Innovative Strategies for Drug Repurposing (약품 재창출을 위한 혁신적인 전략)

Rather than chasing new compounds, pharmaceutical companies can reduce risk and costs by finding new uses for existing products

Daniel Grau, M.Phil, and George Serbedzija, PhD

Grau is vice president of commercial operation and Serbedzija is associate director of corporate development for CombinatoRx Inc., Boston.

In recent years, an increasing number of biotechnology companies have been focusing on drug repurposing, the development of novel uses for existing drugs. Although repurposing is not new to the pharmaceutical industry—large companies using classical life-cycle management strategies often extend drug use into new indications to preserve or extend the value of a pharmaceutical brand—the emergence of companies founded exclusively on repurposing reflects a general trend evident in biotechnology today that seeks to reduce the risks of drug development. Three of the most prevalent strategies for seeking to reduce the risks of drug development are (a) developing new formulations of existing drugs, (b) in-licensing of clinical stage programs, frequently the core strategy of so-called NRDO (no research, development only) companies, and (c) repurposing of existing drugs or discontinued compounds to identify novel uses or therapeutic properties.

click the image to enlarge A matrix representation of the drug development landscape as a function of risk. (Source: CombinatoRx)

Repurposing companies fit naturally within the risk reduction model because often they start with approved compounds with established safety and bioavailability profiles, proven formulation and manufacturing routes, and well-characterized

 

pharmacology. Theoretically, repurposed compounds can enter clinical testing more rapidly, and at less cost, than new chemical entities. But all risk reduction strategies are not created equal. There is a striking difference between formulation companies that develop new deliveries for old drugs, or those that in-license clinical stage programs from pharmaceutical companies, and today's newest repurposing groups. In contrast to new delivery companies, some of today's repurposing companies are distinguished by their use of proprietary discovery engines and their focus on discovering new therapeutic properties and mechanisms. In contrast to NRDO companies, leading repurposing companies leverage a research-based lead generation capability. This capacity can involve wet biology or entirely in silico methods. Although the precise mix of research tools may vary, several repurposing companies have created proprietary discovery engines capable of bringing new drug candidates into clinical development on an ongoing basis. By virtue of their research-based discovery engines, these repurposing companies have the potential to expand and refresh their product portfolios.

One of the mistaken objections against repurposing is that exploiting old drugs for new uses is not novel drug discovery. However, novelty is defined as discovering new therapeutic options to treat a patient's disease and there are many ways in which to create novelty in drug development. The current situation in drug discovery can be defined as existing chemical structures hitting established targets for relevant diseases. one approach to novelty in drug discovery (upper left quadrant of figure to the left) is the creation of new chemical entities designed to hit existing proven targets, many times referred to as "me too" therapies. Although this approach usually offers only an incremental benefit over already marketed therapies, it shields a company from the risks associated with developing a new target. Another approach (upper right quadrant of figure on page 56) is to create a new chemical entity working through a brand new mechanism of action. Obviously, this classical ideal of drug development generates the highest level of novelty; however, it also has the highest level of associated risk. The repurposing approach (lower right quadrant of figure on page 56), uses new biological understanding to discover new mechanisms of action for existing compounds or new relevance for an existing target in a new disease area. The repurposing approach has the potential to identify new first-in-class mechanisms to treat disease, while at the same time, avoiding some of the challenges associated with the development of a new chemical entity. one interesting facet of the repurposing approach is that the discovery of new targets can be parlayed directly into the creation of NCEs that further enhance the new mechanism or target activity. Here the benefit is starting with a drug-like template that is known to interact with a new disease-relevant target.

 

Two types of drug repurposing
Drug repurposing is supported by two core scientific concepts (see figure above). The first is that a single drug often interacts with multiple targets. Taking advantage of this, one repurposing approach focuses on the identification of secondary or so-called "off-target" drug actions, followed by the development of the compound in a new indication where the secondary target is relevant. Historically, compounds with significant off-target effects have been labeled "dirty" because of the side effects they induce. However, the undesirable side effect of a compound in one indication may sometimes provide a desirable effect in another indication. Repurposing efforts based upon a compound's potentially "desirable promiscuity" follow what can be called the "known compound-new target" approach.

click the image to enlarge Drug repurposing is supported by two core scientific concepts. The first is that a single drug often interacts with multiple targets (right).The second is that targets relevant to one disease or biological process are often involved in several biological processes (left). (Source: CombinatoRx)

The second concept is that targets relevant to one disease or biological process are often involved in several biological processes. Capitalizing on this, a second repurposing approach is to establish the relevance of a known drug target to a new disease. In many instances, scientific links have been established between the target and the disease, and between the target and the compound, but not between the compound and the disease. In other instances, the link between the compound and the target is well established, but the new medical significance of the target is discovered serendipitously during clinical studies of the compound's original indication. Repurposing efforts based upon the new medical potential of a known target follow what can be called a "known target-new indication" approach.

Examples of repurposed drugs invariably fit within one or both of these models. one of the most dramatic examples of the "known compound-new target" approach is the revitalization of thalidomide by Celgene Corp., Summit, N.J. Thalidomide, prescribed in the 1950s for nausea and insomnia in pregnant women, was found to cause severe birth defects in children whose mothers took the drug in the first trimester of pregnancy. Scientists later discovered that in addition to its sedation effect, thalidomide had antiangiogenic and immunomodulatory effects, including the inhibition of TNF alpha. In 1998, Celgene received approval from the US Food and Drug Administration (FDA) to market Thalomid (thalidomide) as a treatment for leprosy. Since its release, Thalomid has become the flagship product for Celgene.

Merck's finesteride, originally prescribed to treat prostate enlargement, presents a clear example of the "known target-new indication" repurposing approach. In the early 1990s, finasteride, which blocks the enzyme that converts testosterone to dihydrotestosterone, was discovered to have the side effect of preventing male pattern baldness. Subsequent clinical studies revealed that much lower doses of finasteride can be used to treat male pattern baldness than those used to treat prostate conditions. In 1998, the FDA approved finasteride as a hair loss treatment under the brand name Propecia.

Chlorpromazine is a less well-known example of a repurposed compound, but its evolution as a pharmaceutical exemplifies both the "known compound-new target" and the "known target-new indication" approach. In 1952, French surgeon Henri Laboriot was experimenting with drugs that could reduce surgical shock and found that chlorpromazine, originally marketed by Rhone Poulenc as an antihistamine, had sedative and antinausea effects when given at higher dosages, an effect attributable to chlorpromazine's action as a dopamine receptor antagonist. In 1952, Smith Kline licensed the US rights for chlorpromazine and marketed the compound as a sedative and anti-emetic, prompting psychiatrists to explore higher doses of chlorpromazine in the treatment of severe psychosis. More recently, CombinatoRx developed CRx-026, a dual action antitumor drug containing chlorpromazine and a second compound in a proprietary composition. CombinatoRx showed chlorpromazine's role in inhibition of an important mitotic kinesin, a previously unknown target for chlorpromazine.

Repurposing today
Today's repurposing companies follow the same typology as that which led to the successful repositioning of thalomide, finesteride, and chlorpromazine. But the current focus on repurposing is fueled by different drivers, including the increasing supply and general availability of novel targets, the emergence of new information technologies, and the ongoing expiration of key patents for major pharmaceutical brands.

Repurposing strategies
Repurposing companies tend to deploy one of four possible strategies, although unique proprietary approaches and technologies are used within each strategic case.

Strategy 1: Virtual Discovery Using analysis tools to screen published data to identify repurposing opportunities
The first path takes advantage of the vast amount of publicly available pharmacological, biological, and chemical data generated by the drug industry and academia. By incorporating this information into large databases and developing analysis tools to sift through the data, repurposing companies can perform virtual screens that uncover previously unrecognized connections between a drug, target, and disease.

For example, Arachnova has developed a proprietary database called SwitchBase to find common links between existing drugs and a target disease, and seeks to exploit a secondary-target common to both drug and disease. These connections are analyzed to determine if there is a new use for the existing drug.

The virtual discovery approach to repurposing has several attractive features. Because by definition this approach relies upon interactions that already have been identified and reported in the scientific literature, there is potentially less risk associated with programs derived from it. The investments are directed toward verifying and optimizing a connection that has already been established, and away from risks of de novo discovery. At the same time, virtual discovery repurposing provides a relatively weak position in terms of proprietary discovery engines. By definition, the information used in this approach is available to anyone, and groups possessing the requisite expertise and tools can make new drug/target connections. Thus, success with virtual repurposing often will depend on being the first to observe and exploit a connection.

Strategy 2: Favored Target Rescreening the pharmacopeia against new targets
The second strategy takes advantage of advances in biology and screening technology that allow companies to rescreen known drugs against an array of previously inaccessible disease-relevant targets. This target-focused approach allows for the discovery of novel interactions between existing drugs and previously unexplored or incompletely explored targets. Target-focused discovery can identify new therapeutic agents for validated targets, as well as identify and validate new disease-relevant targets. By screening all compounds against these new targets, a company may identify an unexpected new use for existing drugs found to hit the targets.

Repurposing using the favored target approach can provide a useful strategy for jump-starting therapeutic programs. Because existing drugs rapidly can be mobilized into clinical testing, one has the opportunity to conduct proof-of-concept clinical studies with an existing drug to demonstrate that the target is being hit and that hitting the target provides the desired clinical result. In some cases, especially for smaller companies seeking to validate their investments in a novel target, it is urgent to demonstrate the relationship between clinical effect and target modulation, and an existing drug repurposed to hit the novel target can provide a practical method of accelerating this demonstration. An additional benefit of this approach is that, if one were to find an existing drug that acted on the novel target, the existing drug's chemical scaffold would provide a helpful starting point for identifying new chemical entities that could be developed as drugs for the novel target.

Strategy 3: Model Insight Applying specific biological insight about a target's role in a new indication
The third path takes advantage of a known interaction between an existing drug and a specific target and combines this with new knowledge about the target's role in a new indication. This method can be used to identify new therapeutic agents and validate new therapeutic targets. As with strategies one and two, the model-focused approach has the advantage that any new use will have a clearly defined mechanism of action. Furthermore, model-focused discovery can elucidate new biological information about disease and be used to identify both "known compound-new target" and "known target-new indication" classes of repurposed drugs.

The critical advantage of the model insight approach is that, by definition, the new insight has not yet reached the public domain. It remains a proprietary secret to the insight holder. Compounds with the right biology then can be identified and developed in an atmosphere that is relatively free from competitive pressure. This gives the model insight company the opportunity to acquire or license compound rights and establish intellectual property positions on their new uses. A potential disadvantage of the model insight approach is that it typically is limited to a specific therapeutic area. Using the model insight approach typically requires a highly sophisticated understanding of a particular disease. This makes it both a resource and intellectual challenge to possess the necessary level of sophisticated understanding for many diseases.

Strategy 4: Agnostic Screening End-point screening to discover new uses for both on- and off-target effects of existing drug
The fourth strategy uses end-point screening to discover both on- and off-target effects of compounds that may have significant therapeutic impact. This approach has the potential to identify a broad range of new and unexpected existing drug activities and target interactions, as well as provide a wealth of new biological information about disease. The agnostic screening strategy identifies both "known compound-new target" and "known target-new indication" classes of repurposed drugs.

Agnostic screening of existing drugs has all the perils and all the promise of traditional function screening. By focusing on a validated end point of interest, agnostic screening can identify existing drugs that produce an unanticipated, yet desired, phenotypic result. once identified, these drugs can rapidly be introduced into clinical testing to validate the screening hit. Unfortunately, this approach often provides little or no mechanistic insight and, therefore, requires additional investments into mechanistic analysis to determine precisely how the existing drug is working to achieve the desired effect. This is not always easy to do, but may be worth the effort to discover that an existing drug hits a new target and that hitting this target is relevant to disease. By casting the broadest possible net, the agnostic screening approach has the potential to generate novel scientific discoveries.

Given the relative youth of the new class of repurposing companies discussed above—the majority have yet to translate their discoveries in clinical trials—the jury is still out on whether this new strategy will yield profitable and biologically interesting results. Biotech fads come and go, and repurposing may well turn out to be transient. However, historical examples of repurposing from large pharma provide a clear precedent for today's repurposing companies, suggesting that success is possible. If the products of the current class of repurposing firms succeed, more capital may be attracted to repurposing endeavors with a potential concomitant expansion of repurposing strategies and technologies.

Some have questioned whether the existing drug pharmacopia, an admittedly large but also finite supply of compounds, is rich enough to sustain substantially larger numbers of repurposing efforts over time. Repurposing companies are competing to find new biology in the old pharmacopoeia, but there are only a limited number of bona fide repurposing opportunities. It is true that the most obvious opportunities, available to anyone with access to widely available scientific databases, are likely to be exhausted first. To this extent, the virtual discovery approach to repurposing, by definition the most accessible strategy, will provide the least competitive advantage.

Yet even with conservative assumptions regarding either the number of new therapeutic uses for known targets of existing drugs or the number of still undiscovered additional targets of existing drugs, the pharmacopia library may allow companies to find connections that are not already observed and reported in the literature. This may be especially true for companies linking new targets to existing compounds, since the diversity of targets provides a second pool of opportunities beyond the compounds themselves. It would not be surprising, finally, to see large pharmaceutical companies themselves increasingly return to existing compounds as underleveraged assets and seek to rescue them via repurposing strategies.