Burden of Proof for Tolvaptan in ADPKD

Implications for Clinical Practice

On the basis of the treatment effect size in the REPRISE Trial, Torres et al. (1–4) estimated that tolvaptan treatment started in a patient with ADPKD and an eGFR of 41 would extend the time to reach CKD stage 5 from 6.2 to 9.0 years. Most would consider this a highly meaningful clinical benefit. Its magnitude compares favorably with that of other well accepted therapies for kidney disease, such as angiotensin receptor antagonists for type 2 diabetes and nephropathy, which delay ESKD by an average of 2 years (5).

The important question of which subpopulations ought to be offered tolvaptan remains incompletely answered. That question will be even more pressing in the United States if the FDA approves tolvaptan as a treatment for ADPKD. In other countries, there are typically national bodies that make recommendations about who should be offered a new treatment in the health care system. In the United States, access is limited by insurance companies and their policies. This highlights the need for an evidence-based decision-making process to guide who should get the medication.

The consistency of effect size in the TEMPO 3:4 Study and the REPRISE Trial suggests that tolvaptan may be beneficial across a broad range of ages and GFRs (>25 ml/min per 1.73 m²). However, in patients with preserved kidney function (GFR>60 ml/min per 1.73 m²) who are presumably in an early stage of disease, additional biomarkers are needed to identify those who are at higher risk of disease progression and hence, more likely to benefit from treatment. Arguably, the best individual biomarker available in ADPKD is still TKV (6), which has been approved as a prognostic enrichment biomarker in polycystic kidney disease trials. The imaging classification devised by Irazabal et al. (7) improves on this by adjusting TKV for age and height in patients with typical cyst distribution. The TEMPO 3:4 Study included only patients with a TKV≥750 ml, and those with TKV≥1500 ml had a tendency to benefit more from tolvaptan. Moreover, 90% of them were in intermediate- or high-risk groups by the classification of Irazabal et al. (8).

However, the Predicting Renal Outcomes in ADPKD (PROPKD) Score takes a different approach, modeling outcome on the basis of patients’ genotype and clinical data (9). In a post hoc analysis of the TEMPO 3:4 Study, tolvaptan slowed the decline in GFR in patients at intermediate and high risk by PROPKD Score but not in those in the low-risk group (10). Although such classifications are not validated to guide clinical decisions, it is plausible to think that they might be useful to guide treatment judgments. A major limitation to their use is the limited access to genetic testing and the expense of both genetic testing and the imaging studies.

The REPRISE Trial did raise questions about whether tolvaptan should be used in older patients (>55 years old). In this prespecified subgroup, tolvaptan did not significantly slow the decline in eGFR. This is likely because patients who are much older with still relatively preserved GFR tend to be slow progressors. However, the small number of patients in this subgroup does not allow a firm conclusion to be reached.

Although the trial conduct and robustness of the results in the REPRISE Trial benefited from the randomized withdrawal design, this also limited the broad applicability of the results. Of the patients who entered the tolvaptan run-in period, 6.8% were excluded from randomization due to adverse events that led to the discontinuation of tolvaptan. Most of these were due to aquaretic events, namely polyuria, nocturia, thirst, dry mouth, and polydipsia. The substantial rate of drug intolerance is an important point to be considered for implementation. Additionally, nephrologists should remember that implementation of tolvaptan in the clinic brings some additional challenges that this trial did not directly address. Although tolvaptan did not lead to the report of any patients with hypernatremia in this trial, it is known that this is a potential side effect if patients do not adhere strictly to instructions to remain very well hydrated by consuming several liters of fluids every day. Nephrologists will have to be very diligent in discussing with their patients the potential side effects, the need for monthly laboratory surveillance of liver function, and the potential for harm if patients do not follow instructions. Another important factor that could influence treatment decisions with tolvaptan is its cost, especially for uninsured patients or those who have high copayments for medications.

Future Research

Longer follow-up studies that assess the effects of tolvaptan use on different patient-important outcomes, including progression to ESKD, are now needed. Also, postapproval studies that ensure continued safety and efficacy will be necessary. Studying combination therapy that may synergistically tackle different pathophysiologic mechanisms and additional innovative medications that do not share a similar side effect profile will continue to be of interest.

This is an exciting time for the ADPKD community at large and especially for our patients. The REPRISE Trial is a landmark study that provides strong evidence supporting the efficacy and safety of tolvaptan in patients with ADPKD. We hope that this answers the concerns of the FDA and will be sufficient to support approval of tolvaptan so that, for the first time in the United States, nephrologists will be able to offer a treatment that slows the decline of kidney function in ADPKD.

Disclosures

A.S.L.Y. served on an advisory board for Sanofi and as a consultant for Regulus Therapeutics.