Drugs Deliver

The Ernst & Young's 2010 global pharmaceutical report described non-traditional companies that will induce pharmaceutical companies to broaden their focus in creating partnerships for innovation. This report led me to consider a company not mentioned in their review. “Dominos Delivers” is a phrase that encompassed a significant accomplishment in a competitive industry that served to promote a product that was consistent in quality and available to customers almost anywhere and at anytime. In the world of pizza, with thousands of competitors making essentially a generic product, Dominos Pizza emerged as a powerhouse that delivered quality and convenience. The generic drug industry faces a conundrum not unlike the pizza world which may provide fresh ideas for drug developers. Recent patent expirations for many efficacious drugs with established safety profiles along with an ever increasing plethora of efficient delivery and formulation technologies have set the stage for differentiated products that can satisfy the unmet needs of many patients. The key issue is differentiation via leveraging the relevant delivery technology coupled with effective presentation of scientific evidence that patients and practitioners will recognize and government regulators will approve. While drug delivery and formulation technologies hold great promise for the development of enhanced versions of generic drugs, sound strategies based upon a clear understanding of the needs to be met are a must. Analogous to the potential seen by Tom Monaghan fifty years ago when he founded Dominos, significant clinical and commercial achievements are on the horizon for companies that carefully analyze key therapeutic areas for unmet needs that may be resolved by combining existing drugs with the optimal delivery technology.

The utilization of drug delivery technology to improve a drug’s therapeutic profile is certainly not new. High profile companies such as Elan, Eurand and Skye Pharma have documented success in either greatly improving the efficacy and/or safety of drugs as well as implementing effective life cycle management (LCM) strategies based upon their technology. Several large pharmaceutical companies have drug delivery divisions for internal programs as well as provision of services to other companies. Going forward, these and other companies must not only continue to effectively leverage their delivery platforms in key therapeutic areas, they must do so in an increasingly competitive marketplace comprising upstart companies with state of the art technology platforms and a growing track record of success. According to a recent report from BCC Research, the market for drug delivery systems was estimated to be approximately $139 billion in 2009 and with a projection of more than $196 billion by 2014. Specific to the pain market, the launch of at least 20 new formulations of analgesics is anticipated to increase growth by 3% according to a report from Decision Resources. The drugs will be reformulations of conventional analgesics such as fentanyl, oxycodone, diclofenac and bupivacaine. Evidence for these projections can be seen from the recent US FDA approval of a reformulated version of Purdue Pharma’s OxyContin. The new version slowly releases oxycodone making the drug less prone to overdosing and abuse. In addition, the new formulation allows patients to take the drug less frequently. Another relevant application of drug delivery technology in the CNS arena involves Boehringer Ingelheim’s recently launched Mirapexin (pramipexole) in a new once-daily formulation to help patients deal with the debilitating symptoms of Parkinson's disease (PD). The new formulation is anticipated to benefit patients who are awakened in the middle of the night due to PD symptoms; clinical studies documented that the once a day prolonged release formulation was as effective as the three-times-a-day formulation at the same daily dose.

Considering the extensive R&D around the globe, including prolific activity in China and India, some may consider projected revenue from reformulated drugs to be on the conservative side. So what strategies may prove effective in maximizing the potential for enhancing the benefits of key drugs using drug delivery technology? Will the winners be companies with the most or the best tools or will they be the ones that utilize existing tools in the most efficient and prudent manner? Perhaps the greatest achievements will be made by companies that recognize the needs to be met and fill those needs with the best technology available. In my experience, the conventional process for identifying key unmet needs comprises a comprehensive therapeutic review of target disease indications. Such reviews can be conducted via contributions from market research, technical and competitive intelligence as well as information from medical liaison resources. The research should focus on not only existing therapies and their deficiencies, but also a thorough analysis of the disease indication pipeline. The analyses will reveal clues regarding the likelihood for approval, key safety issues as well as the potential efficacy of the drugs, all of which taken together can reveal unmet needs. This approach may work well for medium to larger size companies, but what about smaller firms with limited resources? Even if a thorough review is conducted within a key disease indication, what is the likelihood that the results can be exploited with a presumed limited technology range? Considering that smaller companies will most likely target larger firms as partners in their drug development efforts, I advocate a strategic review of potential partners as a starting point for setting the overall R&D strategy. Such a review will, by default, include a more thorough therapeutic review done by the target partners. The identification of potential deficiencies in existing and development-stage drugs of potential partners can be an effective, inexpensive and yet comprehensive means of setting an R&D strategy focused on the enhancement of the therapeutic profiles of known drugs. In fact, now is an ideal time to conduct such reviews since several companies have recently announced realignment of therapeutic focus due to completed M&A milestones and other justifications. Within the US and a few other countries, public companies must disclose their R&D investments and most do in a very transparent manner. For instance, at the beginning of the year, Pfizer announced that it will cut 100 drug development programs from its pipeline swollen by the merger with Wyeth. The remaining programs are focused on six key areas: oncology, pain, inflammation, Alzheimer's disease, psychoses and diabetes. Another pharma giant, Novartis, announced that it will focus on cardiovascular & metabolism, oncology, CNS and ophthalmics, respiratory, immunology and infectious disease. Relevant to drug delivery and its stated focus within respiratory, Novartis (Sandoz) recently announced the acquisition of Oriel Therapeutics, a company with a portfolio of generic drugs and technologies targeting asthma and COPD. Oriel will be integrated as a development unit within Sandoz including its FreePath drug delivery technology. The company stated that the Oriel technology has the potential to address several of the hurdles in regulatory approval of generic inhaled medicines in the US. Oriel also brings to Sandoz the Solis disposable dry powder inhaler based on the FreePath delivery technology. Sandoz believes the acquisition of Oriel will enable the company to better leverage its existing range of in-market products. At the very least, the acquisition should provide valuable insight to companies with comparable technology to better position their R&D programs for collaboration with Novartis or a competitor. This strategy makes sense considering the recent announcement by the Food and Drug Administration (FDA) that it will more stringently regulate the use of long-acting beta agonists (LABAs) as treatments for asthma. Also, the FDA has mandated additional studies be conducted by manufacturers of LABAs to validate the safety of the drugs when used in combination with inhaled corticosteroids. As an example, the utilization of nanotech / micron and related platforms to reduce dosage while maintaining efficacy of LABAs makes a lot of sense in light of this increase in regulatory scrutiny.

These are just a few examples of recent developments involving drug delivery / formulation that support the premise of establishing an effective strategy as the basis for utilizing technology platforms for enhanced therapeutic benefits. This strategy can be employed using existing technology or can form the basis of a licensing effort to acquire new platforms or even build an effort from scratch. The seminal item, to draw again on the pizza analogy, is the improvement of a known commodity, the drug, via optimized formulation and delivery. The analogy reminds me of the college student who was delivering pizza. When asked about the usual tip, the student stated that if he got a quarter, he would be fine. The customer, feeling somewhat insulted, handed him a five dollar tip and asked him about his major, to which the student replied, “applied psychology.” The drug industry can use a little applied psychology to look for opportunities in what seems to be not so obvious places.

Robert Morrison, Ph.D. is Director, The Invotex Group, a specialty consulting firm that provides a range of financial and technical services to companies and academic institutions. Dr. Morrison’s practice focuses on issues associated with clinical development and intellectual property of pharmaceuticals and medical diagnostic applications.

1-267-679-2024
ramorrison@invotex.com
www.invotex.com

New Tricks Make Old Drugs New Again

The saying “you can’t teach an old dog new tricks” may not apply to old drugs. Perhaps the song, “Everything Old Is New Again” more appropriately describes what some in the industry are referring to as the three Rs, repositioning, repurposing or redirecting of drugs. These terms describe the determination of whether an approved drug can be used for additional disease indications. Some may include additional Rs, for rescue or re-profiling, that refer to obtaining an approval for a drug that failed in development for a different indication yet exhibited a favorable safety profile. Whatever R term is used or preferred for drug repositioning (DR), there is no doubt that indentifying and achieving approval for a new indication makes sense considering the established safety profile of approved drugs coupled with savings in costs and time during development.

There are many examples of drugs that have been successfully repositioned for additional indications.

From a drug rescue perspective, a notable example is sildenafil. Although the drug failed in development for a cardiovascular indication, a “significant side effect” led to development for the treatment of erectile dysfunction(ED). Subsequent to the approval for treatment of ED, sildenafil was repositioned for the treatment of pulmonary arterial hypertension (PAH), an indication related to the initial indication for which sildenafil failed. Vaso-constriction is an underlying disease factor of ED and PAH; the vasodilation effect of sildenafil was the basis for the successful PAH repositioning effort.

An understanding of common disease factors among different indications is an important first step in determining whether a drug repositioning approach makes sense. A low-hanging fruit example of this point involves the TNF-alpha inhibitor drug Etanercept. The excessive production of TNF-alpha within arthritic joints and in psoriatic plaques led the developer of the drug to rationalize the potential of the drug to treat both diseases. Such a scenario was not the case for dimebon (latrepirdine), an antihistamine drug under development for the treatment of Alzheimer’s Disease (AD). Co-developers Medivation and Pfizer recently announced no apparent efficacy for the drug that has a proposed mechanism of action for AD based upon protection of brain cells from damage by stabilizing and improving mitochondrial function and which is unrelated to the antihistamine activity. Such a result raises serious questions concerning disease factors, especially within a complex disorder such as AD. For instance, one school of thought suggests that the decline of the histamine receptor binding might play a substantial role in the cognitive deficits of Alzheimer’s disease patients. Since the proposed mode of action of dimebon involves enhanced brain cell survival, it is conceivable that the antihistamine effects may have played a role in the drug not meeting its co-primary or secondary efficacy endpoints for AD.

The recent results concerning dimebon and other failed as well as successful DR projects supports a thesis and strategy that I have developed and employed which focuses on key disease factors between existing and proposed indications. Over the last several years I have studied many case histories in DR that resulted in the refinement of a process for candidate selection. The process comprises scientific and intellectual property literature analysis, chemical structure comparison, reviews of clinical research records from related diseases as well as other features. A comprehensive scientific summary is generated for further preclinical or clinical development consideration. Application of the process has resulted in the identification of candidates for new indications comparable to that from companies that utilize proprietary analytical in vitro and in silico methods. The closer the match for drug effects on basic disease factors between existing and proposed indications, the better the probability for success.

While the scientific case is an important first step which has served as the basis for several DR approvals, an approval does not necessarily translate into commercial success. To achieve commercial objectives, I advocate a comprehensive analysis culminating in a cohesive strategy prior to embarking on a development program. An established safety profile coupled with clinical or pharmacological evidence should not be the driving force in pursuing the added indication. Fulfilling an unmet need in a patient population should be at the forefront of the decision process with consideration of not only the traditional factors but also a few that are unique to DR when making a clinical development decision. Before embarking on a DR effort, drug developers should understand that there is no generic (pun intended) path or process to achieve success. Each drug is different as are the relevant therapeutic areas. A thorough analysis of key technical and commercial factors is a prerequisite for a successful program. These factors include current usage of the drug relevant to dose, formulation, treatment methods and intellectual property (IP). A comprehensive approach to accommodate all relevant factors is advised to ensure the development of a safe and efficacious therapeutic.

Commercial Strategy
Despite the potential positives mentioned previously, adding indications to an improved medication may have profound clinical and commercial implications for the current and / or pending uses. In general, the current usage is the priority from a commercial and/or therapeutic perspective. One must consider the ramifications relevant to this priority indication when adding indications. The dose and/or formulation should be sufficiently differentiated from that already approved to avoid confusion among practitioners and patients as well as providing insulation from prescribing of a lower cost version of the drug and/or generic versions. This is best done when a single company develops the drug for each indication (e.g. Lilly and duloxetine; GSK and bupropion). For duloxetine, Lilly maintained the same brand name, Cymbalta, but utilized different dosages in clinical trials for the various indications. On the other hand, GSK developed novel formulations of bupropion (presumably as a life cycle management strategy for Wellbutrin) and adopted a separate brand name, Zyban, for the smoking cessation indication. Since control of the molecule is not always the case, the company considering the additional indication should ensure that the medication for the new use is sufficiently differentiated from what is currently marketed. If such a scenario is not possible, the company should consider a comparable drug that exhibits a similar pharmacological and safety profile. There are additional strategies that can be considered (e.g. enantiomers, metabolites, etc.).
Insert bupropion graphic

Dose & Formulation Considerations
As stated previously, a careful consideration of the dose for the new indication should be made. In addition to the standard safety / efficacy analysis, dosage should be considered within the context of treatment methods specific to the new indication as well as within existing or potential intellectual property. Unlike duloxetine, a one size fits all scenario is not likely and the optimal dose and formulation must be determined within the above mentioned framework. The sub-anti-microbial formulation of doxycycline (trade name Oracea) is a good example. The anti-inflammatory effects of doxycycline were well known which led to the development of a 20 mg formulation for the treatment of inflammation associated with periodontitis. Although the medication exhibited efficacy in other inflammation-based diseases such as rosacea, the 20 mg dose was not an optimal treatment. Optimization of the doxycycline dose for treatment of rosacea was achieved by a formulation that comprised a total of 40 mg (30 mg immediate release and 10 mg in the form of delayed release beads). The formulation was approved as the first oral drug for the treatment of rosacea. According to a 2009 press release, sales of Oracea were approximately $104 million, a substantial success for a DR candidate in dermatology.

Doxepin is a tricyclic anti-depressant which was repositioned as an active ingredient in a cream-based formuation (trade name Zonalon) for the treatment of dermatological itch. More recently, doxepin was approved for the treatment of insomnia under the trade name Silenor. The scientific rationale for doxepin as a sleep aid is based upon the high affinity of the drug for the histamine 1 (H1) receptor. Anyone who has given their child a dose of Benadryl (diphenhydramine) can understand the rationale for using an antihistamine to induce sleep. The commercial opportunity for using doxepin for insomnia was based upon the exceptional affinity of the drug for the H1 receptor versus the target for its anti-depression effects. This factor enabled a dose for insomnia of approximately one tenth of that used to treat depression (however, lower doses close to the Silenor dose are available as generics for depression). Although the jury is still out regarding the commercial success for the doxepin insomnia treatment, the lower dose and label may sufficiently distinguish Silenor from the generic versions of doxepin indicated for depression as well as generate off-label script for depression patients requiring a lower dose of doxepin.

Intellectual Property Issues
The examples of doxycycline and doxepin demonstrate the importance of developing novel formulations and/or dosages to support development for additional indications from both a clinical and commercial perspective. In addition, both drugs feature patents covering the novel formulations as well as claims for methods to treat the new indications. In the absence of a patent for drug substance composition of matter, such IP positions are critical to justify the expense and risk associated with a repositioned drug. While a new indication approval triggers a three year data exclusivity period in the US, an extended period of market exclusivity via patent protection is desired to maximize the commercial opportunity. Unless the new indication is justified by an unexpected discovery, it is likely that published data supporting the scientific rationale, vis a vis relevant disease factors, may represent prior art challenges in obtaining comprehensive patent coverage. It is critical to have the scientific case reviewed by a patent attorney coupled with a thorough consideration of potential IP and other exclusivity options. Treatment methods, dose range, formulation, etc. should all be considered within the context of the relevant data that provided the scientific rationale and within the context of the safety profile of the drug. An additional element that should be considered when determining the IP options is information from the patients and the practitioners. Is there an opportunity to minimize side effects, are there issues related to compliance that can be resolved that may lead to innovation and thus patentable matter? Such questions should be asked so that a key IP option is not overlooked. The opportunity to develop a drug with a proven safety profile should be incentive enough to determine whether an IP position can be established to effectively protect the new franchise.
The song “Everything Old Is New Again” may not apply for repositioning of all drugs, but for those coming off patent which have a good safety profile and support for treatments in additional indications, perhaps a line from the Grateful Dead song “St. Stephen” would be more apt: “Talk about your plenty, talk about your ills, one man gathers what another man spills.”

Robert Morrison, Ph.D. is Director, The Invotex Group, a specialty consulting firm that provides a range of financial and technical services to companies and academic institutions. Dr. Morrison’s practice focuses on issues associated with clinical development and intellectual property of pharmaceuticals and medical diagnostic applications.

1-267-679-2024
ramorrison@invotex.com
www.invotex.com