Article by Dr Sanjay Bajaj
The Discovery of a new drug molecule is estimated to take over 2.5 billion and over 10 years of extensive research. It is not that the new molecules are hardly discovered but a large number of molecules qualifying as drugs fail during Phase II or Phase III clinical trials mainly because of safety and toxicity issues. Several new technologies of the 90s like combinatorial chemistry, high-throughput screening, and bioinformatics have also failed to accelerate the pace of new drug discovery. Despite these being an integral part of the current discovery process, there has not been a substantial difference in the de novo drug discovery rate during the last 2 decades. Pharmaceutical scientists, therefore, have been trying to think out of the box to come out with the novel idea of introducing new drugs and/or products.
The serendipitous idea of looking back at an old, in use or withdrawn drug molecule and turning it into a successful proposition gave birth to what is known today as drug repurposing, reprofiling, reusing, repositioning, or rediscovery. Certainly, it is not only about giving a new life to an otherwise shelved or even rejected or dropped drug molecule, but it is looking at an existing molecule in an entirely different way. Repurposing a drug molecule for a new indication has also been followed as an approach for the life cycle management of a molecule. Big pharmaceutical innovators use this as an extension strategy to retain their market exclusivity and continue to earn profits from an existing brand. On the other hand, generic manufacturers can use this strategy to gain market advantage by introducing a novel and rediscovered product to fulfill an unmet medical need. Regulatory authorities also encourage such out-of-box thinking and innovations.
A definite advantage of this approach is that we do not have to go in for its safety and tolerability profile since the molecule had been in use following successful Phase I or Phase II clinical trials. This certainly can save about 60-80% of the cost and 50-80% of the time required for bringing a new drug molecule to market. Therefore, drug repurposing or rediscovery is increasingly being adopted, by the pharmaceutical industry across the globe, as an alternative approach to introducing new products in the market. According to one estimate, the total market for repurposed drugs was around the US $ 31.3 billion in 2020.
The rediscovery of thalidomide, in the 1960s, as an effective anti-inflammatory treatment for patients with leprosy has been the first known example of this approach. This was followed by several successful re-propositions like that for sildenafil, minoxidil, metformin, aspirin, valproic acid, methotrexate, propranolol, simvastatin, colchicine for diverse indications and very recently azithromycin, chloroquine, hydroxychloroquine, favipiravir, remdesivir and ivermectin for Covid-19. Consideration of rediscovery for a drug molecule is not always based on the introduction of a newer indication but it can be considered in a variety of ways like new drug target, new route of administration, new dosage form, improved bioavailability, new drug combinations, new dosage regimens, use for an expanded population of patients as well as the development of drug-device combinations. In the year 2020, the CDER, US FDA has approved 25 already approved drugs for a new use or indication, 7 drugs for use in an expanded population of patients, 6 new formulations of already approved drugs, and 5 new dosage forms. However, apart from these pharmaceutical considerations, there are other strategic, commercial, clinical, patient, healthcare, regulatory and technical issues that have to be sorted out before commercialization of such rediscovered drug products.
In order to repropose drugs effectively, the approaches which can be followed include in silico screening and rescreening of existing molecules for new indications and targets, bioinformatics for the identification of possible clinical target proteins, molecular approaches for matching existing drugs with another existing disease based on mechanism of action of drug and disease, studies involving gene-expression data for understanding disease indications, exploring real-world data of patients for the effect of drugs in the patient population, reformulation using modified drug delivery and dosage-regimens approaches and fixed-dose combinations and so on. For example, an innovator company launches a molecule initially as a single dosage form like an enteric-coated tablet. But after a decade another generic company may come up with the same molecule in the form of an injection or inhaler to address the need for a quick response or better patient compliance. Many novel fixed-dose combinations (FDC) in the market today also address the same value proposition.
On the regulatory landscape, such repurposed drug products may be eligible for submission and approval via the 505(b)(2) pathways with FDA or as a hybrid application with EMA. According to US FDA “A 505(b)(2) application is an NDA that contains full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant, and for which the applicant has not obtained a right of reference or use, including, for example, the Agency’s finding of safety and/or effectiveness for a listed drug or published literature.” Similar provisions exist with regulatory agencies of other regions and countries also.
Despite the advantages and regulatory provisions, drug rediscovery is not free from challenges and hurdles. These approaches, as mentioned above, are actually very cumbersome and cannot give results unless combined with a sound understanding of the drug mechanism of action as well as disease. Moreover, several propositions may actually require lengthy clinical and developmental studies before being considered eligible for approval as a repurposed new drug under 505(b)(2) pathways, which certainly means higher discovery cost. On top of it the dilemma for pharmaceutical scientists is where to begin from, which approach to follow, is there any time-tested pathway, will the new product be able to change the way it is currently being used, and so on. Intellectual property issues may further pose challenges for the discovery scientists and companies and may seriously impact the rediscovery process. Nevertheless, the benefits seem to outweigh the hurdles and therefore Drug Rediscovery is going to be the approach to be followed more and more in the future.
New drug discovery research has its own standing and nothing can replace the process of discovery. The idea of repositioning of existing and/or approved drugs gives us an opportunity to make best use of the already discovered molecule and save a substantial amount of time and money making the healthcare affordable and effective.
- Innovating Lifecycle Management with Data-Driven and Enabling Technologies (pharmtech.com)
About the Author
Dr Sanjay Bajaj, PhD, MBA is the CEO & Managing Director at Glostem Private Limited, a global science, technology, event, marketing & management organization. Email: email@example.com.
Disclaimer: The views expressed in this article are the author’s personal views and Glostem Private Limited does not hold any responsibility for any information or claims. The information provided in this article is not for medical and/or research purposes.