Discovering and Developing Drugs:
The CF Foundation Way

Robert J. Beall

Many readers of the CFW Newsletter may already know that the U.S. cystic fibrosis (CF) community has an active CF drug development ‘pipeline’ to bring new therapies to people with CF, safely and quickly. Finding new drugs is a dynamic process that is constantly “on the move.” In many ways, so is the U.S. CF Foundation—we spearheaded groups of outstanding scientists over the years to anticipate and apply the cutting edge technologies needed to make advances in CF. Today, we have built the ‘infrastructure’ to set the pipeline in place and important candidate drugs are moving along.

Let me first emphasize that it is clearly the individuals with CF who are partners in this research and the pivotal contributing factor in CF drug development. A robust drug development pipeline may be churning out exciting new therapies, but clinical research would grind to a halt if there were not enough patient volunteers. My hope is that this article will generate enthusiasm for clinical studies, lay the path to success and serve as a ‘call to arms’ for volunteers to help cure this disease.

Setting the ‘Bar’ High
When our organization created the Therapeutics Development Program, we wanted to bring new therapies to the CF community in half the time and at a much lower cost than is commonly reported by the biopharmaceutical industry. The typical ‘industry’ (biopharmaceutical) timeline for identifying a potential compound, developing that into a drug-like substance, performing laboratory safety studies and then conducting clinical trials, is about 14 years. And the price tag can be a jolting $500-800 million per drug. These may be the industry standards, but the CF Foundation vowed to take an entrepreneurial approach that could defy the odds.

“Getting companies to be interested in CF is not easy…”

Forbes Magazine has described our foundation as a “virtual biotech company.” It is virtual in the sense that the CF Foundation does not build the high-tech laboratories, brick by brick, to discover compounds or develop them, but rather, taps biopharmaceutical industry leaders to apply what they have to CF. Getting companies to be interested in CF is not easy because the relatively small CF patient population of 30,000 (in the United States) and 80,000 worldwide does not offer a large return on their financial investment. Therefore, the CF Foundation strives to attract these companies by offering some unique, time and money saving resources.

Resources Galore
Through the Therapeutics Development Program, we provide ‘matching funds’ to biopharmaceutical companies to pursue the discovery and development of CF drugs. In other words, “If you invest in a new CF drug, we will match that investment dollar for dollar.” Further, as the study is being designed, the CF Foundation offers access to leaders in CF research and care and a Blue-Ribbon scientific advisory panel that provides ideas and feedback throughout the project. We also monitor progress through agreed-upon ‘milestones’ that must be met before the next payment is given. Not only does this ensure progress is made, but it also protects our investment in the long run by not chasing drugs that will

Expediting CF Clinical Trials
When a new CF drug successfully moves through the laboratory studies (including proof of concept and safety, and the ability to produce enough of the drug), and is approved for human trials by the Food and Drug Administration (FDA), researchers have the opportunity to use our Therapeutics Development Network (TDN). This specially-trained network of CF care centers, coordinated by the CF center at Children’s Hospital and Regional Medical Center in Seattle, uses the latest clinical research tools to quickly assess the safety and efficacy of a new CF drug. Before the network was established in 1998, drug companies had to identify CF care centers one by one to participate in a given study and then provide training to each. This cost precious time and effort—the TDN alleviates this problem.

“These trials are considered to hold more risk…”

Most of the TDN studies have focused on Phase I and II clinical trials. These trials are considered to hold more risk because this is usually the first time the drug has been examined in CF patients. The TDN has safeguards in place, including a data safety monitoring board and CF experts to observe patients’ health and take steps to alter or halt a trial if necessary. Ideally, the CF Foundation’s support of these early phases will encourage large drug companies to fund the much more expensive Phase III trials.

The TDN began with eight core centers and was recently expanded to 18 to accommodate demand—a sure sign of its potential. This model system has been heralded by the U.S. Congress and federal agencies as an idea that works! Moreover, if imitation is the sincerest form of flattery, we should be flattered that other disease groups are following our lead by establishing their own networks of clinical trial sites.

Laying the Pipeline Through Knowledge
In the 1980s, we lacked sufficient knowledge about the basic science underlying CF to suggest innovative therapies. Now, after years of CF Foundation support, new research technologies, and the incredible efforts of scientists from many diverse fields, we have gained a solid foothold on CF. The knowledge base grew particularly fast after the CF gene was discovered in 1989 by a team of CF Foundation-supported scientists. We now understand the CF gene and its protein product CFTR, what CFTR should be doing in cells and what goes wrong in CF cells. Understanding this very complex process has pointed the way to a host of new approaches to CF therapies.

Identifying ‘Targets’ to Fuel the Pipeline
There are three basic ways for CF researchers to uncover new compounds that might pan out to be effective CF therapeutics. One method is high-throughput screening. The CF Foundation has committed millions of research dollars in this approach that takes advantage of rapid technology and robotics to discover new molecular compounds. Once discovered, these compounds enter the drug development pipeline to be examined. The second method involves traditional drug discovery which we continue to support, and a third method uses what we call “low hanging fruit” to identify potential new CF drugs.

Screening Compounds by the Millions: A New Avenue
Research has revealed that CFTR, which acts as a chloride channel, is defective in CF cells. This faulty channel in the cell membrane traps chloride inside the cells and draws excess sodium into cells. It results in thick, sticky mucus—the hallmark of many aspects of CF. Fortunately, our better understanding of the disease process now permits scientists to

Recently, researchers reported that after screening millions of compounds, they had discovered approximately 10 innovative “candidate” chemical compounds that appear to correct the defective movement of chloride in CF cells. Scientists in the field have told us that this is a very good ‘yield’ in terms of candidates. Research is exploring these promising compounds more closely to identify their usefulness. It is important to note that these compounds would not have been identified so quickly as potential CF drugs if we had relied on the conventional drug discovery process.

Making a Difference Through Traditional Methods
Traditional drug discovery is based upon in-depth knowledge of a particular biological process and carefully planned experiments to tease out chemical compounds that steer the biological studies toward the desired goal of treating CF. This has been the mainstay of biopharmaceutical companies and the CF Foundation for many years and has yielded drugs currently in clinical trials for CF. (More on these later.)

Harvesting Fruit

How Long Will It Take: A History Lesson
Every new CF drug has a history of its own. So generalizing a timeframe as to how long it takes from when a scientist first gets the idea to when the drug reaches the market is next to impossible. As described earlier, some compounds are developed first in the lab specifically to correct CF cells; these compounds must travel through extensive steps to test safety and efficacy. They enter the ‘classic’ pipeline and ideally, leave the other end of the pipeline—the drugstore—for CF in 7-8 years (half the industry average.) Drugs that have been on the market for another disease but might yet prove useful for CF go through fewer ‘hoops’ in terms of regulatory review. In the azithromycin case, it took less than two years to harvest this low-hanging fruit.

“…when the proverbial light bulb goes off in the scientist’s head.”

What has our past told us? The first drug developed specifically for CF was Pulmozyme® (DNase), approved by the FDA in 1993. In the ‘70s, scientists discovered that bovine (cow) DNase was a mucus thinner by cutting DNA. This could be called the “Eureka Moment”—when the proverbial light bulb goes off in the scientist’s head. Unfortunately, the animal enzyme caused an immune response in people; the idea was put on hold. Then in the late 80s, technology became available to clone human DNase. This enzyme also cut DNA in mucus, but did not cause an immune response in people. From that point on, the drug was developed and sailed through large clinical trials in about four years. Although the basic concept was percolating all along, the gestation period, so to speak, was close to 17 years. So calculating how long a drug takes to develop, of course, all depends on when you want the clock to start.

Another drug that has become a mainstay in the CF drug arsenal is TOBI ®. Tobramycin, an antibiotic, had been used in intravenous form to treat CF lung infections. Research to refine the drug to TOBI, an aerosol form, required seven years of effort and CF Foundation support. This was the first time that an antibiotic had been aerosolized to treat the lungs.

“…the time and effort spent in clinical trials is never wasted…”

Over the years, CF drugs have been evaluated in clinical trials with very different results. Some stall in Phase I or II, while others end up in the medicine chest. What is important to remember is that the time and effort spent in clinical trials is never wasted; most often, results from one trial pave the way for a new generation of drugs to evolve. For example, about 10 years ago, amiloride appeared to be a drug that could block excess sodium from entering CF cells. Although the effects were positive, the drug was metabolized by the body too fast. Therefore, amiloride was reconsidered, but the idea behind its use persisted. Today, Parion Corporation, in conjunction with Dr. Richard Boucher, a luminary in CF research, is focusing on new types of sodium channel blockers.

Paving the Way
The FDA serves as a gatekeeper, ensuring that only safe and effective drugs are allowed on the U.S. market. By establishing an excellent working relationship with the FDA, through invitations to CF Foundation meetings and workshops, we capture FDA input to ensure that clinical trials are designed to evaluate what is important to federal regulators. The efficiency of Pulmozyme’s development is often cited as a benchmark for how smooth the process can be.

Targets, Targets and More Targets
The words “genomics” and “proteomics” have become familiar as the next biomedical frontiers about how to cure human disease. These technologies help to identify genes and proteins that affect disease processes. By identifying the genes and proteins necessary to cause disease, the scientific community is revealing the targets for new drugs in the 21st century.

There was much publicity in 2000 when scientists divulged the fact that a crude copy of the human genome (the genetic instructions that go into making a person), had been mapped. Even though the CF gene had been identified more than a decade earlier, this human genome map helps to identify modifier genes—genes that when coupled with the CF gene, can determine the disease’s severity and progression.

“…the entire Pseudomonas genome has been encoded on a microchip about the size of a postage stamp…”

While some were focused on the human genome, other scientists were describing the genome of the bacterium, Pseudomonas aeruginosa. This is by far the most common cause of chronic bacterial infection found in CF lungs. Support from the CF Foundation, this time joined by the University of Washington and PathoGenesis Corp. (now Chiron Corp.) drove a collaborative effort to map this organism’s DNA, which was published in the journal Nature in 2000. Since then, the entire Pseudomonas genome has been encoded on a microchip about the size of a postage stamp, allowing researchers around the world the opportunity to tease out vital information about Pseudomonas’ biology. For instance, by finding the exact genes that turn on to help the organism attach to lung cells in the first place, or to morph into an antibiotic-resistant bug, scientists may design drugs to disable the organism.

“…doctors may be able to predict the onset of a pulmonary exacerbation before it occurs.”

Proteins interact with each other in cells to carry out functions critical to life. However, these same proteins can interact in nonproductive ways resulting in disease. Scientists in Australia, Canada, the United Kingdom and the U.S., supported by the CF Foundation, are exploiting proteomics technology to identify proteins and describe their function in relation to CF. Some of these researchers are studying the relationship between the CFTR protein and other proteins in the cell while others are examining the development of biomarkers of CF lung disease. Identifying those proteins that interact with malfunctioning CFTR opens up the possibility of designing tests to see if these diseases causing protein to protein interactions can be corrected by drugs. A biomarker, on the other hand, holds the promise of making the clinical trials process more efficient and potentially the delivery of CF healthcare more timely. In other words, clinical trials may not need to depend upon measurements of pulmonary function as an outcome and CF doctors may be able to predict the onset of a pulmonary exacerbation before it occurs.

Raising the Bar
The CF Foundation is always seeking new ways to shape the process of drug discovery and development so that we shorten the time required (and the dollars needed) to develop new therapies. Our watchwords are: safety, success and speed. Despite successes in CF research, we recognize that the pace will never be fast enough for those battling this disease.

“You never know what drug will unlock the secret to curing this disease.”

As I’ve tried to describe, the CF Foundation is pursuing several different strategies to find a cure for CF. We have committed more than $131 million in a five year period in science that uses the latest technology to discover new CF-specific drugs and potential targets for future drugs. The opportunities to cure this disease keep growing by leaps and bounds. You never know what drug will unlock the secret to curing this disease.

We are fortunate to have many possible avenues before us to try to cure CF. As a result of the steady science, a rate-limiting factor is the participation of patients in clinical trials. In order to examine new drug candidates, we must bring these drugs into the pipeline, and see if they work in patients.

If you look for what has led to the many successes made by the CF research community, be it in the clinic or in the lab, you will discover that the key has been to combine the ‘right’ people in the right place, time and again! Today, for us to succeed in curing this disease, we need patients to be in the ‘right places’ at the right time—volunteering for clinical trials. As more and more patients partner with researchers, innovative new CF therapies will have the power to move robustly ahead!

Robert J. Beall, Ph.D.
President and CEO of the Cystic Fibrosis Foundation
Bethesda
MD
USA

Editor’s Note: For information on the latest in CF clinical trials, or on how you can participate (if you are in the USA), contact the CF Foundation at 800 FIGHT CF, or visit its Web site: www.cff.org.

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