FUEL up! PD-5 inhibitor and exercise

capacity in Fontan patients. (The Fontan Udenafil Exercise Longitudinal Trial)

Stephen M Paridon, M.D.,

Professor of Pediatrics

Division of Cardiology, The Children’s Hospital of Philadelphia

The Perelman School of Medicine at the University of Pennsylvania

Disclosures

• I have no disclosures.

PD-5 inhibitor and exercise capacity in Fontan patients

Spring 2010

• The Phillies will go the World Series for the 3rd straight year.

• The Eagles are poised to return to the Super Bowl.

• I will beat Meryl Cohen and Chitra Ravishankar to Bob Shaddy’s office to explain why one of them, rather than me, should be the CHOP primary investigator on the next PHN grant cycle submission.

• None of these things happened.

• So, we needed a proposal for a multicenter interventional trial to submit with the renewal.

PD-5 inhibitor and exercise capacity in Fontan patients

When we think about medical therapies for the patient with Fontan palliation, we need to consider:

• Myocardial function.

• Atrio-ventricular and semilunar valve function.

• Physiology unique to the Fontan palliation.

• Acute versus chronic therapy.

PD-5 inhibitor and exercise capacity in Fontan patients

When dealing with myocardial and/or valvular dysfunction in single ventricle physiology, our default has been to use what is known from heart failure in adults with structurally normal hearts. The mainstays being remodeling agents including:

• Ace inhibitors

• Beta blockers

• Aldosterone antagonists

• Inotropic drugs

PD-5 inhibitor and exercise capacity in Fontan patients

However, it is becoming increasingly clear that a relatively

elevated pulmonary vascular resistance is a major mechanism

in both acute, and more importantly, chronic medical conditions

associated with Fontan physiology.

• Exercise intolerance.

• PLE/PB.

• Hepatic dysfunction.

• Renal dysfunction.

PD-5 inhibitor and exercise capacity in Fontan patients

Navaratnam et al: Am J Cardiol 2016;117:1667e1671

PD-5 inhibitor and exercise capacity in Fontan patients

Giardini et al,Ann Thorac Surg 2008;85:818 –22

PD-5 inhibitor and exercise capacity in Fontan patients

Diller et al: European Heart Journal (2010) 31, 3073–3083

PD-5 inhibitor and exercise capacity in Fontan patients

Atz et al: J Am Coll Cardiol. 2017

PD-5 inhibitor and exercise capacity in Fontan patients

So, do PDE-5 inhibitors make sense?

• Single dose studies show a significant drop in PVR.

• About a 5 to 10% increase in maximal VO2.

H. Mori et al. International Journal of Cardiology 221 (2016) 122–127

PD-5 inhibitor and exercise capacity in Fontan patients

So, do PDE-5 inhibitors make sense?

• Ventricular function.

• Peripheral vascular function.

• FALD.

• What about more chronic studies?

• SAFO.

PD-5 inhibitor and exercise capacity in Fontan patients

SAFO: An 18 week double blind, placebo controlled, cross-over trial of sildenafil in 28 children and adolescents.

Goldberg et al: Circulation. 2011;123:1185-1193

PD-5 inhibitor and exercise capacity in Fontan patients

Based on these data in the fall of 2011, the PHN approved the development of a phase III clinical trial of a PDE-5 inhibitor in asymptomatic Fontan subjects. We needed to know:

• The right protocol.

• The right endpoints.

• The right drug.

• The right number of sites.

• A three year multi-center trial assessing the rate of decline in %ed maximal VO2 in 12 to 18 year old Fontan subjects.

PD-5 inhibitor and exercise capacity in Fontan patients

The right drug: Fall 2011 to Fall 2012

• Sildenafil: no teenager is going to take a TID drug.

• Tadalafil:

• Udenafil: sometimes serendipity can be a wonderful thing, The beginning of a long relationship with Mezzion Pharma.

PD-5 inhibitor and exercise capacity in Fontan patients

Late 2012 to early 2016: Sand in the gears, or wouldn’t it be great to get a clinical indication and pediatric orphan drug status.

• We need a Phase I/II clinical trial to establish dosage.

• We need to involve the FDA.

• The cost of the study balloons several fold.

• Arranging a working interface between NHLBI and Mezzion Pharma- a first for the NIH.

PD-5 inhibitor and exercise capacity in Fontan patients

Phase I/II trial: early 2013 through late 2014. Five sites and 36 subjects with endpoints of safety and pharmacokinetics.

Goldberg et al: Am Heart J 2017;188:42-52.

PD-5 inhibitor and exercise capacity in Fontan patients

The FDA: Spring of 2014.

• Unrealistic protocol: change to a 6 month double bind placebo control trial with change in unindexed maximal VO2 as the primary endpoint.

• Additional safety monitoring at randomization and early in the follow up period.

• A follow on, one year open label extension trial to assess long term safety (FUEL/OLE).

• Special protocol assessment: fast tract to an indication.

• The clock starts to tick faster.

• Bring in the statisticians and lawyers.

PD-5 inhibitor and exercise capacity in Fontan patients

Sites and Stats:

• Due to FDA time constraints, recruitment time was limited to approximately 18 months.

• Need for relatively conservative power estimates: 400 subjects, randomized 1:1, blocked by site, stratified by sex and ventricular morphology.

• Based on surveys of potential subjects at PHN Core and Auxiliary sites, 24 sites in North America and the Republic of Korea were enlisted in the study.

PD-5 inhibitor and exercise capacity in Fontan patients

The end result is a 6 month study with a very busy first and last day.

PD-5 inhibitor and exercise capacity in Fontan patients

The end result is a 6 month study with a very busy first and last day.

At the FDA’s request, additional

in person visits at 2 weeks and

13 weeks to check heart rate

and blood pressure.

PD-5 inhibitor and exercise capacity in Fontan patients

Problems going forward:

• Final site approvals 08/2016.

• First subject randomized 08/20/2016.

• We missed our first summer enrollment window.

• Recruitment was slower than expected- many families were

put off by the 2 and 13 week in person visits.

PD-5 inhibitor and exercise capacity in Fontan patients

Creative work arounds:

• Visiting nurses to do home visits for the 2 and 13 week data collection.

• Petition the FDA to change the in person visits to telephone visits.

• Add 6 more auxiliary sites, bringing the total number of sites up to 30.

PD-5 inhibitor and exercise capacity in Fontan patients

Current status:

• Approximately 310 subjects randomized.

• Expected enrollment completion in February 2018.

• Largest clinical trial in the Fontan population.

• Data analysis to begin in late Summer of 2018.

• Report to the FDA early 2019.

• Decision by the FDA mid to late 2019.

PD-5 inhibitor and exercise capacity in Fontan patients

Next steps:

• Extended access enrollment.

• Younger ages.

• Different preparations- liquid, gel, intravenous.

• Combination therapies- Udenafil/aldosterone antagonist.

PD-5 inhibitor and exercise capacity in Fontan patients

Thank You.