One of the great stories of drug discovery in the recent past is that for treatment of the genetic disease cystic fibrosis. That story follows. The tale is a bit long but then so is the road to novel therapies that benefit people everywhere.

Getting this story together right was greatly assisted by several of the people directly involved in the drug discovery work: Mark Murcko, Paul Negulescu, Melissa Ashlock, and Eric Olson. My thanks to all.

I originally wrote this story a couple of years ago. Some things may have changed a bit since then but the story is accurate at the time.

Kalydeco and Its

Successors

“Alex barely lived eight years. That’s not long at all. Why, looking back, it seems that it took her much longer than that just to die. The dying seemed to take forever. But still, even for all that, for all the time I had to prepare myself, when the end finally came, I wouldn’t let it. At the last, I denied that Alex could die. We knew she was going to die, knew she had to, knew there was no hope, even knew it was best. But still, I started telling myself that it was a couple of weeks away.”

Those are the words with which the late Frank Deford, sportswriter and novelist, opens his memoir: “Alex, the life of a child”. Alex is Alexandra Deford, daughter of Frank and Carol. Alex was a remarkable young child: pretty, flirtatious, social, kind, loving, mature beyond her years, and courageous. Alex was not well and was not going to get well. As her health failed, these are the anguished thoughts of her father: “I suppose that is why, if it is just a matter of keeping her alive, I would be hard-pressed to want her to struggle on. Or am I only being selfish when I think that? Do I just want this awful thing to be resolved so that I can drive a car without crying again, so that I can have some peace, so that I can get on with my life? I don’t know. God, I don’t. I only know one thing for sure. That we have had this extraordinary little creature with us for seven years of joy, and I fear that it must be all diminishing returns from here on in. I think it would be best for God to take her now, while she can still believe in the tooth fairy.”

Alexandra Deford died In January, 1980 at the age of eight. She had cystic fibrosis. It killed her before she had the opportunity to explore the fruits of her imagination or pursue her dreams.

In 1980, there was little hope for victims of cystic fibrosis. The underlying cause of the disease was unknown. There was no life-saving therapy. Treatment consisted in part of physical manipulations: a partner pounding on chest, sides and back while inverted, designed to free the thick mucus that lined the airways of the lungs. Alex Deford referred to this treatment as “my therapy” and dreaded it. Antibiotics to fight persistent lung infections and dietary supplementation with digestive enzymes to offset an ineffective pancreas completed the array of therapeutic options.

Thanks to insights gained from basic scientific research, the efforts of chemists and biologists in the pharmaceutical industry, and financial support from the National Institutes of Health and the Cystic Fibrosis Foundation, that has changed. The change has been a long time coming but it is here and it is dramatic.

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Cystic fibrosis is a progressive, unrelenting, incapacitating, and ultimately fatal disease. About 70,000 people have cystic fibrosis in North America and Europe; of these, about 30,000 reside in the United States. Cystic fibrosis is a genetic disease. The involved gene, CFTR, that codes for a protein known as the cystic fibrosis transmembrane regulator, CFTR, is defective in the genome of both parents of cystic fibrosis (CF) victims. Each parent carries one normal and one defective CFTR gene copy. A child of such parents has a one in four probability of being born with CF. Alex’s older brother Chris is free of the disease. Alex was not so fortunate.

Carriers of CF, who have one intact and one defective gene, are not victims of the disease. They are silent carriers of CF. There are about ten million of them in the United States. Save for a family history of CF or genetic testing, silent carriers will not be aware of their potential to have children with CF.

In the United States, all newborns are tested for a panel of diseases including CF. All include a measure of a protein known as immunoreactive trypsinogen, IRT, in a blood sample of the newborn. A result suggestive of CF is followed up by a sweat test, the gold standard for diagnosis of CF. The sweat of CF victims is unusually salty, having an excess of sodium chloride. That test may confirm the diagnosis of CF.

Dr. Dorothy Hansine Andersen identified CF as a disease in 1935. A graduate of the Johns Hopkins School of Medicine, she was a pathologist and pediatrician at Babies Hospital at Columbia University in New York City. She developed a diagnostic test for CF and was the first to treat CF children with pancreatic enzymes. She was highly honored for her breakthrough achievements.

Cystic fibrosis affects many of the tissues and organs of the human body. Symptoms result from the accumulation of thick mucus in tissues. Mucus is a slippery natural secretion that is protective of tissues. In CF, the mucus is markedly thickened: a thin syrup is replaced by molasses. In the lung, accumulation of thick mucus impedes the action of the cilia, waving organelles that act to clear the lungs of mucus and bacteria. Accumulation of mucus in the airways provides a fertile environment for bacterial growth. The consequences include persistent coughing, wheezing and shortness of breath, inflammation, infections, and progressively declining lung function eventually leading to respiratory failure. In the pancreas, thick mucus inhibits the release of digestive enzymes into the gut leading to food malabsorption. The result is failure to thrive, malnutrition, and poor growth.

The most damaging effects of CF occur in the lungs. Lung pathology usually leads to death in CF patients. Drug candidates having potential for use in CF are evaluated in clinical trials by assays that reflect activity in the lung. Activity to reduce deficits in lung function is key to drug approval.

For many years, treatment of CF patients focused on symptoms, not the underlying cause of the disease: agents such as Pulmozyme to soften the mucus in the lung, antibiotics including aerosolized tobramycin and azithromycin to combat lung infections, replacements for inadequate levels of digestive enzymes, vitamin supplementation, and physical manipulations to loosen lung mucus.

Symptomatic treatment innovations have had a positive effect on life expectancy for CF patients. In the 1980s, about half of all CF patients died in their teens. For patients born in 1995, estimated life expectancy was 31 years. For those born in 2006, 37 years. But CF remains a dreadful disease with a shortened life expectancy and a diminished quality of life.

Remarkably, advances in biomedical sciences have now delivered a series of drugs that attack cystic fibrosis at its foundation: the variant CFTR gene and its CFTR protein. That story follows.

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We need to get a sense for the CFTR, a rather large protein molecule. CFTR is a composed of a single chain of 1480 amino acids. The amino acids, which commonly include 20 different ones, are linked one after another to form a chain. Once formed, the CFTR protein then spontaneously wraps up into a complex three-dimensional structure that is essential for its function.

CFTR acts as a channel through which chloride ions may pass across the membrane that surrounds epithelial cells. A defective CFTR limits the transport of chloride ions out of the cell and leads to reabsorption of sodium ions and water. The reabsorption of water dehydrates and thickens the mucus that lines epithelial cells.

Epithelial cells are the interface where self meets non-self. They line the surface of the lung airways where they act to prevent airborne toxins to gain access to the bloodstream while permitting oxygen to enter and carbon dioxide to leave. They line the intestines where they permit nutrients and water to enter the bloodstream while keeping toxins and microbes out. A specialized form of epithelial cells known as endothelial cells line blood vessels where they control what gets from the blood to the tissues and what gets from the tissues into the blood. Epithelial cells include those that secrete digestive enzymes, sweat, tears and saliva. To carry out thier functions, these cells possess a variety of specialized proteins. One of these is CFTR.

CFTR is not a passive channel through which chloride ions may pass but is subject to metabolic controls that open and close the channels as required to meet the needs of the organism. CFTR is a really important protein.

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In publications in the journal Science in 1989, teams led by Francis Collins of the University of Michigan and by John R. Riordan and Lap-Chee Tsui at the Hospital for Sick Children in Toronto revealed the nature of the CF gene and the most common amino acid sequence variant in the CFTR protein underlying CF, known as Phe508del. These breakthroughs were supported in part by the Cystic Fibrosis Foundation, about which more follows later. Riordan and Tsui were awarded the Gairdner Foundation International Award for their work. Francis Collins went on to lead the Human Genome Project and, subsequently, the National Institutes of Health. He has been awarded the National Medal of Science and the Presidential Medal of Freedom.

The gene that codes for the sequence of amino acids in the CFTR protein is a sequence of nucleotides, each bearing one of the four DNA bases – A,T,G,C – about 189,000 long. It is located on the long arm of chromosome 7, precisely at position 7q31.2. The CFTR gene is complex containing 26 regions that code for amino acids in the CFTR protein interrupted by 25 regions that do not. The non-coding regions are spliced out in the process of creating the messenger RNA from which the CFTR protein is translated.

Like all our protein-coding genes, that for CFTR is subject to sequence variations. Variations take several forms: deletions of one or more nucleotides, replacements of one nucleotide by another, duplication of a string of nucleotides, or loss of a string of nucleotides. Such variations have a number of potential consequences for the CFTR protein varying from no protein at all to proteins that are altered one way or another in their amino acid sequence. About 2000 sequence variations in the CFTR gene have been identified with a variety of consequences for the people who bear them. Most variations lead to modestly altered CFTR proteins that are nearly or fully functional. Individuals bearing these proteins are physiologically normal and will likely not know that they have them. Variants that lead to no CFTR protein or CFTR proteins of compromised function are the underlying cause of cystic fibrosis.

About one-half of all CF patients have the Phe508del variation on both copies of the CFTR gene. More than 90% of CF patients have have one or two Phe508del variations in their genome. It takes three nucleotides to code for one amino acid. In the case of this variation, three nucleotides in the CFTR gene that code for the amino acid phenylalanine, abbreviated Phe, at position 508 in the CFTR protein are deleted (identified by the “del” designation). The result is a CFTR protein that is 1479 amino acids in length, missing the Phe at position 508. The remaining amino acid sequence in the CFTR protein is entirely normal. However, the altered protein lacking the single amino acid at position 508 cannot fold properly, does not escape its site of synthesis, and nearly all of it is degraded. Cystic fibrosis is the result.

The much rarer G551D variant in the CFTR gene provides a second example. G is the single letter abbreviation for the amino acid glycine and D is that for the amino acid aspartic acid. (F is the single letter abbreviation for phenylalanine and the Phe508del variation is also designated F508del). In this case, the nucleotide triplet that codes for aspartic acid replaces that for glycine. The altered protein has aspartic acid at position 551 in the chain in place of glycine. This simple, small change in the structure of a large protein yields one that is not fully functional, though it does escape its site of synthesis and makes it way to the epithelial cell membrane. But once there, it fails to act as a fully functional chloride ion channel (sometimes referred to as a rusty gate). It is very rare to possess both copies of the G551D variant In one’s genome. Most of the time, it occurs along with the Phe508del variant or other less common variants.

Not all victims of CF have the same severity of this disease. Patients with variations of the CFTR gene that lead to no CFTR protein, that lead to a protein that cannot escape its site of synthesis, or that cannot find its way to the epithelial cell membrane all have no chloride channel function. Patients with the Phe508del variation fall into this class. In contrast, variations that lead to CFTR proteins that escape their site of synthesis, find their way to the epithelial cell membrane, and have some functional chloride channel activity, though diminished, such as G551D, are in a different class. Victims generally have a less severe form of cystic fibrosis.

This understanding forms the basis for the classification of CFTR proteins generated from variations. Class 1 are those for which no CTFR protein is made. Class 2 includes those in which some CFTR protein is made, fails to fold properly, cannot traffic to the epithelial cell membrane, and is degraded. Classes 3 through 6 are characterized by CFTR proteins that make it to the epithelial cell membrane but, one way or another, are not fully functional: (3) no channel activity due to a failure to respond to regulatory signals to open; (4) diminished channel activity; (5) diminished amount of CFTR protein on the epithelial cell membrane; and (6) unstable CFTR protein that is subject to rapid degradation. The Phe508del variation belongs to Class 2; the G551D variation belongs to Class 3.

Because we each have two CFTR genes, CF patients can have two different variations in two different classes. In that case, they may benefit from a drug developed for one of the variations. They may benefit optimally from a combination of two drugs that treat the two variations. For the small number of CF patients who harbor two Class 1 variations and thus make no CFTR protein, perhaps gene therapy or remodeling of the genome employing the CRISPR/Cas9 editing technology may provide an answer. Drugs cannot.

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An attractive approach to diseases, including CF, that derive from an altered gene is gene therapy. In this case, an intact gene enclosed in a viral genome is delivered to the patient. If the intact gene is expressed, a normal protein is produced and, if it gets to the right place, the problem may be solved. The discovery of the CFTR gene opened the way for gene therapy for CF. Scientists pursued it. In 1990, the New York Times reported: “Scientists have cured cystic fibrosis in the laboratory by inserting a healthy version of the gene that causes the disease, an unexpectedly swift advance that left researchers giddy with delight. The result throws open the door to using human gene therapy to treat the deadly respiratory disorder, the most common fatal genetic ailment in the United States.” Unhappily, the laboratory results did not translate to the clinic (as frequently happens). CF patients developed an immune response to the viral particle carrying the intact gene and that nullified the effort. Perhaps the more recent technology of gene editing will succeed where gene therapy failed. At the time, drug discovery, rather than gene therapy, offered hope for the cystic fibrosis patient.

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To fully appreciate the heavy lift facing drug discovery scientists who work to create drugs effective in treating CF and related diseases, it is useful to understand a bit about how typical small molecule drugs work. In general, they target one of the molecules involved in control of metabolism, those chemical reactions that make or degrade the molecules of life. The may activate or inhibit the action of those control molecules, though inhibition is far more common. Here are a few examples.

The statins – Zocor, Lipitor, Crestor and others – are effective in lowering blood cholesterol levels and reducing the incidence of cardiovascular disease. These drugs inhibit an enzyme that promotes a chemical reaction on the route to cholesterol. The ACE inhibitors – Capoten, Renitec, Prinivil, and others – are an important class of drugs for control of blood pressure. They inhibit an enzyme involved in synthesis of a molecule that contracts the vasculature and retains water, effects that raise blood pressure. Many antibiotics – the penicillins and cephalosporins for example – inhibit enzymes that catalyze reactions involved in the synthesis of bacterial cell walls. These are three examples of out of a large number of drugs that target specific metabolic control molecules. Scientists have created drugs that act in this way for decades, know how to do it, and are very good at doing it. But that experience and knowledge cannot be directly applied to the search for drugs for diseases such as CF. There is no normal metabolic control molecule to inhibit or activate.

The challenge for CF is to discover molecules that will interact with altered CFTR proteins with the consequence that they will gain, rather than inhibit, function and behave like or more nearly like the normal protein. That is, this interaction will form an altered CFTR.drug complex that more nearly has the properties of normal CFTR. Function will be partially or fully restored. To find such drugs is a daunting challenge. Until recently, there were zero examples of such drugs. For CF patients, that has changed and they are far better off for it. Getting from the discovery of the CF gene and the CF protein to such drugs took thirty years.

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The discovery of the CFTR gene and the CFTR protein and their altered forms described above largely depended on basic research support from the National Institutes of Health. These discoveries provided one basic research triumph that opened the door to effective therapy for CF. There are two others.

The second is the outcome of research by Michael J. Welsh and his collaborators at the University of Iowa Medical School in the 1990’s: the characterization of the epithelial cells of the human airways and their relationship to CF. Welsh identified the CFTR protein as a regulated chloride ion channel in airway epithelial cells. His research revealed that expression of the normal CFTR protein in airway epithelial cells that harbor variant CFTR corrects ion channel behavior. Welsh developed continuous epithelial cells lines that harbor variants from normals and CF patients. He expressed the CFTR protein in NIH-3T3 and other cell lines. These proved to be essential tools for evaluation of candidate drug molecules for therapy of CF. This is developed later.

In 1995, three scientists at the University of California, San Diego – Roger Y. Tsien, Charles Zuker, Geoffrey Rosenfeld – and the venture capitalist Kevin Kinsella of Avalon Ventures, founded Aurora Biosciences in San Diego. Aurora Biosciences was a company whose technology platform was founded on the basic research of Tsien, the third basic research triumph underlying therapy for CF. Tsien had discovered a green fluorescent protein in jellyfish and developed a rainbow of colored, fluorescent proteins from it. These have proved invaluable as probes of cellular activity. Tsien also developed a series of dyes sensitive to changes in cellular membrane electrical potential. These were widely used by Aurora scientists in searches for promising drug molecules. Tsien shared the Nobel Prize for Chemistry in 2008.

These tools were used to develop high-throughput assays employed in drug discovery. The likelihood of finding promising molecules with a novel function in compound libraries is often low. Thus, the ability to search rapidly and broadly – thousands of molecules a day – is a key to success. Assays developed at Aurora were automated, robotic, and efficient.

At a time when the Human Genome Project had unleashed an avalanche of potential drug targets on the pharmaceutical industry in the form of newly identified proteins derived from DNA sequences, these assays were very valuable. Aurora marketed them to many pharma houses in exchange for upfront payments, milestone payments, and royalties on products derived from their use. Aurora Biosciences was the industry leader in assay development. It went public in 1997, just two short years after its founding.

The market environment for startup companies can be fickle. By 2000, the market devalued technology platform companies such as Aurora in favor of drug discovery companies. Aurora needed to pivot to become a drug discovery company, a venture in which it had no experience and little expertise. Aurora began by establishing a series of drug discovery projects focused on rare diseases, including cystic fibrosis.

In 2001, Vertex Pharmaceuticals acquired Aurora for $592 million in stock. Vertex was a mid-size, clinical stage, drug discovery company with corporate headquarters in Cambridge MA (now in Boston) founded by Joshua Boger, a Harvard-trained medicinal chemist formerly of Merck, and Kevin Kinsella of Avalon Ventures (same guy) in 1989. The Vertex acquisition of Aurora was motivated largely by the desire to get the drug screening technology and to a much less extent by the drug discovery projects alive at Aurora. Nonetheless, Joshua Boger Chairman and CEO, Vicki Sato, Senior VP and COO, and, later, Peter Mueller, the remarkable head of R&D at Vertex, as well as other Vertex leaders quickly became supportive of the drug discovery efforts at Aurora. As we shall see, the CF drug discovery project proved to be the salvation of Vertex.

Aurora welcomed the acquisition by Vertex: it offered Aurora scientists the opportunity to gain valuable drug discovery and development knowledge and expertise from a company with both. Vertex benefitted from the engineering, problem-solving mindset and expertise at Aurora.

When you acquire a company, you acquire its people (though people have legs and can walk away and people can also be shown the way out). Many of the people who came to Vertex through its acquisition of Aurora played critical roles in the tale that follows: Paul Negulescu and Eric Olson, among host of others. The former was Senior Vice-President of Drug Discovery at Aurora and is now Senior Vice-President and Site Head of Vertex, San Diego Research. The latter was an experienced pharmaceutical biologist lured away from Warner-Lambert who became the Project Executive for the cystic fibrosis project work at Vertex. Eric Olson is now the Chief Scientific Officer at Syros Pharma in Cambridge MA and a member of the Cystic Fibrosis Foundation Advisory Board.

Bringing capable scientists at Aurora up to speed in drug discovery involved a number of scientists at Vertex. Principal among them was Mark Murcko (now the Chief Scientific Officer at Dewpoint Therapeutics) and Roger Tung (now co-founder, President and CEO of Concert Pharmaceuticals), the former the leader of computational chemistry and the latter an experienced medicinal chemist at Vertex. For three years after the Vertex acquisition, Paul Negulescu reputed to Murcko, who made multiple trips between Cambridge and San Diego. Roger Tung simply relocated to San Diego on a permanent basis.

The work of Murcko, Tung and others was effective at weaving the San Diego site into the fabric of Vertex. While no merger of independent organizations in pharma is ever without its issues, that between Aurora and Vertex was as smooth as one could reasonably hope. The outcome of the merger has been remarkably successful. The 3000 mile separation between Cambridge and San Diego may well have been a positive for the merger as it gave the San Diego scientists breathing room from continuous oversight from those at Cambridge. Sometimes a bit of distance can be a good thing.

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The story of revolutionary treatments for CF is one of a fully collaborative effort between Vertex and the Cystic Fibrosis Foundation built on basic scientific research. The CF Foundation, founded in 1955, is a non-profit whose mission “is to cure cystic fibrosis and to provide all people with the disease the opportunity to lead full, productive lives by funding research and drug development, promoting individualized treatment, and ensuring access to high-quality, specialized care”.

Doris Tulcin, a long term, effective advocate for cystic fibrosis patients (and the parent of a CF-afflicted child) and Wynne Sharpless (Ballinger), a pediatrician and CF advocate founded the Cystic Fibrosis Foundation. It has been a highly effective organization in support of its mission: a prolific raiser of funds and a careful steward of them. The Cystic Fibrosis Foundation has funded some of the very best work – basic research and drug discovery – in the cystic fibrosis field.

In the 1960’s, the CF Foundation created a CF Patient Registry, identifying CF patients across the country. The Registry “collects information on the health care status of patients with cystic fibrosis who receive care in CF Foundation accredited care centers and who agree to participate in the Registry … Researchers also use the Patient Registry to study CF treatments and outcomes and aid in the design of CF clinical trials”. This database did indeed facilitate clinical trials of novel candidates for therapy of CF.

Robert Beall moved from the NIH to the CF Foundation in 1980 and served there for 35 years, the final 21 as CEO and President before stepping down at year-end in 2015. Preston Campbell III, a pediatric pulmonologist who had treated CF patients before joining the CF Foundation in 1998 as Executive Vice-President for Medical Affairs, succeeded Beall. Beall has created the Therapeutic Development Program in 1997, an interface between the Foundation and the biotechnology world. That formed the basis for “venture philanthropy” in search of better care for CF patients. The includes the investment in the Vertex drug discovery effort in CF, as well as support for other drug discovery efforts. There are many patient advocacy non-profit groups that work to benefit their patients. They try to emulate the success of the CF Foundation.

Three things came together: (i) the discovery that the CFTR protein functions as a chloride ion channel. (ii) the Aurora high-throughput screening technology; and (iii) the outreach by the CF Foundation to the biotech community.

High-throughput screens in search of molecules that modulate ion channel activity, such as that for CFTR, were hard to come by prior to development of the Aurora technology. It proved ideal for the purpose. Beall attended a presentation of the technology by Roger Tsien in 1998. Beall recognized that the Aurora technology offered a novel approach to therapy for CF: finding molecules that modulated the activity of CFTR. Until then, the CF Foundation had largely focused on gene therapy for CF. A subsequent meeting between Bob Beall, Preston Campbell, and Paul Negulescu in a Red Carpet Club of United Airlines led to a small, pilot project funded by the CF Foundation at Aurora to establish feasibility of Aurora technology for CF drug discovery work. Preston Campbell recalls that: “We were like kids at a candy store with the prospect of screening thousands of molecules a day” in a search for promising ones for CF. Following progress on the pilot project, Aurora pulled together a broader proposal and presented it to the CF Foundation leadership and their advisors near the end of 1999. That proposal was approved in May 2000 with $40 million of funding for Aurora over five years. Aurora was rewarded on a milestone basis, not as fee-for-service. No accomplishments meant that support would go away. That is an example of venture philanthropy.

The Gates Foundation, founded by Bill and Melinda Gates of Microsoft fame, made a $20 million grant to the CF Foundation that, in turn, made a portion of the grant to Aurora. One of the executives at Microsoft was the parent of two children with CF. Whatever the motivation for the Gates Foundation, it proved to be money well-spent.

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While work on therapy for CF was ongoing at Vertex San Diego, Vertex Cambridge was strongly focused on another disease: hepatitis C. This disease is caused by hepatitis C virus (HCV) infections. I served on the Scientific Advisory Board of Vertex for a decade and on the Board of Directors for another six years and was well aware of, and supported, the Vertex focus on HepC. (I have no present affiliation with Vertex and no financial stake in the company).

At the time, Vertex was engaged in two races in the HepC area. The first was with Merck in the search for inhibitors for HCV protease, an enzyme essential for the replication of the HepC virus. The second was with a number of other drug discovery groups that had chosen alternative molecular targets as therapy for Hep C. It was a complex world in which no one known for sure which was then best target or targets and whether one agent would be optimal or if it would take a combination of drugs.

Therapy for Hep C was far from ideal. Victims of this indolent disease had two choices: (i) a 48 week regimen with weekly injections of PEG-interferon, which causes flu-like symptoms, coupled with daily oral ribavirin, with a 45% probability of a cure, or (ii) do nothing. A lot of patients chose the latter alternative. Everyone understood that the goal was to have all-oral therapy for Hep C and nobody was sure what it would take to do that.

Vertex made an ambitious decision in the HCV protease inhibitor effort: to do most of the development work itself and find a way to pay for it. It was far more common for companies the size of Vertex to develop its discoveries in collaboration with larger companies early on, driven by the cost on doing so alone. The costs are considerable, measured in the tens and hundred of millions of dollars. Vertex was a publicly held company and so had access to capital markets to raise funds by issuing stock. Doing so is trickier that it might seem. Issuing stock dilutes the value of earlier investments by driving down the stock price. More shares at the same corporate valuation means less value per share. That tends to irritate those who have invested early and who may own a significant part of the company. If they choose to dump their stock, that would drive the price lower and irritate everybody. Vertex successfully walked the knife edge, repeatedly going to the public market without losing the faith of key investors. However, if Vertex had had to stop something in order to complete development of its HepC protease inhibitors, that thing would almost certainly have been the CF project. That would have been a tragedy for CF patients, for Vertex, and for its investors. The financial support for the CF discovery work by the CF Foundation materially aided in sustaining enthusiasm for it at a time when the company focus was on the Hep C opportunity.

Vertex and Merck basically tied in the race to gain approval for an HCV protease inhibitor: the FDA approved the two drugs on successive days in 2011. The Vertex drug was telaprevir, marketed as Incivek, and proved to be the superior agent. Vertex captured 75% of the market. The launch of Incivek was spectacular: it set a record for time from launch to $1 billion in sales. Incivek was a huge improvement in therapy for Hep C infections: shorter term of therapy coupled with fewer adverse effects and a dramatically improved cure rate.

For two years, Incivek did great in the market place, repaying the faith of its investors, creating opportunities for its employees, and providing funds for other drug discovery projects, including that for CF. Then one day, Vertex went from riches to rags. Results of clinical studies made clear that better drugs, directed at other molecular targets, would prove superior to Incivek. Since Hep C is a very slowly progressing disease, physicians treating these patients simply stopped therapy and awaited the superior drugs. The wait was well-rewarded. A combination drug marketed as Harvoni by Gilead Sciences is something of a marvel: one pill a day for 8-12 weeks cures 99% of the most common form of Hep C infections. It is a triumph of the pharmaceutical industry.

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At the outset of drug discovery, you have to know what you are trying to achieve. Paul Negulescu, who has been doing CF drug discovery for more than 20 years, recalls: “I remember when we were first getting started with our CF research, we were considering various options. During this time, I met a man living with CF who told me: ‘whatever you do, don’t make another inhaled therapy.’ That moment helped me see that we needed to focus on a pill that would treat the underlying cause of the disease.” That became the goal of the work at Vertex.

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Effective collaborations require people on the ground that make it work. Paul Negulescu and Eric Olson were the key people for Vertex, aided by Mark Murcko and Roger Tung. Melissa Ashlock (also known as Melissa Rosenfeld) played that role for the CF Foundation.

Melissa is a physician-scientist who spent several years at the NIH, including a spell in the Pulmonary Branch of the Heart, Lung, and Blood Institute as a Fellow, working on adenoviral therapy for CF lung disease, and in the Human Genome Institute, as an Investigator working on CF and other rare genetic diseases. That brought her to the attention of Bob Beall at a time when the CF Foundation was focused on gene therapy. Melissa had a great background for what the CF Foundation needed. Bob Beall recruited Melissa to the Foundation where she assumed a leadership role in drug discovery and development.

As the promise of gene therapy for CF waned, Melissa reoriented her work and took a leadership role at the interface between the CF Foundation and Aurora in 1999, and Vertex from 2000-2010. Early on she recruited two outstanding medicinal chemists – Jack Chabala and Eric Gordon – as industry savvy consultants to the project and as CF Foundation representatives on the Joint Research Committee (JRC). The late Jack Chabala was a medicinal chemistry leader at Merck for many years. Eric Gordon was a successful medicinal chemist at Squibb and Bristol Myers Squibb, a founder of biotech companies, and currently the cofounder and Chief Scientific Officer at Arixa Pharmaceuticals.

The JRC met quarterly to evaluate progress and review plans. Collaborations in drug discovery usually involve two pharma companies. This collaboration was unusual, perhaps unique, in being one between a pharma company and a patient advocacy organization. This collaboration went smoothly. The commitment and enthusiasm of scientists working in San Diego established trust and the JRC meetings provided for good communications. But the routine interactions among Melissa, Paul, Eric, Roger, and Mark were essential. As Vice-President for Drug Discovery at the Foundation, Melissa also led translational activities with Vertex and clinical investigators in the CF Foundation’s clinical trials network. Eventually, Melissa moved on to become the Head of Translational Research at the Genomics Institute of the Novartis Research Foundation.

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Let’s see how this worked out for the cystic fibrosis drug discovery effort, specifically for the case of the G551D variant in the CFTR gene.

The CFTR protein in the G551D case traffics to the epithelial cell membrane in the lung and forms a chloride ion channel that fails to respond to signals to open: a gating defect. Now imagine a drug that will bind to the variant CFTR protein and, as a consequence, sensitize it to respond to signals to open and close. That being done, chloride ions can flow across the lung epithelial cell membrane when appropriate. And that would be expected to relieve the symptoms of cystic fibrosis in the lung. Basically, the variant CFTR protein would behave like the normal one.

So the goal was clear: find a small molecule that will bind to the variant CFTR protein and induce it to open and close in response to physiological signals. A drug that acts in this way is known as a potentiator. A drug that acts to assist in trafficking the CFTR protein to its site on the epithelial cell membrane is known as a corrector.

At the outset of work at Vertex to find such drugs, there were some precedents. These proved useful as laboratory standards for comparison with test molecules. The natural product genistein, a molecule found in many foods, notably in soybeans, was known to have potentiator activity. This is comforting since it established that such molecules can be found. Genistein, and related molecules, are unsuitable for development as therapeutics for CF: it has low potency, limited specificity, low bioavailability, and a limited duration of action. Far superior agents needed to be found.

Vertex initiated a search for both potentiators and correctors through screening a large library of molecules, roughly half a million. For screening, Vertex scientists used the Aurora screening technology employing NIH-3T3 cells modified to express the Phe508del variant developed by Michael Welsh back in the 1990’s. Fred Van Goor led the biological work at Vertex. This search yielded a family of molecules worthy of further evaluation: such molecules are known as actives. Identification of actives gives chemists a starting point for their work.

Followup work involved the design, synthesis and testing of novel molecules based on the structure of actives found in the initial screen. Peter Grootenhuis led that effort at Vertex San Diego. Sabine Hadida, one of the chemists in the Grootenhuis team notes: “I can remember every single molecule that I made for the past 15 years. Each one has taught me something.” As you learn what works and what does not, your molecules get better for the intended use. You are focusing in on the molecular properties that matter for drugs.

Doing chemistry around the structure of an active molecule is a complex undertaking. The number of potential chemical modifications is immense: millions or billions of possible changes. Chemists form hypotheses around an active molecule based on information from other sources, perhaps structure of the protein or information science approaches, of how it might bind to the target protein. A family of molecules based on the structure of the active is then created, synthesized, and evaluated biologically to test these hypotheses. Results are employed to refine, reject, or create new hypotheses. There is a continual feedback loop between the chemists who design and make molecules and the biologists that test them for desired activities. Over time, better molecules are generally found.

As the molecules become more promising, you need more refined assays to evaluate them critically. One such assay involved donated lungs from CF patients. Tim Neuberger, a biologist, recalls: “In 2004, I held in my hands the first pair of donated lungs from a young CF patient who had passed away just before Christmas. While this child is no longer with us, a part of him is still alive. Even today, 12 years later, we periodically use his cells to test the newest Vertex research compounds, which may one day become a part of the next approved medicine for people with CF. Since we received he first pair of lungs donated to us for CF research, not a day goes by that there isn’t someone in the laboratory looking after the cells taken from them. Working on this program has changed my life. We are so grateful for the contribution of the CF community.”

What Tim Neuberger did not say is that it took two years of research to get resources in place for those lungs and that they arrived in his laboratory on Christmas Eve. Tim worked through Christmas Eve and Christmas Day to preserve that resource for the cystic fibrosis drug discovery effort. Tim Neuberger fits my definition of a drug discovery hero.

Tim Neuberger has worked on close to 60 donated lungs, gathering cells that are used every day in CF research. He has developed a method – now widely used in CF and other types of research – that isolated human bronchial epithelial cells from lungs and expands and differentiates the cells into functional airway epithelium. Monolayer cultures of these cells show impaired salt and water transport, formation of a viscous mucus layer, and defective cilia beating. All these behaviors are characteristic of bronchial epithelial cells in cystic fibrosis patients. In an device known as an Ussing chamber, modified by Vertex engineers to meet assay needs, one can measure chloride ion flow across the epithelium monolayer and observe the mucus layer and cilia beating. Seeing activity for test molecules in this assay would be a cause for excitement.

Bill Burton. a Vertex scientist puts it this way: “The Ussing chamber allows us to test the activity of our compounds in human epithelial cells. It’s like creating lungs in a dish. The first time that we received these kinds of cells from a patient with CF, we couldn’t wait to test to see if there was activity when we added one of our investigational medicines. I had the experiment scheduled for a Thursday. When I came in that day, the lab was a mess. It turns out that Fred Van Goor was so anxious to run the test that he had come in at 1 a.m. and did the experiment! The rest is history as it was first time that we saw activity – the cilia beating and a decrease in mucus. For me, that’s when knew we were doing something special. I knew that I had more than a just a job and a real shot at helping people living with this disease.”

Fred Van Goor: “When I first saw the proof of concept data for our first CF medicine, it was the day that all the science came together. It confirmed that we were on the right path. But I also recognized we had more work to do to bring a medicine to all people with CF”.

The laboratory proof of concept is always a cause for celebration in a drug search. It tells you that the activity that you have been searching for has been found. Having a proof of concept molecule in hand, synthesis continued and the evaluation process broadened to include other necessary attributes in a drug-like molecule: specificity, bioavailability, lifetime in circulation.

As the work continued, a promising molecule was identified that had good potency and very good specificity. In a panel of 60 other molecular targets, this molecule showed only weak activity in three of them. On the other hand, it showed poor bioavailability in rats and a short blood lifetime in dogs. This molecule was designated a lead. Those properties needed to be improved in future molecules by building in new features without losing potency and specificity.

The Ussing chamber assay requires a bit more explanation. in San Diego, there was a 20 person engineering group headed by Minh Vuong (that also reported to Mark Murcko in early days following the acquisition). That group modified existing low-throughput Ussing chamber technology, hopeless for high-throughput screening, into a miniaturized format with improved throughput. This innovation was critical to moving the CF project ahead without loss of time or quality.

Eventually a series of novel molecules built on the lead molecule was discovered to have 300-fold better potency than the original active, 1200-fold better potency than genistein, and 15-fold better potency than the lead molecule. Of these, one, VX-770, showed acceptable bioavailability and a long lifetime in rats. VX-770 showed no activity when tested against 160 other molecular targets: great specificity.

VX-770 was evaluated in human bronchial epithelial cells carrying the G551D variation. It proved ten times more potent in increasing chloride ion secretion compared to its activity in cells having the Phe508del variation. Finally, VX-770 elicited maximum chloride ion secretion in human bronchial epithelial cells bearing one Phe508del and one G551D variation that reached nearly 50% of that for cells from individuals without cystic fibrosis. That established the potential for excellent clinical efficacy. Recall that individuals carrying one normal gene for CFTR are normal. VX-770 was given the generic name ivacaftor and became a clinical candidate.

Along the way to better and better molecules, there is always the one person who first made the clinical candidate, ivacaftor. In this case, that person was the chemist Viji Arumugan working in lab 272 at the San Diego research site of Vertex.

Having discovered a clinical candidate, moving it forward involved a change in sites: the San Diego site had the discovery portfolio; the Cambridge site had that for development. Development includes scaling up the synthetic route (generally reinventing it as well) to provide sufficient material for toxicology, formulation, and clinical studies, and regulatory document preparation. A transition from discovery to development coupled with a transition in site is a recipe for dropped balls, confusion, loss of time.

At Vertex, the movement of the ivacaftor project from discovery to development and from San Diego to Cambridge, was flawless. The credit goes to Eric Olson who packed up himself and his family and moved, of his own volition, from sunny San Diego to not-so-sunny Cambridge. Eric became the Program Executive for the CF project. Eric understood the discovery work leading to ivacaftor and understood the properties of the molecule from his work in San Diego. He carried that understanding to Cambridge with splendid effect. Although work at both sites was critical, as Eric put it to me: “The magic was in San Diego”.

Of preclinical development assays, the most important is detailed safety assessment in several animal species. Searches include those for multiple signs of toxicity including histological study of nearly all tissues. Many clinical candidates fail at this point, revealing toxicities that make them unacceptable for clinical trials in people. This fate did not befall ivacaftor. It has a safety profile suitable for clinical trials.

Ivacaftor had a problem: in crystalline form when given orally it does not escape the gut to reach the systemic circulation. It is not bioavailable. This problem fell into the lap of Patricia “Trish” Hurter (now CEO of Lyndra Therapeutics), head of the formulation group at Vertex, and her team of scientists. She and her colleagues created a formulation of amorphous ivacaftor that was very stable and had good oral bioavailability. This was no small feat as many amorphous preparations tend to crystallize over time. This formulation was suitable for clinical trials.

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With the exception of drugs for cancer, clinical candidates move through trials in the same sequence. Phase 1 trials are safety trials carried out in well individuals beginning with small, single doses and continuing to higher doses and multiple doses as evidence of safety justifies. Clinical candidates for cancer are frequently expected to be toxic to humans and cannot ethically be given to well people. Drug safety is monitored through all phases of clinical trials.

Phase 2A clinical trials focus on safety and signs of activity against the target, CFTR in this case: is there evidence that the potential drug works in patients? If so, Phase 2B clinical trials determine the optimal dose and dose schedule for pivotal Phase 3 trials. Approval by drug regulatory agencies generally requires demonstration of safety and efficacy for the intended indication in two independent Phase 3 clinical trials. These generally involve large numbers of patients, sometimes for extended periods, and are frequently international. They can be devilishly expensive. Since CF is a rare disease, the required Phase 3 clinical trials were limited in scope.

At Vertex, Claudia Ordonez and her team headed the clinical trials for ivacaftor. The agent succeeded in Phase 1 clinical trials, establishing a basic level of patient safety. Would Phase 2 trials reveal clinically useful activity in CF patients as determined by tests of lung function? The clinical data proved highly encouraging: ivacftor worked as hoped. When Preston Campbell saw the results of the Phase 2 clinical trial: “I cried. I knew that we were going to accomplish something”.

Ivacaftor moved to Phase 3 clinical trials. These focused on lung function. The primary measure of lung function is forced expiratory volume in one second: FEV1. FEV1 is the volume of air that you can exhale in one second when you try as hard as you can. Here is a summary of the Phase 3 clinical trials for ivacaftor.

Trial 1 was known as STRIVE, a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of ivacaftor in patients with cystic fibrosis and the G551D CFTR variant. The G551D CF population is the largest one where a potentiator such as ivacaftor would be expected to be effective. Enrolled patients, 167, were 12 years of age or older and had a percent expected FEV1 between 50 and 90%. Drug was administered twice a day for the duration of a 48 week trial. Ivacaftor achieved significant improvements across multiple clinical endpoints in this patient population. These included absolute changes from baseline in FEV1, time to first pulmonary exacerbation, changes in body weight from baseline, and changes in sweat chloride concentration from baseline. In short, ivcaftor worked in these cystic fibrosis patients.

The statistical data that establish safety and efficacy offer one view of clinical trial success. The personal stories of trial participants offer another. Here is the reaction of Chrissy Falletti, a CF patient enrolled in STRIVE, as told by Jerome Groopman, a Harvard University Medical School Professor in a 2009 New Yorker article: “On the Vertex study, I just felt completely different. My sister said she used to know when I entered church because she could hear my cough. Then, when I was on the study, my sister told me, ‘I can’t tell when you come in anymore’ “. Groopman goes on: “Within two weeks her lung function had improved from a baseline of fifty percent to just over sixty percent. She gained almost ten pounds, and after twenty-eight days her lung function had increased by eighteen percent overall”. The clinical trial ended and all patients came off therapy. Within a week, Chrissy’s lung function had begun to decline: “I call the cystic-fibrosis center all the time asking ‘Do you have any news?’ she said, “when you finally feel what normal feels like, you kind of realize it’s not that much fun being your abnormal self’ “.

Trial 2 was known as ENVISION. It was similar in all respects to the STRIVE trial with the exception that enrolled patients were 6 to 11 years old. Results of the ENVISION trial were entirely consistent with those of STRIVE. This was very good news for younger CF patients with the G551D sequence variant in CFTR.

As (the late) Peter Grootenhuis put it: “I remember sitting across from Paul Negulescu as we heard data from the clinical study of our first CF medicine for the first time. At the moment, I looked at Paul and I knew that this was not only great news for the CF community, but a validation of the science. I remember Paul saying to me: ‘sometimes science really works’. And I felt so proud to be a part of this program”. Later, Peter developed ALS, a fatal disease. As his life neared its end, he remarked that his role in the CF effort gave him great comfort.

On the basis of results from STRIVE and ENVISION, on January 31, 2012 (approximately 12 years after the Aurora and CF Foundation collaboration began), the FDA approved ivacaftor for treatment of cystic fibrosis patients 6 years of age or older who have the specific G551D variant in the CFTR gene. Ivacaftor is marketed under the trade name Kalydeco. It is a highly effective drug for G551D CF patients. It works in the short term to improve lung function and in the longer term to preserve lung health. For eligible patients, Kaydeco is a life-changing breakthrough.

The approval of Kalydeco is notable for four reasons. First, it is the first drug for cystic fibrosis that targets the underlying cause of the disease rather than its symptoms. It was a clinical proof of concept. Second, Kalydeco has a unique mechanism of action: altering the activity of a variant protein in a way that tends to restore its normal function. Third, the approval is a realization of the promise of personalized medicine: targeted drugs that treat patients with a specific genetic makeup. Finally, the collaboration between Vertex and the Cystic Fibrosis Foundation is a beautiful example of what can be achieved by pharmaceutical companies and patient advocacy groups working together. The story of the first approval of Kalydeco is really quite remarkable.

About 4 percent of CF patients in the United States, about 1200 people, have a G551D variation in the CFTR protein. That leaves a lot of potential for further progress. Vertex carried out six other Phase 3 clinical trials to expand the patient population to those having variants other than G551D for which a potentiator drug would be expected to be effective and for patients as young as six months of age. These studies results in a sequence of FDA approvals that expanded the patient population for which Kalydeco is indicated: in 2014 for patients with the R117H (the amino acid arginine is replaced by histidine at position 117) sequence variant; in 2015, for children ages 2 to 5; in 2017 for patients having additional sequence variants in the CFTR protein; in 2018 for children ages 12 to 24 months; and in 2019 for infants with CF as young as six months of age.

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As a general rule, scientists do not need much motivation to get their work done. They like to be given a tough problem and be left alone to solve it. Nonetheless, a little motivation never hurts. In the hunt for therapy for CF, scientists got as much motivation as one could ever hope for. Specifically, Vertex scientists saw CF patients up close and personal.

Paul Negulescu: “I learned about CFTR from scientists, but I learned about CF from patients and their families. Over the years, I had the incredible opportunity to meet so many people with CF”.

Fred Van Goor: “Every person with CF who I’ve met and every memento ‘I’ve received along the way is a reminder that we are not done. I have a bookmark given to me by a six year old child living with CF who is now 18. In one of the most emotional experiences of my life, a man living with CF in Germany gave me a ring he’s worn his entire life. I experience so much joy when I meet someone who is taking our treatment, but then I will meet someone who isn’t eligible and I’m hit with the reality of how much more work we have to do”.

Brian Bear, chemist: “I remember meeting a high school age young man who was taking one of our medicines. I looked into his eyes as he said a simple ‘thank you for what you do’ . At that moment, In couldn’t help but realize the humanity of all the challenges our team has overcome to bring medicine to him and others with CF, I am ever grateful to him for giving that moment to me”.

“Taking CF patients and their families on tours of facilities is the best part of my day. We hear how inspiring it is to see where these discoveries are made, meet the scientists, and feel our passion. But little do they know how motivating it is for us to meet them face-to-face.”

“I have every CF patient sign a (glass laboratory) flask and keep it with me while I work. Chemistry is a very manual, labor-intensive process and experiments usually don’t work out. At those moments of failure, I look over at my flasks on the shelf and they remind me why we keep going every day. There is no better motivation.”

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Kalydeco was a triumph. Still, it was approved only for those CF patients having one of a few specific variations in the CFTR proteins, a small fraction of the CF community.

Kalydeco is a potentiator, acting to improve the efficacy of chloride ion channels already spanning the epithelial cell membrane. Having that in hand, Vertex scientists continued their work in search of a corrector, a molecule that would interact with the variant CFTR proteins to stabilize them, protect them from degradation, and increase the fraction of variant CFTR proteins reaching the epithelial cell membrane and creating chloride ion channels. The target was efficacy in patients bearing one or two copies of the Phe508del variants. The expectation was that the combination of a corrector plus a potentiator would be more effective than either agent alone.

Following a lengthy road of synthesis and testing, the collaboration between chemists and biologists, Vertex scientists brought forward VX-809, given the generic name lumacaftor. The chemist Jason McCartney first made lumacaftor at the Vertex San Diego research site: “Making a new medicine is a lot like putting together Lego pieces of different sizes and shapes until you find what you are looking for. There isn’t a blueprint for what you are trying to do, and the challenge is thrilling.” And so is actually getting it done, as Jason did in chemistry hood #8.

Lumacaftor has not been approved for use as a single agent. Clinical trials focused on the combination of lumacaftor with ivacaftor. Phase 2 trials demonstrated efficacy in CF patients bearing two copies of the Phe508del variant but not in those bearing a single copy. To include as many CF patients as possible in effective therapy required further work.

Vertex carried out two randomized, double-blind, placebo-controlled Phase 3 trials, known as TRAFFIC and TRANSPORT, for the lumacaftor/ivacaftor combination in 1108 patients bearing two copies of the Phe508del variant, 12 years of age and older, for 24 weeks. The results were positive and the FDA approved the combination, known as Orkambi, for this patient population on July 2, 2015. Subsequent Phase 3 trials gained approval for patients in the age range 6-11 in 2016 and, finally, for patients 2 years and older in 2018. Kalydeco and Orkambi were now approved for more than 50% of the CF patient population.

At the time of his retirement as CEO and President of the CF Foundation, Bob Beall wrote the following: “Two weeks ago, the approval of Orkambi was one of the happiest days of my life. It was an important milestone in a personal journey that began 39 years ago when I first met a very impressive group of CF families while I was working at the NIH. At that time, there was very little hope for children with cystic fibrosis. Those parents were desperately searching for a miracle to save their children. I was moved by their passion and commitment. and their mission became mine. Ever since, the quest for the CF cure has been a driving force in my life.”

Discovery work at Vertex San Diego continued. A second corrector molecule, and a better one, was discovered and named tezacaftor. Clinical trials of the combination tezacaftor/ivacaftor plus ivacaftor demonstrated efficacy and safety in CF patients bearing two copies of the Phe508del variant and in patients bearing one copy of the Phe508del variant and a second copy of a variant known to be susceptible to tezacaftor. The combination was approved for use in CF patients 12 years of age and older in February, 2018 and for children 6 years and older in June, 2019. The drug combination was named Symdeko, The regimen is one fixed dose combination of tezacaftor/ivacaftor in the morning and one pill of ivacaftor alone in he evening. Symdeko modestly extends the family of CF patients qualified for treatment by the Vertex family of products. However, there still remained a substantial cohort of CF patients for whom no effective remedy was available.

In a search for correctors having properties with promise to expand the range of CFTR variations that, in combination with the Phe508del variant, would be qualified for treatment, Vertex scientists continued work. The product of that effort was VX-445, known as elaxacaftor. Based on results of preclinical studies in San Diego the combination of elaxacaftor plus tezacaftor plus ivacaftor, the two best correctors plus the potentiator, showed promise for the vast majority of CF patients.

Two Phase 3 clinical trials were conducted with the triple combination, now known as Trikafta. The first trial was a 24-week, randomized, double-blind, placebo-controlled trial in 403 patients who had a Phe508del variation on one chromosome and a variation on the second chromosome that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor or tezacaftor/ivacator alone. The second trial was a four-week, randomized, double-blind, active-controlled trial in 107 patients who had two identical Phe508 del variations.

In both trials, the primary endpoint was increases in percent predicted FEV1. Trikafta increased this measure in both trials. In the first trial, Trikafta also resulted in improvements in sweat chloride concentration, number of pulmonary exacerbations, and body mass index compared to placebo.

On October 21, 2019, Trikafta was approved by the FDA for CF patients 12 years and older bearing at least one copy of the Phe508del variant, nearly 90% of all CF patients!

Thirty years after the discovery of the CF gene and the CF protein, effective therapy for the vast majority of the CF patients was available. That amazing result reflects the work of many scientists, support for basic research from the National Institutes of Health, and especially from the long-term collaboration between the Cystic Fibrosis Foundation and scientists at Vertex Pharmaceuticals.

Francis Collins writes: “Shortly after our identification of CFTR, I wrote a song entitled ‘Dare to Dream’. The lyrics expressed hope that the gene discovery would lead to effective treatments for cystic fibrosis – that someday we would see ‘all our brothers and sisters breathing free’. It is profoundly gratifying to see that this dream is coming true.”

Frank Deford is not the only parent of a child, or children, with CF who has written eloquently about the experience. Margareta Cassalina, a longtime volunteer leader of the CF Foundation, had two CF children with her husband Marc: Jena, who “moved on up” at age 13, and Eric, now 27. Her books include: “Beyond Breathing” and “Beauty in the Broken”.

“Moving up” are words she chooses to use instead of the work “died”. “To me, ‘moving up’ represents the next stage where we go, in another form, in another life. I don’t believe that love ends and I never say goodbye.” Eric is benefitting from the CF therapies available as a consequence of the work of a great many people, each contributing to the miracle of these drugs.

This story is not over. Work on therapy for cystic fibrosis continues at Vertex and elsewhere for better, move effective drugs for those who are treated by Trikafta and the the 5% of CF patients who still have no effective drug therapy. Work has been undertaken on gene editing technologies to correct sequence variants in the CFTR protein. The Cystic Fibrosis Foundation continues to create a competitive environment for those who devote time and resource to the potential benefit of cystic fibrosis patients.

Bob Beall reminded me of the Wayne Gretzky maxim: “You miss 100% of the shots you don’t take”.

Eugene Cordes, February 2022