David Kardatzke is a statistician. He looks like one–a brainy, windblown math Ph.D. with square-framed glasses and a thick goatee–and most days, he feels like one, too. But on February 17, 2014, Kardatzke felt more like a character in a spy movie.
Kardatzke’s hands shook as he fed his dog and grabbed his carry-on. He locked the door and double-checked his pocket for the package. He slipped out of the house, flew to Philadelphia and headed to a nondescript office park in King of Prussia, Pennsylvania, with a secret password hidden in his wallet.
Kardatzke was acutely aware of how critical his role was in this mission. His cross-country trip had been a last-minute booking, but the journey to this moment had been nearly five decades in the making–50 years of time-consuming research and discovery, costly attempts and disappointments. Now, after he had devoted 10 years to the project, Kardatzke would be the first to know whether it was a success–or another failure. With the password, he would finally unlock a mountain of data, which would reveal the secret identity of their agent.
That agent was a biopharmaceutical agent, a molecule that until now had been known by its generic name, pirfenidone. Depending on the success of the mission, it might soon be revealed by a new name: Esbriet ® (pirfenidone). Esbriet is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).
Over the years, generations of researchers had tested the molecule to uncover its potential. No one could say exactly how or why it worked, but pirfenidone had demonstrated a capacity to help slow the progression of a rare disease, providing one of two new treatment options where before, there had been none. (Esbriet causes side effects, such as liver problems, sensitivity to sunlight or stomach problems.)
Six hours later, Kardatzke’s plane touched down in Philadelphia. He checked his pocket again–still there–and then his watch. He hadn’t eaten or showered, but it didn’t matter. He’d been waiting a long time for this moment. And he wasn’t the only one.
Twenty-five hundred miles away, in California’s Napa Valley, Dan was waiting, too. But for Dan, the results of waiting were very personal. For two years, he’d been anxiously waiting to find out whether the agent, pirfenidone, would be approved to treat his rare disease.
For most of Dan’s 66 years, he’d enjoyed spending time outdoors, hiking or cycling with his wife, Susan, and their daughter. But in March 2012, when the family set out hiking at elevation near Lake Tahoe, they’d only gone a half mile when Dan began to have difficulty breathing. He realized he had a problem.
“I didn’t know what it was, but it wasn’t good," Dan says. “At first I figured, hey, maybe I’m just getting old.”
Back in Napa, a pulmonologist tested Dan’s lung function and examined high-resolution computed tomography (HRCT) scans of his lungs, then delivered a grave conclusion. Dan had idiopathic pulmonary fibrosis, or IPF.
Even among the confusing alphabet soup of medical abbreviations, IPF is one of the more confounding. “Idiopathic” is a medical catch-all word for mysterious diseases–meaning a “condition of unknown cause.” “Pulmonary” refers to the lungs, and “fibrosis” is a fibrous scar tissue resulting from the disease. In lay terms, Dan’s diagnosis of IPF meant that his once-elastic, spongy lungs were progressively stiffening because of scar-like tissue, making it more difficult for him to breathe. And medical science couldn’t explain why.
Who has IPF?
The disease affects approximately 100,000 people in the U.S.1 IPF typically occurs in people older than 50.2 Historically more men than women have been diagnosed with IPF.2
Common symptoms include:
Shortness of breath; persistent dry cough; Velcro®-like crackle in the lungs, which a doctor can hear.2
Misdiagnosis is common:
A person may see multiple doctors and specialists before receiving a correct diagnosis of IPF.3 More than 50 percent of people with IPF are initially misdiagnosed with other forms of respiratory illness, including:3,4
- unspecified respiratory ailment
“When you’ve got a disease like that, the worst thing you can do is search the internet,” Dan says. “That knocked the wind right out of me.”
Dan discovered that as time passed, his shortness of breath and fatigue would get worse. Eventually, he would need an oxygen tank to help him breathe. The median survival after diagnosis with IPF is 3-5 years, and even with approved treatments, there is still no impact on survival.5 Unfortunately, even his healthy sense of humor and courage in the face of adversity wouldn’t be much help fighting the disease.
IPF’s common symptoms include a persistent, dry cough, shortness of breath during even normal activities, and the sound of Velcro®-like crackles deep in the lungs, which a doctor can hear.2*
Dan was overwhelmed by the news of his diagnosis, and while he knew there was no cure for IPF, he intended to fight. But then he learned that there were no medicines approved by the U.S. Food and Drug Administration (FDA) to treat the disease.
“My next question for my doctor was, ‘OK, well what should I do now?’”
For the moment, he could only wait.
While IPF affects only a small number of Americans, its impact is severe. The cause and mechanism of IPF isn’t well understood, nor is it on the radar for the general public, either for outreach or large-scale fundraising for research and drug development. “My wife and I have cycled all our lives and done a lot of charity rides. But I’ve never heard of a ride for IPF,” Dan says.
Despite scientists’ efforts with different therapies, there were no FDA-approved medicines for the treatment of IPF.
Then along came pirfenidone.
This molecule was discovered in the mid-1960s, in the laboratory of a Texas chemist. Back then, 5-methyl-1-phenyl-2-(1H)-pyridone was just stuff in a test tube. It would be years before this molecule would show its potential.
In the 1970s, pirfenidone was tested in different trials and thought to have anti-inflammatory benefit, help lower serum uric acid levels and lower glucose levels, as well as be effective in upper respiratory treatment. For many years, it was tested for the possibility that it might have some effect on a number of diseases, but it didn’t; pirfenidone went back on the shelf.
It wasn't until nearly two decades later, in the early ‘90s, that a study examined whether pirfenidone might inhibit fibrosis in rats and hamsters. “Might” is an inspiring word to researchers, which leads them to wonder: Might it have an effect on people? A 1996 study by Dr. Ganesh Raghu at the University of Washington repeated the experiment, this time on human lung fibroblast cells. This study explored whether the compound 5-methyl-1-phenyl-2-(1H)-pyridone–now called by the relatively simple name “pirfenidone”– might have an effect on scar tissue.6
But the petri dish experiment was far from conclusive. And, effects observed in cells in vitro often fail to translate when tested in humans, so nobody knew whether pirfenidone would have an impact on people.
Raghu tested the question in small, preliminary trials. The results were positive: While pirfenidone didn’t cure the disease, it seemed to slow it down.6
A medicine to slow IPF progression would represent real progress and a pathway to study and test the mechanisms of the disease. It would be the first step in learning how to potentially stop IPF altogether.
But the researchers faced an enormous challenge–FDA approval. At the time, neither the compound nor the disease was well understood. Yet pirfenidone would have to prove itself consistently enough to survive the extensive clinical trial process–from Phase I to the expensive and time-consuming process of large-scale Phase III trials.
If pirfenidone could succeed in Phase III trials, it would have a chance to gain FDA approval as an effective therapy for IPF.But behind the dream of FDA approval loomed the sobering reality that many compounds don’t make it that far. The road to approval was littered with false hopes and disappointments, as just one in 10 compounds that enters clinical development in Phase I is expected to gain FDA approval.7
Success was a longshot. But for the one hundred thousand people with IPF, it was their only chance.
Dan accepted his diagnosis. He realized his life had changed. Weekends would no longer mean backpacks and hiking shoes. He’d leave the cycling to his wife and kiss her sweaty cheek when she returned; he’d lie to his friends when they proposed a short hike, blame his bum knee and wait for their return with a glass of wine. But just because his life had changed didn’t mean it had stopped. He’d still walk, garden and do most of the things he’d done before, if slower, with more breaks. Now, even daily tasks like climbing the stairs to his second floor meant resting a half-minute at the last step to catch his breath.
Dan knew IPF was a progressive disease. It wasn’t just a matter of coming to terms with his condition, but with the reality that his lung function would continue to decline. That was terrible news not only for Dan, but for his family. He could hide his disease from his friends, but not from his daughter. She was growing up and heading to college across the country. How could he tell her about his diagnosis and that there was nothing he could take for it and nothing to do?
If he was going to tell his daughter, he wanted to give her more information than just the diagnosis. “I needed to be able to say, I have this disease; it’s IPF, and it’s progressive,” Dan explains. “But then, I wanted to be able to say: however...”
Dan needed the word “however” to hold onto the idea that there was something he could do. That month, instead of taking his local doctor’s advice to wait, Dan went to the University of California at San Francisco Medical Center. “The doctors at UCSF hadn’t seen a lot of me [people with IPF],” Dan remembers. “It’s a rare disease.”
Late in 2012, Dan’s doctor there handed him an article about a new drug for IPF. Dan was excited, but his doctor was frustrated. While pirfenidone had been approved outside of the U.S., including in Europe, Japan and Canada, it had not yet been approved for use in the U.S.
“I knew my lung function was going to get worse, and there was a drug out there that might help slow the decline, but it wasn’t approved in this country,” Dan says.
In 2002, a decade before Dan’s initial IPF diagnosis, the scientific papers outlining the potential effects of pirfenidone had garnered it the attention of a new backer, a Bay Area company called InterMune. InterMune was a small specialty pharmaceutical company, but they were dedicating nearly all their resources to prove to the FDA that pirfenidone was both safe and effective against IPF.
The way to prove the efficacy and safety of pirfenidone would be a series of clinical trials–carefully designed studies overseen by teams of physicians working with people with IPF. Some would be given the medicine, and others would be given the placebo, a substance that does not contain medicine nor affect the disease, and scientists would compare the results between the two groups.
Clinical trial design is always challenging, but the InterMune scientists faced some additional hurdles as they prepared their trials, and on top of that, both the medicine and the disease carried with them a great deal of uncertainty. They knew people like Dan were counting on them, so they forged ahead.
“It’s extremely unusual to try to develop a drug for a disease where nothing had been developed previously,” says Kardatzke, who is now a Senior Statistical Scientist at Genentech. He joined InterMune shortly before they started working on pirfenidone. “There was no precedent for what was going to be approved by agencies, so we were breaking new ground. That was pretty daunting.”
One of the biggest challenges in designing a new study was setting benchmarks. What would demonstrate that pirfenidone could help slow down IPF? The progression of the disease is unpredictable, and, at the time, there was no scientific standard for measuring its progression.
“With IPF, we have no known biomarkers and no measurement to predict how any one patient’s disease would progress,” explains Dr. Ben Kramer, Vice President of Medical Affairs at Genentech. “And that’s part of the challenge in studying a drug for IPF.”
There was no regulatory precedent and no preclinical models. The molecular target of pirfenidone was unknown.
Though the risks involved in the endeavor were high, the team was dedicated to seeing it through.
By 2006, two Phase III clinical trials of pirfenidone were in progress. Known as CAPACITY 004 and CAPACITY 006, these trials involved 779 people with IPF at 110 study centers in 11 countries.8
The trials were randomized and double-blind, which means that no one, including the doctors administering the treatment, knew who received pirfenidone or placebo. Each week, a clinician would make a call, punch in the number assigned to each person and be told which packet of pills to administer. Weekly tests collected data on lung function for each member of the trial. That anonymous data was sent to an independent company to be stored and collected. The big reveal–the unblinding of the study, and the matching of each person to the treatment–would come only after the study had been completed.
The team consulted with the FDA to determine the best way to measure the medicine’s effectiveness for slowing down IPF. They decided to use the measure of lung function called forced vital capacity, or FVC, which is how much air someone can exhale from their lungs with force after a deep breath. As IPF progresses, scarring, or fibrosis, causes the lungs to stiffen. This may damage the lungs' ability to exchange gases such as oxygen with the blood and decrease the volume of air a person can exhale. If people with IPF who took the medicine had less of a decline in FVC over time compared with those who received the placebo, it would demonstrate that pirfenidone could help slow down the disease.
In spring of 2010, the studies were complete. But the results were confusing, and, Kardatzke realized, they weren’t entirely promising.
The two studies had substantially different results. In CAPACITY 004 there was a clear improvement in FVC, the main measure of the trial. But in CAPACITY 006, the results didn’t reach statistical significance–what statisticians call the “p-value.”
The p-value is the bottom line of a clinical study–a statistical measure, derived from calculation, which describes the probability that the observed result isn’t due to chance.
The researchers had designed the studies to be identical. Both studies showed a similar side effect profile–feeling tired, insomnia, upper respiratory tract infections, sinusitis, headache, dizziness, decreased weight, and decreased or loss of appetite–more often in people taking Esbrietthan placebo.9 However, the efficacy results differed wildly–one was positive and one was negative.
To be approved by the FDA, InterMune needed two clinical studies proving pirfenidone worked. InterMune only had one and no reason to explain why the results were different.
At InterMune, the staff was stunned. They gathered in the conference room. A few began to cry. They had worked closely with people living with IPF and heard their stories. Some even had loved ones living with the disease. For years, the InterMune team had worked nights and weekends to get the medicine approved. They thought they would soon deliver pirfenidone to the people who needed it. Now, they weren’t sure if they’d even still have jobs.
The trials hadn’t been a total failure, though; the accumulated evidence would be enough to convince regulators in Japan and much of Asia to approve the medicine. And in 2011, Esbriet was approved for the treatment of IPF in Europe.But before the FDA would approve pirfenidone for treating IPF in the U.S., InterMune had to start all over again.
That was a daunting proposition for a little company. They needed help, and fast.
A new study would be expensive and take three to five years. Giving Europe its first IPF medicine would help raise funds, but it wouldn’t be enough.
The additional multi-year global Phase III trial would only be possible with reliable partners. Fortunately, they already had one: Since 2006, InterMune and Roche had been collaborating on the research, development and commercialization of some InterMune products.
The partnership not only helped finance InterMune’s continued efforts to develop pirfenidone but also created a culture of trust and collaboration between the companies, which would eventually lead to Roche’s acquisition of InterMune in August of 2014.
Now, InterMune could combine forces with Roche’s global resources and Genentech’s experienced biotechnology platforms to give pirfenidone–and everyone counting on it–another chance.
The company needed to design another Phase III study that would work. The first step was to review the first trials and figure out what went wrong.
“As the statistician, I was the person who was supposed to say, ‘OK, this happened because of some reason,’” Kardatzke explains. He coordinated analyses to try to find baseline differences between the two studies–a difference between the groups that could provide an explanation for why one failed, statistically, while the other succeeded.
“I never did find the answer,” Kardatzke says.
The results from CAPACITY 004 indicated that the medicine was indeed meaningfully better than a placebo.The scientists had suffered a setback, but still believed that pirfenidone would work. They conducted a new Phase III clinical trial, called ASCEND.
The ASCEND trial started with 555 people with IPF. This time, patient scans were analyzed with a centralized process to ensure the best consistent baseline measurement across the groups being studied, to confirm diagnosis in the trial.
Kardatzke and his InterMune colleagues hoped the ASCEND trial would succeed, but they were cautiously optimistic. Hope has its own gravity, even in scientific research. Kardatzke had seen other companies ignore the results of a study, dig through numbers until they found a glimmer of hope and spend all of their resources, only to prove that they were still wrong. He believed in the potential of pirfenidone, but as a statistician, he believed more in the scientific method of clinical testing.
“I didn’t want to be a statistician that used data to not learn something,” Kardatzke laughs. When he could finally trust the numbers, he knew that the FDA, and people with IPF, would be able to trust pirfenidone.
In 2014, 10 years into his personal journey with the molecule formerly known as 5-methyl-1-phenyl-2-(1H)-pyridone, Kardatzke arrived in King of Prussia with that secret password in his wallet.
It was time for the independent company that had compiled the ASCEND study data to reveal the results. After Kardatzke took his seat, an employee gave him a sealed envelope with a CD inside.
“It wasn’t like they were presenting the crown jewels, exactly,” Kardatzke laughs. “But there was some ceremony to it. Everyone knew it was a big moment.”
The data on the CD, compiled by another independent company, contained the random and anonymous patient information determining which course of treatment each subject received. Depending upon the results, InterMune might be able to present pirfenidone to the world as a new drug, Esbriet.
Part of the importance of Kardatzke’s mission was its secrecy–the results of the ASCEND study would be big news, and he didn’t want InterMune employees distracted waiting for the results, nor investors speculating on the outcome. Kardatzke dried his hands on his pants and pulled the password from his wallet. The wait was over.
A team had created the data tables, including the safety results that showed liver problems as well as gastrointestinal or skin-related side effects (such as nausea, diarrhea, indigestion, vomiting or rash) were more common among people taking Esbrietthan placebo.10 Long after the sun had set and he’d missed dinner, Kardatzke finally saw the p-value.
“No,” he said. He could feel the sweat beading on his forehead. “That can’t be right.”
Then he reviewed the program and had it calculated again.
For the study to be statistically significant, the p-value needed to be .05 or lower.
The p-value Kardatzke calculated was indeed lower–less than .001.10
It was proof. Pirfenidone’s journey to approval was almost over.
Back in Napa, Dan knew nothing about the data Kardatzke had uncovered.
He didn’t know Kardatzke had arrived back in San Francisco to announce the good news to the executive team holed up in a hotel suite awaiting his return.
Dan also didn’t know that, now, with the investment and support facilitated by Roche’s acquisition of InterMune, the medicine for his rare disease was finally moving ahead toward FDA approval.
On October 15, 2014, the FDA approved Esbriet for the treatment of IPF.Genentech began shipping Esbriet within a week; within a month, more than 1,000 people with IPF were enrolled in Genentech’s access program designed to help people with IPF get the medicine and resources they need. Today, more than 14,000 people with IPF in the U.S. have begun treatment with Esbriet.
All Dan knew was that one day, he felt like he was on a runaway train without brakes. His physician at UCSF was able to prescribe the medicine that he–and so many others–had been waiting for.
“Until that moment, I didn’t even have anything that might slow this thing down,” Dan says. “This disease is rare, but it’s not rare to people who have it. So to have a big company use their power to focus on something like that, and to have it in my hands–it was an incredibly emotional moment. Just awesome.”
Despite the good news, he knew the long-term prognosis. But he also knew what it meant to be given the means to take back some control in his life.
While it could help slow down the worsening of IPF, it does not control the symptoms of the disease and can come with side effects, some serious. It could cause liver problems and sensitivity to sunlight and rash. Dan would need to take precautions, including getting liver function tests, using sunscreen and making sure his skin was covered. The medicine could also upset his stomach or leave him feeling tired with a possibility of headache or dizziness.
Dan remembers when he first held the medicine in his hands. “They may have given me a bottle, but I saw something much, much bigger than that.”
At home that night, Dan and his wife broke out laughing for the first time since March 2012, when he was first diagnosed.
And later, he was finally able to talk to his daughter about his IPF diagnosis and tell her that there was no cure, however, he was on a treatment that might help slow down the progression of the disease.
“Yeah, being able to say that,” Dan said. “That, well – that was everything.”
Update: Since the publication of this piece, Dan received a double lung transplant and is no longer taking Esbriet.
*Esbriet does not improve IPF symptoms. However, Esbriet may preserve more lung function in people with IPF.
What it Treats
Esbriet is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).
It is not known if Esbriet is safe and effective in children.
Select Important Safety Information
Before you take Esbriet, tell your doctor about all of your medical conditions, including if you:
- have liver problems.
- have kidney problems.
- are a smoker.
- are pregnant or plan to become pregnant. It is not known if Esbriet will harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if Esbriet passes into your breast milk.
You and your doctor should decide if you will take Esbriet or breastfeed.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
What should I avoid while taking Esbriet?
- Sunlight. Esbriet can make your skin sensitive to the sun and the light from sunlamps and tanning beds. You could get a severe sunburn. Use sunscreen (SPF 50) and wear a hat and clothes that cover your skin if you have to be in sunlight. Talk to your doctor if you get sunburn or a rash.
- Taking Esbriet with other medicines that can make your skin sensitive to the sun, the light from sunlamps and tanning beds.
- Smoking. Smoking may affect how well Esbriet works.
What are the possible side effects of Esbriet?
Esbriet may cause serious side effects, including:
- liver problems. Call your doctor right away if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea-colored) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. Your doctor will do blood tests to check how your liver is working during your treatment with Esbriet.
- sensitivity to sunlight (photosensitivity) and rash. See “What should I avoid while taking Esbriet?”
- stomach problems. Esbriet may cause stomach problems such as nausea, vomiting, diarrhea, indigestion, heartburn, and stomach pain. Tell your doctor right away if your stomach problems get worse or do not go away. Your doctor may need to change your dose of Esbriet.
The most common side effects of Esbriet include feeling tired, insomnia, upper respiratory tract infections, sinusitis, headache, dizziness, decreased weight and decreased or loss of appetite.
These are not all the possible side effects of Esbriet.
Call your doctor for medical advice about side effects. 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.
Please see full Prescribing Information, including Patient Information, for additional important safety information at esbriet.com.
1 National Institutes of Health. Idiopathic Pulmonary Fibrosis. Available at: http://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis.
2 American Thoracic Society. Patient Information Series. http://www.thoracic.org/patients/patient-resources/resources/idiopathic-pulmonary-fibrosis.pdf. Accessed November 10, 2015
3 Collard HR, et al. (2006). Patient experiences with pulmonary fibrosis. Resp Med. 101(6):1350-4.
4 Coalition for Pulmonary Fibrosis. Action Alert. Available at: http://www.coalitionforpf.org/wp-content/uploads/2013/02/ActionAlert2Q04.pdf.
5 Lee, AS, et al. (2014). The burden of idiopathic pulmonary fibrosis: An unmet public health need. Respiratory Medicine. 108, 955e967.
6 Raghu G, et al. 1999. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med. 159:1061–1069.
7 Hay M, et al. Clinical development success rates for investigational drugs. Nature Biotechnology. 2014. 32: 40-51.
8 Data on file.
9 Noble et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. The Lancet. 2011. 377: 1760–69
10 King TE, et al. A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2014. 370: 2083-92.