PRECISION MEDICINE FOR IPF: DREAM OR REALITY?

IMRE NOTH, MDCLINICAL 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 Initiative2. 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, TobyPersonalized 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?

“Precision” Treatment of Comorbidities in IPF

• GERD• CAD• Thyroid• OSA• Pulmonary hypertension• Pulmonary embolism• Emphysema• Obesity• Depression and anxiety

B. Axial image

A. Coronal with thickened gastric mucosa above the level of the diaphragm

Noth I, et al Eur Respir J. 2012 Feb;39(2):344-51. Epub 2011 Jul 7.

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, TobyPersonalized 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 CurvesStratified 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, TobyPersonalized 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 52-gene 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) Transplant-free 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

Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, TobyPersonalized medicine in idiopathic pulmonary fibrosis: facts and promises. Current Opinion in Pulmonary Medicine. 21(5):470-478, September 2015.

The Future – can we integrate these data?

WGCNA Modules with EMT and T-cell Regulation, Map to Altered Lung Microbial Community

Spagnolo, Paolo; Tzouvelekis, Argyris; Maher, TobyPersonalized 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

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Chicago

Pelito et al JAMA 2013

• 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 StudyIPF 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.

*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.

IPFpatientsn = 341

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NAC alone*n = 131

Placebo*n = 131

Prednisone, azathioprine,and NAC (n = 77)

60-week follow-up

1o endpoint: FVC

2o endpoint:Death; acuteexacerbation;

diseaseprogression

STOP

PANTHER Part A: Results

Raghu G, et al. N Engl J Med. 2012;366(21):1968–1977.

Combination therapy of prednisone, azathioprine, and NACwas stopped early for evidence of harm

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PANTHER Part B: ResultsNAC alone showed no difference in FVC decline or

any secondary endpoints compared to placebo

Martinez FJ, et al. N Engl J Med. 2014;370(22):2093–2101.

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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?