A Drug Development Lesson - The Three Way Tug-Of-War For New Antibiotics

In the tug-of-war between development of resistance in bacterial pathogens and the effort to develop new drugs, is it fair to ask, are we running out of effective antibiotics? Are Food and Drug Administration (FDA) regulatory guidelines sufficiently clear to companies developing new drugs? The answers may be yes and no based upon recent events and our own work concerning an antibiotic business.

A recent announcement by Infectious Diseases Society of America urged for a global commitment to develop 10 new antibiotics by 2020. The plea for U.S. and global action comes in a statement—published in the April 15, 2010 issue of Clinical Infectious Diseases that outlines the dangers and recommends how to address what the World Health Organization has identified as one of the three greatest threats to human health. This announcement coincides with recent testimony by experts to the United States House of Representatives Committee on Energy and Commerce's Subcommittee on Health.

Imagine if the country was under attack from a foreign power and it was determined that a small subset of the enemy was invincible to our weapons of defense. Would we not hasten to develop more effective weapons to defeat the enemy? In fact, a representative of the Biomedical Advanced Research and Development Authority at the Department of Health and Human Services (HHS) provided testimony that likened antibiotic resistance to a bio-defense threat and suggested that the federal government should provide financial incentives to encourage companies to develop new antibiotics. Given such a threat, does it make sense to provide incentives for companies to pick up the pace in discovering and developing new drugs to combat dangerous microbes? A representative from the pharmaceutical industry described antimicrobial resistance as a crisis and charged the government to do much more in aiding drug company efforts to develop more effective antibiotics. The industry expert offered one suggestion - extend the patent term for new antibiotics.

But what about the regulations- is there sufficient incentive from a regulatory perspective to justify new investments in antibiotic drugs? The expert from HHS testified that "The lengthy drug development process means that new classes of drugs to supplement or replace current ones are still years away.” It was also noted that newer drugs are typically saved for the sickest patients, reducing their sales potential. The industry expert noted that the FDA has been inconsistent in guidance to companies regarding the extent of evidence to achieve approval of new antimicrobial drugs.

Testimony from Dr. Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, conceded the government must do more to encourage drug companies to develop new antibiotics. "The pipeline is diminished at a time when the need could not be greater," she said. But, and with the FDA there is always a “but”, she raised the issue of lack of consensus by the scientific community concerning evidence that an antibiotic works as well or better than existing drugs, especially for the treatment of common conditions like sinus or ear infections. Woodcock stated that the FDA would publish additional guidance on testing to generate evidence for antimicrobial drug efficacy within the next six months.

Dr. Woodcock’s recent testimony provides little comfort for patients in need of more efficacious antibiotics and the companies attempting to develop the desired drugs. The fact that the FDA must make good on its promise to provide regulatory transparency to companies is exemplified by an announcement from Theravance early this year. The company stated that the FDA was not satisfied with new data on telavancin (Vibativ) as a treatment for nosocomial pneumonia (NP) and suggested additional clinical studies be conducted to achieve approval. Telavancin is a lipoglycopeptide antibiotic with a dual mechanism of action on bacterial cell wall synthesis and cell membrane function. The drug was approved in September, 2009 as an injection for the treatment of complicated or drug-resistant infections, almost three years after filing the NDA. The FDA accepted the telavancin NDA for the treatment of NP in April, 2009 but later informed the company it did not show sufficient efficacy to achieve approval. Theravance CEO Rick Winningham stated that it was unclear what additional information the FDA required to complete review of the NDA while pointing out that the studies they submitted were “the largest double blind studies ever submitted to the FDA for the evaluation of a new drug to treat NP due to gram positive organisms.” While it is likely that some physicians will prescribe telavancin for the treatment of NP off-label, lack of transparency from the FDA will prevent Theravance from realizing the full potential of the drug to treat multiple infections while delaying development of resistant organisms due to its dual mode of action.

The promised guidelines from the FDA will solve the problems, right? Not so fast there, buckaroo!

We recently conducted a valuation of an antibiotic business and concluded that the commercial prospects for drugs that treat common and rare infections are not good. Over the past several years, antibiotic patent expirations have led to a dearth of less expensive yet efficacious antibiotic drugs which contributed to a significant reduction in the overall market. Starting in 2005, patent expirations hit the industry like a plague. Successful franchises including ceftriaxone (Rocephin), clarithromycin (Biaxin) and cefepime (Maxipime) realized substantial reductions in revenue and margins as generic versions entered the market. The epidemic continues this year with the expiration of the US patent for levofloxacin (Levaquin). Datamonitor has estimated that sales of Levaquin will be reduced by half in 2011 ($0.7B vs $1.4B in 2010) and will be only $72M by 2014.



“Beyond 2010, as the market becomes more saturated, pharmaceutical companies will struggle to generate sufficient revenues to survive in the antibiotic sector. At the heart of this will be difficulties for developers to ensure that conventional antibiotics, from leading classes, generate sufficient revenues to be considered a worthwhile investment”, stated a Datamonitor report from 2006. “The marketplace is already saturated with products that are polarized between a limited number of high-yielding products, and a much greater number of products generating substantially lower revenues.” This excerpt from a 2003 Datamonitor report sounds like a fulfilled prophesy based upon our market analysis.

Patent expirations have lead to a virtual flood of generic antibiotics resulting in a third line in the tug-of-war to develop new antimicrobial drugs. Is there a solution? While a partial answer lies with the FDA relative to the height of the barriers to obtaining marketing approval, our valuation work taught us that a company developing a novel antibiotic (or any drug for that matter) should regularly check the value of their drug candidate relative to available efficacy data and current market factors. This information should be utilized in out-licensing / partnering decisions in terms of timing for when to bring in a partner as well as the type. Depending on the valuation results, it may be necessary to select a partner to participate in designing and funding the late phase trials as well as begin planning how best to market the drug within an ever rising tide of generics.

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

Paying For Drug Development – Know Your Drug Better Than Your Spouse

A young boy once asked his father, “Dad, how much does it cost to get married? His father replied, “I don't know son, I'm still paying.” This humorous exchange hit home relative to recent news articles concerning drug development investments in what some are calling the generics age. According to a recent report from IMS Health, patent expirations are setting the stage for a substantial increase in the availability of generic versions of drugs which will certainly result in a dip in R&D spending over the next few years. Although the report estimated that an emphasis on drug development investments in key chronic therapeutic areas may offset the trend, the report raises serious questions concerning innovation to support future growth of the pharmaceutical industry. Coincidently, data recently released by Thomson Reuters show biotech investments for clinical stage companies being substantially less than last year which could mean the end of several companies desperate for cash to fund their next key trial. Adding fuel to the fire was an analysis from biotech investment specialist Cynthia Roth-Robbins. A key point from her analysis involved the greater number of A-round investments in companies at the research stage versus more advanced clinical development programs. Considering that research-stage drugs will not achieve approval until the end of the decade if at all, a “perfect storm” scenario could develop and contribute to a significant gap in the availability of novel therapeutics.

Another important point from the Roth-Robbins analysis involved investors favoring companies with research / preclinical stage drugs over companies that are pursuing reduced risk strategies such as in-licensing approved drugs or reformulation / repositioning programs. While this may make sense from an investor perspective, i.e. potential bigger payoff from a cutting edge therapy versus an older drug with a perceived lower therapeutic and thus commercial value, the risk factor is something that should raise the eyebrows of both drug developers and their investors. Commentary from Jim Greenwood, President and CEO of the Biotechnology Industry Organization (BIO) during the group’s annual conference earlier this month provided a not so apparent focus point. Greenwood stated, "Investors are still willing to invest, but they want to see real results. They are looking for things that aren't just incremental improvements ... but real innovation." A key question from all of this is how do you achieve real innovation with lower risk and how much will it cost? An additional question, within the context of insurance reform is, who will and how much are they willing to pay for this innovation?

Consider the saga of the cancer vaccine Provenge from Dendreon. The controversy concerning the Provenge approval aside, many are now asking whether the treatment is worth the stated price of $93K. This price is considerably higher than anticipated. A news article in Xconomy summarized projections from analysts with a range of $40,000 to $75,000 per patient, with an average around $62,000. Dendreon spent about $1 billion developing the immunotherapy. Since Provenge will be covered by Medicare Part B, which reimburses the cost of any FDA-approved drug infusion or injection, taxpayers will foot much of the bill (for retirees). If Provenge were a pill, the drug would be covered by Medicare Part D’s new prescription drug coverage program, which makes patients pay at least part of the bill ($4,350 of the total treatment cost). This may explain why the price of Provenge was set higher than analysts expected. It seems that Dendreon’s commercial strategy included the assumption that most patients were Medicare recipients and not private insurance, and that the government’s own rules prevent Medicare from negotiating prices. So what if Provenge were a pill? Would the company have set a much lower price and if so, would it be worth the $1B invested?

While Provenge may not be the best analogy for drug development projects in terms of risk and value, it does bring up an important and yet over-looked facet of drug deals these days. A recent Ernst & Young report on the drug development investments should remind us that marketing approval is no longer the finish line for making a deal. Many deals now include the additional hurdle of reimbursement. Payers must be convinced of the therapeutic value of the drug requiring drug developers invest in pharmacoeconomic analysis. The outcome of this analysis can add a significant element of risk to a drug development program which again begs the question, who will and what we will they pay?

This question regarding who and how much will they pay, is relevant to not only investors and payers but to drug developers as well. Traditionally, investments are made based upon a novel technology that serves as the basis of a therapeutic to meet an unmet need in a key indication which has a clearly articulated development plan to support approval of the drug. However, as the attrition rates for development stage drugs increase, a more balanced approach to managing risk is warranted so that investors and drug developers are more likely to succeed in bringing a drug to market. It is quite possible and probable that the less risky drug achieves approval along with endorsement by payers for reimbursement. The company will also have a source of revenue to help pay bills while pursuing the more risky drug development program. Such an approach could comprise pursuing more than one indication for a single drug or utilizing the company development infrastructure to pursue a less risky development project alongside the lead, higher value program. Drug development companies that propose and achieve approval from investors to pursue high as well as low risk development programs stand a better chance to achieve success.

Provectus Pharmaceuticals is an example of a company pursuing two indications for its lead drug. The company is developing PV-10 (formulated for injection) for oncology indications as well as in topical formulation for several dermatological indications. PV-10 comprises Rose Bengal, a compound that has been in use for nearly thirty years by ophthalmologists to assess damage to the eye. Based upon the anti-proliferative / apoptotic activity of the drug, PV-10 selectively targets and destroys proliferating cancer cells without harm to surrounding healthy cells and tissue. For dermatology, the anti-proliferative effects of PV-10 appear to be efficacious for the treatment of psoriasis and related skin diseases.
Verva Pharmaceuticals has pursued a strategy of developing an old drug (VVP808 or methazolamide) as an insulin sensitizer with novel mode of action for the treatment of diabetes. Methazolamide was used to treat ocular hypertension associated with glaucoma. Verva has initiated clinical trial to validate research conducted at Australian-based Deakin University’s Metabolic Research Unit which developed and utilized a method for rapidly screening compounds with activity at key diabetes targets. The academic screening efforts identified methazolamide based upon an assay that validated the activity of the drug as an insulin sensitizer. As a follow on to the drug repositioning of methazolamide, Verva is also pursuing a higher risk program to identify next-generation molecules with similar characteristics to methazolamide.

Drug repositioning is a a common link between the development programs of Provectus and Verva via their efforts focused on old drugs that have established safety profiles and thus a higher probability of achieving approval for the pending indications. Such development programs represent great potential for the future prospects of the pharmaceutical industry, especially considering the aforementioned prediction of a drop in new drug approvals over the next five to ten years.
Dad, I heard that in some countries a man doesn't know his wife until he marries. His father replied, “that happens everywhere, son, everywhere!” In drug development, a company comes to really know the drug after the clinical program (aka, the marriage) has been consummated. Drug repositioning is one low-risk strategy that can be employed to better ensure that the marriage does not end in a costly divorce.

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

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

The Wrong Medicine – Getting Personal

“I ain’t got a fever, got a permanent disease; It’ll take more than a doctor to prescribe a remedy; I got lots of money but it isn’t what I need; Gonna take more than a shot to get this poison out of me.” These are the opening lyrics to “Bad Medicine” from the rock group Bon Jovi. While the song concerns an addictive love affair, the words and the title bring to mind important issues concerning major challenges for the pharmaceutical industry. Google the term “bad or wrong medicine” and you will get results ranging from political views on healthcare reform to stories about patients exhibiting adverse drug reactions or being prescribed the wrong medication. If you dig hard enough, you will find news articles and commentaries based upon patients being treated with a drug that simply does not work. Within the context of patient efficacy and safety as well as the cost of some drugs, the wrong medicine has profound implications for the future of the pharmaceutical industry. These clinical and commercial aspects call into question issues concerning how patients and physicians will be able to avoid the wrong medications and realize the full benefits of an optimal therapy. Personalized medicine, the use of diagnostic testing to identify those patients most likely to benefit from a particular treatment, may be an answer. However, pharmaceutical companies will have to resolve whether personalized medicine is something of value or a necessary evil to be avoided when possible. If you ask Steve Burrill, CEO of the life sciences merchant bank Burrill & Company, personalized medicine and associated diagnostics will become more valuable than prescription drugs in the future. Mr. Burrill may be right. Pharmaceutical companies have traditionally shied away from targeted patient population markets due to concerns of perceived lower revenue and higher marketing costs. Now, as the prospects from pipelines have dwindled and major drugs face patent expiration, some companies are beginning to realize the potential benefits of targeting certain treatments to smaller patient populations. If the benefits of increased safety and/or efficacy are realized, as well as the higher probability that drugs will make it through development, marketing and R&D experts believe that personalized medicine may the right therapy for an ailing industry. An additional factor involves the recent passing of healthcare reform legislation in the US. The new law is projected to provide significant dividends to drug companies who will gain access to millions of more customers with the ability to pay for high cost treatments. However the situation is not so good for insurers who will have to pay for the expensive treatments. Why pay for a treatment that does not work, or worse, may result in harm to the patient and thus additional payments by the insurer? Such a scenario should bode well for broader development and commercialization of personalized medicines. However, who will lead the way? Will it be the insurers / payers, the drug companies or the test providers? Will all three entities work together or will two defer to the one with the most to gain to lead the way in terms of adoption? The answer may lie in a better understanding of who has the most to gain and what they do to capitalize on the opportunities and challenges associated with this intriguing area of healthcare. So, who has the most to gain?

The basis for personalized medicine lies in the fact that genetic variation within human populations results in patient-to-patient differences in drug response. The response may involve efficacy at the target site or metabolism of the drug to an inactive or active metabolite. There may also be variability for safety where some individuals metabolize the drug into a toxic metabolite. In addition to extensive research studies for drugs and genetic-based response, validity can be found in the recent actions of the US Food and Drug Administration (FDA) in modifying labels for drugs such as warfarin and clopidogrel to advise patients and practitioners that genetic variants warrant consideration of whether to use the drug and, if prescribed, carefully decide on the optimal dosage. There are several additional examples of drugs with available companion diagnostic tests to aid physicians in deciding whether to prescribe the corresponding drug.



Source: Personalized Medicine Coalition; The Case For Personalized Medicine 2009.

The FDA has required that test information be on the labels of several drugs such as tratzumab and the EGFR inhibitors cetuximab and panitumab (highlighted in blue) while for others (e.g. warfarin and clopidogrel) it is only recommended. But testing information on the label is just the beginning and may result in more questions than answers for patients and the medical community. Furthermore, the companion diagnostic test will present unique marketing challenges as well as opportunities for the commercial arms of drug and diagnostic companies. The opportunities and challenges may well revolve around the genetics education of physicians, many of whom may be ill-suited for practicing personalized medicine due to poor training. Of critical importance will be the assurance that physicians understand genetic variation principles in the human population and within the context of complex diseases. While a long term remedy would be for medical schools to improve their curricula relevant to basic concepts in genetics and genomics as well as practical applications in clinical medicine, over the next few years, medical affairs resources from the drug and testing companies will be required to effectively translate the science and the benefits of the tests to determine the optimal therapy. This will require either a divide and conquer strategy between the drug company and test provider or by consolidating the activity within a single organization. Unique skill sets will be needed by these organizations to effectively advise on the requirement for or promote the benefits of testing, depending on the specific circumstances of the drug-test combination. The challenges associated with this activity can be turned into opportunities for communicating the need to test patient populations to ensure that patients receive the optimal therapy. Such marketing activity can be coupled with a specific drug to drive script writing by a target physician audience.
The second component of the question, “who has the most to gain?” in the world of personalized medicine concerns the ratio of value between the drug and the test. This factor is of considerable interest from a licensing perspective relative to deal negotiation including milestone and royalty payments not to mention responsibilities during development of the drug and test. Traditionally, drugs have had much higher financial values compared to diagnostic tests. In fact, during the early days of personalized medicine, many industry experts questioned the viability of the concept given the substantial disparity between drug and test valuation. Unless the commercial rights for the test resided with the drug developer, why would a separate entity invest in development of a test if the bulk of the rewards go to the drug developer? This maxim may change, especially in situations where the test determines whether a patient will or will not receive the drug treatment. If the commercial rights to the diagnostic test belong to a separate test developer / provider, this entity will have considerable leverage with the drug developer in negotiating the terms of a license or collaborative agreement. Also, there now appears to be sufficient incentive for diagnostic companies to invest in the discovery and validation of relevant biomarkers and / or proprietary assay platforms that will enable efficient testing and provision of results during drug development and by physicians in clinical practice.
And what about the payers, what will they do or say regarding the adoption of personalized medicine? If you consider the health insurers that utilize Medco for prescription benefits, they may have already spoken in the positive. Medco Pharmacy claims to be on the cutting edge of personalized medicine via the Medco Research Institute. This institution is dedicated to translating science into clinical practice through research initiatives with an emphasis on comparative effectiveness research that includes personalized medicine. Much of the research is based upon the company’s extensive medical and pharmacy claims database and led by researchers from a personalized medicine division. Other insurers may partner with Medco or duplicate the company’s efforts to adopt a personalized medicine program.
While it appears that everyone has the potential for gain in the application of personalized medicine, the one who gains the most may be the patient. Many physicians, most notably oncologists, have been frustrated by relying on therapeutic regimens that they know will not cure their patients and in many cases have little or no benefit while causing severe side effects. Many of these treatments are very expensive and thus under the watchful eye of the payers. “Whooah, we’re half way there; Whooah, Livin on a prayer; Take my hand and we’ll make it, I swear; Whooah, Livin on a prayer.” These words form the chorus of another Bon Jovi song entitled “Living On A Prayer.” Perhaps personalized medicine will answer the prayers of patients as well as the healthcare industry that collectively must lead the way in avoiding the wrong medicines because of their profound financial as well as physical and emotional costs.

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

Patients & Physicians Know Best

A doctor whispered into the ear of a dying man’s wife, “I’m sorry, he’s gone.” The dying man responded, “I’m not gone yet” to which the wife replied, “Quiet dear, the doctor knows best.” Later, when the doctor complained to another patient that his check bounced, the patient replied, “so did my arthritis.” While some may agree with the expression, “the doctor knows best” and others relate better to the patient with recurring arthritis, both jokes, given the current state of the pharmaceutical industry, may provide very sound advice.
Pharmaceutical industry experts fear that the era of blockbuster drugs is over and that a plethora of efficacious generic drugs will transform the sector while having a negative impact on innovation desperately needed in key diseases. In fact, the market for US generic drugs is expected to increase by approximately 10% over the next several years. This growth will occur at the expense of branded drugs covered by patents which have or will soon expire. Another factor involves the global economic downturn and uncertainties regarding healthcare reform in the US. Most experts agree that there will be extreme pressure on reducing costs which no doubt will further expand the market for generic drugs and other low-cost therapies. Subsequent to a considerable amount of industry consolidation activity, large pharmaceutical companies have responded to these challenges by rationalizing their R&D efforts and abandoning therapeutic areas where treatment options are considered plentiful. While R&D investment by pharmaceutical and biotechnology companies increased by more than 2 percent in 2009 compared to the previous year, some companies have abandoned their research programs altogether while focusing development efforts within priority therapeutic areas. As reduced profitability looms due to patent expiration and with little hope from anemic development pipelines, companies have scoured the globe for deals with smaller enterprises that have innovative therapeutic programs.
To maintain current revenue and in what appears to be in the spirit of “if you can’t beat them, join them”, several pharmaceutical companies have acquired generic drug producers or established partnerships with low cost producers in developing countries. Their plans involve both established and emerging markets. The recent announcement by AstraZeneca that it will enter emerging markets with a branded generics strategy is a good example. The company estimates that approximately 70% of pharmaceutical growth will come from emerging markets over the next five years. Other companies including Pfizer, GlaxoSmithKline and Eli Lilly are eying emerging markets with a similar emphasis on branded generics.
Considering the industry preoccupation with generic drugs, a key question is do the pharmaceutical companies have the right strategy to sustain the industry during the current dry spell caused by patent expirations and not so robust pipelines? Will the flood of generic drugs into the market over the next few years mean reduced R&D investments and a corresponding stifling of innovation? Far be it from me to address such a profound question but I felt compelled to offer a partial answer based upon recent experiences and observations. The challenges facing the pharmaceutical industry are daunting and not easily resolved by spending more or less money. Sir James Black, a physician who never practiced medicine yet made enormous contributions to the pharmaceutical industry may have been a prophet. The Nobel Laureate once stated, “The most fruitful basis for the discovery of a new drug is to start with an old drug.” The problem, generic drugs, may be a key solution to the innovation challenges facing the industry. Off-patent drugs and their generic counter-parts have established efficacy and safety profiles but are these features optimized? If not, what is the best way to optimize key medications that will differentiate them from the generic forms? Optimization can be attained by developing medicines based upon the advice of prescribing physicians and the patients they treat. So how do you find out what the doctor knows or what the patient needs? Starting with old drugs (e.g. generics) and working with physicians to optimize available medications may seem like a daunting task, especially considering the many opinions among practitioners and those for whom they provide care. However, many companies have the resources and infrastructure within their medical affairs effort to obtain key information to design the therapies desired by physicians and needed by their patients. Medical Liaisons are routinely engaged in dialogue with physicians or studying reports for the purpose of identifying key information to support prescribing of their company’s drugs. Traditionally, these professionals provided scientific support to sales. As the market changed due to fewer drug approvals and more stringent regulatory hurdles, companies began to emphasize the fostering of productive relationships with key opinion leaders to help achieve company objectives through medical education. The expertise and relationships of medical liaison professionals can be utilized to obtain critical information on drugs that exhibit deficiencies from a clinical or patient perspective. A comprehensive study of relevant literature and conversations with physicians can identify the limitations of approved drug products and set the stage for optimization. These limitations can be the focus of R&D efforts which may lead to drug products sufficiently differentiated from generic versions in the form of increased efficacy and/or safety. The improvements may be the basis of 505(b)2 registrations for new indications or may support the submission of an NDA. Limited term data exclusivity for these filings may be enhanced by patent protection if the improvement involves the use of a proprietary formulation / delivery method or provides for a new invention via dosing or administration methods.
The field of dermatology offers several examples of therapeutics designed by physicians. EpiCeram® is an emulsion cream comprising an optimal 3:1:1 ratio of ceramides, cholesterol, and free fatty acids that normalizes skin barrier function. EpiCeram was invented by former professor of dermatology at UCSF, Dr. Peter Elias, a practicing dermatologist and now the CMO of Ceragenix (the company that developed the medication). Application of the medication on skin lesions associated with eczema results in resolution of impaired skin barrier that leads to inflammation and itching. Although eczema and related dermatoses are normally treated with topical steroids, Dr. Elias postulated that restoration of the skin barrier by the ceramide and fatty acid emulsion would result in resolution of the inflammation and itching symptoms. Dr. Elias and colleagues at Ceragenix have demonstrated Epiceram exhibits comparable efficacy to the steroid fluticasone propionate 0.05% cream in improving the signs and symptoms of eczema. Since steroids should be used sparingly, especially in pediatric patients, Epiceram cream represents a notable achievement for a disease that has very few treatment options.
Charles Crutchfield, M.D. offers an example from the perspective of a physician who recognized the limitations of standard steroid treatments for psoriasis patients. Dr. Crutchfield developed an aerosol spray formulation of clobetasol that proved more efficacious than other 0.05% clobetasol-containing products including lotions, creams, ointments and foams. Several of Dr. Crutchfield’s patients were able to finally experience full resolution of their psoriasis symptoms not seen for many years with conventional therapies. The formulation was granted a patent and is distributed by Cuticeuticals, Inc. under the brand name Cuticort Spray.
Outside the field of dermatology we have an example that was almost “thrown to the dogs”, literally. Dr. Renee Kaswan, a veterinarian from the University of Georgia, was looking for a treatment for dogs with dry eye. Dr. Kaswan realized from her practice and literature surveys that the vast majority of dry eye patients (dogs and humans) were suffering from an autoimmune disorder that caused destruction of the tear gland tissues. Her selection of the immune suppressant drug cyclosporine resulted in disruption of the immune disorder that proved efficacious for the treatment of dry eye in dogs. As a treatment for dry eye in humans, despite early rejection by several pharmaceutical companies, Dr. Kaswan persevered and ultimately convinced Allergan to develop the drug as a topical preparation which was branded as Restatsis.
Although evidence exists that physicians have succeed in optimizing the use of medications for existing or alternative indications, does it make sense for companies to utilize their medical affairs and liaison professionals to contribute to innovations as a means of adding to development pipelines? While there is information that some companies utilize medical liaison experts in the assessment of licensing opportunities, there are very few examples of coordinated efforts between R&D and the medical liaison efforts in the identification of drug optimization opportunities. The expertise of medical liaison professionals that engage practicing physicians in dialogue concerning the limitations and potential improvements of drugs with established efficacy and safety profiles holds great promise for a source of innovation so desperately needed by an industry facing great challenges in uncertain times.

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

Mid-Stream Changes In Drug Development

“Don't change horses in midstream” is a quote attributed to Abraham Lincoln from a speech in reply to an attempt to persuade “Honest Abe” to change political parties. The advice he attempted to convey was to not change your leader or your basic position when part-way through a campaign or project. While refraining from a change in leadership may have been good advice for politics during Lincoln’s time, changing your horse, even in midstream, may be the most prudent advice relevant to some drug development programs. Or better yet, having options relative to disease indications can substantially increase the probability of a drug making it through the development process. The best laid plans don’t always come to fruition. A change or addition, based upon the most relevant data from preclinical or early human studies, may be warranted to ensure that you and your company achieve success.

From a preclinical perspective, the standard route in research to development comprises the identification of compounds via assays from a validated disease target. Once a compound class is qualified, the best compounds are tested in various assays involving the target resulting in the determination of the lead drug with appropriate backup compounds. This compound then enters a battery of animal studies to qualify the efficacy and safety. If the data justify the initial hypothesis for efficacy and the compound exhibits an acceptable safety profile, a positive decision for human clinical studies is the likely next step. While the safety data is fundamental, for some drug developers, the efficacy results should be considered within a broader context than the initial hypothesis. Does the drug have activity at other targets or is the main target relevant to other disease indications? Answers to these questions are of considerable value to a company with limited resources. It is worth their while to use those resources wisely. Spending a little extra money during the preclinical stage may not only aid in better stewardship of resources during the clinical stage, a broader preclinical profile may offer an additional or alternative development plan for the drug. Having alternatives or additions to your development plan is like having several horses when you are ready to cross the stream or find yourself mid-stream and face key decisions regarding if or how to continue expensive and uncertain human clinical programs.

In my view, the ultimate example of having a team of horses when crossing that stream in the development program is duloxetine (Cymbalta) from Lilly. Duloxetine is often referred to as the “Swiss Army Knife" of drugs considering the multiple indication approvals. The drug is approved by the FDA for the treatment of depression, general anxiety disorder, fibromyalgia and diabetic nerve pain. Lilly is pursuing additional indications including chronic knee and low back pain as well as chronic fatigue. Although Lilly states that the exact mechanism of action of duloxetine is not known, their scientists have generated data that demonstrates the drug causes an increase in activity of serotonin and norepinephrine in the central nervous system along with other data that links these effects with the approved and pending indications. This knowledge of the effects of duloxetine and its translation into clinical evidence and approved indications resulted in annual sales in excess of $2B over the last several years. The anti-TNF (tumor necrosis factor) biological drugs represent another example of a drug class where a good understanding of the target and its implication in other diseases was exploited early in development resulting in additional indications that have contributed substantial value to drugs such as etanercept (Enbrel) and adalimumab (Humira). Both drugs are approved for the treatment of rheumatoid and juvenile idiopathic arthritis as well as the related psoriatic arthritis. The drugs are also approved as treatments for psoriasis and ankylosing spondylitis.. Adalimumab has an added approved indication for Chron’s disease. The fundamental role of TNF in the initiation and progression of these inflammation-based diseases no doubt led to the obvious preclinical studies that ultimately supported the human clinical work and resulting indication approvals. These drugs had combined annual sales of over $8B.

I know what you are thinking – “What do these blockbusters from large pharmaceutical companies have to do with my program?” While these companies may have vast resources compared to your company, the analogy of a robust preclinical program is still relevant. After all, the preclinical program is the most affordable part of your entire development program. Why not pretend you are a large pharmaceutical company and at least consider additional or alternative indications? You may be surprised about what such an exercise presents to you and your colleagues. Need a relevant example? Consider the Janus kinase (JAK) inhibitor program from Incyte. Perhaps by considering the success of the related anti-TNF drug development programs, Incyte scientists explored similar preclinical studies of the JAK inhibitor INC 18424 which ultimately set the stage for justification of several clinical programs for inflammation-based diseases including myelofibrosis, polycythemia vera and essential thrombocythemia. A topical formulation of the drug is in clinical trials for the treatment of psoriasis. In late 2009, Incyte announced that it entered into an agreement with Novartis for INCB18424 for myelofibrosis and the other indications. The company stated that it received upfront and immediate milestone fees totaling $210M (which included rights to an earlier-stage drug), a handsome reward for extending the preclinical effort to justify programs in more than one hematology indication. The company announced that it will engage dermatology companies in discussions concerning the development of the topical psoriasis treatment which may be viewed as “icing on the cake”. Had Incyte not succeeded in advancing the hematology indications, the dermatology treatment may be viewed as an extra horse to carry the company across the stream to the side of a drug approval.

In my experience, more and more companies have extended their preclinical programs to ensure that they achieve an approval of their drug and thus increase prospects of the company. In addition, companies have been responsive to consider additional or alternative development programs when presented with potential value of their drug in an indication that was not contemplated prior to the clinical development decision. While there are concerns such as an adverse events or safety issues arising from trials for an alternative indication affecting the lead treatment under investigation, such issues can be managed by effective preclinical programs and advice from potential partners that have the experience from pursuing multiple indications for a single drug. Development-stage companies should also consider potential partners as a good source of advice on commercial issues (e.g. price differential between indications) that can be invaluable to a small company considering whether to increase investment in an alternative indication. Think about the analogy of crossing the stream. How many horses would you like to have at mid-stream?

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

Predicting The Future During Drug Development

Did you ever wish you had a crystal ball to predict the future? Relevant to drug development, the concept of having a fortune teller with a crystal ball to visualize a desired finished product can be productive. Such a mental exercise can help determine the critical steps necessary to achieve your vision. Too often, drug developers follow a standard path focused on safety and efficacy measurements with minimal consideration of other key factors that may mean the difference between commercial success or failure. Following the standard path to demonstrate adequate safety and efficacy may cause you to lose sight of the fact that the FDA consistently raises standards on safety. This fact necessitates that a drug developer clearly demonstrate product differentiation via prioritizing efficacy or safety compared to approved products as well as those under development. Measuring the value of a development stage drug in comparison with equivalent treatments is the most important driver in achieving success. Of course there is no such thing as a crystal ball but there are tools and concepts that enable you to envision the drug you would like to develop and then design your program to achieve your vision. Utilization of these tools will enable you to perceive the ideal product and then put the pieces in place that will be necessary to make the desired product a reality. In addition to crystal ball-like tools, there are fortune tellers who can help predict the future. Don’t believe in fortune tellers? Experts in drug commercialization and marketing (e.g. market research and medical affairs professionals) can predict the future via their expertise from dialogue with doctors and patients. These folks have a thorough understanding of the needs that are not currently met and can help you design a program to document that your product addresses those needs. By tailoring your program to focus on those needs, you will better ensure the development of a product that will provide benefits to patients and thus contribute to the fortunes of you and your company. The following information describes the crystal ball tools and fortune tellers that may be of value to your vision of the ideal drug and help you and your company increase the probability of success in your development efforts.

Crystal Ball Tools

Translational Research
The translation of basic research into an actual therapy is the ultimate goal of a drug R&D program. The continuous translation of research over the course of drug development, however, is often over-looked resulting in missed opportunities for many drugs. Often referred to as bench to bedside research, translational studies involve a reciprocal relationship between basic researchers and clinicians. Preclinical researchers discover and provide tools for use in patients by clinicians who then utilize the tools and observe their effects the on progression of disease. Their observations often result in additional basic investigations and possibly new indications. The key issue relates to sustaining a dialogue or at the very least, an effective transfer of knowledge from basic researchers to clinical development experts. According to Dr. Dominic Spinella who heads the clinical biomarker work for Pfizer’s oncology portfolio, translational research is about 70 percent from preclinical to clinical. The other 30 percent involves what is learned from clinical trials and from hypothesis-generating work with pharmacogenomics, proteomics and similar types of tools. Key information is fed back to the investigators to benefit the next generation of drugs. If a large organization such as Pfizer can apply translational research to benefit future drug development programs, imagine what smaller, more nimble companies can do to benefit current development programs via utilization of enhanced assays for rapid deployment within clinical trials. Companies can also follow surrogate markers for efficacy or safety or extension of the therapeutic to new indication. From a small company perspective, consider Cytokinetics, which is focused on drugs that affect cytoskeleton factors related to muscle contraction. The Company has exploited translational research and now has three oncology drug candidates in clinical trials. One candidate, GSK-923295, inhibits the mitotic protein CENP-E thus arresting cancer cell division and causing apoptosis. The company is developing the drug with partner GSK which includes a translational research component directed to CENP-E. From a start-up perspective, ApeX Therapeutics has successfully utilized a translational research approach via the commercialization of work that originated at Indiana University. The research program was enhanced via funding from a program that aids researchers in advancing discoveries into development for patient care. ApeX initiated a preclinical program to study inhibitors of the protein APE 1 as a treatment for macular degeneration based upon basic research of APE1 which demonstrated anti-angiogenesis effects. Companies such as ApeX and Cytokinetics have demonstrated the capability to utilize translational research as a crystal ball to justify development of drugs in alternative indications and, in the case of Cytokinetics, attract the interest of a large pharma partner. Additional incentive to consider emphasizing translational approach may come from the US government which has stepped up to the plate in support of translational research. The NIH and FDA recently announced funding for efforts focused on translational and regulatory science to explore ways to move scientific breakthroughs "from the microscope to the marketplace." The agencies will fund research involving new technologies for development and regulatory review of medical products.

Pharmacogenomics
The ability to identify patients with a high likelihood of treatment response or patients that may suffer from an adverse event (and thus excluded from trials) enables the drug developer to better predict therapeutic effects and refine development strategy at an early stage. Large and medium-sized pharmaceutical companies have pharmacogenomic programs that discover and utilize biomarkers in preclinical studies and ultimately in human clinical trials. For smaller companies that lack resources or infrastructure for integrated pharmacogenomic programs, contract research organizations (CROs) are a viable option. Large and specialty CROs have developed biomarker discovery programs along with the capability of utilizing relevant markers in human clinical trials. It is also worth noting that reimbursement for companion diagnostic tests is on the near term horizon with payers now starting to step to the plate as they realize that testing can actually lower overall therapeutic costs by treating only patients that are likely to respond. Relevant to your commercial prospects, targeting patient population subsets for which your drug has better efficacy will be recognized by physicians since they will be confident that their patients will benefit from your drug with a low risk of adverse events. These practitioners are more likely to exhibit product loyalty and their patients will likely realize long-term compliance. In addition to benefiting from the services of CROs, development-stage drug companies may consider partnerships with diagnostic test providers that have a track record for assay development and approval in sync with the therapeutic. The list of such companies continues to grow as more therapeutic – diagnostic combinations advance toward commercial launch. The drug and diagnostic company can work together to generate and utilize data to support marketing efforts by properly positioning the products enabling focus on patient sub-populations which will no doubt raise the value of the treatment. Evidence for this may be the alliance between Vanda Pharmaceuticals and Labcorp related to FanaptaTM, a schizophrenia treatment that involves administration of iloperidone to a sub-set of patients with specific genetic markers that respond to the treatment. Late last year, Vanda licensed the US rights to Novartis for an upfront payment of $200M.

Models & Simulations
A considerable amount of resources are lost during the course of what many experts describe as an inefficient trial-and-error drug development process. Inefficiencies related to unknowns concerning safety or efficacy of the candidate drug can be minimized if critical information is available at the beginning or during the early course of development. The use of models and simulation analysis has been successfully used in various technical disciplines and seems to have applicability in drug development. While even the most comprehensive preclinical program to predict efficacy and safety is not immune to an unexpected result once the drug is administered to human subjects, comprehensive preclinical results can be strengthened with results from various physical and theoretical models as well as simulations. For instance, pharmacokinetic/pharmacodynamic (PK/PD) trial simulation models help investigators improve later-phase trial designs for several parameters. For some drugs, researchers have demonstrated the value of PK/PD forecasting models with Phase II data being used to develop a dose–response model that closely approximated what was eventually observed in an actual Phase III dose–response study. Use of such modeling and trial simulations may increase if adaptive trial methodologies catch on. In addition, software tools that simulate disease and physiological processes using data from relevant published research are now being evaluated and show promise. For instance, the Optimata Virtual Patient tool has been used to estimate changes in tumor size as an important indicator of the disease status and predicts changes by particular treatments while accommodating for toxicity and other key limitations. The Optimata software provides for effective planning and decision-making during the course of clinical trial phases via computer-simulated treatment scenarios for multiple disease indications and patient-populations. Clinical trials based on such software have increased success rates thus shortening the drug development process and reducing costs.

The Fortune Tellers

Marketing / Medical Affairs Expertise
Today, drug approval requires addressing the issues posed by multiple stakeholders such as payers, healthcare providers as well as regulators. These entities have significant influence on a drug’s commercial potential. Marketing and medical affairs professionals are engaged to assist a pharmaceutical developers and manufacturers in developing a value profile of a drug to enable clinical trial design and drive a long-term marketing and pricing strategy. These professionals gain input from researchers payers, clinical advisors, and opinion leaders. Safety and efficacy factors most critical to the drug’s viability are identified from a clinical, reimbursement, and access perspective. The drug’s potential strengths and weaknesses relative to other available treatments are determined to prioritize importance of its features. This information is incorporated into the design of clinical trials to identify the most important points of competitive differentiation in the long-term marketing and pricing of the drug.

Intellectual Property & Regulatory Exclusivity
The Holy Grail of drug intellectual property comprises a comprehensive portfolio of patents that cover composition of matter of the molecule, relevant formulations as well as methods for the treatment of all conceivable diseases. For some drug developers, such a package is only a dream and drugs often do not see the light of day because of a perceived weak patent position. It is very important to have a frank discussion with your patent attorney so that he/she has a full understanding of your commercial vision for your product. Consider your future fortunes by envisioning the type of drug you desire and provide the attorney with the key attributes the drug should have and ask them to work backwards, relative to existing data and that which may come from additional research (including a translational program), to enhance the patent protection of your product. A weak patent case can be strengthened, depending on the amount of prior art, by claiming relevant formulations, manufacturing methods as well as other elements that may hinder or prevent a competitor from developing a comparable product. In addition, data required for regulatory approval should be considered when making decisions on the potential length of exclusivity. When developers are faced with no composition of matter protection (or limited term), the potential of patents covering formulations or delivery methods should be considered with a focus on formulations that cannot be easily substituted. Such a formulation may prohibit ANDA filings by generic companies and should obligate competitors to conduct studies to support an NDA filing. Such a scenario will result in a longer period of exclusivity for your drug. Under normal circumstances, this period of exclusivity may be at least five years. In the case of development programs that initiate well after patent claims have issued, remember that a short term patent may be extended depending on the time required for clinical trials and regulatory review. Another aspect of regulatory exclusivity involves the 505(b)2 application which provides for three years data exclusivity for the first registrant or for a new indication of an already approved drug. Each of these elements concerning patent and data exclusivity should be fully considered at an early stage of drug development to ensure that you maximize your proprietary position once the drug is launched.


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