This blog is a follow up to our recent blog on repurposing drugs. As previously stated, drug repositioning, also known as drug repurposing, is the investigation of potential new uses for approved drugs followed by clinical confirmation of the new indication, and finally commercialization. The National Institutes of Health (NIH) said that the first example of drug repositioning was an accidental discovery in the 1920s. While drug repositioning is not new, since the late 1990’s, the importance of drug repositioning has taken on a more urgent purpose as the cost of original drug development skyrocketed. Today an original discovery is estimated to cost $1.0 - $2.0 billion and require 10 – 15 years of development whereas drug repositioning is proving to be an effective strategy to find new indications for existing drugs in a cost effective manner and within a 3 - 7 year time frame. The strategy is highly efficient, low risk and with a high success rate for commercialization. Traditional drug development strategies usually include five stages: discovery and preclinical, safety review, clinical research, FDA review, and FDA post-market safety monitoring. However, repositioning an old drug at the very least requires its identification, development, and FDA post-market safety monitoring.
One of the critical issues in drug repositioning is the determination of novel drug-disease relationships. To address this issue, a variety of approaches have been developed including computational approaches, biological experimental approaches, clinical trial data driven or mixed approaches. Drug banks such as DrugBank®, ChemB®ank, KEGG®, and Pubmed® have appeared employing biologic combinatorial techniques. Utilizing well designed algorithms, artificial intelligence, and machine learning technologies which can search a network based group of these foregoing databases, scientists can identify novel uses of existing FDA approved, clinically abandoned or clinical trial drugs in far less time than the traditional approach. Other technologies, such as the one developed by Kinentia Biosciences, Lynxbioscience LLC are also available to the drug developer. Kinentia Biosciences, founded in 2007, utilizes its platform chemoinformatics technology called Deep Data Mining (DDM™) to aid researchers in the discovery and development of novel pharmaceutical agents; however this approach also lends itself to repurposing old drugs. DDM™ recognizes key risk factors involved in the drug discovery process and has built in process checks to mitigate this risk and reduce time to market.
Numerous diseases are being approached using existing drugs. For example, Pandey et al. wrote a review on clinically approved drugs that could be repurposed to inhibit ion channels for cancer treatment. Ion channels play critical roles in cancer pathophysiology. Ion channels like Ca2 +, and Na+/K+ control cancer cell proliferation by regulating several key survival signaling pathways and membrane potential. In their review article, Pandey et al., said that a disease based approach is suitable when there is very good information about pathogenesis (with omics data) of a particular cancer. With omics information about the particular cancer the FDA-approved drugs can be screened in silico to target the key pathways: e.g. sunitinib for metastatic breast cancer. On the other hand, when there is a paucity of information about a cancer type, FDA-off label screening is a suitable method: e.g. rituximab for breast cancer. As an example, verapamil, an approved antihypertensive drug, is an L-type Ca2 + channel blocker. Verapamil has shown anti-proliferative effect in breast cancer in a mouse model, and meningiomas in a nude mouse model. In a prospective study of 99 patients with anthracycline-resistant metastatic breast carcinoma, verapamil showed positive survival effects.
Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug-resistant pathogens represents a clear opportunity to consider repurposed drugs as a treatment option. Some successes have been achieved by repurposing existing drugs for treatment of infectious diseases. Enoxacin, a broad-spectrum fluoroquinolone antibacterial agent approved for treatment of urinary tract infections and Gonorrhoea, showed antifungal activity in both a Caenorhabditis elegans and a murine model of Candidiasis. Delamanid, a drug for tuberculosis, exhibited activity against visceral leishmaniasis. The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis. Niclosamide, an anti-worm medicine, showed potent activity against the Zika virus, which can cause birth defects in pregnant women.
As previously discussed in our recent blog, thalidomide represents perhaps the most spectacular example of how an old drug can be put to good use. The drug was originally introduced in the 1950’s as an OTC in several European countries for the treatment of insomnia, morning sickness and motion sickness. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. The drug had not been approved by the FDA at the time. However, in 1998, thalidomide was approved for use in the US, with the warning that pregnant women should not take the drug, to treat inflammation associated with leprosy and also as a chemotherapeutic agent for patients with cancer of the plasma cells in bone marrow (multiple myeloma). Derivatives of this once notorious drug have been synthesized, such as lenalidomide and pomalidomide, and approved by the FDA to treat multiple myeloma, mantle cell lymphoma, and myelodysplastic syndromes associated with the deletion 5q abnormality. Interestingly, thalidomide is an optically active drug and exists as two stereoisomers. While it was determined that the S isomer was the one that was teratogenic and the R isomer was the bioactive form, regrettably, the chiral isomers racemize in a biological environment.
Recent government support has led to many more approved drugs being tested for applications far beyond their initial use. For example, drugs that have “antitussive, sedative, analgesic, antipyretic, anti-arthritic, anesthetic, antidiabetic, muscle relaxant, immunosuppressant, antibiotic, antiepileptic, cardio-protective, antihypertensive, erectile function enhancing, or angina relieving” properties may be used as adjuvant therapies in cancer. The effort to reuse existing drugs for novel therapies is especially important for rare diseases where the cost of discovering new chemical entities is prohibitively high. However, we must be cautious in our search for repurposed drugs. Many approved, older active compounds can have severe side effects, have poor physicochemical properties, and high effective concentrations may not be clinically achievable. Notwithstanding the foregoing, the mission to repurpose old drugs is a worthy approach to curing diseases.
Written by Lawrence D. Jones, PhD, Science Writer
Keywords: Infectious Disease, Repurposing Drugs, Thalidomide, Systematic Drug Repositioning, CureScience
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