Disclosures Discussion of targeted PAH therapies in children is off - - PowerPoint PPT Presentation

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Disclosures

• Discussion of targeted PAH therapies in children is off

label aside from bosentan.

• Investigator – clinical trials (Actelion, Bayer, Gilead,

Lung Rx, United Therapeutics)

Methods

• pubmed search 2017-2018
• pulmonary hypertension

– children – pediatrics – Dunbar Ivy

• Diagnostics
• Genetics
• Drugs
• Collaborative clinical guidance
• And some other things....

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• Aim: To determine the effect of prostacyclin analogues on RV function

assessed by echocardiography in children with PH.

• Retrospective cohort study of children with PH treated with a prostacyclin

analogue (epoprostenol or treprostinil) between January 2001 and August 2015 at CHOP.

• Data were collected before initiation of treatment (baseline) and at 1–3

and 6–12 months after.

Pulm Circ. 2018

RV Function and Clinical improvment in kids with PAH on Prostanoids

• Echocardiogram measurements including TAPSE and RV global longitudinal

strain were made with blinding to clinical information.

• 49 individuals (65% female), aged 0–29 years at the time of prostacyclin

initiation were included.

• Disease types included pulmonary arterial hypertension (idiopathic [35%],

heritable [2%], and congenital heart disease-associated [18%]), developmental lung disease (43%), and chronic thromboembolic PH (2%).

• Participants received intravenous (IV) epoprostenol (14%) and

IV/subcutaneous (SQ) (67%) or inhaled (18%) treprostinil.

Hopper RK, et al. Pulm Circ. 2018

RV Function and Clinical Improvement in Kids with PAH on Prostanoids

Hopper RK, et al. Pulm Circ. 2018 Prostacyclin analogues were associated with improvement in TAPSE (P. 0.007), RV strain (P< 0.001), and qualitative RV function (P. 0.037) by echocardiogram, and BNP (P< 0.001), functional class (P. 0.047) and 6MW distance (P. 0.001).

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RV Function and Clinical improvment in kids with PAH on Prostanoids

• TAPSE and strain improved at early follow up (P. 0.05 and P. 0.002, respectively)

despite minimal RV pressure change.

• In children with PH, prostacyclin analogues are associated with an early and

sustained improvement in RV function measured as TAPSE and strain as well as clinical markers of PH severity.

• RV strain may be a sensitive marker of RV function in this population

Hopper RK, et al. Pulm Circ. 2018

• 42 children with PAH and 26 age- and

size-matched controls underwent comprehensive CMR evaluation.

• Pediatric PAH patients have a focal

increase in the apparent ascending aortic stiffness as assessed by cardiac magnetic resonance studies.

• The apparent aortic stiffness is strongly

associated with the degree of distension of the MPA.

Circ Cardiovasc Imaging, 2017 Schafer M., Circ Cardiovasc Imaging, 2017

• Associations between MPA/Ascending aorta size ratio and LV ejection fraction (left)

and LV ventricular-vascular coupling ratio (right).

• Both trends are suggestive of negative MPA expansion effect on the ascending aorta

resulting in increased LV afterload.

Schafer M., Circ Cardiovasc Imaging, 2017

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“We speculate that distension of the MPA contributes to aortic stiffness due to its role in limiting full aortic expansion during systole within a restricted space of the thoracic cavity. We propose that in addition to ventricular interdependency, vascular interdependency of the MPA and aorta can potentially have negative effects on LV performance in pediatric PAH, which is primarily due to the mechanical effects of MPA distension.”

Schafer M., Circ Cardiovasc Imaging, 2017 European Heart J – CV Imaging, 2017 Pei-Ni J. et al., Eur Heart J –CV imaging, 2017

RV function and strain: prognosis

• Retrospective review of all infants and children <2 years of age with PH from January 2011

to August 2016. Differences in characteristics between survivors and nonsurvivors were analyzed

• 56 patients – most extremely premature; and had BPD. Patients who died were more likely

to have underlying CHD; have a higher increase in the concentration of CO2 in the blood with a corresponding greater mean percentage decrease in pH and percentage rise in NTpro BNP during PH exacerbations; more likely to have been on medications for pulmonary hypertension; and have a higher RVSP/SBP (%) ratio and S/D ratio.

• Positive correlations between percentage rise in NT-pro BNP and pCO2; NT-pro BNP and

RVSP/SBP (%) ratio; and RVSP/SBP (%) ratio and S/D ratio.

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CHD, 2018

Conclusions NT-pro BNP is a useful biomarker for both respiratory exacerbations and mortality, and RVSP/SBP (%) ratio and S/D ratio are echo identifiers for increased mortality.

J Am Heart Assoc. 2018

• All catheterizations in children and young adults, aged 0 to 21 years, with PH at

hospitals submitting data to the IMPACT (Improving Adult and Congenital Treatment) registry between January 1, 2011, and December 31, 2015, were studied.

• Using mixed-effects multivariable regression, assessed the association

between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization.

J Am Heart Assoc. 2018

Observed risk of the composite outcome

• f death, cardiac arrest or MCS during or after

catheterization was 1.4%, and the risk of death before discharge was 5.2%.

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But, who are these PAH patients?

O’Byrne ML, Et al, JAHA, 2018

Many interventions at the time of catheterization not typical for diagnostic PAH catheterization

O’Byrne ML, Et al, JAHA, 2018

Risk Factors for Catastrophic Adverse Events Post Catheterization in pediatric PH

O’Byrne M., J Am Heart Assoc. 2018

Risk Factors for Cardiac Cath in PH

• Catheterization in premature neonates and non-premature infants was

associated with increased risk of catastrophic adverse event, as was pre- catheterization treatment with inotropes and lower systemic arterial saturation.

• Increasing PVR and PAP were associated with increased risk (P<0.0001 for both)
• Increasing volumes of catheterization in patients with PH were associated with

reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures; P=0.002) Young patients with PH are a “high-risk” population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk, independent of total catheterization case volume.

J Am Heart Assoc. 2018

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• Overall progress with identification of novel mutations: BMPR2,

ALK1, ENG, CAV1, KCNK3, EIF2AK4...

• Pediatric specific progress:
• TBX4 – potential role in pediatric PAH (small patella syndrome,

Kerstjens-Frederikse WS, et al. J Med Genetics 2013)

• Levy M, ERJ, 2016 noted that ACVRL1 and TBX4 more common

in children than adults

Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults

– Genetic analysis of 155 pediatric and 257 adult-onset PAH patients, including both FPAH and sporadic idiopathic PAH (IPAH). – After screening for 2 common PAH risk genes, mutation negative FPAH and all IPAH cases were evaluated by exome sequencing. BMPR2 mutations underlie ≈70% of adult familial PAH (FPAH) cases, but genetic basis of PAH in children is less understood

Zhu N, et al. Circ Genom Precis Med 2018

TBX4 and Pediatric PH

Zhu N, et al. Circ Genom Precis Med 2018

• Significant enrichment of TBX4 mutations in pediatric- compared with adult-
• nset patients (IPAH: 10/130 pediatric versus 0/178 adult-onset)
• TBX4 carriers had younger mean age-of-onset compared with BMPR2 carriers.

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Exome sequencing: Conclusions

• Mutations in known PAH risk genes accounted for ≈70% to 80% of

FPAH in both age groups, 21% of pediatric-onset IPAH and 11% of adult-onset IPAH.

• Rare, predicted deleterious variants in TBX4 are enriched in

pediatric patients and de novo variants in novel genes may explain ≈19% of pediatric-onset IPAH cases.

Zhu N, et al. Circ Genom Precis Med 2018

PAH-Specific Treatment Options Approved for Use in Adults With PAH

Oral Therapy Inhaled Therapy Parenteral Therapy ERAs PDE-5 Inhibitors sGC Stimulator Prostacyclin pathway therapy Prostacyclins Bosentan Sildenafil Riociguat Treprostinil Iloprost Epoprostenol Ambrisentan Tadalafil Selexipag Treprostinil Treprostinil (SC or IV) Macitentan RTS Epoprostenol

PAH-Specific Treatment Options Approved for Use in Children With PAH in the US

Oral Therapy Inhaled Therapy Parenteral Therapy ERAs PDE-5 Inhibitors sGC Stimulator Prostacyclin pathway therapy Prostacyclins Bosentan

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• FDA approved bosentan for children aged 3 years and older with

idiopathic or congenital PAH

• Bosentan is an endothelin receptor antagonist indicated for the

treatment of adults with PAH (World Health Organization [WHO] group 1) to improve exercise ability and reduce clinical worsening

• Available in a new 32-mg tablet that is scored to allow weight-based

dose adjustment for younger patients.(dispersed in a teaspoon of water before being given orally).

FIRST FDA-approved medication for children with PAH

September 7, 2017

PAH-Specific Treatment Options Approved for Use in Adults With PAH

Oral Therapy Inhaled Therapy Parenteral Therapy ERAs PDE-5 Inhibitors sGC Stimulator Prostacyclin pathway therapy Prostacyclins Bosentan Riociguat Treprostinil Ambrisentan Tadalafil Macitentan

clinical trials.gov

• Background: 2 adult switch studies, (Blok IM, In J Cardiol 2017; and Safdar et al,

South Med J 2017) – neither showed improved 6MW

• 13 children/young adults (n=5 - children 12-18 years)
• CHD/IPAH, FC II/III
• Background treatments: PDE-5 and/or inhaled prostanoid
• Baseline vs. 24 months prospective/observational

Cardiology in the Young, 2018

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Bosentan to Macitentan switch in children

Aypar E, et al. Cardio in the Young, 2018

• Macitentan did not significantly change (p<0.05)

– functional class – oxygen saturation at rest/after 6-minute walk distance test – brain natriuretic levels – systolic pulmonary artery pressure

• None of the patients had anemia, hepatotoxicity, and

peripheral edema

Bosentan to Macitentan switch in children

NCT02932410: Macitentan “Tomorrow Study”

• Prospective multicenter open label randomized, controlled, parallel group, group

sequential, event-driven Phase 3 study to evaluate efficacy, safety and PK of macitentan in children

• Primary Outcome measure: Time to the first disease progression events in approximately

300 pediatric Group 1 PAH patients (≥2 years and <18 years) diagnosed within 12 mos of

• enrollment. Sufficient number of patients to observe 187 primary endpoint events
• Background therapy: up to 2 PH agents other than macitentan or IV/SC prostanoids

ClinicalTrials.gov Identifier: NCT02932410

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Early experience of selexipag in children: dose titration and transition from IV treprostinil

• Initiation: Selexipag started at a dose of 200 mcg BID, and increased by 200

mcg/dose per week to a total maintenance dosing of 1600 mcg BID. All but one tolerated max dose.

• If selexipag side effects were encountered during the uptitration, dosing increase

was held for one week, allowing 2 weeks between uptitrations.

• Transition: All 4 of the patients on a continuous treprostinil infusion were weaned

from IV to PO using the protocol. While selexipag was uptitrated, treprostinil was weaned by decreasing the treprostinil dose daily by 2 ng/kg/min for 5 days followed by a 2-day rest period. After this rest period, selexipag dosing was increased and again treprostinil was weaned for 5 days followed by a 2-day rest. Cycle repeated until treprostinil was off.

Gallotti R. et al. Pediatric Cardio, 2017 Pulmonary Circulation 2017; 8(3) 1–6.

NCT02562235: Riociguat

• Open-label individual dose titration study to evaluate safety, tolerability and PK of

Riociguat in children from 6 to less than 18 years with PAH

• Designed to evaluate the safety, tolerability, pharmacodynamics of riociguat at age,

sex, body-weight adjusted doses of 0.5mg, 1.0, 1.5, 2.0, and 2.5 mg TID in children from 6 to less than 18 yrs with PAH group 1.

• Two phases: up-tiration up to 8 weeks and maintenance phase up to 16 weeks.

ClinicalTrials.gov

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• Evaluated the safety, efficacy and management of subcutaneous (SC) treprostinil

in children with PAH.

• 56 children (median age 65, range 1–200 months) treated with SC treprostinil.

(clinical status, echocardiography, NT-proBNP, and site pain and infection)

• Right heart catheterization was performed in 54 patients before starting SC

treprostinil infusion and was repeated at 6 months in 31 patients.

Levy M. et al., Int J Cardiol. 2018 Levy M. et al., Int J Cardiol. 2018

At last follow-up (median 37 months), ten patients had died, 2 underwent a lung transplantation and 8 underwent a Potts shunt. In 30 of the 36 remaining treated patients, improvement of clinical status was

• sustained. No children developed sepsis and 12 had minor site infections.

SC treprostinil and pediatric PAH

• Treatment - well tolerated in 79% of patients.
• Site pain resistant to simple analgesics occurred in 12 patients (21%), but

could be managed in 9/12 children.

• Among the 48 treated patients, 40 (83%) showed significant improvement

in WHO functional class, 6 minute walk distance, NT-proBNP and pulmonary vascular resistance (p < 0.01 for all parameters). Conclusion: Subcutaneous treprostinil infusion is an effective therapy without serious side effects in children with PAH. Site pain can be managed with simple analgesics in most children.

Levy M. et al., Int J Cardiol. 2018

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2017 2016 April 5, 2018 Fetus with severe CDH is at risk for LV hypoplasia and decreased systolic and diastolic function, which complicates the management

• f PH in severe CDH.

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LV, CDH and PH: Recs

• Antenatal echo measurements should include assessment of ventricular discordance
• Early postnatal echo – accurately determine relative contributions of PVD and LV

dysfunction to PH and whether pharmacologic pulmonary vasodilator therapy is likely to be of benefit at birth. Serial echocardiography should be used to demonstrate the response to therapy and changes in underlying physiology over time.

• Pharmacologic recruitment of the arterial duct should be considered if there is evidence
• f ductal-dependent systemic blood flow with severe LV dysfunction.
• Preductal ABG measurements more accurately reflect pulmonary gas exchange in the

presence of right-to-left shunting across the duct, and should be used to assist in the management of mechanical ventilation.

• Milrinone, alone or in combination with iNO, may play a role in the management of PH in

CDH, especially when complicated by poor LV performance or underdevelopment, but recommendations for its use awaits randomized trials.

Kinsella J, et al. J Peds, 2018

• No previous studies describe the clinical characteristics of children with PH in

the pediatric intensive care unit (PICU).

• A retrospective multicenter cohort study of 153 centers in the Virtual PICU

Systems database who submitted data between January 2009 and December 2015 performed

Balkin EM, et al. Pulm Circ., 2018

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• Mortality for PH admissions was 6.8%

compared to 2.3% in those admitted without PH (odds ratio = 3.1; 95% confidence interval = 2.9-3.4)

• In a multivariate model, factors

significantly associated with mortality for children with PH included:

– age < 6 months or > 16 years – invasive mechanical ventilation – co-diagnoses of heart failure, sepsis, hemoptysis, disseminated intravascular coagulation, stroke, and multi-organ dysfunction syndrome. (MODS)

. Balkin EM, et al. Pulm Circ., 2018

Compared to patients admitted to the PICU without PH, those with PH were:

• younger
• had longer length of stay
• higher illness severity scores
• were more likely to receive invasive mechanical ventilation,

cardiopulmonary resuscitation, and extracorporeal membrane oxygenation

• co-diagnoses of sepsis, heart failure, and respiratory failure

Pulm Circ, 2018

NCT02249923: Pediatric Pulmonary Hypertension Network (PPHNet) Informatics Registry

• Aim 1:

– Provide a mechanism to store information about newborns, infants and children with PH – Determine the incidence and natural history of the various etiologies of pediatric PH – Define our current diagnostic and therapeutic approaches to the diverse conditions associated with pediatric PH – Determine the response of children with PH to chronic therapies

• Aim 2: Research Infrastructure: Create a robust scalable data architecture and combine

traditional registry data, EHR (electronic health Record), and PRO data in a single resource

• Aim 3: Informatics: Address three classes of unanswered questions crucial for the

characterization and management of PH, comparing the information value of registry vs EHR vs fused data across registry/EHR, in the domains of spectrum of PH comorbidities, PH indicators and endpoints of morbidity and mortality, and response to therapies in PH

ClinicalTrials.gov Identifier: NCT02249923

• An EHR-based computable phenotype identified a pediatric PH cohort more

than 3-fold larger than a traditional disease registry.

• Notably, the 2 populations were phenotypically different, demonstrating that

certain patient populations are not captured effectively by the registry.

• Thus, we have demonstrated the utility of cohort ascertainment through EHR

mining for powering future studies of pediatric PH by directly comparing the cohorts using computable phenotypes versus a traditional registry.

J Pediatr 2017

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Circ Res. 2017 Oct 27;121(10):1136-1139.

Conclusions

In the past year…

– Diagnostic- imaging tools have evolved for use in pediatric PAH – Approval of a targeted PAH medication – Identification of genetic profile that appears to be different in children vs. adults. – and many other advances... paving the way forward

Until Next Year...Thanks!