Tolvaptan and the FDA - A patient's perspective

<$BlogItemBody$>

New potential drug targets in ADPKD

Currently there is no good treatment for the most common inherited cause of ESRD, adult polycystic kidney disease. There have been a number of high profile trials in ADPKD in recent years. These trials have endeavored to show a reduction in cyst growth and GFR decline with everolimus, sirolimus) and most recently Tolvaptan (TEMPO). The longer (2years) and larger (433 patients) of the two mTOR inhibitor trials (everolimus) did show a significant reduction in cyst growth at one year but not in GFR reduction. The shorter sirolimus trial failed to show a reduction in cyst growth or GFR decline. The TEMPO trial was over 3 years, had 1445 patients and did show that the V2 antagonist Tolvaptan slowed GFR decline (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) and cyst growth, 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). The jury is still out about the clinical applicability of these drugs and there have been criticisms. For example, tolvaptan is very expensive and would need to be used long term. In the mTOR inhibitor trials some argue doses could have been higher and the lack of hard end points speaks for itself.

However, all is not lost. A potential new drug target in ADPKD was reported by Rowe et al. in Nature Medicine last month. A good overview of the topic can also be found in the same issue.

Using MEF cells from pkd-/- and pkd+/+ mouse littermates they found that growth medium from the pkd-/- cells was more acidic and that the pkd-/- cells had a higher ATP content. To investigate which metabolic pathways might be causing this difference they used NMR spectroscopy and found lower glucose and higher lactate levels in the knock out cells. They then used a mitochondrial ATPase inhibitor to determine the source of higher ATP and found only wt cell had a reduction in ATP with this treatment.  Then the investigators did a real-time PCR analysis on the pkd-/- cells and found an upregulated glycolysis signature. They thus concluded that the pkd-/- cells rely on aerobic glycolysis for their energy demands. This is known as the Warburg effect described in cancer cells (Otto Warburg, a physician-scientist, received the Nobel Prize in Physiology or Medicine in 1931). To see if these in vitro findings translated into in vivo they used Ksp-Cre; Pkd1flox/− mice, which develop early and severe PKD and measured 13C-glucose or 13C-lactate using 13C-NMR. The findings were the same. The authors then used 2-deoxyglucose (2-DG) an analogue of glucose that is unmetabolised. They treated wt and pkd deficient mice this compound and found that the pkd deficient mice had a lower cyst index and lower 13C-glucose consumption as measured using 13C-NMR.

This interesting study proposes that the use of drugs targeting this pathway in combination with other drugs may reduce cystogenesis and progression of CKD in ADPKD. The authors do stress that their summary with regard to human treatments is speculative. In all I think the future is not so gloomy for ADPKD.

Posted by Andrew Malone

Aquaretics and PCKD

One of the big stories at the ASN this year was the announcement of the results of the TEMPO trial which were simultaneously published in NEJM. It has been known for some time that ADH is implicated in cyst growth in patients with polycystic kidney disease (PCKD) and that suppression of ADH release with high water intake or vasopressin receptor blockade reduces cyst growth in animal models. The TEMPO trial was a 3-year, multicenter controlled trial involving 1445 patients with PCKD who were randomized to receive tolvaptan (a V2-receptor antagonist) or placebo. The primary outcome was the rate of change in total kidney volume while the rate of CKD progression was a secondary outcome.

There was a lower rate of kidney growth in the tolvaptan group (2.8% per year vs. 5.5% per year) and a slower decline in renal function also. These are fantastic results and they should be celebrated, especially considering the disappointment surrounding bardoxolone. However, there are a couple of significant issues which should be considered. All of these patients had normal renal function at the time of entry into the study. The majority of these would progress very slowly to end stage and the cost of treatment with tolvaptan over this period of time would be enormous. Also, about 23% of the participants dropped out due to adverse effects (although, it should be said that 14% of the placebo group also dropped out). The most important side effect was liver toxicity.

So the question arises – who are the patients that will benefit most from vaptan treatment. As the accompanying editorial states – “the development of comprehensive criteria for aquaretic treatment and appropriate patient selection are needed”.

So maybe a recent series of papers from a group in Holland may help provide the answer. Vasopressin is difficult to measure in vivo because of its short half-life and tendency to bind to platelets. However, one of the components of its precursor, copeptin, is stable in plasma and can be used as a surrogate for the serum vasopressin concentration. Last year, this group published a paper which found that, in a group of 102 patients with PCKD, serum copeptin levels were associated with markers of disease severity such as kidney size, GFR and albuminuria. The group published two follow-up longitudinal studies (using historic samples from previous studies) in NDT and AJKD. In a group of 79 patients, higher baseline copeptin levels were associated with more rapid decline in renal function over 11 years follow-up. 8 of the 9 patients that started hemodialysis over the course of the study had copeptin levels above the median. It should be pointed out that baseline copeptin levels were higher in patients with lower GFR at the time of entry to the study and this could have biased the results.

The last paper looked back at 241 patients with normal baseline renal function who were included in a longitudinal study of cyst growth (and measured GFR!) In these patients, higher baseline copeptin levels were associated with a greater change in kidney volume over 8 years follow-up. After full covariate adjustment, there was a trend towards a greater decline in renal function in the higher copeptin group but this was not statistically significant. Again, however, patients with larger kidneys at baseline also had higher copeptin levels. Because of the size of the molecule, there may be some element of reduced clearance in patients with lower GFRs and this could explain some of the differential. Higher copeptin levels have also been noted in patients with other renal diseases so this is not entirely specific. This needs to be further studied.

Still, although not definitive, these studies provide some rationale for a potential means of stratifying patients with PCKD and certainly give a route for further investigation. It would be interesting, perhaps, to go back and measure baseline copeptin levels in the patients in the tolvaptan study to determine if there was a difference in response to therapy based on this promising biomarker.

Rapamycin and PCKD

A couple of years ago, it was noted that mTOR inhibitors slowed the growth of cysts in animal models of Polycystic Kidney Disease. Although the activity of mTOR is minimal in normal renal epithelial cells, in cyst epithelial cells, expression is markedly increased. At the time, there was understandably a lot of excitement about this and the potential for a role for rapamycin for treating patients with PCKD. (We got in on this ourselves and had two posts from Nate and Conall about this possible therapeutic pathway) Unfortunately, the clinical studies were not very impressive and the excitement has since faded somewhat. One of the reasons put forward for why it was ineffective was that the doses were inadequate. The dose of rapamycin needed to suppress cyst growth in mice was far higher than was tolerable for humans. Anyone who has used rapamycin in transplant recipients knows about the side-effect profile which prevents many people from taking the drug,

An article was just published in JASN which raises the possibility that rapamycin could be used in higher doses than previously thought possible. The folate receptor is selectively expressed on cancer cells and renal epithelial cells. As a result, there has been some work done on combining drugs with folate to increase the specificity of drug delivery, particularly chemotherapeutic agents and thus limiting toxicity. The beauty of this is that folic acid is taken up into most cells by an alternative pathway and this pathway is not available to conjugated folate. In this study, the authors conjugated rapamycin to folate and gave it to mice with PKD. They showed that it was effective both at reducing expression of downstream targets of mTOR and slowing cyst growth. This suggests that the combined compound could be given in large doses to humans with PKD and offer targeted therapy with less chance of significant extra-renal side effects.

Photo from the University of Indiana website

Cell Polarity and Cystic Diseases

There was an interesting article and accompanying editorial in JASN this month about the role of polarity in the development of cystic renal diseases. The maintenance of epithelial cell polarity is vital for the normal functioning of the renal tubules and the usual interpretation of this is the way in which a cell is organized into basolateral and luminal compartments (e.g. in intercalated cells, there is a luminal H+ ATPase and a basolateral anion exchanger and it is this polarity that facilitates acid excretion). In a similar way, mislocalization of the Na-K-ATPase has been noted in patients with ADPKD and is a putative mechanism for cyst formation.

However, there is another facet to polarity which appears to be just as important – planar polarity – this is the correct orientation of cells and specialized structures within cells along the plane of the epithelial sheet. Much research is continuing into the genes responsible for the development and maintenance of polarity. One of the means by which a loss of planar polarity may induce the formation of cysts is through the loss or dysfunction of primary cilia.

The authors in JASN found that both a gain and loss of function mutation in ErbB4 led to a loss of cell polarity. Members of this receptor family have been shown to be responsible for the development of polarity in neurons and in certain cancers.