To increase the success rate of drug discovery

In Japan, it takes a very long time for a single drug to be developed, and the success rate of drug development is declining year by year. In recent years, the success rate from compound screening (discovery phase) to approval has fallen to about "1 in 22,000 to 1 in 31,000."

This article summarizes the success rates and high drop-out rates by process in new drug development, and the key to drug discovery success rates.

Success rates by development process

Here is the success rate for each development process. The table below shows the average next phase transition rate.

*The overall success rate from the start of clinical trials to approval is 13%

Reasons for the high drop rate in Phase II

From the table above, we can see that the drop-out rate in Phase II is high. For this stage, reasons cited include "the efficacy observed in animal experiments (non-clinical trials) was not reproduced in the human disease environment (= translational gap)" in Phase II (studies involving a small number of patients). In this way, drop-outs can occur in each process due to various factors.

Causes of drops in each process

From 1991 to 2000 (and even up to the present), challenges in pharmacokinetics (PK) have been overcome with advanced technologies such as high-precision bioanalysis. However, the barrier of "efficacy" still remains and is a cause for dropouts.

Lack of efficacy

"Lack of efficacy" refers to a situation where the expected therapeutic effect in a patient cannot be confirmed. The dropout rate due to this reason showed little change for about 10 years from 1991 and was reported as one of the major reasons for discontinuation in 2000.

Safety concerns in the clinical stage

"Safety concerns during the clinical phase" refer to cases where a trial was discontinued due to concerns that unacceptable adverse events would occur if the drug were administered to humans (healthy adults or patients). As of 1991, the discontinuation rate was approximately 10%, and by 2000, it had risen to slightly over 10%.

Toxicity issues

"Toxicity issues" are primarily identified during the nonclinical phase (animal testing). For example, organ damage, genotoxicity, and carcinogenicity—which pose serious risks to survival and health—are common causes of program termination. The termination rate due to these causes was approximately 10.1% in 1991, but had increased to about 20.1% by 2000.

Pharmacokinetics / Bioavailability

"Pharmacokinetics/Bioavailability" refers to situations where a drug is not sufficiently absorbed into the body or does not reach the target tissue after administration, or where its effects do not last because it is metabolized or excreted too quickly. As of 1991, the dropout rate was approximately 40.1%, making it the primary cause of dropout at that time. By 2000, this rate had fallen to less than 10.1%, representing a significant improvement.

Formulation and prescription issues

Even if a substance (active pharmaceutical ingredient) is excellent in its own right, there are cases where it is dropped due to “formulation and dosage form issues.” This refers to situations where it is difficult to process and store the substance stably in the form of a pharmaceutical product, such as an injection or tablet. While the drop rate was nearly 0% in 1991, it had risen to approximately 51% by 2000.

Rising manufacturing costs (cost of sales)

"Soaring manufacturing costs (cost of goods sold)" refers to a situation where the costs associated with manufacturing a drug—such as raw material expenses and the complexity of the manufacturing process—are deemed too high, making it impossible to secure a profit once the drug is released to the market. The drop rate was nearly 0.1% in 1991, but by 2000, it had risen to just under 10.1%.

Decline in commercial value (loss of marketability)

This refers to cases where competitors release superior new drugs before a company can launch its own, or where management decides it cannot recoup massive investments because the market size turned out to be smaller than anticipated.As for the causes of this, the dropout rate, which was approximately 51% in 1991, increased significantly to about 20% by 2000.

Overcoming the "Translational Gap" Key to Drug Discovery Success

Obtaining data with a high efficacy barrier and a small translational gap can improve the success rate of drug discovery, leading to time savings and avoidance of losses.

One of the causes of the translational gap is said to be the "limitations of animal models." Even if dramatic effects are observed in preclinical studies, there are four definitive biological and anatomical gaps that explain why these effects are not reproduced in humans. The four gaps are explained below.

[Anatomy/Target Factor] Dissociation of Receptor and Signal Structure Due to Species Difference

First, there are "differences in receptors and signaling structures due to species differences." In some cases, even if an inhibitor shows a strong effect in animals, it may not sufficiently bind to human receptors, resulting in a lack of expected efficacy in clinical trials.

This is because even a slight difference in the molecular structure of the target receptor or signaling molecules between humans and animals can result in a critical difference in a drug’s binding affinity—that is, its “effectiveness.”

【Metabolism/Physiology】 Presence or absence of active metabolites due to interspecies differences in pharmacokinetic pathways (ADME)

Another gap is the "presence of active metabolites due to species differences in pharmacokinetic pathways (ADME)." For example, even if a "metabolite" produced in the body of an animal was primarily responsible for the drug's efficacy, there are cases where the expected efficacy in the clinical stage is hard to achieve because that metabolite is hardly formed in humans.

Such gaps occur because the activity of drug-metabolizing enzymes (such as CYPs) and the metabolic pathways themselves differ significantly between animals and humans.

[Pathophysiology] Artificially created "acute, simple models" and
Dissociation in Human Chronic and Complex Diseases

Many animal models are simple models where pathology is artificially induced over a short period through specific feeders or drug administration, or genetic manipulation. Therefore, a gap arises between "artificially created acute, simple models" and "human chronic, complex diseases."

For example, human MASH is a complex chronic disease that progresses over decades in the background of lifestyle-related diseases such as diabetes and dyslipidemia, manifesting as "fat deposition," "inflammation," and "fibrosis." Simple mouse models that merely accumulate fat in a short period may not adequately reflect drug accessibility to highly advanced fibrotic tissue seen in humans or the long-term inflammatory signals that develop.

[Immunology] Immunological immaturity due to the rearing environment (SPF environment)

The experimental animals used in tests are raised in an extremely clean SPF (Specific Pathogen-Free) environment in a near-sterile condition, which results in their immune systems being very immature and uniform.

Compared to humans (actual patients), who are exposed to various environmental factors and commensal bacteria and exhibit significant individual differences, animal models can be said to have an overly simplified immune response. This difference in "immune system reality" is the biggest reason for the lack of efficacy (dropout) in Phase II, especially in diseases like MASH where immune cells cause chronic inflammation leading to fibrosis.

Bridge the translational gap
Approaches to obtaining "human-like data" in non-clinical studies

Specifically, to avoid dropouts in Phase II, the key is to obtain data that closely mimics the human biological environment in the early non-clinical stages. To increase the success rate of drug discovery, it is important to proceed with verification of "three approaches" at the non-clinical trial stage. Furthermore, strategically selecting CROs according to the research content can be effective in properly advancing non-clinical trials.

Here are three checkpoints for your reference.

1. [Verification of Efficacy] Is it an "advanced disease model" with a proven correlation to human pathological conditions?

Confirming "whether it is an advanced disease model" is an approach to bridge the "discrepancy between artificial models and human chronic diseases" that causes the translational gap. Instead of catalog models that simply show fat accumulation or temporary inflammation, it is essential to select advanced models that can faithfully reproduce the human disease progression timeline and tissue structure.

Specific checkpoints include the following:

• Is a parallel evaluation with clinical data possible?
  For the MASH domain, the key points are whether scientific verification has been conducted on the correlation with clinical diagnostic criteria such as "NAS (NAFLD Activity Score)" and "fibrosis stage (Stage 0-4)," and gene expression patterns.
• Check the accumulated amount of background data.
  Focus on whether the CRO possesses a historical data foundation that can suppress data variability due to bait composition and animal age, thereby ensuring stable reproducibility.

2. Extrapolation to Humans: Using Human Cells
Are you combining 3D tissue models (organoids/MPS)?

The confirmation of whether 3D tissue models (organoids and MPS) using human cells are being combined can be considered an approach to completely eliminate the gap caused by "species differences." This technology utilizes methods that can replicate "three-dimensional interactions between cells and the microenvironment," which were impossible with conventional 2D cell cultures.

Specific checkpoints include the following:

• Are biomimetic systems (MPS) being introduced?
  To confirm whether a screening system using "3D organoids" created from human iPS cells and patient-derived cells, or "Organ-on-a-chip" which can mimic blood flow and physical stimulation on a chip, is available.

3. Visualize Internal Dynamics: Capture "Intra-organizational PK/PD"
Is there high-precision bioanalysis technology?

This is an approach to visualize drug accessibility to target organizations and cells. Simply measuring blood drug concentrations (conventional PK) cannot determine whether a drug has penetrated deeply into diseased tissues that are highly degenerated or organized. Therefore, there is a need for technology that can proactively eliminate "uneven efficacy" in clinical practice.

Specific checkpoints are as follows:

• Microscopic imaging technology
  To confirm that there are means to quantify drug analysis in fine compartments within organs, such as "Mass Spectrometry Imaging (MSI)" and "3D imaging using tissue clearing techniques."
• PK/PD analysis with a clinical perspective
  Confirm that we have the analytical power to strictly profile the correlation between the behavior of cells at the tissue level and drug efficacy (tissue PK/PD), without relying solely on blood data.

Conclusion: Improving drug discovery success rates depends on selecting "strategic partners."

Currently, the success rate in drug development has fallen to between 1 in 20,000 and 1 in 30,000. In modern times, where "lack of efficacy" accounts for more than half of the reasons for dropout, the era of choosing a CRO solely based on criteria such as "low price" and "conducts studies as instructed" is over.

What's important is to choose a partner with whom you can discuss advanced approaches tailored to the modality of your company's candidate compounds and the characteristics of the target diseases, such as "chronic," "acute," or "immune-mediated," and thereby optimize the trial design.

Supervisor Introductions

Yuichiro Eguchi, MD, PhD

Locomedical Medical Corporation Locomedical Vice Chairman, Locomedical Research Institute Director.

After graduating from Saga Medical University in 1994, he joined the Department of Internal Medicine at the same university. He served as an assistant in the Department of Gastroenterology and Hepatology at Saitama Medical University and as an assistant in the Department of Internal Medicine at Saga University Faculty of Medicine before being appointed as a lecturer in the Department of General Medicine at Saga University in 2010. From 2012 to 2021, he served as a professor of Hepatology Support and Director of the Center for Liver Diseases at Saga University Hospital.

Currently serving as Vice Chairman of Rocomedical Medical Corporation and Director of the Rocomedical Integrated Research Institute, I am involved in clinical research and support for research in the medical field.

Served as a councilor for the Japan Society of Hepatology, the Japan Society of Gastroenterology, and the Japan Society for the Study of Obesity. Special advisor for NHK Educational's "Choice @ When You Get Sick."

Specialties include viral hepatitis and non-alcoholic fatty liver disease (NAFLD/NASH).

Roco Medical Corporation