Pulmonary Vascular Research Institute

PVRI

4th PVRI Annual Drug Discovery& Development Symposium for

Pulmonary Hypertension

4th PVRI Annual Drug Discovery& Development Symposium for

Pulmonary Hypertension

Programme // Berlin 2017

A few comments from those who attendedour symposium in 2016...

“What a greatsymposium...please let me knowwhen next year’smeeting is.”

“The discussionswere veryprovocative...perhaps

the best part of the meeting.”

“The meeting wasfantastic...thepresentations werefirst rate.”

“This was the finestscientific meeting onpulmonaryhypertension I haveever attended.”

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The pathway to breakthrough therapies...

“I will be attending thismeeting every year......people involved indeveloping therapies forpulmonary hypertensionor right ventricular failureshould not miss this.”

Welcome to our4th Annual DrugDiscovery & DevelopmentSymposium for PulmonaryHypertension

The Drug Discovery and Development for PulmonaryHypertension Symposium is held annually each summer tobring leading scientists, in the fields of pulmonary vasculardisease, right heart failure, and clinical trial designs, togetherwith the pharmaceutical industry and regulatory authoritiesto help identify the most promising treatments for futuredevelopment. For each meeting we assemble a faculty withexceptional achievements and expertise, and choose topicsin areas that will influence the development of therapiesimmediately. Each topic will be critically reviewed by anexpert panel and open dialogue will allow your voice to beheard. Attendees will experience how novel therapies canbest be developed towards successful clinical trials from theinput of the world’s leading authorities.

This symposium serves as a unique forum for stakeholdersinterested in the treatment of pulmonary vascular diseasesfor the sharing of cutting-edge science with the input ofinternational thought leaders.

For researchers involved in the treatment of pulmonaryhypertension this meeting should stimulate new ideas andapproaches.

For the pharmaceutical and biotechnology industries thathave an interest in pulmonary vascular diseases, right heartfailure or orphan diseases, it is a meeting that should not bemissed. The meeting is designed to allow opportunities forinteraction among colleagues during sessions and at theevening reception.

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Pulmonary Vascular Research Institute

PVRI

Professor Paul A Corris MD

President PVRINewcastle, UK

Introducing ourCo-Chairs...

Stuart Rich

Dr Stuart Rich is a Cardiologistand Director of NorthwesternMedicine’s Pulmonary VascularDisease Programme at the BluhmCardiovascular Institute and a

Professor of Medicine,Northwestern University Feinberg

School of Medicine, USA.

Dr Rich is one of the world’s most recognised experts onpulmonary vascular diseases. For more than threedecades he has dedicated his research and clinical effortsto finding better solutions for pulmonary hypertension.

Dr Rich completed his residency training in medicine atWashington University in St Louis, and fellowship incardiology at the University of Chicago. His career beganat the University of Illinois where he was principalinvestigator for the National Institutes of Health (NIH)Registry on Primary Pulmonary Hypertension, the first ofits kind, and has been the leader of the largest clinicalcentre in the US for evaluating and treating patients withpulmonary hypertension since 1980. Dr Rich hasconducted cutting-edge research on the molecularmechanisms, epidemiology, clinical presentation, naturalhistory and treatments of the disease and been at theforefront of the development of virtually every newtreatment for pulmonary hypertension, as well as the useof therapeutic procedures and devices. His pioneeringresearch has led to a greater understanding of all types ofpulmonary hypertension.

He has published hundreds of clinical articles and bookchapters on pulmonary hypertension and is a foundingmember of the Pulmonary Vascular Research Institute, aglobal health professional organisation committed tobringing advances in treating pulmonary vascular diseasesto the world. In 2014, he received the Heart for HopeLegacy Award from the Pulmonary HypertensionAssociation and in 2015 he was awarded the LifetimeAchievement Award from the Pulmonary VascularResearch Institute.

Dr Rich’s clinical interests include: pulmonaryhypertension, pulmonary vascular disease, pulmonarythromboembolism, adult congenital heart disease, rightheart failure and complex and rare forms of heartdiseases.

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John Newman

Dr John Newman,together withDr James Loyd, isco-founder of thePulmonaryCirculation Center at

Vanderbilt PulmonaryCirculation Center, USA.

The centre has conducted a continuousclinical research programme ofphenotyping and genotyping patients withpulmonary hypertension for more than30 years.

Dr Newman authored the New EnglandJournal of Medicine paper, reporting thenovel insights in BMPR2 and clinicalpresentation from the largest known familywith heritable PH.  He mentors and assistsin the development of multiple fellows andfaculty in studies of pulmonaryhypertension, leading Vanderbilt to a largecomprehensive pulmonary hypertensionprogramme spanning clinics, clinical trialsand genomics and signalling studies. He isfunded by NIH, together with Co-investigator Dr Anna Hemnes, for studies inthe metabolic syndrome through the NIHPO1 and the NIH PVDOMICS network.

Dr Newman, together with John Phillips, isalso Co-primary Investigator of the newUndiagnosed Disease Network atVanderbilt, a multicentre programme todiagnose ultra-rare diseases. He is Presidentof the CMREF, a non-profit fund thatconceived and supports the PulmonaryHypertension Breakthrough Initiative(PHBI), which is a consortium that harvestsPH lungs during transplantation andcoordinates scientific studies on the tissues,DNA, cells and fluids from these lungs.Dr Newman and Dr Rizwan Hamid foundthe variant in HIF2a that causes Brisketdisease in cattle, a form of high altitudepulmonary hypertension.

Ardeschir Ghofrani

Dr Ardeschir Ghofraniis Professor ofPulmonary VascularResearch at JustusLiebig University,Giessen, Germany

and Head of thePulmonary Hypertension

Division at the UniversityHospital in Giessen, Germany.

Professor Ghofrani is also Director ofPneumology, as well as Medical ExecutiveDirector at the Kerckhoff Clinic in BadNauheim, Germany, and part-time Professorfor Pulmonary Vascular Medicine at ImperialCollege, London.

He leads a translational research group ondevelopment of new therapeutics forcardiopulmonary vascular disease and is amember of the steering committee of theExcellence Cluster Cardio-PulmonarySystem (www.eccps.de). He is also a foundingmember of the Pulmonary Vascular ResearchInstitute (www.pvrinstitute.org).

He has participated in the development ofseveral therapeutics for chronic lungdiseases and pulmonary hypertension,including prostanoids, phosphodiesteraseinhibitors, endothelin receptor antagonists,tyrosine kinase inhibitors and stimulators ofthe soluble guanylate cyclase.

Professor Ghofrani has received fourawards for investigations in pulmonaryvascular science, is a Fellow of the EuropeanRespiratory Society (FERS) and a reviewerfor several medical scientific journals.

Pulmonary Vascular Research Institute

PVRI

Monday 10 July 08:30 - 12:30

New Drugs for PulmonaryHypertension Entering Clinical TrialsModerator: John Newman

Expert Panel: Marion Delcroix, Nazzareno Galie

08:30 - 09:30

A Study of Ubenimex in Patients With PulmonaryArterial Hypertension The ‘LIBERTY’ Trial

• Inhibitor of Leukotriene A4 Hydrolase

• ClinicalTrials.gov NCT02664558

• Phase 2 (active)

• Sponsor: Eiger BioPharmaceuticals

• Presenter: Norbert Voelkel, VU University MedicalCenter

09:30 - 10:30

Tocilizumab in the Treatment of Pulmonary ArterialHypertension (TRANSFORM-UK)

• Monoclonal Antibody Against the Interleukin-6Receptor (IL-6R)

• ClinicalTrials.gov NCT02676947

• Phase 2 (open label)

• Sponsor: Papworth Hospital NHS Foundation Trustand Roche Pharma AG

• Presenter: Mark Toshner, University of Cambridge

10:30 - 11:30

ABI-009 for Severe Pulmonary Arterial Hypertension(WHO FC III and IV)

• mTOR Inhibitor (inhibits the mechanistic target ofrapamycin)

• ClinicalTrials.gov NCT02587325

• Sponsor: Aadi, LLC, and University of Pittsburgh

• Presenter: Mark Simon

11:30 - 12:30

UPDATE: Tyrosine Kinase Inhibitors as a Treatment ofPulmonary Hypertension - Lessons Learned and FutureChallenges

• Presenter: Ralph Schermuly, University of Giessen

12:30 - 13:30

Lunch

12:30 - 13:30 Held in Salon Humboldt

PVRI Pharma Task Force Breakout SessionLunch included

• Presenter: Peter Fernandes see p.9 for full agenda

Day 1 // Session 1

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A Study of Ubenimex in Patients withPulmonary Arterial Hypertension:The ‘LIBERTY’ TrialNorbert Voelkel

The ‘LIBERTY ’ trial, sponsored by Eiger Biopharmaceuticals Inc[Palo Alto, CA], is a proof of concept Phase 2 study to assesswhether ubenimex (bestatin) decreases PVR, the primaryendpoint, in WHO Group I PAH patients. The patients arerandomised 2:1, ubenimex vs placebo in a 24 week double blindstudy. The rationale for choosing ubenimex is based on the resultsfrom preclinical studies [Tian W. et al, Sci Transl Med, 2013] andon inhibition of leukotriene A4 synthase (LTA4 synthase), theenzyme responsible for the synthesis of LTB4 and possibly dueto its anti-aminopeptidase activity. The preclinical studiesdemonstrated that LTB4 levels were elevated in the lungs fromseverely pulmonary hypertensive athymic rats and that treatmentof the animals with ubenimex prevented, and reversed, PAH.LTB4 is chemotactic for neutrophils and in the above study wasshown to cause endothelial cell (EC) apoptosis; in culture,inhibition of macrophage LTB4 synthesis by bestatin preventedEC apoptosis. In this PAH disease model in rats that lackT lymphocytes, LTB4 synthesis inhibition hypothetically interruptsthe initial inflammatory trigger of pulmonary vascularmacrophage activation and LTB4 - dependent endothelial celldeath. This mechanism is likely also contributing to the chronicpulmonary vascular inflammation.

A second mechanism of ubenimex action appears to be its abilityto kill abnormal proliferating vascular lumen cells, and a thirdmechanism, so far not experimentally investigated in pulmonaryhypertension models, relates to its aminopeptidase inhibitingproperties. Inhibition of aminopeptidase has been shown toinhibit angiogenesis, and ubenimex is presently used in cancerpatients to synergistically enhance the effects of chemotherapy.

In conclusion: The ‘LIBERTY’ trial repurposes the anti-cancer drugubenimex to target the pulmonary vascular immune response andpotentially angioobliterative vascular remodelling.

Tocilizumab in the Treatment of PulmonaryArterial Hypertension (TRANSFORM-UK)Mark Toshner

Pulmonary arterial hypertension still carries a poor prognosisdespite the therapeutic advances of the last 20 years. Thereremains an urgent need for the development of new treatments,particularly as the results from combination studies of vasoactivetherapies has been, to date, mixed and arguably disappointing 1.The strong association of PAH with dysregulated immunity andinflammation has been established with auto-immune diseases,most prominently scleroderma, but also notably rheumatoidarthritis, SLE and MCTD. Auto-immune diseases are recognisedas causally associated with PAH but there is also an association ofIPAH with auto-immune thyroid disease, links to HLA subtypes 2

and the presence of auto-antibodies 3. IPAH has previously been

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speculated to be an auto-immune disease 4. Within the pulmonaryvascular lesions there is accumulation of inflammatory cellsincluding T and B lymphocytes 5 with altered T regulatory cellfunction 6,7. It is clear that inflammation and dysregulated immunityplay a significant role in a spectrum of causes of PAH. From theperspective of identifying pathways that are targetable, IL-6 hasemerged as a strong candidate. IL-6 is raised in peripheral bloodand within the lung in PAH 5 and is an independent markerof prognosis 8. Over-expression of IL-6 in animal models usingtransgenic mice leads to pulmonary hypertension 9 and in hypoxia,IL-6 deficient mice are protected 10. Tocilizumab is an IL-6 receptorantagonist established as safe, well tolerated and effective,primarily in rheumatoid arthritis and has shown promise inscleroderma 11. We will explore the background rationale for IL-6therapies and outline the trial design of the first phase 2 trial oftocilizumab in selected patients in group 1 PAH.

References

1. Coeytaux RR, Schmit KM, Kraft BD, et al. Comparativeeffectiveness and safety of drug therapy for pulmonary arterialhypertension: a systematic review and meta-analysis. Chest2014;145:1055-63.

2. Barst RJ, Flaster ER, Menon A, Fotino M, Morse JH. Evidence forthe association of unexplained pulmonary hypertension inchildren with the major histocompatibility complex. Circulation1992;85:249-58.

3. Isern RA, Yaneva M, Weiner E, et al. Autoantibodies in patientswith primary pulmonary hypertension: association with anti-Ku.The American journal of medicine 1992;93:307-12.

4. Mouthon L, Guillevin L, Humbert M. Pulmonary arterialhypertension: an autoimmune disease? The Europeanrespiratory journal 2005;26:986-8.

5. Hassoun PM, Mouthon L, Barbera JA, et al. Inflammation, growthfactors, and pulmonary vascular remodelling. Journal of theAmerican College of Cardiology 2009;54:S10-9.

6. Tamosiuniene R, Tian W, Dhillon G, et al. Regulatory T cells limitvascular endothelial injury and prevent pulmonary hypertension.Circulation research 2011;109:867-79.

7. Austin ED, Rock MT, Mosse CA, et al. T lymphocyte subsetabnormalities in the blood and lung in pulmonary arterialhypertension. Respiratory medicine 2010;104:454-62.

8. Soon E, Holmes AM, Treacy CM, et al. Elevated levels ofinflammatory cytokines predict survival in idiopathic and familialpulmonary arterial hypertension. Circulation 2010;122:920-7.

9. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, WaxmanAB. Interleukin-6 overexpression induces pulmonaryhypertension. Circulation research 2009;104:236-44, 28pfollowing 44.

10. Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice.Respiratory research 2009;10:6.

11. Elhai M, Meunier M, Matucci-Cerinic M, et al. Outcomes ofpatients with systemic sclerosis-associated polyarthritis andmyopathy treated with tocilizumab or abatacept: a EUSTARobservational study. Ann Rheum Dis 2013;72:1217-20.

ABI-009 for Severe Pulmonary ArterialHypertension (WHO FC III and IV)Elena Goncharova presented by Mark Simon

Increased proliferation and resistance to apoptosis of pulmonaryvascular cells in small pulmonary arteries (PAs) is a key componentof pulmonary vascular remodelling in PAH, and effective anti-proliferative remodelling-focused therapies are needed.

The mechanistic (formerly mammalian) target of rapamycin(mTOR) is a master-regulator of cell metabolism, proliferation andsurvival. mTOR acts through two functionally distinct complexes,mTOR complex 1 (mTORC1), which controls cell growth via p70 S6kinase 1 (S6K1), and mTORC2 that activates Akt and reducesapoptosis. Recent studies from many research groups, includingours, have shown that both mTORC1-S6K1 and mTORC2-Akt areactivated in vascular smooth muscle cells in small remodelled PAs(PAVSMC) in human PAH and experimental PH, which is requiredfor glycolytic energy production, increased apoptosis resistance,cell proliferation, and pulmonary vascular remodelling. mTORinhibition selectively reduces proliferation and induces apoptosisin human PAH PAVSMC, attenuates human PAH PA endothelialcell proliferation and neointimal occlusion of small PAs andreverses or regresses PH in animal models. Our new data show thatmTOR inhibition reverses right ventricle (RV) cardiomyocytehypertrophy and improves RV function in experimental PH.Together these findings strongly suggest potential attractivenessof mTOR inhibition as anti-proliferative remodelling-focusedtherapeutic strategy for patients with PAH.

Rapamycin is an allosteric mTORC1 inhibitor with strong anti-proliferative activity. It is approved by FDA for the prevention ofgraft rejection in kidney transplant recipients, as an anti-restenosisagent following balloon angioplasty in coronary arterial stents andfor the treatment of pulmonary lymphangioleyomyomatosis, andis entered cancer clinical trials as an additive anti-proliferativeagent. Rapamycin prevents development of PH in animal modelsand was well tolerated in pilot clinical trial for patients withidiopathic PAH and chronic thromboembolic pulmonaryhypertension (CTEPH). The challenges of the rapamycin use inhuman PAH lie in its failure to promote apoptosis when given inclinically relevant doses and in clinical risks for adverse side-effectsthat include hyperglycemia, hyperlipidemia, insulin resistance,and increased incidence of new-onset type 2 diabetes andinterstitial pneumonitis.

ABI-009 (nab-Rapamycin) is a long acting nanoparticle humanalbumin-bound formulation of rapamycin with improvedpenetration in lung tissue. ABI-009 has shown preferentialaccumulation in lung, improved effect on cell viability, strongantiproliferative activity in several pre-clinical tumor xenograftmodels and demonstrated significant anti-remodelling effects inporcine model of peripheral artery restenosis. ABI-009 was welltolerated in a phase 1 clinical trial in patients with solid tumors withevidence of responses in renal cell carcinoma and bladder cancer,both of which typically have up-regulated mTOR. Despite higherdoses, the safety and pharmacokinetic profile compared favorablyto oral rapamycin (historical comparison).

Based on pre-clinical evidence of improved lung accumulation,anti-remodelling potential and better safety profile, AADi, LLC andthe University of Pittsburgh are initiating a clinical trial of ABI-009as antiproliferative therapy for patients with severe PAH. This is a

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phase 1 single arm, open-label dose-escalation study. Enrolleesare 18 years or older with a current diagnosis of WHO Group 1PAH, receiving background therapy and without other majorcomorbidities, (e.g. heart or liver disease, malignancy),uncontrolled diabetes mellitus or hyperlipidemia. ABI-009 will beadministrated once weekly for 16 weeks. The primary outcomesare maximum tolerated dose, dose limiting toxicities and safetyprofile of 16 weeks ABI-009 given IV. As secondary endpoints,pulmonary vascular resistance by right heart catheterisation,pulmonary artery pressure, pulmonary artery occlusion pressure,pulmonary capillary wedge pressure, and central venous pressurewill be measured. Other metrics will include Doppler-echocardiographic assessments of right ventricular structure andfunction, six-minute walk distance, WHO functional class, andpulmonary function test. Exploratory objectives are to evaluatepharmacokinetic information that may be correlated with safetyand/or efficacy observations. If effective, the ABI-009 dose forphase 2 study will be determined and phase 2 study will beplanned.

UPDATE: Tyrosine Kinase Inhibitors as aTreatment of Pulmonary Hypertension -Lessons Learned and Future ChallengesRalph Schermuly

Pulmonary arterial hypertension (PAH) is a disease of smallpulmonary arteries that results in increased pulmonary vascularresistance and right heart hypertrophy. There has been enormousprogress in the understanding of the mechanisms of pulmonaryvascular remodelling that led to the introduction of vasoactivedrugs like prostanoids, endothelin antagonists, andphosphodiesterase 5 inhibitors for treatment of PAH. Thesecompounds either alone or in combination improvehaemodynamics, exercise capacity, and survival of patients withPAH, but are not able to reverse the disease. Based on theobservation that dysregulated proliferation, apoptosis,inflammation, and metabolism underlie pulmonary vascularchanges, the functional importance of several new signallingpathways has been described in preclinical and clinical studies 1.Among them, the dysregulation of growth factors and theirrespective receptors in pulmonary vascular diseases gainedattention. The binding of growth factors like epidermal growthfactor, fibroblast growth factor, or platelet-derived growthfactor (PDGF) to their corresponding receptor tyrosine kinase(RTK) activates a complex signalling network, which results inproliferation and survival of cells. With the introduction ofRTK inhibitors in the field of cancer, the efficacy of thesecompounds was also investigated in nonmalignant diseases 2. Inthis line, the RTK inhibitor imatinib was shown to reverseexperimental pulmonary hypertension (PH) via inhibition ofPDGF receptor (PDGFR) 3 and to improve hemodynamics inpatients with PAH 4,5.

References

1. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F.Mechanisms of disease: pulmonary arterial hypertension. Nat RevCardiol 2011;8:443–455.

2. Grimminger F, Schermuly RT, Ghofrani HA. Targeting non-malignant disorders with tyrosine kinase inhibitors. Nat Rev DrugDiscov 2010;9:956–970.

3. Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, RothM, Sydykov A, Lai YJ, Weissmann N, Seeger W, et al. Reversal ofexperimental pulmonary hypertension by PDGF inhibition. J ClinInvest 2005;115:2811–2821.

4. Ghofrani HA, Morrell NW, Hoeper MM, Olschewski H, PeacockAJ, Barst RJ, Shapiro S, Golpon H, Toshner M, Grimminger F, et al.Imatinib in pulmonary arterial hypertension patients withinadequate response to established therapy. Am J Respir Crit CareMed 2010;182: 1171–1177.

5. Ghofrani HA, Seeger W, Grimminger F. Imatinib for the treatmentof pulmonary arterial hypertension. N Engl J Med2005;353:1412– 1413.

Day 1 // Session 2

Monday 10July 13:30 - 17:30

Novel Drugs for Pulmonary VascularDiseases Ready for Clinical TrialsModerator: Ardeschir Ghofrani

Expert Panel: Jean-Luc Vachiery, Laura Price

13:30 - 14:30

KAR5585

• The Serotonin Hypothesis Revisited-Clinical Implications

for TPH1 Inhibition

• ClinicalTrials.gov NCT02746237

• Phase 1 Completed

• Sponsor: Karos Pharmaceuticals

• Presenter: Mandy MacLean, University of Glasgow

14:30 - 15:30

MFC1040

• MIF inhibitor that Blocks Vascular Cell Proliferation and

Perivascular Inflammation

• Orally Available, Small Molecule Antagonist of MIF

• Sponsor: MIFCARE

• Presenter: Marc Humbert, Université Paris-Sud

15:30 - 16:30

CXA-10 (10-nitro-oleic-acid) for Pulmonary Hypertension

• Modulator of Nrf2 and NF-KB,

• Phase 1 Completed, Phase 2 Planned

• Sponsor: Complexa Inc

• Presenter: Tanja Rudolph, University of Cologne

16:30 - 17:30

Inhaled Sodium Nitrite in Pulmonary Hypertension Associated

with Heart Failure with Preserved Ejection Fraction

• ClinicalTrials.gov NCT01431313

• Phase 2 Trial Completed

• Sponsor: Mast Therapeutics and NIH

• Presenter: Marc Simon, University of Pittsburgh

17:30 - 17:45

Demonstration of the PVRI ‘Digital Clinic’

• Presenters: Martin Johnson, Colin Church,

University of Glasgow

17:45 - 19:00

Cocktail Reception

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PVRI Pharma Task ForceBREAKOUT SESSION AGENDAPeter Fernandes

12:30 - 13:30 Held in Salon Humboldt

Lunch included

Discussion on two key initiatives (work inprogress)

Initiative 1Harmonise Innovative Approaches Through Clinical TrialDesigns, Endpoints, Biomarkers Peter Fernandes, Sylvia Nikkho, Larry Zisman

OverviewThe PVRI Pharma Task Force’s mission is to create and provide aplatform for early and continuous dialogue on innovative clinicaland regulatory development strategies where there is free andopen discussion between Pharma, Academics and RegulatorsWorldwide.

One of the goal of the PVRI Pharma Task Force is to investigatepossible approaches for small population clinical trials fordeveloping orphan drugs in the field of pulmonary hypertension(PH). Such approaches should be directed towards ultimatelymaking safe and effective therapies available to these critically illpatients in a timely manner. In order to maximise the scarceresources available for recruiting subjects for clinical trials in rarediseases, there is a critical need to coordinate and harmoniseinnovative approaches through clinical trial designs, endpoints,biomarkers, translational research, and enrichment strategies.

In order to further encourage and support this mission, a PVRIPharma Steering Committee was formed in February 2017. Thiscommittee will foster and facilitate the creation of this platformto gather the relevant information and organise workshops withPharma, Academic and Regulators to discuss and harmonise thesepossible options and solutions in a non-competitive manner.

We will present the preliminary concepts of this initiative (workin progress) for your feedback and discussion and will solicitvolunteers to help take this to the next level.

Initiative 2Matching Industry Projects/Interests with IndividualInvestigator Interests and Core StrengthsAndrew Nelson, Jonathan Langley

OverviewA summary document articulating research interests amongstindustry partners and academic members will be presented. Thisdocument will include top line areas of interest, as well as contactinformation. We will present the concepts of this research interestdocument for feedback and discussion, with the objective ofdissemination to the broader PVRI Industry-Academia.

The current goal would be to populate this with industry andacademics similar weighted information and then post it on thePVRI website. This should be accompanied by a search tool for thepage so one could then peruse at leisure matching interests.

We can get more sophisticated as we develop this tool. We lookfor your support to populate this document and to take this to thenext level.

The Serotonin Hypothesis Revisited-ClinicalImplications for TPH1 InhibitionMandy MacLean

The serotonin hypothesis of pulmonary hypertension (PAH) aroseafter an outbreak of PH in patients taking the anorexigenic drugsaminorex and dexfenfluramine. These are serotonin transporter(SERT) substrates and indirect serotinergic agonists. There hasbeen accumulating evidence over the last 20 years implicatingserotonin in the pathobiology of PH. In human pulmonary arteries,serotonin is synthesised by tryptophan hydroxylase 1 (TPH1) inendothelial cells and acts at the 5-HT1B receptor and the SERT tomediate constriction and proliferation of pulmonary artery smoothmuscle cells (PASMC). Serotonin has been shown to cause lunginflammation, apoptosis, fibrosis, PASMC migration, contractionand proliferation in models of PH. This makes inhibition ofserotonin an attractive concept for PH treatment. Indeed of theover 700 papers published on the potential role of serotonin inPAH, less than 0.006% suggest that it does not play a pathogenicrole. In the 1980s, the hypothesis was however somewhatdismissed because ketanserin, a 5HT2A antagonist, failed toreduce pulmonary pressures in PH patients and indeed causedsystemic hypotension. However this approach was driven by theassumption that it is the 5HT2A receptor that mediated the effectsof serotonin. Indeed, in rats, this is the case. However, in the humanpulmonary artery it is the 5HT1B receptor in cooperation with theSERT, whilst only systemic arterial constriction is mediated by the5HT2A receptor. Serotonin may also interact with the bonemorphogenetic receptor type II (BMPRII) to provide a ‘second hit’risk factor for hPAH. Proliferation to serotonin in hPASMCs is inpart due to serotonin-induced, Nox-dependent oxidative stress. InhPASMCs, estrogen can upregulate TPH1, SERT and 5HT1Bexpression and in some models of PH, serotonin can causepathogenic dysregulated estrogen syntheses. 5HT1B receptorexpression is extremely highly upregulated in human distalhPASMCs from female PAH patients, in an oestrogen-dependentfashion, and mediates proliferation that can be reduced either by5HT1B antagonists or microRNA96 which targets the gene for5HT1B. Pharmacology dictates that to treat PH you would eitherneed to inhibit both the SERT and the 5HT1B receptor together orinhibit serotonin synthesis. We are not aware of drugs that willinhibit both the 5HT1B receptor and SERT and so targetingserotonin through its synthesis is an attractive option. Severalpapers have demonstrated that TPH1 is the rate limiting step inthe synthesis of peripheral serotonin and inhibition of this leavesthe central effects of serotonin intact. Many studies have shownthat inhibition of TPH1 has either protected or reversedexperimental PH and that TPH1 knockout mice are protectedagainst hypoxia-induced PH. PAH patients with greaterhaemodynamic impairment show significantly reduced serotoninplasma levels after imatinib treatment compared with placebo andthis has been attributed to imatinib-induced TPH1 down-regulation via inhibition of PDGFR-ß signalling. A very recent studyconvincingly demonstrates the effectiveness of the novel TPH1inhibitor KAR5585 in the monocrotaline and sugen/hypoxic ratmodels of PH. This compound is reported to demonstrate a dose-dependent reduction in serotonin synthesis with excellent safety,tolerability and robust pharmacokinetics. Hence there isconvincing evidence and some anticipation that TPH1 inhibitionmay be an effective new approach for the treatment of PH.

Preclinical Studies of a New Potent OrallyActive Antagonist for the MIF-CD74 Axis inDevelopment for Pulmonary HypertensionMarc Humbert

Background: We have recently identified that macrophagemigration inhibitory factor (MIF) and its signalling through CD74are key players at the crossroad of inflammation, cancer-likephenotype and endothelial dysfunction in the pathogenesis ofpulmonary hypertension (PH). Although several classes of smallmolecule MIF inhibitors have been described in the literature, nonehave yet been approved for clinical use. Therefore, we havedesigned and synthetised a new potent orally active antagonist, N-(phenylmethyl)-benzoxazol-2-thione 29, and herein we investigateits chronic pharmacological effect in PH in vitro and in vivo.

Methods and Results: We have used an integrated approach toscreen 26 new bioactive compounds for their ability to attenuateDU-145 cell survival, a human cancer cell line that requires MIF-CD74 activated signal transduction pathways for their cell survival.The best response was achieved with the N-(phenylmethyl)-benzoxazol-2-thione 29, an observation that was replicated invitro, with cultured pulmonary endothelial cells (ECs) from patientsidiopathic PH exhibiting diminished sensitivity to apoptoticinduction. Interestingly, we found a beneficial curative effect ofchronic treatment with N-(phenylmethyl)-benzoxazol-2-thione 29in two pre-clinical models of severe PH, namely monocrotaline(MCT) and the SU5416-hypoxia (SuHx) rat models. Compound 29showed significant protective effect against PH as it delayeddisease progression, decreased values of mean pulmonary arterialpressure, pulmonary vascular resistance, degree of pulmonaryvascular remodelling and reversed right ventricular hypertrophy.

Conclusion: Our study demonstrates the in vitro and in vivoefficacy of N-(phenylmethyl)-benzoxazol-2-thione 29, a new orallybioavailable MIF/CD74 antagonist. Additional optimisation ofactivity and drug properties of this compound are ongoing.

Keywords: Inflammation; Pulmonary vascular remodelling; Cell survival;Migration inhibitory factor; CD74; Therapeutic innovation.

CXA-10 (10-nitro-oleic-acid) for PulmonaryHypertensionTanja Rudolph

Pulmonary arterial hypertension (PAH) is characterised by adverseremodelling of pulmonary arteries. Although the origin of thedisease and its underlying pathophysiology remain incompletelyunderstood, inflammation has been identified as a central mediatorof disease progression. Oxidative inflammatory conditions supportthe formation of electrophilic fatty acid nitroalkene derivatives,which exert potent anti-inflammatory effects. The current studyinvestigated the role of 10-nitro-oleic acid (OA-NO2) in modulatingthe pathophysiology of PAH in mice. Mice were kept for 28 daysunder normoxic or hypoxic conditions, andOA-NO2 was infusedsubcutaneously. Right ventricular systolic pressure (RVPsys) wasdetermined, and right ventricular and lung tissue was analysed.

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The effect ofOA-NO2 on cultured pulmonary artery smoothmuscle cells (PASMCs) and macrophages was also investigated.Changes in RVPsys revealed increased pulmonary hypertension inmice on hypoxia, which was significantly decreased by OA-NO2administration. Right ventricular hypertrophy and fibrosis werealso attenuated by OA-NO2 treatment. The infiltration ofmacrophages and the generation of reactive oxygen species wereelevated in lung tissue of mice on hypoxia and were diminishedbyOANO2 treatment. Moreover, OA-NO2 decreased superoxideproduction of activated macrophages and PASMCs in vitro.Vascular structural remodelling was also limited by OA-NO2.In support of these findings, proliferation and activation ofextracellular signal-regulated kinases 1/2 in cultured PASMCs wasless pronounced on application of OA-NO2. Our results showthat the oleic acid nitroalkene derivative OA-NO2 attenuateshypoxia-induced pulmonary hypertension in mice. Thus, OA-NO2represents a potential therapeutic agent for the treatment of PAH.

Inhaled Sodium Nitrite in PulmonaryHypertension Associated with Heart Failurewith Preserved Ejection FractionMarc Simon

The most common form of pulmonary hypertension (PH) is thatassociated with left heart disease (Group 2 PH, PH-LHD), for whichthere is no approved therapy. Interventions specifically targetingpatients with PH-LHD have had mixed results, in large part due tophenotypic heterogeneity. Of left heart diseases, heart failure withpreserved ejection fraction (HFpEF) is perhaps the most prevalentand also suffers from a lack of specific therapies. Chronicallyelevated pulmonary venous pressures from left ventriculardiastolic dysfunction may result in pathological pulmonaryvascular remodelling and PH, referred to as PH with heart failureand preserved ejection fraction (PH-HFpEF). PH-HFpEF isassociated with poor clinical outcomes and may represent aspecific, targetable phenotype for developing therapies. Nitrite(NO2-) is an anion that is reduced to nitric oxide (NO), particularlyduring hypoxia and acidosis, with a half life of about 40 minutes.Preclinical and phase I studies indicate that exogenouslyadministered nitrite is a potent vasodilator.

We performed a phase IIa safety and efficacy trial of the acuteeffects of an inhaled formulation of sodium nitrite oncardiopulmonary haemodynamics in PH-HFpEF patients (definedas mean pulmonary artery pressure ≥25, pulmonary artery wedgepressures [PAWP] >15, and transpulmonary gradient >12 mm Hg)as compared with WHO Group 1 PAH or Group 3 PH patients.Nebulised doses of 45mg and 90mg were administeredsequentially and haemodynamics monitored for 1 hour after eachdose.

Thirty-six patients were enrolled (10 PH-HFpEF, 20 Group 1 PAHpatients on background PH specific therapy, and 6 Group 3 PH).Drug administration was well tolerated. Nitrite inhalationsignificantly lowered pulmonary, right atrial and PAWP, mostpronounced in patients with PH-HFpEF. There was a modestasymptomatic decrease in cardiac output and systemic bloodpressure. Pulmonary vascular resistance decreased only in

Group 3 PH patients. Pulmonary artery compliance increasedsubstantially, particularly in patients with PH-HFpEF. There wasa trend towards improvement in the resistance-compliancerelationship in PH-HFpEF after the administration of inhaledsodium nitrite, associated with the decrease in PAWP. We havesince enrolled an additional 5 PH-HFpEF patients with consistentresults.

Inhaled nitrite appears safe acutely in PH patients and may beefficacious in PH-HFpEF and Group 3 PH primarily viaimprovements in left and right ventricular filling pressures andpulmonary artery compliance. The lack of change in PVR likely maylimit efficacy for Group 1 patients. Currently there is a phase IItrial of inhaled sodium nitrite in HFpEF and a phase II trial of anoral formulation in PH-HFpEF.

Precision Medicine Approach to Rare DiseaseTherapiesKrishna Prasad

Personalised medicine is a move away from traditional medicine(one size fits all approach) and to all patients affected by a diseaseregardless of specific differences in their genetic make-up.Precision medicine tailors medical treatment to the individualcharacteristics of each patient and allows identification ofsubpopulations that differ in their disease susceptibility or in theirresponse to a specific treatment.

There have been several initiatives, collectively and independently,in many countries in Europe. The EMA has a lead role in bringingforward efforts to enhance delivery of safe and efficaciousmedicines across Europe while addressing multiple regulatorychallenges, to support innovation and facilitate clinical trialmethodologies. Within Europe, there is active regulatoryengagement with personalised medicine/precision medicineconcept1 and, efforts include scientific support for drugdevelopment, regulatory guidance, and protocol assistance forSMEs and stakeholders.

Regulatory aspects dealing with rare disease (orphan) therapiesare complex with have geographically varied criteria for orphandesignations. In Europe orphan designation are the remit of theCommittee of Orphan Medicines (COMP)2. The recognition ofmolecular subtypes or genomic subpopulations in many diseaseentities provides new opportunities and challenges. Challengesinclude approaches that are agnostic to traditional diseaseclassification or taxonomy but are mechanism based relating tomolecular heterogeneity, genotype/phenotype interactionsnecessitating moving regulatory paradigms from conventionalRCTs to use of adaptive design studies. The new clinical trialregulation (2016)3 and voluntary harmonisation procedure (forCTAs) have facilitated use of pragmatic clinical trials duringdevelopment and enhanced use of novel trial designs such asbasket and umbrella trials. With rare disease therapies, datageneration in the context of drug development using small studypopulations or novel trial methodologies are at the forefront ofdiscussion between the EMA committees and industry andstakeholders. The biomarker development aspects for rarediseases (and others) are aided by several guidelines generated bythe working parties (SAWP, PGWP4 and CVSWP etc.). Thebiomarker qualification process (from SAWP/CHMP) aidsdevelopment of BMs for use in the regulatory developmentprogrammes (endpoints or surrogates). The PGWP has providedseveral guidance documents5 for genomic biomarker andcompanion diagnostic developments, additionally publishing datademonstrating increasing number of genomic markers indevelopment of approval of new therapies.

The EMA/CHMP have facilitated evaluation and approvalprocesses in Europe to the use of small data sets and offer anumber of opportunities. These include accelerated assessment toaddress unmet medical need, conditional marketing authorisations(CMA) based on emerging data and exceptional circumstances. Thepresentation will show examples of CMAs in certain diseasesubpopulations. The approval process requires close engagementwith stakeholders and academia to facilitate appropriate datagathering and enhancing the post - marketing monitoring. TheEMA/CHMP have adopted to this process successfully leadingglobal regulatory initiatives, including setting regulatory standards

Day 2 // Session 3

Tuesday 11 July 08:30 - 12:45

Issues and Challenges in ClinicalTrials for Pulmonary VascularDiseasesModerator: Stuart Rich

Expert Panel: Gérald Simonneau, Joanna Pepke-Zaba

08:30 - 09:30

Precision Medicine Approach to Rare Disease Therapies.

The European Medicines Agency View.

• Presenter: Krishna Prasad, Member, Cardiovascular

Working Party, The European Medicines Agency

09:30 - 10:30

UPDATE: Strategies to Alter miRNA Expression that can

be Employed in Clinical Trials for Pulmonary Vascular

Disease and Right Ventricular Failure.

• Presenter: Stefanie Dimmeler, University of Frankfurt

10:30 - 11:30

Peripheral Balloon Angioplasty in the Treatment of

CTEPH: Review of the Clinical Experience.

• Presenter: Christoph Wiedenroth, Kerckhoff-Klinik,

Bad Nauheim

11:30 - 12:30

UPDATE: Implantable Drug Delivery Pumps for Chronic

Intravenous Therapies for Pulmonary Vascular Disease

and Right Ventricular Failure.

• Presenter: Manuel Richter, University of Giessen

12:30 - 12:45

INTRODUCTION & KEY INITIATIVES:

The PVRI/Pharma Taskforce Leader

• Presenters:

Paul Corris, President of the PVRI

Peter Fernandes, PVRI Pharma Task Force Lead

12:45

Adjourn

12

as well as setting the norms for pharmacogenomic studies duringpharma covigilance evaluation. The presentation will discusssome exemplars and identify some successful approaches whileidentifying the challenges. Newer initiatives such as adaptivedesign trials and PRIME initiative6 are taking shape and beingtaken up eagerly by several stakeholders. The recent workshopon personalised medicine in collaboration with patient groupsis an example of ongoing efforts.

Requirements for rare disease therapies and their development tosucceed include the need for understanding of multiple facetsincluding causality, disease prevalence, inheritance patterns andpenetrance, and availability of targeted agents including advancedtherapy medical products (ATMPs) or gene therapies. Thepresentation will discuss the potential for development of ATMPsor other therapies using a combined traditional and advancedmethodology approach including omics technologies particularlyin rare diseases. 1 https://ec.europa.eu/research/health/pdf/event06/13052011/marisa-papaluca-

amati_en.pdf

2 http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000263.jsp

3 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000629.jsp

4 http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CHMP/people_listing_000018.jsp&mid=WC0b01ac0580028d91

5 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000411.jsp&mid=WC0b01 ac058002958

6 http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/

general_content_000660.jsp

UPDATE: Strategies to Alter miRNAExpression that can be Employed in ClinicalTrials for Pulmonary Vascular Disease andRight Ventricular FailureStefanie Dimmeler

Recent studies suggest that the majority of the human genome istranscribed, but only ≈2% account for protein coding exons. Theremaining noncoding sequences include small noncoding RNAs,particularly microRNAs, which are ≈22 nucleotides in length.MicroRNAs posttranscriptionally control gene expression bytargeting multiple mRNAs. By binding to the 3’UTR (untranslatedregion) of mRNAs, microRNAs induce degradation of the targetedmRNA or they block protein translation. Thereby, one microRNAis able to repress up to hundreds of genes in parallel. In addition toit, long noncoding RNAs (lncRNAs) with a length of >200nucleotides comprise a more heterogenic class of noncoding RNAsthat include, for example, intergenic lncRNAs, antisensetranscripts, and enhancer RNAs. LncRNAs primarily act asepigenetic and transcriptional regulators but may also haveadditional functions as microRNA sponges or regulators of splicing.Finally, alternative splicing can lead to the formation of circularRNAs, which are highly stable RNAs that may act as microRNAsponges. Among the noncoding RNAs, many of them weredescribed to control the cardiovascular system and may comprisenovel therapeutic targets for the treatment of cardiovasculardiseases. However, targeting coding RNAs is far more advanced incomparison to noncoding RNAs and has Food and Drug Agency–

approved products. The tools to target coding mRNAs includedifferent flavours of antisense oligonucleotides (ASO). Silencingcan be achieved by morpholinos or GapmeRs with phosphothioatebackbone linkages or silencing RNAs (siRNAs), which are double-stranded RNAs (≈18–30 base pairs in length) that are chemicallymodified, for example, by 2’O-methyl nucleotides to increasestability and limit immunogenicity. Locked nucleic acids (LNAs) areRNA nucleotides with an extra bridge connecting the 2’ oxygen and4’ carbon in the ribose sugar, which increases the meltingtemperature and, thereby, augments the efficiency. Most clinicalstudies used such agents to target genes expressed in liver to eithertreat liver or metabolic diseases (for review, see Sehgal et al ). Forexample, siRNA- mediated silencing of PCSK9, an enzyme thatregulates cholesterol transport and is highly expressed in livertissue, was recently reported to efficiently reduce low-densitylipoprotein cholesterol and was safely used in a phase I clinical trial.Thus, one may consider using these or other approaches also fortargeting the noncoding genome.

Peripheral Balloon Pulmonary Angioplasty inthe Treatment of CTEPH: Review of theClinical ExperienceChristoph Wiedenroth

Multiple clinical guidelines recommend pulmonaryendarterectomy (PEA) as the therapy of choice in the treatment ofchronic thromboembolic pulmonary hypertension (CTEPH)patients. Since 1/3 of all CTEPH patients are not amenable tosurgery, treatment alternatives are needed: currently, riociguat, asoluble guanylate cyclase stimulator, is available in many countriesas the only approved drug for inoperable CTEPH patients.

Balloon pulmonary angioplasty (BPA) is an evolving interventionalapproach for selected, inoperable CTEPH patients. Since the firstpublication of 18 patients in 2001, substantial improvements tothe technique have been made. Recently, BPA is performedregularly in various centres worldwide. In addition, hybridprocedures combining PEA with intraoperative BPA for carefullyselected patients have been described.

Recent publications from BPA centres reported promisingimprovements in pulmonary haemodynamics and physicalcapacity. Complication rates vary inbetween different studies,including vascular injury, bleeding and reperfusion oedema, beingthe most important. Mortality rates up to 10 % have beendescribed, but may actually be around 2 to 3 %. Until today, thereis no standardised BPA technique: patient and target-vesselselection, imaging modality, monitoring and clinical follow-upvaries among different centres.

Despite mid-term data are indicating BPA may be a promisingtherapy for patients with inoperable CTEPH, it is not yetconsidered an established procedure, because of limited long-termdata and a lack of controlled, multicentre trials.

However, data from national and international registries are stilloutstanding and standardisation of indication, definition ofcomplications and the interventional concepts are needed togenerate more evidence.

13

14

UPDATE: Implantable Drug Delivery Pumpsfor Chronic Intravenous Therapies forPulmonary Vascular Disease and RightVentricular FailureManuel Richter

Pulmonary hypertension (PH) is characterised by increasedpulmonary vascular resistance (PVR) and mean pulmonary arterialpressure (mPAP) eventually leading to right ventriculardysfunction and without treatment resulting in right heart failure.Over the past decades, various prostanoids with different routesof administration have been approved for the treatment of patientswith pulmonary arterial hypertension (PAH). To date, intravenousprostanoids are the treatment of choice for advanced, rapidlyprogressive, and end-stage PAH. However, the inconvenient routeof administration via external, battery driven pumps or cathetersand the consequent risk of catheter-associated infections, blood-stream and central-line infections or local side-effects are limitingthe use of parenteral prostanoids. Recently, two fully implantablepumps for the delivery of intravenous prostanoids were introducedto overcome these limitations. A US-based study evaluated theSynchroMed® II implantable pump for the delivery of intravenoustreprostinil 1 while in Europe the LENUS Pro® pump was recentlyassessed in a periprocedural safety study 2 and in a prospectiveobservational safety study 3. Although, the available studiesincluded patients with end-stage disease, the data supports theusage of fully implantable prostanoid infusion pumps as alternativetreatment options for patients with PAH. However, implantation,monitoring, filling, and follow-up assessments should be carriedout in expert centres.

References

1. Bourge RC, Waxman AB, Gomberg-Maitland M, et al.: TreprostinilAdministered to Treat Pulmonary Arterial Hypertension Using aFully Implantable Programmable Intravascular Delivery System:Results of the DelIVery for PAH Trial. Chest 2016;150:27-34.

2. Richter MJ, Ewert R, Warnke C, et al.: Procedural safety of afully implantable intravenous prostanoid pump for pulmonaryhypertension. Clin Res Cardiol 2016.

3. Ewert R, Richter MJ, Steringer-Mascherbauer R, et al.: Intravenoustreprostinil infusion via a fully implantable pump for pulmonaryarterial hypertension. Clinical Research in Cardiology 2017.

The meeting isdesigned to allowopportunities for

interactionamong colleagues

during sessionsand at the evening

reception.

15

Our Invited Faculty...

Pulmonary Vascular Research Institute

PVRI

16

Our Invited Faculty LISTED IN ALPHABETICAL ORDER

Paul A CorrisMDProfessor of Thoracic Medicine• Institute of Cellular Medicine• University of Newcastle, UK

Marc HumbertMD, PhDProfessor of Respiratory Medicine• Vice Chair National Reference Centre forPulmonary Hypertension

• Université Paris-Sud, France

Marion DelcroixMDDepartment of Clinical and Experimental Medicine• Service Pneumology• University Hospitals, Leuven, Belgium

Mandy MacLean PhDProfessor of Pulmonary Pharmacology• Research Institute of Cardiovascular andMedical Sciences

• University of Glasgow, UK

Stefanie Dimmeler PhDHead of Molecular Cardiology Institute ofCardiovascular Regeneration• Goethe-University Frankfurt, Germany

John NewmanMDProfessor of Medicine • Elsa S. Hanigan Chair in Pulmonary Medicine • Vanderbilt University School of Medicine,Nashville, USA

Nazzareno GalieMDHead, Pulmonary Hypertension Center Institute of Cardiology, University ofBologna, Italy

Joanna Pepke-Zaba PhD, FRCPDirector of National Pulmonary VascularDiseases Unit• Papworth Hospital NHS Foundation Trust• University of Cambridge, UK

Hossein Ardeschir GhofraniMDProfessor for Pulmonary Vascular Research• Head of Pulmonary Hypertension Division• Medical Clinics II/V• Department of Internal Medicine• University Hospitals Giessen and MarburgGmbH (UKGM)

• Justus-Liebig University, Giessen, Germany

Krishna PrasadMD, MRCP, FRCPMember, Cardiovascular Working Party,European Medicines Agency• Medicines and Healthcare ProductsRegulatory Agency

• Member of Pharmacogenomics, UK

Elena Goncharova PhDAssociate Professor of Medicine• Head of PH Basic Research• Center for Pulmonary Vascular Biology andMedicine, Pittsburgh

• Heart, Lung, Blood, and Vascular MedicineInstitute, University of Pittsburgh School ofMedicine, USA

Laura PriceBSc PhD MBChB MCRPConsultant Respiratory Physician• National Pulmonary Hypertension Service• Royal Brompton Hospital• Imperial College London, UK

17

Stuart Rich MDProfessor of Medicine• Northwestern University Feinberg School of

Medicine• Director, Pulmonary Vascular Disease Program• Bluhm Cardiovascular Institute• Northwestern Memorial Hospital, Chicago, USA

Mark Toshner MDConsultant Respiratory Physician, PapworthHospital• Pulmonary Vascular Diseases Unit,

Papworth Hospital, • University of Cambridge, UK

Manuel Richter MDDepartment of Pneumology• Kerckhoff Heart, Rheuma and Thoracic

Center, Bad Nauheim, University of Giessen,Germany

Jean-Luc Vachiery MDDirector of the Pulmonary Vascular Diseasesand Heart Failure Clinic.• Associate Professor in Cardiology ErasmeUniversity Hospital in Brussels, Belgium

Tanja K. Rudolph MDDepartment of Cardiology • University Heart Center Cologne • University of Cologne, Germany

Norbert Voelkel MDAffiliate Professor• VU University Medical Center, Amsterdam,Netherlands

Ralph Schermuly PhDExtraordinary Professor• Pathophysiology and Experimental

Pulmonology, • Justus-Liebig University of Giessen,

Germany

Christoph Wiedenroth MDKerckhoff Heart and Lung Center• German Centre for Cardiovascular Research• Bad Nauheim, Germany

Marc A. Simon MD, MSAssociate Professor of Medicine, Bioengineering,and Clinical Translational Science• Head of Translational Research, UPMC

Comprehensive Pulmonary HypertensionProgram

• UPMC Heart & Vascular Institute• University of Pittsburgh, Pittsburgh, USA

Gérald Simonneau MDNational Reference Center for PulmonaryHypertension• Service de Pneumologie et Réanimation• Hôpital Bicetre• Université Paris-Sud 11, France

Symposium // Berlin 2017

12th PVRI Annual WorldCongress on PVD inSingapore 22 - 25 January 2018

After the success of 2017, we have an even more exciting programme for 2018.

Martin Wilkins

Ardeschir Ghofrani

Our two Lead Scientific Organisers warmly invite you to attend the PVRI’s 12thAnnual World Congress. The full four-day scientific programme features amplediscussion time and will provide a great platform for active debate among peers.

Experts will present scientific and medical themes, such as stem cells, lungdevelopment and regeneration, oxygen sensing and inflammation, which are all hottopics in our field of research.

This Congress also marks a milestone in the life of the organisation as we reach our10th year of operation. To celebrate, we will reflect on achievements both in the field of PVD and oursociety as a whole, with named lectureships, a rich social programme and, of course, our Gala Dinner.

All sessions allow for active delegate debate and there will be an opportunity to take advantage oforganised sightseeing tours around Singapore.

Lead Scientific Organisers:

12th PVRI Annual WorldCongress on PVD inSingapore 22 - 25 January 2018

JAN2018

SAVE THE DATE

Date // 22 - 25 January 2018Pre-Congress & Task Force Meetings // 21 January

LOCATION

Soon to be announced.

HOTEL BOOKINGS

Once registered, each registree will receivean email containing a private link giving themthe opportunity to book rooms at discountedrates with additional gratuities.

REGISTRATION

This event is currently not yet open forregistration, but if you would like moreinformation, please do not hesitate tocontact us at admin@pvrinstitute.org or goto www.pvrinstitute.org

WE LOOK FORWARD TO SEEING YOU IN SINGAPORE

Pulmonary Vascular Research Institute

PVRI

Pulmonary Vascular Research Institute

PVRI

www.pvrinstitute.org

The PVRI is a Registered Charity in the UK, No: 1127115. In the USA, the PVRI is registered as a not-for-profit organisation (501c3) in the State of Illinois (IN26: 0420959).

The official journal of the PVRI,Pulmonary Circulation is a leading forumfor communication in the field ofpulmonary vascular disease.

Why publish inPulmonary Circulation?

• Impact Factor of 2.178.• Articles posted online

within 48 hours ofacceptance.

• 20-day target fromsubmission to firstdecision.

• Immediatedissemination ofarticles to 6,000 PVRImembers and affiliates, the global populationof leading scientists and physicians studyingthe pulmonary circulation and pulmonaryvascular disease.

• Increasing influence - article downloadsincreasing 50% per year.

• Article-level metrics for real-time updates onwhen your article has been read, cited orshared.

• Articles published Open Access allowingimmediate access to all readers.

First Impact Factor of 2.178!After just six years, we are delighted to see a firstImpact Factor higher than 2.0 - a confirmationthat the journal is widely considered a seriousvenue for authors of high quality articles in ourfield. This ranks Pulmonary Circulation 69th out of126 journals in cardiology, a high entry positionfor a niche journal. This is a very strong basis fromwhich to develop Pulmonary Circulation into thejournal of choice for clinical and basic research inthe pulmonary vascular field.

With a focus on translational science, the journalconnects researchers and physicians in all parts ofthe world. An Open Access journal, articles arefreely available to read immediately on publication.The journal’s goal is to increase survival rates anddevelop new therapeutic approaches for pulmonaryhypertension and other pulmonary vasculardiseases. 

The Editors welcome article submissions includingclinical and basic research in humans and animals,randomised controlled trials, intervention studies,and outcome studies. Articles published inPulmonary Circulation will make a major impact notonly on future research but also on improvement ofhealth outcomes.

Chief Editors:Jason X.-J. Yuan MD, Tucson, USA and Nicholas W. Morrell MD, Cambridge, UK

Deputy Editors:Kurt R. Stenmark MD, Denver, USA and Irene Lang MD, Vienna, Austria

Call for Article Submissions