This is the second significant set back for tolvaptan. Otsuka had investigated it for heart failure with the flawed (in my mind) Everest Trial. Tolvaptan never sought an indication for heart failure because their trial was negative. This is what makes the FDA’s decision so upsetting, the TEMPO trial was positive, the drug met its primary end point (P=0.001), it slowed cyst growth. The secondary end-point, and more clinically relevant end-point, of decreased change in GFR was also positive (P=0.001).
Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P=0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P=0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P=0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).
Side-note about the choice of change in kidney volume rather than change in GFR for the primary end-point: This was used because ADPKD is such a slowly progressive disease that investigators feared if a treatment was required to slow the change in GFR, it would be prohibitively expensive and slow to evaluate therapies. The change in kidney volume was adopted by the ADPKD research community as an acceptable intermediate end-point after observational imaging studies found a tight relationship between change in kidney volume and renal prognosis.
When I heard about the denial I figured the liver toxicity must have much more severe than I suspected. That turns out not to be the case. Bill Brazell (Bill is a former board member of the PKD Foundation and reader of PBFluids, who was at the FDA hearing) described the liver toxicity founding the TEMPO trial:
A small number of patients experienced potentially important elevations of liver enzymes (4.9 percent, compared to 1.2 percent of those who took a placebo), but the panel focused for hours on the simultaneous elevations in both liver-enzyme levels and bilirubin that occurred in just three patients out of the 860 who took the drug. In all three, the elevations occurred within 18 months. After those patients stopped taking tolvaptan, their levels returned to normal. No one suffered permanent damageCertainly tolerable to my eyes, especially considering the health implications of dialysis and kidney transplant.
The thing that frustrates me the most is that there are no other proven treatments. We have nothing to offer our patients that works, the only effective therapy was denied approval. Silly FDA what do they expect these patients to do?
I hope Otsuka stays the course, provides additional outcomes data so we can get this approved and I hope the FDA opens it's eyes and begins to see that in the absence of perfect we should accept good.
The article I linked to by Bill Brazell is an excellent discussion of the same issue from a patient perspective. Read it.