Otsuka Announces Phase 3 Results for Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

November 04, 2017 12:03 PM Eastern Daylight Time

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced detailed results from the Phase 3 REPRISE trial of tolvaptan, which is under investigation in the United States in patients with autosomal dominant polycystic kidney disease (ADPKD).

According to trial results, tolvaptan showed greater reduction on the primary endpoint, the rate of change in estimated glomerular filtration rate (eGFR) compared to placebo. Estimated GFR, the primary endpoint of the trial, is a key measure of kidney function. Change in estimated eGFR from pre-treatment baseline to post-treatment follow-up, adjusted by the duration of the trial for each patient and expressed per year was -2.34 mL/min/1.73 m2-year with tolvaptan versus -3.61 mL/min/1.73 m2-year with placebo, representing a 35% reduction of 1.27 mL/min/1.73 m2-year (95% CI 0.86 to 1.68; P<0.001). These data were presented today as a late breaking oral abstract at the American Society of Nephrology (ASN) 2017 Kidney Week in New Orleans,2 and were simultaneously published online in the New England Journal of Medicine.

Polycystic kidney disease (PKD) is a progressive genetic disorder affecting the kidneys, in which fluid-filled cysts develop in the kidneys over time, enlarging these organs and inhibiting their ability to function normally, leading to kidney failure in most patients (see here). Autosomal dominant PKD, known as ADPKD, is the most common type, and is the fourth leading cause of kidney failure.4 By age 57, more than half of people with ADPKD will need dialysis or a kidney transplant (see here and here)

Vicente Torres, MD, PhD, Director of the Mayo Clinic Translational Polycystic Kidney Disease Center, and lead investigator on the REPRISE trial, commented, “Tolvaptan slowed the rate of kidney function decline in this trial. These data represent a significant milestone in the investigation of this condition, for which there are currently no approved treatments in the U.S.”

“It is gratifying to see the significance of findings from the REPRISE trial, which further support the utility of tolvaptan in patients with ADPKD,” said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “These robust findings provide evidence that tolvaptan, if approved in the U.S., may be an important new treatment option with the potential to help patients with this debilitating disease, and we look forward to discussing these data with regulatory agencies.”

Along with results from previous pivotal studies, findings from the REPRISE trial have formed the basis of a response to the Complete Response Letter (CRL) that FDA issued in August 2013, which Otsuka has submitted to the U.S. Food and Drug Administration (FDA) for tolvaptan as a treatment for patients with ADPKD.

About the Phase 3 REPRISE Trial

REPRISE was a Phase 3, multi-center, randomized withdrawal, placebo-controlled, double-blind trial in adult patients with late-stage 2 to early-stage 4 chronic kidney disease due to ADPKD. After an 8-week pre-randomization period including sequential placebo and tolvaptan treatments, 1,370 ADPKD patients were randomized 1:1 to tolvaptan (90 or 120 mg per day) or placebo and treated for 12 months. The primary endpoint measured change in estimated GFR from pre-treatment baseline to post-treatment follow-up adjusted by the duration of the trial for each patient. The key secondary endpoint was the estimated GFR slope derived from the individual slopes in each patient adjusted for the duration of the observations and expressed per year. This analysis used all serum creatinine values from placebo run-in, tolvaptan run-in (not including tolvaptan titration), 12-month double-blind treatment, and posttreatment follow-up measurements. In the trial, tolvaptan patients had a significantly smaller decline, of 3.16mL/min/1.73m2/year compared with 4.17 mL/min/1.73m2/year for placebo treated patients (p<0.0001).

Key safety findings (collected monthly) were generally consistent with previous pivotal data with the majority of events across the study. Following randomization, patients who received tolvaptan experienced more frequent polyuria, nocturia, thirst, polydipsia, dry mouth, fatigue and diarrhea, whereas those who received placebo experienced more frequent peripheral edema, renal pain, and urinary tract infection; most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. In the double-blind treatment period, 5.6 percent of patients taking tolvaptan had significantly abnormal liver blood tests (greater than 3 times the upper limit of normal), compared with 1.2 percent of those taking placebo. Transaminase elevations were reversible after stopping tolvaptan and no patients showed concomitant bilirubin elevations greater than 2 times the upper limit of normal. In the study, risk minimization measures consisting of monthly monitoring of liver parameters helped minimize the risk of serious liver toxicity.

Otsuka collaborated on the development of the protocol for this clinical trial with the FDA through the special protocol assessment process in order to address a CRL issued by the agency for a New Drug Application (NDA) for tolvaptan in ADPKD in 2013. In the coming weeks the FDA will acknowledge whether the company’s response is complete and whether their regulatory review can proceed.


Commentary and opinion

As discussed in this forum in November 2012 (see here), following the publication of the data for TEMPO 3:4 trial (see here), the investigators of this study (sponsored by Otsuka Pharmaceuticals) showed moderate slowing in the rate of increase in total kidney volume (TKV) and reduced kidney pain, but this was negated by higher discontinuation rate (23% for Tolvaptan versus 14% in the placebo group), as well as by hepatic adverse events.

Due to the increased risk of hepatic toxicity, the FDA issued a Drug Safety Communication for tolvaptan (Samsca®) and convened an Advisory Committee to review the data from TEMPO 3:4 trial.  The Advisory Committee voted 9 to 6 against approval of Tolvaptan for the treatment of ADPKD (see here).  The panel cited excessive dropouts and limited efficacy in slowing progression of renal disease, despite reductions in kidney volume and pain.  The overall risk was assessed to be higher than the benefit observed, despite a high unmet medical need in this patient population.  The FDA issued a Complete Response Letter, requiring submission of additional data before considering evaluating tolvaptan for this indication. Now, armed with the data from REPRISE trial, the Sponsor is seeking approval of tolvaptan for the treatment of ADPKD.  Since FDA provided advice through Special Protocol Assessment, and since the Sponsors are bound to follow this advice, it is likely that the new data, supported by TEMPO 4:4 extension trial, will provide sufficient evidence of efficacy and a manageable safety profile, to grant approval of tolvaptan for the new indication of treatment of ADPKD if certain severity criteria are met.  This would represent a deviation from the FDA standards that require demonstration of a significant difference in time to doubling of serum Cr or time to 50% decline in eGFR.  However, given that the results of TEMPO 3:4 and REPRISE trials complement each other and both show slowing of the slope of decline in renal function (measured either by reciprocal of serum Cr or by eGFR), and given a high unmet medical need, it is likely that a full approval or a conditional approval will be granted.  In case of conditional approval, there will be a post-approval requirement to continue to follow the subjects to ascertain that the beneficial effects on GFR and other clinically relevant parameters are sustained as well as a REMS requirement, given the hepatotoxicity seen in TEMPO 3:4 trial.

The study design of REPRISE and the overall clinical program for the development of tolvaptan will now set a precedence to guide the development of other drugs for the treatment of ADPKD as well as for other types of slowly progressive chronic kidney disease (CKD).

Tolvaptan is currently approved for the treatment of adult patients with ADPKD in Japan, the EU, Canada, South Korea, Switzerland, Hong Kong and Australia (see EPAR).  However, it has multiple side effects, including aquaresis accompanied by thirst, nocturia and polyuria. It also can result in hepatotoxicity, which can be managed with monthly monitoring of liver function tests.  As a condition of approval, the European Medicines Agency (EMA) has required a non-interventional post-authorization safety study (PASS) to investigate the risks of hepatotoxicity, basal cell carcinoma and glaucoma associated with the use of tolvaptan (marketed under the brand names Smsca and Jinrac)

While we do not know what label restrictions will be imposed by the FDA, due to the above safety issues, tolvaptan may only be suitable for ADPKD patients who have shown rapid progression or who are likely to progress rapidly.  This subset of ADPKD patients are most likely to benefit from long-term therapy with tolvaptan. It is hoped that another V2 receptor antagonist could be developed that would be devoid of organ toxicity. However, the aquaretic effect is an integral part of the mechanism of action of all V2 antagonists and will have to be managed by increased fluid intake and administration of the second dose in the afternoon instead of in the evening (Ron Perrone, MD personal communication).  Drugs targeting other pathways in the pathogenesis of ADPKD are currently in early stage development [see here and here], but it remains to be seen if they will be successful in clinical trials and whether their safety profile will be better than tolvaptan.

Update April 24, 2018

TOKYO–(BUSINESS WIRE)-Otsuka Pharmaceutical Co., Ltd. (Otsuka) announced that the U.S. Food and Drug Administration (FDA) has approved JYNARQUE (tolvaptan) as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).  As was discussed in the previous post above, due to the risk of serious liver injury, Jynraque label will contain a box warning and the drug will be available only through a REMS (Risk Evaluation and Mitigation Strategy) program, which requires frequent monitoring of liver function as well as certification of providers that prescribe it for the treatment of ADPKD.  The wholesale price of Jynarque has been set to $13,041.10 for a 28-day treatment pack, so reimbursement hurdles could emerge until additional health evaluation and outcome research data become available showing a clear cost/benefit ratio of Jynarque over current standard of care.

Copyright © M. Loghman-Adham, MD

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