Q&A: The Biology of Respiratory Diseases
Respiratory diseases like idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and severe asthma take a serious toll on people’s lives. Significant progress has been achieved over the past decades, but new treatment options are still needed. Now, years of research are culminating in breakthroughs that may ultimately enable personalized therapies that go beyond just managing symptoms to actually treat the underlying disease.
We had a conversation with Jeffrey M. Harris, M.D., Ph.D., Group Medical Director of Early Clinical Development at Genentech, to learn more about these diseases and how treatments are changing. An immunology specialist trained at the University of California San Francisco, Jeff has been involved in this field for more than 15 years.
Why is this disease area important to you?
Jeff Harris: As a physician, I have seen the effects of respiratory diseases firsthand. These are conditions that have a tremendous impact on people living with the diseases, their loved ones, and society as a whole. Asthma, for example, is one of the most common respiratory disorders and causes thousands of hospitalizations and millions of missed work and school days each year.1 The five to 10 percent of people with a severe form of the disease drive half of all asthma-related healthcare costs in this country.2,3 On the more rare and even more severe end of the respiratory disease spectrum is IPF. People with IPF face a median survival time of only three to five years after diagnosis.4 In total, there are millions of people in the U.S. coping with respiratory diseases that can limit their daily activities, cause significant psychological burden and even be fatal.5
As both a doctor and a scientist, how have you seen the field of respiratory disease and the treatment landscape change? Where do you think it’s headed?
Jeff Harris: Historically, treatments for respiratory diseases have focused primarily on managing symptoms. This is of course important, but it doesn’t impact the disease itself. The ultimate goal of treatment is to cure or change the course of these diseases through personalized therapies that target the underlying biology. This is an ambitious endeavor, but in the years since I started working on respiratory diseases, I’ve seen real progress. As our understanding of the science has grown more sophisticated in recent decades, treatments — and patient outcomes — have improved substantially. We simply must keep digging deeper into the biology to continue advancing treatments.
Is there evidence of a biology-driven approach having been successful in the past?
Jeff Harris: Cystic fibrosis (CF) is a great early example. Research in the mid-20th century revealed that the thick mucus present in the lungs of people with CF contains large amounts of DNA. In fact, the stringy structure of DNA actually contributes to the high viscosity of the mucus. This discovery sparked the insight that enzymes capable of cutting DNA might be effective at loosening mucus and helping these people breathe easier.
More recently, we’ve seen a biology-driven transformation in asthma. What was once considered a single disease of airway constriction is now recognized as a clinical condition with different forms caused by various types of inflammation. These insights led to a new era of treatments targeting specific molecular subtypes of asthma, with investigation of diverse targets including leukotrines, interleukins, and other immune system proteins.
What has contributed to this transformation in asthma?
Jeff Harris: This fundamental shift in our understanding of asthma is the result of decades of pioneering research, which has shed more light on the complexity of respiratory diseases and variability in responses to therapy.
One of the things I’m most proud of in my time at Genentech is my involvement in an observational study called BOBCAT (Bronchoscopic exploratory study Of Biomarkers in Corticosteroid-refractory AsThma). The findings laid critical groundwork for understanding the different types of inflammation that can contribute to asthma. For example, immune cells known as T-helper 2 (Th2) cells are often involved in one form of asthma known as Type 2-high, but about half of asthma cases do not fit into this category – and do not respond well to existing therapies. The other form of the disease, referred to as Type 2-low asthma, seems to involve a very different assortment of immune system cells and molecules, including Th17 cells and proteins known as interleukin-17 (IL-17) and IL-33.
These findings have implications beyond asthma too. For example, some of these same disease pathways have now been observed in subsets of patients with COPD. By targeting the different cell types or molecular signals involved in specific forms of disease, we may have a bigger impact.
What about IPF? What are the latest advances there?
Jeff Harris: Ongoing research in IPF is still identifying cells and signals that may contribute to the disease process. Genentech scientists are casting a wide net, with potential therapeutic targets including the immune system protein IL-13 and a series of molecular signals known as the hedgehog pathway. Combination therapies to target multiple signaling pathways may be especially promising for the treatment of IPF.
We are also looking at ways to expedite clinical progress, such as novel imaging techniques that may enable investigators to better assess disease progression in IPF and the impact of treatments. Innovative trial designs using these imaging techniques along with new blood biomarker tests could provide evidence of efficacy in a shorter amount of time while also requiring fewer study participants – an important consideration given IPF is a rare disease that affects only about 100,000 people in the United States.13
How is Genentech’s approach to respiratory disease research unique?
Jeff Harris: I think Genentech is in a unique place because it’s always been a highly data-driven company. We have a lot of early research delving into the biological complexities of respiratory diseases. For example, we’re exploring molecular commonalities between diseases that could mean understanding fibrosis in IPF reveals insight into airway remodeling in asthma, and medicines for other diseases may be beneficial in cystic fibrosis or COPD. We’re also beginning to understand how other organ systems like the nervous system – which is not typically considered as central to the disease – can influence inflammation as well as other disease processes within the lung. These are still emerging areas of research, but at Genentech, early insights like these can actually come to fruition in the clinic.
It also helps to be surrounded by smart people across disciplines. In all of our respiratory-focused work, we're applying lessons learned in other disease areas like oncology to advance personalized approaches, using biomarkers to define the patient populations most likely to benefit from specific treatments.
In what ways are biomarkers important for respiratory disease?
Jeff Harris: The future of treatment for respiratory disease is personalized medicine, and biomarkers are an essential part of that. When I started working at Genentech a decade ago, my focus was actually biomarker discovery. At the time, we were just starting to explore the use of companion diagnostics, primarily within oncology. Today, studies of biomarker-defined patient groups are central in everything we do in clinical trials so that we can more readily identify the right people for the right medicines earlier in the clinical development process.
How close are we to realizing this vision?
Jeff Harris: Having a personalized, effective treatment for every person with a serious respiratory disease is an ambitious goal indeed, but I’m confident it’s possible. Trying to change the course of the disease itself instead of just treating the symptoms is ambitious too. But we've seen substantial progress on both fronts. And ultimately, this is where a path guided by the science will continue to lead us.
Learn more about a few respiratory diseases below:
Asthma is a common, chronic respiratory disease.
The number of people with asthma in the U.S. is greater than the entire population of Australia.6,7
Asthma takes a serious toll.
Asthma can place a tremendous burden on people’s lives, disrupting sleep, work, exercise and daily activities. People with severe asthma face a higher risk of asthma attacks, which can be life-threatening.
MORE THAN 14 MILLION
work days are missed every year due to asthma.1
3 IN 5 PEOPLE
with asthma limit their usual physical activity.1
1 IN 4 PEOPLE
with severe asthma have had a near fatal event in their lifetime.10
What is the impact of COPD?
COPD is a common disease and the third leading cause of death in the United States.11
MORE THAN 11 MILLION PEOPLE
in the United States have been diagnosed with COPD.11
NEARLY 1 IN 5 PEOPLE
with COPD is forced to retire prematurely due to their condition.12
Treatment for IPF is often delayed.
In IPF, it’s important to discuss disease management as early as possible.
Mortality rate increases the longer the delay in access to specialist care.14
1. Centers for Disease Control and Prevention. Asthma Fact Sheet. http://www.cdc.gov/asthma/impacts_nation/asthmafactsheet.pdf. Accessed September 28, 2016.
2. Chung KF, et al. International ERS/ARS guidelines on definition, evaluation, and treatment of severe asthma. Eur Respir J. 2014; 43(2): 343-373.
3. Cisternas MG, Blanc PD, Yen IH, … Yelin EH. A comprehensive study of the direct and indirect costs of adult asthma. J Allergy Clin Immunol. 2003; 111(6): 1212-1218.
4. Bjoraker JA, et al. Prognostic significance of histopathological subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 1998; 157(1): 199–203.
5. American Lung Association. Estimated Prevalence and Incidence of Lung Disease. http://www.lung.org/our-initiatives/research/monitoring-trends-in-lung-disease/estimated-prevalence-and-incidence-of-lung-disease/. Accessed September 28, 2016.
6. Centers for Disease Control and Prevention. Most Recent Asthma Data. http://www.cdc.gov/asthma/most_recent_data.htm. Accessed September 28, 2016.
7. Central Intelligence Agency. The World Factbook: Australia. https://www.cia.gov/library/publications/the-world-factbook/geos/as.html. Accessed September 28, 2016.
8. Cystic Fibrosis Foundation. About Cystic Fibrosis. https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/. Accessed September 28, 2016.
9. Cystic Fibrosis Foundation. Highlights of the 2014 Patient Registry Data. https://www.cff.org/Our-Research/CF-Patient-Registry/Highlights-of-the-2014-Patient-Registry-Data/. Accessed September 28, 2016.
10. Moore WC, et al. Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program. J Allergy Clin Immunol. 2007; 119(2): 405-413.
11. American Lung Association. How Serious is COPD. http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/copd/learn-about-copd/how-serious-is-copd.html. Accessed September 28, 2016.
12. Fletcher MJ, et al. COPD uncovered: an international survey on the impact of chronic obstructive pulmonary disease [COPD] on a working age population. BMC Public Health. 2011; 11(612).
13. National Institutes of Health. Idiopathic Pulmonary Fibrosis. http://ghr.nlm.nih.gov/condition/idiopathic-pulmonary-fibrosis. Accessed September 28, 2016.
14. Lamas DJ, et al. Delayed Access and Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2011; 184(7): 842-847.
15. Hutchinson JP, et al. Increasing Global Mortality from Idiopathic Pulmonary Fibrosis in the Twenty-First Century. Annals of the American Thoracic Society. 2014; 11(8): 1176-1185.