PRECISION MEDICINE FOR IPF:
DREAM OR REALITY?
IMRE NOTH, MD
CLINICAL CARE: NEW AND EVOLVING TREATMENT
STRATEGIES
NOVEMBER 14, 2015
What is “Precision” Medicine?
• Precision medicine is an emerging approach for disease treatment and
prevention that takes into account individual variability in genes,
environment, and lifestyle for each person.
– Environment/Lifestyle
– Genes
– Treatments
• “IPF, like other complex, multipathway diseases, has the potential to benefit
from developments in personalized care in several ways, including
identification of individuals at risk, development of more accurate and less
invasive diagnostic tools, improved understanding of the multitude of
profibrotic pathways involved in disease biology, identification of therapeutic
targets and improved early phase clinical trial design, prediction of outcome
and prioritization of lung transplant and prediction of response to treatment
(e.g. efficacy and toxicity markers). The availability of effective therapeutic
options for patients with IPF makes the need for markers of diagnosis,
prognosis and disease behavior greater than ever”
1. NIH Precision Medicine Initiative
2. Spagnolo P, Tzouvelekis A, Maher TM. Personalized medicine in idiopathic pulmonary fibrosis: facts and promises.
Curr Opin Pulm Med. 2015. Sep;21(5):470-8.
Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby
Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary
Medicine. 21(5):470-478, September 2015.
What “Promises/Dreams” for the Future?
• GERD
“Precision” Treatment of
Comorbidities in IPF
• CAD
• Thyroid
• OSA
• Pulmonary hypertension
• Pulmonary embolism
• Emphysema
• Obesity
• Depression and anxiety
A. Coronal with thickened
gastric mucosa above the
level of the diaphragm
Noth I, et al Eur
Respir J. 2012
Feb;39(2):34451. Epub 2011
Jul 7.
B. Axial image
GERD: Improved Survival with Treatment
Lee. AJRCCM. 2011;184:1390-1394.
WRAP trial
• Can Nissen fundoplication alter disease progression
in IPF in patients with positive pH probes?
• Randomized trial.
Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby
Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary Medicine.
21(5):470-478, September 2015.
IPF Patients Had Higher Bacterial Load
than COPD or Healthy Controls
Molyneaux et al; AJRCCM 2014; 190: 906-13
Differences in OTU Frequencies Between
IPF and Control Subjects
Molyneaux et al; AJRCCM 2014; 190: 906-13
IPF Patients in the Tertile With the Highest
Bacterial Load Have Worst Prognosis
Molyneaux et al; AJRCCM 2014; 190: 906-13
Adjusted Event Free Survival Curves
Stratified by Presence of
Staphylococcus & Streptococcus
Han et al; Lancet Respir Med 2014; 2: 548-56
Co-trimoxazole Decreases All Cause Mortality in
Per Protocol Analysis in 181 Fibrotic IIP (89% IPF)
Shulgina et al; Thorax 2013; 68: 155-62
Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby
Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary
Medicine. 21(5):470-478, September 2015.
Figure 2. Hierarchical clustering discriminates subgroups with outcome differences in the replication
cohort (A) Hierarchical clustering of IPF patients from the replication cohort (n=75) based on the 52gene signature found in the discovery cohort to be associated with TFS (FDR<5%, Cox score above 2.5
or below -2.5). Two major clusters of IPF patients were identified. Every row represents a gene and
every column a patient. Color scale is shown adjacent to heatmap in log based two scale – generally,
yellow denotes increase over the geometric mean of samples and purple decrease. (B) Transplantfree survival differs between clusters in the replication cohort. P-value determined by the Log-rank
test.
Herazo-Maya et al Science Trans Med 2013
Herazo-Maya et al Science Trans Med 2013
The Future – can we integrate these data?
Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby
Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary
Medicine. 21(5):470-478, September 2015.
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Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, Toby
Personalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary
Medicine. 21(5):470-478, September 2015.
TLR3 and IPF
Figure 5. The Toll-like receptor 3 L412F polymorphism is associated with accelerated disease progression in idiopathic
pulmonary fibrosis (IPF). FVC is an established measure of disease progression in IPF. The longitudinal rate of decline in
FVC (% of predicted value) in variant-CT/TT genotype patients with IPF compared with CC genotype wild-type patients
is significantly greater at 48 weeks and 96 weeks follow-up, respectively. Absolute difference of −7.1% (P = 0.012) and
−8.9% (P = 0.024) change from baseline % predicted.
O’Dwyer et al. Am J Respir Crit Care Med 188, 1442-1450.
MUC5B, a Genetic Determinant of
Survival in Idiopathic Pulmonary Fibrosis
Chicago
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1000
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0
500
1000
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• Multivariable analysis of
known variables
associated survival
– FVC%, DLCO%, Age,
Gender, tobacco
• TOLLIP (HR 1.72) and
MUC5B (HR 1.70)
maintained significance
Additive Predictive Value of
TOLLIP and MUC5B
KM plot for TOLLIP*/MUC5B risk alleles. Black =0,0 Blue = 0,1 (presence of
risk alleles in both TOLLIP and MUC5B) Green = 1,0 Brown = 1,1 Red = 2,0
(absence of risk alleles in both TOLLIP and MUC5B). *homozygote minor
cases in TOLLIP not included.
“Precision” therapy by genotype?
PANTHER Study
IPF patients ages 35–85 years with FVC ≥ 50%, DLco ≥ 3% were randomized
to either N-acetylcysteine (NAC) alone; prednisone, azathioprine,
and NAC combination; or placebo. Combination therapy stopped early.
NAC alone*
n = 131
IPF
patients
n = 341
R
Prednisone, azathioprine,
and NAC (n = 77)
Placebo*
n = 131
1o endpoint:
FVC
STOP
2o endpoint:
Death; acute
exacerbation;
disease
progression
60-week follow-up
*At time of clinical alert, NAC alone (n = 81) and placebo (n = 78).
PANTHER = Prednisone, Azathioprine and N-acetylcysteine: A Study That Evaluates
Response in IPF; FVC = forced vital capacity.
Raghu G, et al. N Engl J Med. 2012;366(21):1968–1977. Martinez FJ, et al. N Engl J Med. 2014;370(22):2093–
2101.
PANTHER Part A: Results
Combination therapy of prednisone, azathioprine, and NAC
was stopped early for evidence of harm
1.0
Probability of death
or hospitalization
0.9
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0.8
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0.7
0.6
0.5
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Raghu G, et al. N Engl J Med. 2012;366(21):1968–1977.
60
PANTHER Part B: Results
NAC alone showed no difference in FVC decline or
any secondary endpoints compared to placebo
0
FVC (liters)
−0.05
−0.10
Acetylcysteine
−0.15
−0.20
Baseline
Placebo
15
30
Week
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093–2101.
45
60
NAC Effectiveness by TOLLIP Genotype
Composite endpoint of FVC decline, hospitalization,
death or transplant
Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA,
Valenzi E, Witt L, Lee C, Vij R, Huang Y, Strek ME, Noth I. Am J Respir
Crit Care Med. 2015 Sep 2.
Conclusions
•
•
•
•
“Precision” in IPF is already a reality and growing
Genetics can predict outcomes
Validated biomarkers have been growing
Treatment strategies focused on comorbidities is a
“precision” approach
• Pharmacogenomics – is it possible that we’ll treat IPF
the same way we do breast cancer?