Tolvaptan for ADPKD: Use in Adolescents

Caitlin Carter, MD

Western Society of Pediatric Nephrology Meeting

San Diego, California

January 26, 2019

Our patient

• 16 year old male with ADPKD and uncontrolled hypertension and mild LVH on echocardiogram

• R kidney 1975 mL, L kidney 2016 mL

• Cr 1.0 mg/dL, eGFR 77 mL/min

• Meds: • Losartan 100 mg daily

• Lisinopril 40 mg daily

• Clonidine #3 patch weekly

Questions

• Management • BP control <110/75 with RAAS inhibition

• Increase fluid intake

• Moderate protein restriction

• Could he benefit from therapy with tolvaptan? • Is it efficacious in patients with his clinical characteristics?

• What are the risks of treatment?

• Are we risking long term damage by waiting until he turns 18?

• What are the other limitations to treatment with tolvaptan?

Tolvaptan, FDA approved April 2018 in ADPKD

Tolvaptan around the world

• Japan: Indicated for those with >5% rate of increase in total kidney volume, no GFR or age criteria

• Canada: Indicated for Mayo class 1 C-E; no GFR or age criteria

• EU: Indicated for adults with CKD 1-3 and rapidly progressing disease

• Also approved in Australia, South Korea, Hong Kong, Switzerland

TEMPO 3:4 • 1445 patients aged 18-50 years; mean age 39 y

• eGFR > 60 mL/min/1.73 m2 by CG, mean eGFR 80 mL/min/m2

• Total kidney volume >750 mL, 20% had TKV >1000 mL

• Randomized 2:1 to tolvaptan:placebo, titrated to highest tolerable dose, maximum dose 90 mg q am, 30 mg q pm

• 3 year follow up, 1157 subjects completed the trial

• Primary end point: Change in TKV

• Secondary end points: • Composite end point: Time to clinical progression

• 25% GFR reduction, pain, HTN, albuminuria

• Change in slope of 1/Cr

Torres, NEJM 2012.

TEMPO3:4 Results

Torres, NEJM 2012.

TEMPO 3:4 Subgroup analysis

Torres, NEJM 2012.

TEMPO 4:4

Torres NDT 2017.

REPRISE

• 1370 patients age 18-65 yo

• Age stratified GFR criteria • Age 18-55y: eGFR 25-65 ml/min/1.73 m2

• Age 56-65y: eGFR 25-44 mL/min/1.73 m2

• Randomized 1:1 tolvaptan:placebo for 12 months

• Dose determined during prerandomization run-in

• Primary end point : change in eGFR

Torres NEJM 2017.

REPRISE

• Greatest benefit: • Age <55

• CKD 3a

Torres NEJM 2017.

Predictive models

Chebib. JASN 2018.

Chebib JASN 2018.

Conclusions regarding efficacy

• Tolvaptan appears to slow progression of ADPKD as measured by TKV and change in GFR over time • Greatest benefit in TKV seen in first year on treatment

• Unclear if delayed initiation impacts TKV over time

• eGFR benefit is sustained with longer treatment

• Subgroups who benefit most from treatment • In TEMPO age >35, in REPRISE age <55

• CKD 3

• Higher TKV at baseline, Mayo Class 1C-1E

• Truncating PKD1 mutations

Unanswered Questions

• What is the target age group for treatment?

• How should we stratify risk in young people to target those at highest risk of progressive disease? • Imaging

• Genetics

• Family history

• CKD stage

• PROPKD score

Mayo Imaging Characteristics Predict Renal Outcomes

Irazabel. JASN 2015.

Back to our patient…

https://www.mayo.edu/research/documents/pkd-center-adpkd-classification/doc-20094754

Gansevoort NDT 2016.

Chebib JASN 2018.

Side effects

• Aquaresis—polyuria, nocturia, thirst, hypernatremia >150 mmol/L

• LFT abnormalities—0.2% of treated patients

• Chest pain

• Headache

• Uric acid elevations

• CYP3A inhibition

• Drug interactions (CYP3A inhibitors, OATP1B1/3 and OAT3 substrates, BCRP transporter substrates)

• 23% of patients DC’d tolvaptan (TEMPO), more likely to be related to ADE

Potential hepatotoxicity

• LFTs monitoring • Before treatment

• q 2 weeks x 2

• Monthly x 18 months

• Q 3 months

• Contraindicated if underlying liver disease other than PCLD

• Rare cases of fatal hepatitis, acute hepatitis requiring liver transplant

Study in Progress

• Safety, Pharmacokinetics, Tolerability and Efficacy of Tolvaptan in Children and Adolescents with ADPKD (NCT02964273) • Stage 3B RCT of tolvaptan in subjects aged 12-17

• 1 year randomized followed by 2 year open label

• Tolvaptan dosing is weight based

• Primary outcomes: • Change in Urine osm, urine spec gravity at 1 week

• Secondary outcomes • % change htTKV at 12 months

• Change in EGFR

• Weight change, fluid balance

Summary

• Data in adolescents is pending but tolvaptan may be indicated in those at high risk

• Close monitoring after initiation of treatment is essential

• ?may be some loss of efficacy in time off treatment in regards to TKV

• Cost ($13,000/month) remains a major barrier to treatment

• REMS required for prescribing in US

• Thank you