Treatment of Pulmonary Hypertension in COPD patients

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1 Treatment of Pulmonary Hypertension in COPD patients Airway Vista, March 26, 2017 Norbert F, Voelkel, Affiliate Professor Frije University Amsterdam

2 Speculation The prevailing dominant emphasis on the airways (bronchial wall thickness and FEV1) is likely explained by the availability of an increasing number of inhaled drugs that target bronchial muscle tone and bronchial inflammation. A therapeutic nihilism stating that the PH in COPD can t be treated ---contributes to the lack of interest in PH in COPD patients.

3 Rationale Dyspnea is a symptom of COPD and of PH. Exercise limitation or intolerance is a symptom of PH and of COPD.

4 Portillo K. et al, 2015: Resting and exercise induced PH

5 Treatment of PH 1) Reduction of hyperinflation tiotropium 2) Prevention of pulmonary embolism 3) Inflammation/immune imbalance 4) Improvement of right heart function

6 Pathophysiology Figure 1 Inhiibition of vasoconstriction is problematic

7 Outline Hypothesis :Tiotropium, can decrease hyperinflation, likely by decreasing inflammation LTA4 hydrolase inhibitor bestatin, ubenimex inhibits LTB4 synthesis Inhaled Iloprost can reverse myocardial fibrosis Exercise improves cardiac function

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9 Tiotropium & Pulmonary Vascular Disease A PubMed search found not a single publication---including experimental PH models. Disease modification by inhibiting inflammation.

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13 BA Lavage Serum

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15 Is it macrophage produced LTB4 that is critical? Clodronate kills selectively macs in vivo.

16 Are Leukotrienes involved in? an academic exercise of running in circles.

17 Bestatin/Ubenimex Inhibitor of LTA4 hydrolase= aminopeptidase

18 Bestatin

19 Ubenimex for PAH Clinical Liberty Trial-a proof of concept Phase 2 study 45 PAH patients are randomized 2:1 (ubenimex [150 mg p.o. TID for 24 wks] vs placebo), double blind study. 44 recruiting centers WHO PAH Group I, NYHAC-FC II & III; all patients must be on at least one PH drug. Primary endpoint: PVR change Rationale:1) bestatin works in a model of severe PAH [Sugen, sc. In athymic rats], 2) there is a favorable risk/benefit ratio.

20 Human serum LTB4 levels

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23 From Start of proof of concept studies and $150K later the start of first clinical trial : 3 years. First PAH patient enrolled in LIBERTY trial Bestatin/ubenimex December of 2016

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26 Inhaled iloprost Rats with established severe PAH were treated 3 times/day with INHALED iloprost. Hypothesis: improvenent of right heart function.

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34 Volume (ml) Volume (ml) RV cavity LV epicardium LV cavity Right ventricle (RV) ml SV 65 ml EF 32% Median Change: EF +8% (P=0.028) SV +14 ml (P=0.028) Diastolic 207 ml SV 86 ml EF 38% RV cavity ml Systolic 130 ml 50 End-diastole Figure. Six patients with severe PAH and RV failure completed the 6-month open label study with carvedilol. Sample cardiac MR images are shown: a short axis midventricular section of the left ventricle (LV) and right ventricle (RV) is shown in the left panels, without delineation of the cavity and epicardium in the top left panel and with delineation of RV cavity (yellow), the LV cavity (red) and the LV epicardium (green). The 3D reconstruction of the RV cavity and LV epicardium and cavity is shown in the right panel using the CVI42 software. All patients experienced an improvement in right ventricular ejection fraction (RVEF), RV stroke volume (SV) and all but one patient had an increase in left ventricular (LV) stroke volume. Median values are shown in the column graphs. Baseline Left ventricle (LV) ml SV 54 ml EF 58% 39 ml After Carvedilol Median Change: EF -2% (P=0.90) SV +12 ml (P=0.046) Diastolic Systolic 105 ml SV 70 ml EF 62% 50 ml

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36 Summary & conclusion We need a greater focus on the PH phenotype of COPD. We do not really understand Cor Pulmonale. A suspicion of significant PH and RV dysfunction can be supported by measuring BNP. Supplement. O2 and exercise are accepted treatment strategies. There is a rationale for experimental treatment with existing drugs like ubenimex, inhaled iloprost.statins, carvedilol.

37 Conclusion Instead of practicing a form of depressing therapeutic nihilism----we should design clinical trials which investigate whether anti-inflammatory drug effects and cardiotonic drug effects have an impact on PVR and RVEF in patients with COPDassociated PH.

38 Acknowledgement Harm Jan Bogaard Mark Nicolls Antonio Abbate, Daniel Grinnan Jose Gomez-Arroyo Ayser Al Husseini Donatas Kraskauskas

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