The Sad State of Drug Discovery

The process of discovering and developing a new drug can be a long and expensive journey, with less than 10% of candidate targets turning out to be valid after the investment of millions of dollars and six to seven years of work. This means that the vast majority of drug discovery efforts fail at some point during the process.

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Developing therapeutics, whether they are small molecules or biologics, is a complex and iterative process that involves multiple stages of discovery, optimization, and testing. Each stage presents unique challenges that must be overcome to ensure that the therapeutic is effective, safe, and able to be manufactured at scale.

One of the key challenges in developing therapeutics is understanding the structure, activity, and mechanism of action of the therapeutic. This requires a broad range of assays and reagents that can measure various aspects of the drug’s pharmacology, including its potency, selectivity, and efficacy. In addition, it requires expertise in a range of disciplines, including chemistry, pharmacology, and biology.

For small molecule therapeutics, understanding the structure-activity relationship (SAR) is a critical aspect of drug discovery. This involves synthesizing and testing a range of compounds with variations in their chemical structure to identify compounds with optimal pharmacological properties. This process requires access to high-quality reagents and assays that can measure key pharmacological parameters, such as binding affinity, enzymatic activity, and cellular potency.

For biologics, such as monoclonal antibodies, understanding the mechanism of action is a critical aspect of drug development. This involves studying how the drug interacts with its target and modulates the biological pathways that drive disease. This requires a range of functional assays that can measure the impact of the drug on various cellular and molecular processes.

In addition to the challenges of understanding the pharmacology of the therapeutic, drug development also requires expertise in manufacturing, formulation, and clinical development. These aspects of drug development require specialized knowledge and infrastructure to ensure that the drug is safe, effective, and can be manufactured at scale.

Even after a promising candidate drug passes through preclinical testing and advances to clinical trials, more than 50% of drugs fail at phase II clinical trials due to the lack of efficacy. In other words, the drug may be safe for humans, bind to the intended target, and have drug-like properties, but it does not significantly affect the disease being targeted.

Key Challenges

The following are some of the key challenges in the process.

1. Unknown pathophysiology: Many nervous system disorders have poorly understood underlying pathophysiology, which can make target identification challenging. Without a clear understanding of the biological mechanisms driving the disease, it can be difficult to develop drugs that effectively treat the disorder.
2. Animal models: Animal models are commonly used in preclinical drug development to test the efficacy and safety of new compounds. However, these models often cannot recapitulate the entire disorder or disease, which can limit their predictive power for human disease.
3. Patient heterogeneity: Nervous system disorders often display significant heterogeneity across patient populations, which can make it difficult to develop drugs that are effective for all patients. Increased clinical phenotyping and endotyping can help to identify patient subgroups that may respond differently to a given treatment, which can aid in drug development.
4. Human data: Despite the limitations of animal models, drug development has historically relied heavily on preclinical data generated in animals. Greater emphasis on human data, including data from clinical studies and patient registries, may lead to improved target identification and validation.
5. Lack of biomarkers: Biomarkers are objective measures that can be used to detect and measure biological states, and they are critical for assessing the efficacy of new drugs. However, there is currently a lack of validated diagnostic and therapeutic biomarkers for many nervous system disorders, which can make it difficult to assess the efficacy of new drugs.
6. Regulatory processes: The regulatory processes governing the development and approval of new drugs are complex and constantly evolving. Many drug developers may be unfamiliar with these processes, which can lead to delays and setbacks. Pre-IND meetings with regulatory agencies can help to clarify the requirements for drug development and ensure that studies are designed to meet these requirements.

This high failure rate highlights the challenges and complexities of drug discovery and development and the significant financial risks involved in the process. The process of de novo drug discovery and development typically takes 10–17 years from idea to market, and the probability of success is lower than 10%.

Lately, Artificial Intelligence is helping in efficacy and efficiency across all areas of multi-omics. (more about this later)

In summary, drug discovery is a complex and challenging process. Overcoming these challenges will require a combination of innovative technologies, increased collaboration across disciplines, and a greater focus on patient needs and outcomes. By addressing these challenges, drug developers can improve the chances of developing effective and safe drugs for nervous system disorders.