January 1, 1970 (Vol. , No. )

Seth Lederman, M.D. Tonix Pharmaceuticals

In addition to providing new treatments, repurposing can aid in dissecting complex disorders, discovering molecular targets, and unraveling disease processes.

Finding new uses for approved drugs continues to produce important therapeutics, particularly for disorders where no animal model, physiologic abnormality, biochemical pathway, or molecular target has been identified. Repurposing allows human investigation early in the process of drug discovery. In addition to providing new treatments, repurposing can be an important tool in dissecting complex disorders, discovering molecular targets, and unraveling disease processes. In recent years, an increasing number of pharmaceutical development programs have been focusing on the development of new therapeutics based on existing agents, so a brief overview of this endeavor, along with some classic and recent examples, seems timely.

The illusion that molecular target-based drug design would yield a vast treasure of new drugs for central nervous system (CNS) disorders, cardiovascular disease (CVD), metabolic disorders, and cancer was shattered by the realization that the human genome encodes fewer than 30,000 proteins. The low number of druggable targets was only the beginning of the problem. Each protein has to perform diverse functions in different cells and at different stages of development, so agents that are potent and specific can still have off-target effects on nonaffected organs or on developing or replenishing tissues. In practice, certain drugs that affect more than one target at different potencies can be more effective or better tolerated than highly potent and specifically targeted agents. Repurposing drugs often starts with the premise of therapeutic effect and tolerability, so the dissection of mechanism is typically backfilled after critical path activities like formulation and dose-finding.

New markets for repurposed drugs could be the key to research and development productivity while existing products lose patent protection, and managed care and government payors have stopped reimbursing for new premium brands that are only “me-too” products or control-release drugs that only improve compliance. Depending on the amount of existing human exposure data, repurposing an existing drug has the potential to eliminate or reduce preclinical testing and early clinical trials, and cut some of the estimated 10–15 years, and the more than $1 billion it takes to bring a new chemical entity to market. Repurposing also reduces the risk of late-stage product failure from unexpected toxicity. Repurposing is breathing new confidence into an industry whose research managers have been trained to fail fast.

Repurposing drugs is particularly important in the treatment of CNS disorders, CVD, metabolic disorders, and cancer. Pathological processes in these conditions are carried out by proteins and processes that differ from their normal counterparts only in a subtle way such as the level or pattern of expression. Sometimes these subtleties are only discovered by anecdotal observations of patients or patients reporting unexpected therapeutic benefits, and the repurposing activity depends on improving the formulation or optimizing a treatment regimen. In contrast, molecular target-based screening and rational drug design remain the standard for targeting infectious agents (i.e., HIV and HCV) because the pathogen’s targets are either unique or sufficiently different from their human homologues so as to increase the likelihood of developing specific inhibitors.

Reflecting the appeal of drug repurposing, 2012 witnessed several conferences for researchers, including the 2nd Annual Drug Repositioning & Indications Discovery Conference in San Francisco in October, and the World Drug Repositioning Congress in Washington, D.C. in December. A few years ago, no such conferences existed. Additionally, initiatives related to drug repurposing are growing. For example, in spring 2012, eight major drug firms joined the National Center for Advancing Translational Sciences (a division of NIH) to create the Discovering New Therapeutic Uses for Existing Molecules program.

Many drug repurposing projects are supported by the FDA’s intention to encourage innovation without creating duplicate work under the 505(b)(2) provision. Filing a New Drug Application (NDA) under the 505(b)(2) provision allows a sponsor to rely, in part, on FDA’s earlier findings of safety and/or effectiveness for the previously approved drug, therefore simplifying the drug development pathway, allowing for a less expensive development program and faster access to market.

Drug repurposing holds the promise of delivering new treatments for some of the most intractable CNS disorders, CVD, metabolic disorders, and cancer. [© sil – Fotolia.com]

Classic and Recent Examples of Repurposing

As with the strategies involved, a complete list of successfully repurposed drugs is obviously too large to recount here (and new examples are continually appearing). What follows must be considered merely a selective snapshot.

A major triumph for repurposing was the use of thalidomide to treat the blood cancer multiple myeloma. Thalidomide was originally developed as a hypnotic in the 1950s and taken off the market because of its teratogenic effects. Thalidomide was relegated to orphan status for the treatment of a rare form of leprosy, erythema nodosum leprosum. Cephalon repurposed thalidomide for multiple myeloma and fundamentally changed the treatment and outcome of this common malignancy. Thalidomide also revealed a new target for treating multiple myeloma and led to the improved, second-generation agent Revlimid. This case shows how repurposing led not only to a new treatment, but also to a fundamental new treatment approach that also yielded second-generation agents.

After the first beta-blocker, propranolol (Inderal), was discovered by J.W. Black, M.D., in the mid-1960s, beta-blockers found widespread use for treating hypertension. Anecdotal experience led to repurposing certain beta-blockers for migraine prophylaxis and the treatment of congestive heart failure (CHF). Although CHF for many years was a contraindication for using beta-blockers, physicians noticed their benefit in certain patients and ultimately long-acting metoprolol (Toprol-XL) achieved blockbuster status as a treatment for CHF.

Leucovorin was first introduced for the rescuing of patients from high-dose methotrexate treatment. Later it was discovered to work synergistically with fluorouracil (5-FU) in treating colorectal cancer, since it stabilizes the interaction of 5-FU with its molecular target thymidylate synthase. The effects of leucovorin were found to be exerted by the levo-isomer exclusively, so levo-leucovorin is a second-generation agent that was introduced in Europe by Lederle, developed in the U.S. by Targent Pharmaceuticals and now marketed by Spectrum Pharmaceuticals for both methotrexate rescue and colorectal cancer treatment.

Some approaches to repurposing start by screening known drugs in animal models. In February 2012, Eisai’s cancer drug Targretin was reported to show promise at fighting Alzheimer’s disease; the drug acted dramatically in mice, lowering levels of beta amyloid, a hallmark of the disease, and improving the rodents’ memories. The same month, the Novartis multiple sclerosis drug Gilenya slowed the progression of another neurological problem—Lou Gehrig’s disease—also in mice. Should these findings in animals translate into effects on human diseases, it could stimulate more research into systematic approaches to screen existing drugs on animal models.

Finally, Tonix Pharmaceuticals has recently been seeking to fill an unmet need for a non-habit-forming, relatively safe pharmaceutical treatment for fibromyalgia syndrome (FM) and post-traumatic stress disorder (PTSD), and is working on one such repurposing drug candidate that focuses on improving sleep quality as the key to treating both of these conditions. The company is developing a novel treatment based on cyclobenzaprine, a compound that is FDA-approved as a muscle relaxant for short-term use over a range of doses but has off-label use as a slow-acting sleep aid in fibromyalgia. The company is testing the experimental drug TNX-102 SL as an under-the-tongue tablet at bedtime, to determine whether it will decrease pain and improve other symptoms of FM. The company expects TNX-102 SL to enter an efficacy and safety trial in FM in the first half of 2013.

In summary, drug repurposing holds the promise of delivering new treatments for some of the most intractable CNS disorders, CVD, metabolic disorders, and cancer. Repurposed drugs can also provide the tools and understanding needed to develop second-generation drugs. Given the stringent demands of managed care for truly differentiated products, drug repurposing is a beacon of hope to developers of drugs for conditions that have not been advanced by molecular target-based design. Ultimately, a greater range of patients with a wide range of conditions may benefit from this class of drugs that have gone through the regulatory approval process at least once and have an abundance of human experience.

Seth Lederman, M.D., is co-founder, CEO, and chairman of Tonix Pharmaceuticals, a specialty pharmaceutical company developing treatments for disorders of the central nervous system including fibromyalgia and post-traumatic stress disorder. He can be reached at (212) 980-9155.

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