Teaching an old drug new tricks…

Fourteen years…$800 million…fewer than one out of 10 compounds entering the clinic ultimately approved by the FDA and for pharmaceutical companies developing new drugs these statistics are getting worse. How can pharmaceutical companies stem the tide of clinical stage drug failures and manage the burgeoning costs associated with discovering and developing new therapeutics? The answer may be found on the shelf of unwanted, unused compounds that never quite made it into the clinic or that made it into the clinic but did not reach appropriate clinical endpoints.

Indications Discovery: the practice of discovering and understanding new therapeutic uses for a compound. Where does one start? You can’t entertain a serious discussion of Indications Discovery without citing Sir James Black: “The most fruitful basis for the discovery of a new drug is to start with an old drug.” If we consider compounds that have been discontinued in the clinic for reasons other than safety, it intuitively makes sense to look at failed compounds first when identifying new chemical entities to satisfy unmet medical need. After all, these have already been proven to be safe, just not effective in the original indication. Notable examples include:

• sildenafil (Viagra) repositioned from a candidate for hypertension to a successful drug for erectile dysfunctio
• gemcitabine (Gemzar) switched from use as an antiviral candidate to a successful anticancer agent
• finasteride expanded use from prostate cancer (Proscar) to hair loss (Propecia)
• raloxifene (Evista) repositioned from birth control to osteoporosis
• minoxidil (Rogaine) switched from a hypertension candidate to a successful hair loss drug.
• thalidomide (Thalidomid) repositioned from a discontinued antiemetic drug to a successful cancer therapeutic
• hydroxychloroquine (Plaquenil). Expanded use from an antiparasitic to an approved antiarthritic agent
• doxepin (Sinequan, Adapin) expanded use from an approved antidepressant to a topical antipruritic agent.
• naltrexone expanded use from an opioid addiction therapeutic to alcohol withdrawal therapy

With the increasing pressures of cost and risk associated with drug development, the number of companies using this approach to identify new therapeutic vistas for old drugs is growing. Large multinational pharmaceutical and small biotechnology companies alike are exploiting their pharmacopoeia ‘dustbins’ in the search for new uses of old drugs. Innovation is coming not just in terms of new uses of existing drugs, but also in the form of creative patent strategies, alternative formulations and novel combinations of both marketed drugs and failed compounds.

How do companies find these new uses? Is there a way to ‘manage serendipity’ in order to develop new drugs? There are now a number of approaches being pursued by various companies dedicated to Indications Discovery that cross a wide spectrum of technologies and scientific biases. Examples of some of the strategies that have been used or devised to develop new drugs from old include: selective optimization of side activities (SOSA), reverse chemical genetics, in silico modeling and phenotypic screening. A hypothesis is typically developed to direct which therapeutic area should be explored for a given compound. However, the common thread amongst all of these diverse approaches is that virtually all of these will ultimately rely upon the use of animal models of disease to confirm the clinical candidacy of a compound.

Melior Discovery’s Indications Discovery Approach

Melior Discovery takes the approach that, in order to discover a use for a drug, it must demonstrate activity in functional animal models of disease. The hypotheses that are normally used to identify appropriate animal models for testing are often based upon an incomplete knowledge-base, making the discovery of new indications difficult when using a hypothesis-driven approach. Arguably a more effective way to uncover the unexpected would be to indiscriminately test for efficacy across a broad spectrum of animal (disease) models.

Melior has now enjoyed repeated success in uncovering new therapeutic potential by evaluating test compounds through 40 different animal models of disease across 14 broad therapeutic areas. Normally, this would be a costly and impractical endeavor, particularly with regards to the resources and time required. However, Melior Discovery has made the approach practical by multiplexing all of these validated disease models via theraTRACE^SM, an integrated, comprehensive suite of validated animal models of disease that can be used to accelerate drug development.

Using theraTRACE^SM, Melior is able to develop an optimized drug dosing regimen and evaluate a compound across a range of doses in all disease models in approximately 8 weeks. Melior’s mission is to help find unexpected therapeutic uses for compounds. Molecules currently being screened using theraTRACE^SM range in stage of development from preclinical to Phase III.

Core to Melior’s philosophy is that testing a compound in vivo is a “garbage-in/garbage-out” proposition. The company believes that if sufficient care is not taken to thoroughly understand the pharmacokinetic (PK) characteristics of a compound in the species where a specific efficacy test is to be performed, then the compound is probably not being tested properly. As a result, in all likelihood, a good deal of potential for that compound as a therapeutic candidate may be overlooked. Accordingly, before compounds are entered into the theraTRACE^SM platform, Melior routinely conducts PK studies across four routes of administration as well as determining the maximal tolerated dose (MTD). Then, working interactively with the partner company, an optimal route of administration and dosing regimen are chosen that are ideally suited for each particular in vivo model.

As MTD does not translate to a maximum effective dose, all compounds are tested across a three- point dose curve using a route of administration appropriate for the particular compound’s in vivo properties. Similarly, biological response does not necessarily relate to dose as well as it relates to plasma level or total exposure. Accordingly, plasma levels of test compound are monitored during all experimental procedures. This careful planning around route of administration, dose, and formulation, coupled with monitoring of plasma levels during the course of the experiment, significantly enhance the power of a study. Melior adheres to the philosophy that the better we understand the optimal dose and behavior of a compound or a particular model and strain, the more valuable the information that is generated.

Another strength Melior brings to drug repurposing is the company’s exclusive relationship with Dr. Chris Lipinski, head of Melior’s Scientific Advisory Board. Dr. Lipinski's rule-of-five guidelines have played a pivotal role in raising awareness about the properties and structural features that make molecules more or less drug-like. The guidelines were quickly adopted by the pharmaceutical and biotechnology industries and are widely cited as seminal observations in the field of drug discovery.

Compounds considered for development by Melior are subjected to a review by Dr. Lipinski prior to their introduction into the platform. Because of this rigorous pre-screening analyses and the inherent power of the theraTRACE^SM platform, three clinical candidates with novel indications have been successfully identified with IND–enabling studies being initiated in less than 18 months. The significant savings in time, compound, cost and FTE’s resources has been significant compared to conventional drug discovery efforts.

Such profiling of compounds earlier in the drug discovery process can help companies prioritize the compound’s potential uses, as well as providing more robust patent protection moving forward. Having alternative indications at the ready can be critical to a company’s survival, should the original indication not reach satisfactory endpoints in clinical trials. Melior Discovery’s clients are using the platform for compounds along the entire drug development spectrum. Because the platform is not ‘hypothesis driven’, bias is not introduced into the mix by trying to fit a result into a chosen indication. For example, Melior’s own internal efforts have resulted in the identification of a diabetes clinical candidate repurposed from an anti-ulcer drug, an Alzheimer’s disease drug repositioned for atopic dermatitis, and a vascular drug repositioned for urinary incontinence. Taking such a ‘blue sky’ investigative approach to drug discovery and development is another aspect that sets Melior Discovery apart from any other companies that purport to offer repositioning capabilities.

Off-the-Shelf Solution?

The challenges facing the pharmaceutical industry are multifactorial and continue to escalate. The industry will certainly continue to face increasing pricing pressures driven by significant issues including efforts to contain healthcare costs, drug patent expiries, healthcare reimbursement concerns, and the challenges of drug re-importation (parallel imports). At the same time, pharmaceutical companies face an increasingly stringent regulatory environment and heightened public concerns over drug safety, particularly in the wake of high profile drug failures including Vioxx and Avandia. These pressures combine to force the need to drastically reduce drug discovery costs whilst maximizing drug safety. Indications discovery is increasingly appearing to be the ideal solution to this dilemma. Melior Discovery’s birth, and now successful growth, is not only a symptom of the problem’s existence but, fortunately, also a solution.