Bottom Line

Beyond tolvaptan, what lies ahead: New therapies in the treatment of polycystic kidney disease

Tolvaptan, a V2 receptor antagonist, has recently was approved by the FDA as the first drug specifically designed to treat polycystic kidney disease. This disease has impacted the quality of life of approximately 600,000 patients in the United States and more than 12 million worldwide, being the fourth leading cause of ESRD.

The PKD population has been encouraged by the approval of tolvaptan (Jynarque, Otsuka America Phar-maceutical Inc.) after years of no medication targeting progressive chronic kidney disease. Results from the seminal HALT PKD Study1 changed the natural course of history of PKD by addressing lifestyle maneuvers, such as:

1) using an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to achieve rigorous BP control;

2) realizing the benefit of a tightly controlled dietary sodium (Na+) intake (less than 2 grams/day);

3) encouraging active exercise and a healthy lifestyle; and

4) close medical follow up. There was a 14.2% slower rate of total kidney volume (TKV) growth in the study during 5 years with an ACEI or ARB, as measured by MRI using the ellipsoid equation.

Theodore I. Steinman

The potential benefits from tolvaptan were assessed in the original TEMPO 3:4 trial.2 In the United States, however, the FDA initially denied approval of the drug based on concerns about hepatotoxicity. In other countries, this drug was approved as treatment for PKD based on the same TEMPO trial results, which showed that twice daily dosing (60 to 30 mg) to maintain urine osmolality (Uosm) less than 300 mosm, a surrogate for suppression of arginine vasopressin (AVP) action in the kidney, produced a 77% effect on TKV measurement (slight, but notable).

Results from REPRISE

The follow-up REPRISE study3 was a 1-year investigation of a large cohort of PKD patients (with a lower eGFR of 25 to 65 mL/min as compared to the greater than 60 mL/min in the TEMPO 3:4 trial) to address the significance of liver toxicity in the TEMPO 3:4 trial, while confirming the reduction in TKV. Results from this second trial showed reversible hemodynamic consequences (decreased GFR, renal blood flow and filtration fraction) from tolvaptan in the study group who had an overall lower eGFR at baseline. The result was a decrease in Na+ reabsorption in the thick ascending loop of Henle, with an increase in Na+ reabsorption in the macula densa region.

A retrospective analysis of patients with autosomal dominant polycystic kidney disease3 treated with tolvaptan for up to 11 years demonstrated lower GFR slopes and a 33% reduction in GFR from baseline as compared to a control cohort. The GFR slopes of the tolvaptan-treated group did not change with the duration of follow-up.

The beneficial effects of this V2 receptor antagonist accumulates over time; it was associated with a decrease in kidney pain, nephrolithiasis, urine albumin excretion and urinary MCP-1 excretion (a useful biomarker in PKD). Aberrations in liver enzymes were confirmed, along with ALT/AST increases greater than two times the upper limits of normal (ULN) on average. In 5% of patients, the transaminase elevations were greater than three times the ULN. Liver enzymes returned to normal with discontinuation of the drug, but the beneficial aspects disappeared when the drug was stopped.

The FDA approved this medication on the basis that the reversible hepatic toxicity did not outweigh the small, but clinically important, GFR benefit of 1.27 mL/min/1.73 m² with treatment in the REPRISE study. Can this small benefit be sustained on a chronic basis without accumulation of the chronic liver effects? There was a high percentage of study non-completers, mainly because of the adverse side effects of polyuria, frequent nocturia that impacted quality of sleep, and thirst with tolvaptan.

Cost of treatment, alternatives

The cost factor will come into play with tolvaptan as its manufacturer announced it will be sold in a 30-day treatment pack at a wholesale cost of $13,041.10. The cost of the medication must be weighed against the financial implications of the projected delay in reaching ESRD, with treatment of approximately 6 to 9 years before reaching stage 5 CKD. Other potential products in the pipeline include the following:

Tesevatinib: This drug is now in a phase 3 study. Preliminary results from phase 1 and 2 studies of this multitargeted tyrosine kinase inhibitor were encouraging with regard to statistically significant slowing of TKV as compared to a control group. The phase 3 study will determine if the short- and long-term positive effects are sustained and what will be the adverse effects with chronic use.

Bardoxolone methyl and mRNA 1792: This is in the early stages of PKD investigation. We will wait to see what results come from this work.

Metformin: Results of a collaborative study with this drug will be reported soon, but use of this medication in the non-diabetic carries significant risks.

Increasing water intake: An exciting area of investigation is with simple water intake to match the urine output achieved with tolvaptan. If the patient can reach a urine output of approximately 4 L/day or greater that results in a Uosm of 280 mosm/L or less on a chronic basis, then the impact of aquaresis can be studied to determine if tolvaptan (and other V2 receptor antagonists) have an effect independent of inhibiting AVP and hence increasing urine output. The challenge is to make sure the patient can comply with the required large fluid intake (it was achieved with tolvaptan) while monitoring at home the goal of urine hypo-osmolality.

A physiologic study that supports trying water intake only as a potential therapy for PKD was undertaken by Mayo Clinic investigators (led by Vicente Torres, MD, and Peter Harris, MD) and demonstrated AVP directly regulates cyst growth in PKD.4 They showed aquaresis downregulates cAMP signaling (mediated by calcium), cell proliferation and chloride-rich fluid secretion by human epithelial cells.

Conclusion

Tolvaptan is the first specific drug approved by the FDA that is designed to slow the progressive course of PKD. Both patients and the nephrology caregivers are optimistic that the high cost for tolvaptan will not limit the access to this drug and a mechanism will be found to deliver this agent to those who need it. Hopefully, the door is now open to other agents under study to be added to our treatment regimen for patients bearing the burden of this disease, assuming these prove to have a positive impact on this genetic disorder and an acceptable safety profile.

References:

1. Schrier RW, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402685.

2. Torres VE, et al. N Engl J Med. 2012; doi:10.1056/NEJMoa1205511.

3. Torres VE, et al. N Engl J Med. 2017; doi:10.1056/NEJMoa1710030.

4. Torres VE, et al. Nephrol Dial Transplant. 2017;doi:10.1093/ndt/gfx043.

For more information:

Theodore I. Steinman, MD, is a clinical professor of medicine at Harvard Medical School and senior physician at both Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital in Boston. His primary interest is in collaborative research investigation and clinical management of polycystic kidney disease. He is past chair of the scientific advisory committee and past member of the board of directors for the PKD Foundation. He also is a member of Nephrology News & Issue’s Editorial Advisory Board. Disclosure: Steinman reports no relevant financial disclosures.

Tolvaptan, a V2 receptor antagonist, has recently was approved by the FDA as the first drug specifically designed to treat polycystic kidney disease. This disease has impacted the quality of life of approximately 600,000 patients in the United States and more than 12 million worldwide, being the fourth leading cause of ESRD.

The PKD population has been encouraged by the approval of tolvaptan (Jynarque, Otsuka America Phar-maceutical Inc.) after years of no medication targeting progressive chronic kidney disease. Results from the seminal HALT PKD Study1 changed the natural course of history of PKD by addressing lifestyle maneuvers, such as:

1) using an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to achieve rigorous BP control;

2) realizing the benefit of a tightly controlled dietary sodium (Na+) intake (less than 2 grams/day);

3) encouraging active exercise and a healthy lifestyle; and

4) close medical follow up. There was a 14.2% slower rate of total kidney volume (TKV) growth in the study during 5 years with an ACEI or ARB, as measured by MRI using the ellipsoid equation.

Theodore I. Steinman

The potential benefits from tolvaptan were assessed in the original TEMPO 3:4 trial.2 In the United States, however, the FDA initially denied approval of the drug based on concerns about hepatotoxicity. In other countries, this drug was approved as treatment for PKD based on the same TEMPO trial results, which showed that twice daily dosing (60 to 30 mg) to maintain urine osmolality (Uosm) less than 300 mosm, a surrogate for suppression of arginine vasopressin (AVP) action in the kidney, produced a 77% effect on TKV measurement (slight, but notable).

Results from REPRISE

The follow-up REPRISE study3 was a 1-year investigation of a large cohort of PKD patients (with a lower eGFR of 25 to 65 mL/min as compared to the greater than 60 mL/min in the TEMPO 3:4 trial) to address the significance of liver toxicity in the TEMPO 3:4 trial, while confirming the reduction in TKV. Results from this second trial showed reversible hemodynamic consequences (decreased GFR, renal blood flow and filtration fraction) from tolvaptan in the study group who had an overall lower eGFR at baseline. The result was a decrease in Na+ reabsorption in the thick ascending loop of Henle, with an increase in Na+ reabsorption in the macula densa region.

A retrospective analysis of patients with autosomal dominant polycystic kidney disease3 treated with tolvaptan for up to 11 years demonstrated lower GFR slopes and a 33% reduction in GFR from baseline as compared to a control cohort. The GFR slopes of the tolvaptan-treated group did not change with the duration of follow-up.

The beneficial effects of this V2 receptor antagonist accumulates over time; it was associated with a decrease in kidney pain, nephrolithiasis, urine albumin excretion and urinary MCP-1 excretion (a useful biomarker in PKD). Aberrations in liver enzymes were confirmed, along with ALT/AST increases greater than two times the upper limits of normal (ULN) on average. In 5% of patients, the transaminase elevations were greater than three times the ULN. Liver enzymes returned to normal with discontinuation of the drug, but the beneficial aspects disappeared when the drug was stopped.

The FDA approved this medication on the basis that the reversible hepatic toxicity did not outweigh the small, but clinically important, GFR benefit of 1.27 mL/min/1.73 m² with treatment in the REPRISE study. Can this small benefit be sustained on a chronic basis without accumulation of the chronic liver effects? There was a high percentage of study non-completers, mainly because of the adverse side effects of polyuria, frequent nocturia that impacted quality of sleep, and thirst with tolvaptan.

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Cost of treatment, alternatives

The cost factor will come into play with tolvaptan as its manufacturer announced it will be sold in a 30-day treatment pack at a wholesale cost of $13,041.10. The cost of the medication must be weighed against the financial implications of the projected delay in reaching ESRD, with treatment of approximately 6 to 9 years before reaching stage 5 CKD. Other potential products in the pipeline include the following:

Tesevatinib: This drug is now in a phase 3 study. Preliminary results from phase 1 and 2 studies of this multitargeted tyrosine kinase inhibitor were encouraging with regard to statistically significant slowing of TKV as compared to a control group. The phase 3 study will determine if the short- and long-term positive effects are sustained and what will be the adverse effects with chronic use.

Bardoxolone methyl and mRNA 1792: This is in the early stages of PKD investigation. We will wait to see what results come from this work.

Metformin: Results of a collaborative study with this drug will be reported soon, but use of this medication in the non-diabetic carries significant risks.

Increasing water intake: An exciting area of investigation is with simple water intake to match the urine output achieved with tolvaptan. If the patient can reach a urine output of approximately 4 L/day or greater that results in a Uosm of 280 mosm/L or less on a chronic basis, then the impact of aquaresis can be studied to determine if tolvaptan (and other V2 receptor antagonists) have an effect independent of inhibiting AVP and hence increasing urine output. The challenge is to make sure the patient can comply with the required large fluid intake (it was achieved with tolvaptan) while monitoring at home the goal of urine hypo-osmolality.

A physiologic study that supports trying water intake only as a potential therapy for PKD was undertaken by Mayo Clinic investigators (led by Vicente Torres, MD, and Peter Harris, MD) and demonstrated AVP directly regulates cyst growth in PKD.4 They showed aquaresis downregulates cAMP signaling (mediated by calcium), cell proliferation and chloride-rich fluid secretion by human epithelial cells.

Conclusion

Tolvaptan is the first specific drug approved by the FDA that is designed to slow the progressive course of PKD. Both patients and the nephrology caregivers are optimistic that the high cost for tolvaptan will not limit the access to this drug and a mechanism will be found to deliver this agent to those who need it. Hopefully, the door is now open to other agents under study to be added to our treatment regimen for patients bearing the burden of this disease, assuming these prove to have a positive impact on this genetic disorder and an acceptable safety profile.

PAGE BREAK

References:

1. Schrier RW, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402685.

2. Torres VE, et al. N Engl J Med. 2012; doi:10.1056/NEJMoa1205511.

3. Torres VE, et al. N Engl J Med. 2017; doi:10.1056/NEJMoa1710030.

4. Torres VE, et al. Nephrol Dial Transplant. 2017;doi:10.1093/ndt/gfx043.

For more information:

Theodore I. Steinman, MD, is a clinical professor of medicine at Harvard Medical School and senior physician at both Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital in Boston. His primary interest is in collaborative research investigation and clinical management of polycystic kidney disease. He is past chair of the scientific advisory committee and past member of the board of directors for the PKD Foundation. He also is a member of Nephrology News & Issue’s Editorial Advisory Board. Disclosure: Steinman reports no relevant financial disclosures.