Redefining Drug Discovery: Development and Repurposing

Written By chris korban

Millions of doses of Pfizer’s Paxlovid will go to waste in the EU as COVID demands decrease; imagine if a couple of years later, these drugs can treat another illness or disease. This is just one of hundreds of examples that could be solved with the fundamental idea of “drug repurposing.”

Importance of Drug Development and Repurposing Drugs

The drug development process is a framework put out by the FDA to ensure that companies create safe drugs for humanity. It drives scientific discovery and innovation, advancing our understanding of human biology and disease mechanisms. Economically this process provides jobs and successful drugs, resulting in economic growth and leading to more research in a subject area. Through various trials, scientists gather information that can be helpful for further studies using the same drug. Drug development is also the response to emerging health threats such as pandemics.

Repurposing drugs is a solution to the thousands if not millions of drugs that expire on shelves. This process allows researchers to find new uses for existing medication potentially speeding up the availability of treatments for various diseases. These drugs can be well-known names in the form of previous medications, increasing public trust. Repurposing can also provide solutions for unmet medical needs, including rare diseases and emerging health threats that have not yet been addressed. It leverages existing research and clinical data, maximizing the value of previous investments in drug development and minimizing wasted money and drug potential. Ultimately, drug repurposing can enhance patient care by offering new therapeutic options more quickly and efficiently.

Introduction to Drug Development

In drug development, the goal is to bring a new pharmaceutical drug to the market once a lead compound has been identified through drug discovery.  On average, this process takes about 10-15 years and over $2 billion to complete. As seen in the picture on the right, there are 4 critical stages in drug development with an added 5th stage by the FDA to track the drug in the market. Drug discovery and development, the first step in drug development, is where researchers identify and design potential new medicines. The second stage is called preclinical research, a stage that takes about 1-6 years according to the FDA. Researchers and scientists try to discover the effects of the drugs and determine if it is safe to use in human trials by using in vivo and in vitro experiments. After preclinical research confirms that the drug is safe to use on humans, researchers and scientists then begin clinical research and trials. Throughout clinical trials, there are four main phases. Each of the stages answers different questions and has a different sample size. The drug/compound then goes into the FDA drug review stage, which takes about 6-10 months. Following the successful clinical trials and the drug has been determined safe and effective for its intended use, the company can file for the application to market the drug through a New Drug Application (NDA). The FDA review team will examine the NDA and either approve or reject it. After the FDA review team’s approval, the drug can now enter the market to be sold to the general public. Finally, stage 5 includes the FDA Post-Market Drug Safety Monitoring, after the drug enters the market the FDA reviews reports of problems with the drug such as prescription, and can add caution to the dosage or usage information. Now with the basic framework of the drug discovery timeline, we can dive deeper into each stage.

First off, Stage 1 (Discovery and Development) is an ongoing process for multiple large pharmaceutical corporations. This stage can be initiated by a new disease, existing treatments having unanticipated effects, or trial and error on new combinations of elements. After discovering the drug the development phase of the stage begins with scientists learning about the drug. Some critical questions to answer are: How is it absorbed; What are the potential benefits and side effects from the drug; How does it interact with other drugs and treatments?

After the formula and basic questions are answered about the drug, Stage 2 (Preclinical Research) begins. As mentioned above, the drugs are tested in two methods: in vitro and in vivo. Tests typically start in vitro (ie. cell lines) before transitioning to in vivo (animal models). The experiments are run to answer more questions about the drug to determine if it is safe enough to use on humans in the next stage. During this stage, the FDA requires researchers to use good laboratory practices (GLP) defined in medical product development regulations

Adapted from Paul et. al 2010 - The drug discovery and development model outlines the process from target identification to drug launch. It uses industry benchmarks and data from Eli Lilly to define R&D performance at each stage, including transition success rates, phase costs, cycle times, and capital costs. The model calculates the number of projects needed in each stage to achieve one new drug launch, estimating an 'out of pocket' cost of $873 million and a 'capitalized' cost of $1,778 million over 13 years. This excludes exploratory research, post-launch expenses, and overhead costs.

Stage 3 consists of 3 major phases (Phase I, II, and III of clinical trials). During each one of these phases, scientists and researchers test the drugs on humans in different sample sizes to discover more information about the drug. Before starting the phase clinical trials, the lead researcher or scientists must decide what questions they want to answer in each phase.  Before any of the phases start, the drug developed must submit an Investigational New Drug Application (IND) to the FDA. The application consists of information about the preclinical research, manufacturing information, information about the investigator, and more. The FDA IND review team consisting of multiple experts in the pharmaceutical field has to approve the company’s IND for the clinical research to begin. The FDA review team has the power to either approve or put the company on clinical hold to delay or stop the investigation of the new drug. Phase I usually consists of 30 patients or less and a safe dosage, the most effective intake method, and effects on the human body are discovered. This phase takes only a couple of months and around 70% of drugs pass this phase. Phase II has a sample size of 100 patients or less. This phase is focused on the effectiveness of the drug and its side effects. Questions such as how long it takes to react to targeted disease are answered during this phase. This phase can take from a couple of months to two years and about 33% of the previous drugs pass this phase. Finally, in Phase III, the sample size increased to the hundreds and in some cases the thousands. This phase compares the new drug to the previous drug to find out its effectiveness. It takes about one to four years and about 25-30% of the drug passes through this phase. Most drugs after Phase 3 become FDA approved, but in some rare cases there is a Phase IV where any new questions that were raised during the previous trials are answered for the safety of the public and the data is checked by the FDA. All drugs will usually also undergo post-market surveillance by the FDA to ensure that the drug’s safety and efficacy remain high.

FDA Drug Review or Stage 4 of the Drug Development Timeline occurs once the drug successfully passes through all clinical trials and is deemed safe for the market and the public by the FDA. After the drug finishes the clinical trials, the company must submit a New Drug Application (NDA) for the FDA to review before approving the drug. While reviewing the NDA, each member of the review team conducts a full review of their section of expertise in the application. Other FDA inspectors travel to clinical sites to conduct a routine inspection to look for fabrication, manipulation, or withholding of data. After all members approve the application the project manager assembles the reviews into an “action package” and the company is allowed to produce and sell the product.

Adapted from Rebelo et al. - A comparative schematic of drug commercialization pipelines, comparing de novo drug discovery to drug repurposing; outlining the shortened time frame to commercialization with re-investigating drugs.

After the drug enters the market, it enters Stage 5, FDA Post-Market Drug Safety Monitoring. Even after countless months put into the previous stages of drug discovery, there is still the possibility of problems with the drug arising. The FDA reviews reports with the drug such as prescription or side effects that do not match the data. In some cases, the company may want to make a change to their drug such as increasing dosage or changing the labeled indication. The company must send in a supplemental application and wait for the FDA to approve it before making the change. Throughout this stage, the FDA will also conduct manufacturer inspections and can shut down facilities if minimum standards are not met. They also have several programs for manufacturers, health professionals, and consumers to report problems associated with the approved drug. The FDA is currently using the Sentinel Initiative but plans to continue developing a new national system to more quickly spot possible safety issues.

Repurposing Drugs

The science of repurposing drugs is claimed to date back to 1950 under the term drug reprofiling, but credit is given to Ted T. Ashburn and Karl B. Thar to introduce the inception of drug repositioning in 2004 (Langedijk et al., 2015). The FDA defines drug repurposing as the process of identifying new uses for drugs that have been already approved by the FDA. Drug repositioning is often taken up by smaller clinics due to several factors such as regulatory and administrative challenges, research priorities and funding, clinical trial infrastructure, and many more. Major clinics are often focused on groundbreaking research and new drug development because they have the resources to do so (money and staff), therefore smaller clinics on a limited budget and staff choose the cost-effective process of drug repurposing. Smaller clinics also benefit from this process as the limited drugs they hold in storage could be used as a cure for a multitude of conditions.

The process of drug repurposing is very similar to drug development. It starts with a discovery and development phase followed by both preclinical and clinical trials then finally approval and post-market surveillance. This process takes from about 3-8 years which is much shorter than the 10-15 years for drug discovery. The previous data allows the drug to skip or speed up preclinical testing and Phase 1 of clinical trials. After the drug passes through all the trials, the company must submit a Supplemental New Drug Application (sNDA) and wait for the FDA review team to approve it. Then the drug is ready to enter the market where the FDA will conduct post-market surveillance to ensure no issues arise. Drug repurposing offers a promising avenue for developing new therapies by making efficient use of existing pharmacological knowledge and resources.

Adapted from Pushpakom et al. 2018 - A computational model approach to be used in a combinatorial or individual analysis of drug repurposing hypotheses. Challenges and limitations are outlined along with data driven experimental hypotheses approach.

In terms of repurposing drugs from the pharmaceutical standpoint, there arises challenges in the development of these drugs like high outstanding costs of re-evaluating research and development strategies after previously failing. There are several approaches to drug repurposing hypothesis testing in- silico, all of which aim to reduce the cost of re-evaluation. From the chemical structure point of view signature matching and molecular docking dynamics open up the field to investigate drug - target interactions and drug intrinsic properties whereas the genetic and pathway perspective allow for novel target ID and a further analysis of regulated signaling pathways that are activated after drug interactions.

Although drug repurposing sounds great with a shortened process timeline and previous data for the FDA review team, it faces many challenges. Some of these challenges are patent laws, scientific validation, regulatory hurdles, high risks and costs,  and market demand. While small clinics operate most repurposing drug processes the original drug is most likely a result of a major pharmaceutical company’s drug discovery so patent holders or the original drug makers might need to be negotiated with for rights to use the drug for new indications. The FDA can also provide market exclusivity to drugs, which can both help and harm repurposed drugs as they can create brand loyalty in an untapped market or prevent companies from getting into the market until other drug exclusivity/ patent clauses expire to allow market entry. The company also has a limited period of time with data exclusivity to prevent competitive companies from obtaining  a market advantage. The competition for repurposing is high as multiple companies can be working on the same drug and it is harder for smaller companies to establish themselves with a customer base. During the trials, clinics can also struggle to reproduce results with limited resources. Drug repurposing offers a promising route to new treatments, leveraging existing knowledge to reduce development time, cost, and risk. However, the process is fraught with challenges, including intellectual property issues, the need for robust scientific validation, regulatory hurdles, and ensuring commercial viability. Addressing these challenges requires strategic planning, collaboration, mitigation of risks and costs,  and a thorough understanding of both scientific and regulatory landscapes.

Current Stage of Drug Development and Repurposing Drugs

Recent developments in drug research highlight several significant advances. The Alzheimer's disease pipeline shows promising results, including donanemab, which slowed cognitive decline by 32% in clinical trials and reduced amyloid plaques significantly. Donanemab is currently in Phase 3 clinical trials as this article is being written. Other drugs have also shown a hopeful future for Alzheimer’s treatments like remternetug and gantenerumab, both drugs are also in Phase 3 trials following the progress of donaemab.

Additionally, the FDA has recently approved several new drugs. Some of the approved drugs to highlight are rytelo (imetelstat) which treats lower-risk myelodysplastic syndromes with transfusion-dependent anemia, and mRESVIA, a modified RNA vaccine by Moderna, which was approved to protect older adults from respiratory syncytial virus (RSV). Merck's new pneumococcal vaccine and a combined COVID-19/influenza vaccine finally received FDA approval and CDC backing, promising improved immunization strategies. Previously the serotypes covered by CAPVAXINE were responsible for more cases of IPD in adults compared to the current medication PCV20. After the FDA approval, CAPVAXIVE is the new These advancements reflect ongoing efforts to address critical health issues through innovative drug development and regulatory support.

Recent developments in drug repurposing have brought new hope for curing various diseases. Researchers are actively investigating existing drugs for their potential to treat acute myeloid leukemia. At the Institute of Experimental Virology, scientists have identified lonafarnib, originally approved for Hutchinson-Gilford progeria syndrome, as a promising treatment for respiratory syncytial virus (RSV). This finding could lead to more effective RSV treatments, especially if optimized for local application to minimize side effects. Additionally, Sildenafil, better known as Viagra, was repurposed from a blood pressure treatment to a sexual dysfunction medication and is now being explored for its potential in treating Alzheimer’s disease. A study from the Cleveland Clinic Genome Center revealed that patients taking sildenafil had a significantly lower prevalence of Alzheimer's disease, suggesting that the drug may reduce neurotoxic tau protein levels in the brain, a hallmark of the disease. These advancements highlight the value of drug repurposing in offering quicker and cost-effective solutions for various conditions by utilizing existing medications.

Potential for AI Implementations

AI is making strides in the drug development field as it has expanded the market size to $11.93 b according to BioSpace. This is a significant increase in market size as previously it was $9.32 b. In addition, the first AI drug claimed to be discovered and designed by generative AI, INS018 055, is currently in Phase 2 clinical trials. In 2023, Sanofi R&D teams identified 90 new targets and advanced 7 targets in the pipeline, and AI was applied to 75% of the small-molecule drug discovery portfolio. Virtual patient engines helped accelerate molecules in 12 different therapeutic indications.” (Collaborative AI Partnership Hopes To Shape the Future of Drug Discovery). The rapid growth of AI in drug discovery has affected the drug development timeline. The potential for AI intervention in the drug repurposing space also has the potential to reduce the risk of re-evaluation and manufacture as well as reduce the costs for actual investigation for speedier preclinical evaluations.  De novo design and property prediction are some of the computation approaches that are currently being used. Scientists are hopeful for the impact AI will have in the future of drug discovery. In next week’s article, we will dive deeper into how AI aids in the process and the significant advances the field has made.

Written and Constructed by Joshua Minami, Christopher Korban, Christian Chung

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