Guest Column | January 12, 2024

Finding New Treatments In Old Therapies

By Robert L. Quigley, MD, D.Phil.

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The urgent need for effective and safe therapeutic treatments continues to conflict with the time-consuming process of drug development. From bench (research) to shelf (pharmacy), it takes more than 10 years to advance a new drug through four development phases, at an average cost over $1 billion, to secure FDA approval. Moreover, the process has a high risk of failure — only 12% of drugs in clinical trials ever obtain FDA approval.1

Despite improvements in technology, the reality that the inflation-adjusted cost of bringing a new drug to market doubles every nine years, known as Eroom’s law, has discouraged many in the industry from undertaking the journey.2 As such, the idea of discovering new therapeutic applications for already approved existing medicines seems — at least on the surface — very appealing.

Repurposing, or repositioning, of drugs received renewed attention throughout the COVID-19 pandemic. During this time, the FDA granted Emergency Use Authorization (EUA) for several repurposed drugs to treat SARS-CoV-2. This included consideration of several antiviral and anti-parasitic medications.

No longer serendipitous in which drugs are discovered by coincidence, drug repurposing has become more systematic by advances in human genomics, chemoproteomics, systems biology, and in silico screening with computer modeling. Since the FDA has already approved more than 19,000 drugs for clinical use, leveraging accessible data and technology easily enables drug repurposing.

It is now possible to identify compelling new uses for approved drugs by identifying what proteins or genetic pathways are involved in a specific disease and determining which are targets of existing drugs. To that end, drugs supported by genetic data and evidence are much more likely to succeed in the pharmaceutical pipeline.4 Stakeholders looking to repurpose drugs now recognize a paradigm shift in the industry, in which a disease is no longer considered to be malfunctions or failures of certain organs, but attention is now paid to the molecular pathway or mechanism implicated in the pathogenesis of a disease.

Drug repurposing is expanding in the space of rare and neglected diseases, as repurposing represents an approach to medicines and targets that have already been “de-risked” to a certain extent during drug development stages. This helps to accelerate the process, making it fiscally attractive to drug manufacturers in the rare disease space because of the ease with which an approved drug may be produced and marketed, compared to other treatments. Today, drug repurposing is also recognized as a time and cost-effective strategy for treating serious chronic diseases and is particularly applicable to novel zoonoses, i.e., COVID-19, not previously encountered in humans.

Types Of Repurposed Drugs

Potential repurposing candidates typically fall into one of three categories: generic, patented, and failed drugs. Each has its own advantages and constraints.5,6

Generic drugs are those that are off-patent, already approved by regulatory agencies, and typically readily available in pharmacies. For the most part, data relating to these drugs’ safety and efficacy are both easily accessible and comprehensive because of the extensive testing in preclinical and clinical trials that led to their approval, as well as monitored use in the population over an extended period of time. Consequently, generic drugs are usually favored for repurposing by small biotech companies, nonprofit research organizations, and even academia because they are often less expensive and less risky to produce.

Patented drugs, which include clinical investigational compounds or those in the late stages of clinical trials, whether approved or not, are considered protected or proprietary. As such, data relating to the safety and efficacy of such compounds is not easily accessible except to the respective pharmaceutical companies that developed them.

Failed drugs, which have been through some stages of clinical trials but did not reach approval are similarly protected and therefore data are limited or inaccessible except to  certain developers. These drugs may stall due to several issues, including inadequate efficacy against the intended indication, safety concerns, or even lack of funding. As such, these medications are sometimes referred to as abandoned or discontinued pharmaceutical agents.

Tips For Repurposing Generic Drugs

In many cases, a lack of financial incentives exists for drug companies to explore the repurposing of a compound if it’s already categorized as generic. Physicians can prescribe a drug off-label and pharmacists can switch the branded version for a cheaper generic alternative. Because of this, unfortunately for the pharmaceutical industry, if a generic version of a drug is available, developers often have little or no opportunity to get a return on their investment in the repurposing of the drug for a new indication.

However, this lack of marketing protection does not need to always be an obstacle. Repurposed generic drugs can be patented, with exclusivity, through a patent office, be it only short-term (three years in the U.S.) with limited published or even experimental data in the case of “second medical use” claims.7

Another deterrent to repurposing generic drugs always has been the fixed price associated with the medication. This, too, can be overcome by repurposing the generic medication in another country as a new drug rather than a generic drug with a new indication. This was successfully done with viloxazine, a selective norepinephrine reuptake inhibitor originally marketed in Europe as an antidepressant in 1974. Despite having met generic status, viloxazine was repurposed in the U.S. for the treatment of attention deficit hyperactivity disorder (ADHD) with a new pricing ceiling.8

Lastly, another critical decision in generic drug repurposing is drug selection. For example, drugs with an unlimited target population will have large annual production and can offset any lack of marketing protection. Public funding, when available, also can reduce any financial exposure when repurposing generic drugs.8

General Considerations For Repurposing Drugs

When it comes to drug repurposing, there are often several challenges to overcome. First, the dosage required for the treatment of a unique disease will typically differ from that of its original approved disease indication. If this is the case, the discovery team or manufacturer oftentimes has to initiate new Phase 1 clinical trials, effectively negating any advantages of drug repositioning over de novo drug discovery. Second, the process of drug repurposing rarely includes the efforts of the initial pharmaceutical and toxicological scientists who designed the preliminary compound tests, and so transition of existing drugs to the novel intended disease may require a new formulation or distribution mechanism. Third, due to the lack of experts in drug repositioning, patent right issues can be very complicated.9

Despite the challenges and barriers, drug repositioning has already helped to mitigate failures in drug discovery and has even been associated with therapeutic breakthroughs.   Thalidomide, for example, was used in the 1950s and 1960s as an anti-emetic in pregnancy; however, it was withdrawn from the market due to its teratogenic effects in newborns. The drug was revitalized many decades later as a chemotherapeutic agent in hematologic malignancies.10

Old Drug, New Therapeutic Uses

Another more recent repurposing success involves the anti-inflammatory agent colchicine. The FDA recently approved LODOCO (colchicine) 0.5 mg tablets to reduce the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular death in adult patients with established atherosclerotic disease or with multiple risk factors for cardiovascular disease.11 In previous studies, LODOCO was shown to reduce the level of the inflammation biomarker high-sensitivity C-reactive protein (hs-CRP), while clinically decreasing adverse cardiovascular events by 31% when added to high-intensity statins and other cardiology prevention therapies.12,13

Historically, colchicine has been used as an anti-inflammatory alternative for those unable to consume non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of gout. For this indication, colchicine is commonly prescribed at 1.8 mg/day for a short period of time to counteract acute flare-ups. In contrast, the recommended dose of LODOCO to mitigate cardiovascular events is 0.5 mg/day, making it less than one-third of the recommended dose for the treatment of gout, to be used safely alone or in combination with standard-of-care lipid-lowering medications and other therapies.11

In this case, AGEPHA Pharma, the organization responsible for the repurposing of colchicine, did not connect a known drug to a new target and its associated indication, i.e., a drug-centric approach, nor expand an existing drug to an adjacent indication in the same therapeutic area, i.e., a target-centric approach. Rather, the company identified a disease with homologous underlying biological mechanisms, here inflammation, to a similar indication treated by the original drug in a disease-centric approach.

Repurposing in healthcare is not limited to just the pharmaceutical industry and medications. In fact, when all modern-day procedures to treat the ischemic myocardium have been exhausted in coronary artery disease (CAD), practitioners have repurposed old procedures. One example is when Henry Ford’s cardiologists percutaneously created a fistula between a chronically diseased coronary artery and the coronary sinus, recreating a lifesaving open-heart procedure introduced in the 1950s before the first coronary artery bypass surgery (CABG) operation.14 Another example, at Jefferson Health, is the open-heart use of the Vineberg procedure in combination with transmyocardial laser revascularization (TMLR) in those circumstances where there are no target coronary arteries to bypass.15 The two historic treatment modalities work synergistically to create new blood vessels in ischemic muscle.

With advanced technologies including AI, genome-wide association study (GWAS), and in silico screening, clinicians and scientists continue to collaborate to discover new medicines and treatments that can address acute and chronic diseases. Some of these medicines will be the result of drug discovery and work as stand-alone agents, while others will work synergistically to enhance existing drug regimens. In the exploration for new medicines, drug repurposing remains one method through which new therapeutic applications may be discovered to help treat patients in need.


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About The Author:

Robert L. Quigley, MD, D.Phil., is an international healthcare consultant and a senior consultant for International SOS. He is the cofounder and executive chairman of the International Corporate Health Leadership Council, a 501(c) (6) organization. He formerly served as senior vice president and global medical director, corporate health solutions at International SOS Assistance & MedAire, Americas Region, and was responsible for leading the delivery of high-quality medical assistance, healthcare management, and medical transportation services. Prior to joining International SOS, Quigley was a triple board recertified cardiovascular and thoracic surgeon who directed two open heart programs within the Jefferson Health System in Philadelphia, where he was a professor of surgery at Jefferson Medical College. He holds a doctorate in immunology.