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First In Human: AbbVie encourages risk-taking; man vs. mouse; 1st CRISPR trials

This is a recurring column on clinical research in the early stages of development, what is referred to as phase 1. These are treatments that are being used for the first time in a small number of human patients to determine safety, dosing and general pharmacological activity.

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Calculated risk in AbbVie's early-stage research

For a large pharmaceutical company like Chicago's AbbVie Inc., early-stage research is a place to take risks and stay focused on the science and patients, AbbVie Chief Scientific Officer and Senior Vice President of R&D Tom Hudson told S&P Global Market Intelligence.

According to a study published in the journal Biostatistics in April, only an estimated 13.8% of all drug development programs eventually lead to approval, and early-stage development represents the highest risk of failure.

"Our scientists know that transformative leaps often require taking risks," Hudson said in an email. "AbbVie provides an environment where risk-taking is encouraged, even if this may lead to setbacks."

Moving from preclinical testing to human trials requires consideration of the risk and potential benefit, and learning from past failures and successes is critical, Hudson said.

"When conducting clinical trials, what we are trying to do is prove that a certain regimen is better for patients when compared to another — is A better than B?" Hudson said. "However, what is sometimes more important to understand is the why — why is A better than B? Why did a study fail when preclinical data clearly showed a benefit?"

Hudson said translational science — which applies clinical observations to drug development — has helped AbbVie understand a therapy's activity during a trial, as well as why some approaches work better than others. This way they can see clearly, at an earlier time, when a study is not working.

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AbbVie Chief Scientific Officer and Senior Vice President of R&D Tom Hudson

Source: AbbVie

Biomarkers, which are measurable indications of a disease or condition in a specific patient, also provide crucial information about the success or failure of a certain treatment.

"If we do not instantly see the validation of the mechanism, we are able to have the insights to stop the trial and dig deeper into why something did not work," Hudson said.

AbbVie has several ongoing early-stage cancer studies that explore various approaches such as regulated cell death, tumor-specific antigen targeting and immuno-oncology, among others, Hudson said.

"The biology tells us there are many suppressing mechanisms in different types of tumors, and that's why we're exploring a number of assets targeting the tumor microenvironment, several of which are first-in-class," Hudson said.

One such program AbbVie is conducting is a phase 1 clinical trial of its treatment dubbed ABBV-621, which is a TNF-related apoptosis-inducing ligand, or TRAIL-receptor agonist, for patients with tumors both solid and blood-related. The drug is first in its class of second-generation TRAIL-receptor agonists, which induce cell death in tumors.

In early results from the study released in May, the treatment was effective against tumors and within the threshold for safety, which are key components of a phase 1 study.

"Our pipeline is very dynamic in the early stages, especially in oncology," Hudson said. "Today, we have a deeper understanding of the underlying biologies that help us determine quickly which areas are the most promising to study."

Hudson said AbbVie aims to have its scientists working on unmet medical needs while avoiding thoughts about the endgame of commercial value.

"We have a culture in our R&D organization where our early discovery scientists are never asked to put a value on a particular area of research — unless we're talking about the value to patients," Hudson said.

From mouse to man, results differ

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Brain cells in mice appear to be the same as humans, but successes in animal tests do not always translate to clinical trials because of fundamental differences.

Source: The Associated Press

Moving a treatment from animal studies to human studies can have surprising results — often what worked in mice may be ineffective in humans, and a study published in August in the journal Nature suggested that there is a reason brain studies, specifically, do not always translate.

The study showed that the mouse and human species have diverged in gene expression at the level of single genes and the overall cell structure, even if on the surface brain function appears similar.

So while treatments for Alzheimer's disease or brain cancer can show promising results in mice by taking advantage of certain pathways, those pathways may not be as prevalent in humans, the study said.

The authors of the study concluded that to develop treatments for human brain diseases, a better understanding of the human brain and its differences from those of animals is crucial.

"[T]hese results help to resolve the paradox of failures in the use of mouse for preclinical studies despite conserved structure across mammals, and highlight the need to analyze the human brain in addition to model organisms," the study said.

CRISPR's entry into human trials

The question of early-stage human research is nowhere more contentious than around the gene-editing technique CRISPR, which has now entered human trials in the U.S. for the first time through a phase 1 study conducted by the University of Pennsylvania.

According to the registration with the U.S. Food and Drug Administration, the trial's leaders expect to treat 18 patients with multiple myeloma, melanoma and certain types of sarcoma.

CRISPR's use in humans has been a hotbed of ethical concerns, particularly after a scientist in China claimed to have created the world's first genetically edited babies, leading to his ousting from the university where he worked.