming off patent in the next four years and increasing generic competition, they are under intense pressure to replace these losses with new or improved drugs. Against this background, pharmaceutical companies are recognizing that drug delivery technologies are a powerful strategic marketing tool to differentiate products and extend product life cycles, thereby overcoming many marketplace challenges. They are pursuing stronger alliances with drug-delivery companies, including acquisitions, to enable them to develop superior drugs and remain competitive. The market for advanced drug-delivery systems is expected to mushroom, from $15.5 billion in 2002, according to a report from Business Communications Company, and is expected to grow to $27.35 billion in 2005.

2 The application of drug delivery is a valuable, cost-effective life cycle management resource. By infusing drugs with new and innovative therapeutic benefits, drug-delivery systems extend products profitable life cycle, giving pharmaceutical companies competitive and financial advantages, and providing patients with improved medications. How Drug-Delivery Systems Benefit Pharmaceutical Companies and Patients Advanced drug-delivery technologies can improve a product s clinical and commercial value, differentiate a product, and serve as an effective resource to outdo competitors. Clinically, they improve the pharmacoeconomics of drugs by reducing adverse effects, identifying new indications, and improving therapy, safety, efficacy, convenience and compliance. Drug delivery technologies make medicines more convenient and acceptable to patients. They can simplify the dosing regimen, and improve administration. These improvements, in turn, bolster compliance, which improves patient outcomes and quality of life and reduces costs. By reducing dosing frequency, these improved medications reduce the frequency of caregiver interactions. Fewer visits from doctors and nurses saves administration costs and time and reduces inconvenience for patients and caregivers. With medications for chronic diseases that display time-dependent symptoms, such as ulcers or asthma, drug-delivery systems can control the formulation release according to the timing of symptoms. For example, they can enable a drug to release when asthma attacks

3 occur, generally in the early morning hours. This chronotherapeutic technology can provide valuable clinically proven therapeutic benefits, and another means for marketers to differentiate their product. Commercially, delivery technologies give new life to drugs, repositioning them with a new or improved therapeutic benefit and a competitive edge. By extending the product s life cycle with a line extension, they sustain the drug s market value. When To Use Drug-Delivery Systems to Extend Product Life Cycle?? To give a product a competitive edge. When a competitor is introducing a new drug with superior benefits that threatens to erode your drug s market share, a drug-delivery technology can be an effective defensive marketing strategy. By adding a relevant new benefit, such as reduced side effects, it can boost your drug s value and revive its marketplace position. In the same way, these systems can jump-start products in a mature life cycle stage (see below, patent expiration).?? To enable or accelerate market entry. Drug-delivery systems reduce the attrition rates and development time for new active substances. Each year, more companies assess and dismiss thousands of active substances for reasons such as insolubility or unacceptable toxicity. Ten percent are terminated because of adverse effects. Others never come to market because of high dosing frequency or the inability to formulate the drug. Drugdelivery systems can overcome these issues, enabling more active substances to proceed to clinical trials and more products to reach the market.?? When patents expire. Novel drug-delivery systems can protect or prolong a product s patent exclusivity. When patents are expiring, the patented-drug

4 company and companies seeking to benefit from the patent expiration can use drug-development technologies to seize this market opportunity. Below are some commonly used strategies. Develop a generic. Developing a generic requires use of sophisticated drug-delivery technologies that must not only match the pharmacokinetic profile of the reference drug, but must also avoid the innovators patents. Technologies known for ease, flexibility and rapid development time will increase the chances of being first to market. For example, in 1994 Penwest partnered with Mylan Laboratories to develop a generic equivalent of Pfizer s 30 mg Procardia? XL, joining the industry race to produce a controlled-release nifedipine tablet. Industry leaders said it couldn t be done because Alza s patented technology could not be duplicated to resolve the solubility challenge and deliver a zeroorder release. But the speed and flexibility of Penwest s TIMERx controlled-release technology enabled the two companies to develop a generic and Mylan to gain the first-to-file status. Develop an improved product. Drug-delivery technologies give formulators a value-added opportunity to develop innovative, therapeutically enhanced alternatives to compete against generics and branded products. They enable the patented-drug company to extend exclusivity by developing an enhanced version with therapeutic benefits such as improved efficacy or dosing frequency, or new therapeutic indications. To gain a marketplace advantage, the development of enhanced products should begin at least two to three years prior to patent expiration. The patented-drug company should comprehensively analyze the generic threat, identify all available strategies and potential

5 development partners for maintaining the post-patent value of the product, and then determine the best option. When Cardizem, a three-times-daily cardiovascular drug, achieved revenues of $260 million in 1988, Hoechst Marion Roussel and Elan extended the product s life cycle by introducing Cardizem SR (diltiazem, twice-daily). Revenues peaked in 1989 at $400 million, remaining steady until 1991, when Cardizem CD was introduced for once-daily dosage. By 1996, revenues for Cardizem CD soared to nearly $900 million. (Figure 1) Drug Delivery and Product Life Cycle Management The Cardizem Story Figure 1 Introduce a new product. To replace sales of a product with an expiring patent, drug-delivery technologies can be used to develop a new product with a different chemical entity and brand name. Or transfer value from the branded drug to a successor product by switching the ethical drug to an over the counter product. Extend exclusivity. From the earliest stage of development of an NCE, speed to market should be a key consideration. A product that is first to market may soon lose that advantage, as similar products with improved

6 formulations erode its market share. Using a drug-delivery technology to introduce a novel new drug with enhanced benefits such as optimal dosing can deter competition and lengthen the period of product exclusivity. For mature products, a drug-delivery system can extend patent life only if it provides a significant enough benefit to warrant the inevitable price premium that can occur after patent expiration. Another strategy to extend exclusivity is to expand the overall market for original patented compound, such as developing a palatable antibiotic for children or a smaller tablet size for elderly patients or children, or to determine new therapeutic indications. Which Drugs to Select for Oral Drug Delivery When selecting drug candidates for the application of drug delivery technologies, consider the following factors:?? Clinical. Identify clearly defined unmet medical needs. Choose therapeutically relevant products that can be altered by drug delivery technology to provide significant clinical advantages, such as: reduced side effects, improved efficacy, or delivery of the active based on circadian rhythm. (Figure 2)

7 Key Clinical Parameters Figure 2?? Technical. Weigh the ease of achieving the clinical end-point, the ease of formulation and the cost of negative evidence against the magnitude of the clinical benefit.?? Commercial. Consider peak year sales, development costs and the competitive dynamics will the enhanced product have a significantly distinctive benefit over products of current or anticipated competitors? Will the product yield maximum return on investment? Penwest s Drug Delivery Technologies Penwest s oral drug delivery technologies were designed to enable all of the above criteria to be met. Penwest utilizes its drug delivery technologies in the formulation and development of pharmaceutical products. Our drug delivery technologies serve as strategic tools which extend a product s life cycle and/or boost a drug s position in the marketplace. The overall goal of Penwest is to build a strong pipeline of products that fulfill unmet medical needs, improve compliance and offer clinical benefits.

8 Penwest is developing a diverse pipeline of pharmaceutical products enhanced with our drug delivery technologies. Our product strategy is to reformulate drugs that are already on the market that can benefit from our proprietary oral drug delivery technologies - TIMERx for extended release, Geminex for dual delivery, and our newest technology for chronotherapeutic delivery - SyncroDose. These technologies can be applied to a wide range of drugs with different physical and chemical properties. Penwest s patented TIMERx, an established broad-based oral drug delivery platform, is used for controlled release, dual delivery of drugs and chronotherapeutic release. The TIMERx system is based on the synergistic interaction of heteropolysaccharide (xanthan) and galactomannan (locust bean gums), which in the presence of a sugar form a strong binder gel in water. Drug release is controlled by the rate of water penetrating into the hydrophilic matrix and the subsequent expansion of gel, which releases the active drug. The TIMERx platform, which includes a broad range of flexible release profiles, works with soluble or insoluble drugs, low- to high-dose drugs, and those with a short half-life or narrow therapeutic window. The system allows for rapid formulation and development, which means reduced costs and shorter time to market. TIMERx also enables ease of scale-up and technology transfer, with no capital costs to the manufacturing partner. Two newer generations of TIMERx are Geminex and SyncroDose. Geminex is a bilayered dual-delivery tablet technology that incorporates both an immediate-release and one or two controlled-release components. The dualdelivery capability of Geminex can deliver drugs or isomers with two different and unique release profiles at two different rates. Penwest is actively applying our Geminex technology to the following therapeutic areas: cardiovascular

9 disorders, chemotherapy induced emesis, and disorders of the central nervous system. SyncroDose is a chronotherapeutic drug delivery system that releases drug at the desired time and to the targeted site in the body. SyncroDose is the first delivery technology to provide true chronotherapy delivery options that offer a variety of pre-determined lag times, followed by a variety of customized profiles to include immediate and controlled release. SyncroDose can be effective for disease states such as arthritis, asthma, cardiovascular disorders, neurological disorders and cancer. Summary In response to today s challenging environment, where new chemical entities are limited and are costly to develop, Penwest thrives to provide the pharmaceutical industry with low-risk, innovative patent-protected products. We have active development programs in therapeutic categories such as pain management, rheumatoid arthritis and hypertension. We intend to expand our core offerings by developing, licensing or acquiring those technologies that are deemed to be synergistic with our current product development pipeline. Oral drug delivery technologies provide an opportunity to add therapeutically relevant new products to drug pipelines in a time- and cost-efficient manner utilizing mature drugs. Drug-delivery companies will play an increasingly important role in the future of pharmaceutical marketing, as pharmaceutical companies recognize new ways they can be used to extend a product s life cycle and sustain profitability. There will also be an increasing demand for more technological advances in drug delivery to meet new drug challenges in the future.

10 Acknowledgements The content of this manuscript was taken from a previously published article in Drug Delivery Technology magazine October The authors would like to acknowledge the efforts of Diane D Alessandro Marketing Associate, in the preparation of this manuscript. Anand Baichwal, Ph.D. Sr. VP of Research & New Technology Development, and Chief Scientific Officer Deborah Neville Director of Marketing