Drug repurposing: New concept in pharmacy profession

The drug repurposing also known as drug reprofiling, involves identifying new therapeutic uses for existing or investigational drug beyond their original therapeutic use. In traditional drug discovery the journey begins from idea to an approved therapy is time consuming, failure rate high and a costlier affair. The new concept has become the need to expedite the drug discovery process to find quick solutions for the drug needs.

The drug repurposing is the alternative strategy that allows the time and costs of pharmaceutical research, in which new uses are discovered for already approved or under investigation. The concept of drug repurposing excludes any structural modifications of drug and instead the repurposing makes use of new indication of either biological properties for which the drug has already been approved, many successful examples of repositioning have been identified for the treatment of different pathologic conditions in last decades.

The drug repositioning is employed for increasing the success rate of drug development. This technology is more advantageous over the traditional drug discovery process by reducing time for drug development with high efficiency, minimum risk of failure and low cost.  The concept is particularly useful where traditional denovo drug development is not cost effective or a cure is needed urgently.

In rare diseases, there are currently limited treatment options. The development of new therapies for rare diseases is often challenging due to factors, which include limited patient populations, lack of understanding of disease pathology, high development cost and disease complexity. The drug development efforts are made more efficient and effective by these collaborative approaches by pooling the resources, expertise and data collection.

The drug repurposing often involves collaboration between academia, pharmaceutical companies, and patient advocacy groups. These collaborative approaches may pool resources, expertise, and data, leading to more efficient and effective drug development efforts.

The drug repurposing is defined as serendipitous process which happens unexpectedly. The repurposing of drugs are discovered by chance and are benefited from the advances made in human genomics, network biology and chemoproteomics.

The advances have created the possibilities of identifying serious repurposing candidates by finding genes involved in a specific disease and checking the possible interaction with cell, with other genes which are targets of known drugs.

The drug repurposing is initiated through any of the three approaches, namely drug centric, disease centric and target centric. The approaches explore the relationships between the drugs, disease and targets in different ways based on the therapeutic action of a drug.

In drug centric approach expands the application of an off-label use of an approved drug for a new patient population or medical condition outside the scope of a medicine existing license or patent. The approach is carried out by reviewing the investigational or abandoned drugs, which showed poor efficacy for another medical condition or did not secure regulatory approval.

The drug centric method can be adopted by identifying new uses for drugs which is pulled from circulation due to safety or post-market issues that are still efficacious for other medicinal uses.  The disease centric is initiated when diseases which have no treatments or with partially effective treatments with approved/failed compounds having therapeutic impact.

The process involved in disease centric is initiated by identifying diseases having a biological mechanism for the indication of original drug treats. The target-centric approach involves investigating the specific molecular targets that are indicated in the pathology of a disease and use the existing drug to modulate those targets. The disease and target centric methods are specifically designed for treating rare diseases.

The two scientific bases for drug repurposing include the discovery, through the human genome elucidation, where some diseases share common biological targets. The data mining, ligand-based and structure-based approaches, machine learning are key components for drug repurposing.

In current system, it is possible to describe diseases by their molecular profile and use computational methods like data mining to determine the degree of similarity between diseases that share a number of these molecular features.

The disease like Parkinson’s and Alzheimer’s share 48 genes and four signaling pathways, so existence of a protein targets common to several diseases suggests that a given drug might have efficacy against both conditions.  The drugs that are existing in market today are phenotypically well characterized in terms of their therapeutic efficacy and side effect.

These therapeutic effect results from the pleiotropic interactions between the drug and several biological targets. So a drug can have efficacy against a disease other than the one for which it was initially designed if one of its secondary targets has a role in the new disease. These interactions make it possible to develop therapeutic agents with multiple effects.

The main challenge involved in drug repurposing is that relatively weak intellectual property protection afforded to such drugs, which can reduce their return on investment and discourage the companies from developing them.

The drug which already been patented as a new chemical entity, the subsequent medicines containing the same entity can only be protected by a new application patent, possibly backed up by a new formulation process. Patents on applications are necessarily narrower than those for a new chemical entity in terms of the therapeutic uses they cover.

The drug aspirin was first repositioned in 1980s, at low dose, as an antiplatelet aggregation drug.  It is still widely used today in this second indication to prevent cardiovascular. Aspirin’s analgesic and anti-inflammatory effects due to inhibition of cyclooxygenase 2 (COX-2), in particular vascular COX-2, an enzyme involved in the synthesis of prostaglandins that generate pain and inhibit platelet aggregation.

At low doses (<300 mg/day), aspirin has partial selectivity for COX-1 and exerts its antiplatelet aggregation effect, which at higher doses is circumvented by concomitant COX-2 inhibition. Aspirin remains a cornerstone in preventing heart attacks and strokes, demonstrating how dosage can define therapeutic outcomes.

 The drug Thalidomide is a drug banned by World Health Organization (WHO) due to its teratogenicity, which affected thousands of victims worldwide, and continues to affect a second generation, mainly through its use as an antiemetic for pregnant women.

The dramatic efficacy of thalidomide was observed against erythema nodosum leprosum, an autoimmune complication in leprosy. Thalidomide, which achieves this effect by inhibiting the synthesis of the proinflammatory cytokine tumour necrosis factor-alpha (TNF-a). The drug consequently repositioned as an orphan drug for treating complications of leprosy. Thalidomide was repositioned for a second time in the field of oncology.

The mechanism underlying thalidomide’s teratogenicity demonstrated its antiangiogenic activity, responsible for the arrested limb development (phocomelia) that occurs after in utero exposure. This activity led to research into its potential use to block or destroy blood vessels supplying malignant tumours, culminating in 2006 in its second repositioning as a first-line treatment for multiple myeloma.

The drug sildenafil is an example of a pharmaceutical substance that was repurposed before it reached the market.  Sildenafil was initially investigated by Pfizer in 1985 as a potential antihypertensive drug. It was shown to produce vasodilation and to inhibit platelet aggregation by inhibiting phosphodiesterase type-5 (PDE5), the enzyme that degrades cGMP.

In light of these properties, the focus was shifted onto its potential in the treatment for angina. The drug Sildenafil was initially investigated by Pfizer in 1985 as a potential antihypertensive drug.

It was shown to produce vasodilation and to inhibit platelet aggregation by inhibiting phosphodiesterase type-5 (PDE5), the enzyme that degrades cGMP and demonstrated its potential in the treatment for angina.  The unexpected side effect emerged during clinical trials conducted showed penile erections.

Sildenafil only produces an erection however in the presence of sexual stimulation to release nitric oxide (NO) leading to production of cGMP. The drug can be termed an aphrodisiac for treating erectile dysfunction, under the brand name Viagra and was subsequently repositioned for a second time.

The dimethyl fumarate marketed as a drug since 1994, to treat psoriasis, under the brand name Fumaderm.  The drug was proposed for treating multiple sclerosis (MS), at higher doses. The drug constitute a major advance in the treatment of MS, as drug can be taken orally and is less cardiotoxic and hepatotoxic than other drugs used in this condition.

The drug minoxidil was first investigated for its antihypertensive activity, interestingly in following decades the drug showed hypertrichosis side effect. Presently the drug is used as topical formulation for treating alopecia with a net sale of $ 1.5 billion in 2022.

The drug cyclosporine was used as an antifungal agent. Scientists discovered an immunosuppressive effect and now used as selective immune-regulatory drug acting on lymphocytes.

The warfarin was first used as pesticide and now several studies have shown its potential as anticoagulant. The lithium was initially discovered for its use to dissolve urate stones in gout disease. The clinicians observed that patient treated with lithium showed improvement in behavior and the anti-maniac effect was established.