In 1988, a new Genentech scientist was walking down a hall in Building 4 when he suddenly had an idea. A pulmonologist by training, Steven Shak, M.D., frequently found his thoughts turning to lung disease. That day, he recalled the kids with cystic fibrosis (CF) he'd treated over the years, picturing the thick secretions that clogged their airways, bringing suffering to them and their families. It was then that a connection sparked in his mind.
“I said, ‘Boy, those thick secretions in the airways look just like the clots that we’re now dissolving in the arteries of people having heart attacks,’” he recalls. If one kind of clot could be dissolved, couldn't another?
If he could figure out what was responsible for the viscosity of that sputum—if he could identify which factors made those secretions so thick—he reasoned that a treatment might not be far off. He envisioned an enzyme that could be inhaled to chop up those thick secretions like scissors.
Shak began spending his free time in research mode, which in pre-internet days meant burrowing into the musty journals in the basement library of the University of California, San Francisco (UCSF). It was there that a trove of articles, going back decades, caught his attention. Back in the 1950s, researchers had found that a certain enzyme from a cow's pancreas seemed to be adept at breaking up the very high concentrations of DNA found in those lung secretions.1 Given that people with CF were frequently allergic to the enzyme, that discovery had languished. Now, Shak wondered, what if the corresponding gene in humans, DNase, could be cloned and expressed? It had never been done, but it seemed possible.
Shak would eventually go on to become cofounder and chief scientific officer of Genomic Health, Inc, a leading company in personalized medicine. But when he was a young molecular biologist at Genentech, the statistics were daunting for CF, a disease which affects more than 30,000 people in the U.S.2 Shak went back and asked David W. Martin, Jr., M.D., then senior vice president of research and development at Genentech, what might have been considered an outlandish question: Could he drop everything and focus entirely on cloning DNase? Martin's answer reflected the company's practice of encouraging its scientists to pursue passion projects: Go for it.
After reviewing Genentech scientists’ earlier research around groundbreaking cloning projects, Shak isolated a full-length human gene for DNase I, the human enzyme, within a matter of weeks. Immediately, he set out to see if his theory would work, doing experiments on sputum, which, he says, was not exactly glamorous work.
As every researcher knows, progress frequently comes in fits and spurts, often over a period of years. But every now and then a breakthrough unfolds in an instant. Shak says he'll never forget that critical moment when he first tested his theory. In his test tube was a sample of sputum from a person with CF. It was so thick it wouldn't even roll down the side of the tube. Shak added a tiny amount of DNase I. Within 15 minutes, his sample had transformed entirely. He watched as it flowed right down the tube.
Shak couldn't resist showing his colleagues what he'd found. "People still tell stories of me running around with a tube of sputum," he says.
By December of 1989, Shak met with the leadership team of the CF Foundation at the time, Robert Dressing and Robert Beall, and outlined the project for the first time.3 One thing was clear: If the treatment were to work, a large supply of DNase I would be required. Art Levinson, a scientist and director of cell genetics at Genentech who would go on to become CEO, volunteered to create the cell line to produce it. The team knew that individuals with CF would theoretically need to take the medication daily for years, so a high-expressing line would be essential. That's precisely what Levinson delivered.
The next step was the most exciting and nerve-wracking: testing it on actual patients. Would the DNase I react the same way in human airways? "We scientists are not dry and unemotional," Shak says. Being passionate about this work meant waiting anxiously for results—and then feeling elated when those results were as promising as they'd hoped.
In the summer of 1990, Genentech began Phase I studies of DNase in CF patients.4 Only a few years later in December of 1993, Pulmozyme® (dornase alfa) Indication and Important Safety Information received approval from the U.S. Food and Drug Administration (FDA) for the treatment of CF, just nine months after the company submitted a Product License Application.5 There was still much work to be done—making the medication available was no less important than establishing its merits—but for Shak and the rest of the team, a vital hurdle had been crossed. Pulmozyme was the first ever FDA-approved treatment for people with CF.
CF still has no cure, but the picture has improved markedly since Shak's work began. With recent scientific research and advancements, including new treatment options, and improvements in the diagnosis and management of the disease, the median predicted age of survival for people with CF has risen from 10 years in 1962 to 39 years today.6,7 As Shak sees it, strides like these are only possible when a healthy approach to innovation is in place.
"To succeed, Pulmozyme didn’t require just excellence in the laboratory and in manufacturing the protein,” he says. “It didn’t require just excellence in the clinical studies. It didn’t require just excellence in biostatistics or in doing the studies. It didn’t require just excellence in regulatory and how we worked together. On the contrary, it required all of that.” The Pulmozyme team succeeded because it emerged from a culture and leadership that actively encouraged creativity, flexibility and cross-pollination—all starting with that stroll through Building 4, when Shak's thoughts focused on a problem in desperate need of a solution.
What it Treats
Pulmozyme (dornase alfa) is indicated, along with standard therapies, for the management of pediatric and adult patients with cystic fibrosis (CF) to improve pulmonary function.
In CF patients with an FVC ≥ 40% of predicted, daily administration of Pulmozyme has also been shown to reduce the risk of respiratory tract infections requiring injectable antibiotics.
Important Safety Information
Pulmozyme should not be used in patients who are allergic to any of its ingredients.
Patients may experience the following when using Pulmozyme: change in or loss of their voice, discomfort in the throat, rash, chest pain, red watery eyes, runny nose, lowering of lung function, fever, indigestion, and shortness of breath. There have been no reports of severe allergic reactions caused by the administration of Pulmozyme. Mild to moderate hives and mild skin rash have been observed and have been short-lived.
Pediatric Use
The safety and effectiveness of Pulmozyme along with standard therapies for cystic fibrosis have been established in pediatric patients. The use of Pulmozyme in pediatric patients at 5 to 17 years of age is supported by evidence from a randomized, controlled trial. The use of Pulmozyme in patients less than 5 years of age is supported by the efficacy data from the same randomized, controlled trial and additional safety data in pediatric patients aged 3 months to less than 5 years who received Pulmozyme.
You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at 1-888-835-2555.
For further information, please see the full Pulmozyme Prescribing Information. If you have questions, please discuss them with your CF Care Team.
1. Cystic Fibrosis Research, Inc. The Making of Pulmozyme. Retrieved August 5, 2016 from: http://www.cfri.org/news/94spring/trtm194s.html
2. Cystic Fibrosis Foundation. What is Cystic Fibrosis? Retrieved August 5, 2016 from: https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/
3. Marcus, George E. Corporate Futures: The Diffusion of the Culturally Sensitive Corporate Form. University of Chicago Press, 20 July 1998. Pg. 233.
4. Genentech. FDA Grants Genentech Orphan Drug Status for DNase, a Potential Cystic Fibrosis Treatment. January 29, 1991. Retrieved August 5, 2016 from: http://www.gene.com/media/press-releases/4338/1991-01-29/fda-grants-genentech-orphan-drug-status-
5. Genentech. FDA Grants Genentech License to Market Pulmozyme. December 30, 1993. Retrieved August 5, 2016 from: http://www.gene.com/media/press-releases/4395/1993-12-30/fda-grants-genentech-license-to-market-p
6. National Institutes of Health. NIH Fact Sheets - Cystic Fibrosis. Last updated March 23, 2013. Retrieved August 5, 2016: https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=36
7. Cystic Fibrosis Foundation. Patient Registry Annual Report 2014. Retrieved August 8, 2016: https://www.cff.org/2014-Annual-Data-Report.pdf