Slide 1

Thank you very much. I would like to thank the organisers for the kind invitation here to this exciting place and also for the opportunity to present some of the ongoing trials on ADPKD.

Slide 2

As most of you know, these are the kidneys of a patient with autosomal dominant polycystic kidney disease.

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This is one of the most common hereditary diseases. Typically patients present it in the fifth decade of life. It’s a slowly progressive disease that leads to ESRD in approximately 50% of all patients.

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We know that this is a systemic disease, it doesn’t only affect the kidneys but it also very often affects the liver. There are heart valve abnormalities and of course, most threatening are the cerebral aneurysms that can be found in patients with a positive family history in up to 16%.

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Most patients have mutations in PKD1, 85%. This is a large integral membrane protein, has several domains that suggests that this molecule is involved in adhesion. However, we really don’t know what this protein does.

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The remaining 15% have mutations in PKD2. This is a calcium- permeable ion channel that interacts with the other proteins, polycystin-1. Principally the mutations of this protein cause very similar symptoms, however the progression of disease is much slower. Patients typically experience ESRD at their 6, 7th decade of life and also the survival rates are much better.

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Now, also the molecular basis of the disease has now been known for more than a decade. It’s only been just for the last couple of months basically that new clinical trials have been evolving. The NIH site now lists 9 trials that are either recruiting patients or planning to recruit patients in the near future. These trials are based on 3 different columns. They’re based on, they’re trying to target risk factors, they’re trying to target the pathogenesis and some of them are just trying something new.

Slide 8

Now what are the risk factors in ADPKD that accelerate the progression of disease? We know several of them, they are genetic, PKD1 versus PKD2, I just mentioned it. Males have the worst prognosis. Presentation at young age or parents that ended up on dialysis very early on. But there are two significant risk factors, hypertension and another one hyperlipidemia that are now addressed in two clinical trials.

Slide 9

This is a large clinical trial, it’s a HALT PKD trial that will enrol about more than 1000 patients that will be either treated with ACE inhibitor monotherapy or in combination with angiotensin receptor blockade. The trial will go for 5-6 years and is divided up in 2 different groups. One group is patients with better function, a GFR above 60 will be followed by MRI. The other patients will be followed until their renal function declines to 50%.

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This trial really will treat very early on will treat children at age 8 and young adults with a normal GFR and test hypotheses that early intervention with lipid lowering agents such as pravastatin results in a positive effect on disease progression.

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Again, this study uses MRI to evaluate the success of this study. Why are both of these studies using MRI? Why are they not using kidney function, the primary endpoints that all interest us?

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Typically ADPKD patients experience a decrease in GFR of about 5 ml/year but only once the kidneys are significantly enlarged. As we all know, most of these patients have stable creatinines for a very long period of time and a change in GFR that’s too small to measure reliably the success of an intervention.

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However, we know that cyst growth and kidney growth starts very early on. This leaves us a much broader window for interventions.

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Grantham and – in the U.S. have followed this growth very precisely over several years and they have documented that once kidneys reach a certain size, 7 or 50 ml or more they grow about 5% per year or more. And this can be very accurately assessed by MRI analysis.

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Now, since only about 67% of our patients will have a positive family history here discussion arises whether we need genetic diagnostics before we can enrol patients.

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Typically, there are more than 20 genes now available and also as I mentioned, ADPKD is the most common disease, there are several more entities that cause very similar clinical pictures.

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We use 5 criteria to establish a clinical diagnosis. We use the size of the kidneys that is typically tremendously enlarged in ADPKD, for example, in contrast to nephronophthisis.

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We use the location of the cysts that are very disorderly in ADPKD versus a line up very nicely along the corticomedullary junction in nephronophthisis.

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We use the age of the patient that ADPKD typically presents at higher ages than many of the recessive forms.

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Extrarenal manifestations, especially the liver cysts very often help to establish the clinical diagnosis.

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Finally, the mode of inheritance of course, it’s autosomal dominant in ADPKD and it’s recessive in most of the juvenile forms or the forms that occur in young adolescents.

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So we can principally in most patients establish a clinical diagnosis and don’t need a genetic diagnosis. However, we have to bear in mind that there might be differences depending on where the mutations are PKD1, PKD 2 and how these patients respond to therapy.

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Now, how can we target the pathogenesis of ADPKD? We have recently learnt that all proteins that are mutated in polycystic kidney disease all localise to the cilium of tubular epithelial cells.

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The flexion of this cilium causes a calcium transient and this calcium transient requires the present of these intact polycystin-1 and 2 proteins.

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And we think that this calcium transient somehow endows the tubular epithelial cell in the cilium with the capacity to act as a mechanosensor, sort of a GPS that you use in your car.

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This kind of GPS seems to be required to orient the tubuloepithelial cells especially when they divide along the nephron. If there are mutations such as ADPKD mutations, then these cells are disoriented and cause cyst formation.

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Once cyst formation occurs there is secretion. Fluid secretion, cyst expansion and fibrosis go hand in hand. We know that the fluid that is secreted contains several different growth factors and one of them is vasopressin.

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Vasopressin binds to the vasopressin 2 receptor and increases intracellular amounts of cAMP.

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And this in turn augments the fluid secretion and probably is a major contributing factor to cyst expansion.

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There are now several components available to block this receptor and hence block fluid secretion. This has now been successfully translated into several animal experiments and it was shown that these compounds cannot only inhibit cyst formation but they inhibit kidney volume, they reduce cyst formation and they also improve renal function.

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Based on these exciting experimental findings Otsuka now has planned a large clinical trial and I’ve heard that it has just been initiated a few weeks ago that will enrol 1500 patients with a GFR of more than 60ml/min and a kidney volume of more than 750 ml and will either treat these patients with placebo or Tolvaptan. Again the endpoints measured at yearly intervals are going to be MRIs.

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Now there’s one other curiosity in the cyst epithelia of patients with ADPKD. There is a dramatic upregulation of mTor  here shown by antibody staining for mTor or a distal target of mTor.

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We believe that polycystin typically interacts with a tuberous sclerosis complex to keep the mTor activity in check. If there are mutations of polycystin that lead to a ciliary signalling defect, then there is a dramatic upregulation of mTor activity.

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This upregulation of mTor activity then leads to cell proliferation,

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cyst formation and cyst expansion.

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Now, we know that we can control mTor activity with rapamycin. This principal also has been translated by several groups successfully in the treatment of various mouse models of PKD.

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Again you have inhibition of cyst growth, as well as reduction of kidney volume. You can even follow the efficacy of this drug in mouse models of polycystic kidney disease using very similar MRI protocols.

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So based on these findings we have initiated in collaboration with Novartis a clinical trial that will look at the effect of everolimus in patients with ADPKD that have a GFR between 30 and 89 ml/min or a kidney volume of more than 1000 ml. These patients will be followed for 2 years again by MRI. This study has enrolled more than ¾ of the desired numbers and there will be an interim analysis in a year and so we expect first results by the end of 2008.

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A very similar study that uses a fixed dose of rapamycin is currently performed in Zurich.

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Finally, something new.

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Based on pilot experiments with somatostatin there is now a clinical study underway at the Mario Negri Institute to test the effect of somatostatin in 66 patients. Again they will be followed for 3 years with MRI to evaluate for changes in kidney and cyst size.

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So, after many decades of research there seems to be some light at the end of the tunnel and at least we will find out within the next couple of years whether we can actually treat this hereditary disease efficiently. Thank you very much for your attention.

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Chairman: Thank you very much indeed Gerd for a very thought provoking and stimulating piece of information. Any questions from the audience to Gerd about these trials?

Question: Here. A critical point in this kind of research I mean in patients with --- polycystic kidney disease is that we have to understand whether a therapy is effective based on surrogate endpoints and this is particularly difficult in my opinion because therapy should start quite early when the cysts are growing quite slowly. So what is in your opinion the best surrogate endpoint to be measured?

Prof. Walz: Yes, I have to say the FDA shares your concerns. There has been just a recent workshop a few weeks ago at the NIH regarding this surrogate parameter MRI. This is currently the best established parameter. We know that cyst growth and kidney growth basically correlates very well with subsequent renal failure. This relationship has been very well established. So I think that’s a current point and there have been very long and extensive studies especially by the CRISP Consortium in the U.S. to establish as this as a surrogate parameter. So I think currently there’s nothing better than that.

Chairman: Ok, we have one question up there.Question: Thank you very much for the information you gave us. Would it be possible to give us more data on the Tolvaptan study? You said 2 weeks ago you only started. Which countries are participating and how long will the recruitment last? When are the first results going to be available? I’ve been trying with the company and they don’t want to know.

Prof. Walz: Yes, I think there has been a fairly lengthy discussion between the company and he FDA and that’s the reason why they have been postponing the initiation of the trial for many months. I think they planned it already in 2006 and they have been postponing it because the FDA has not been accepting MRIs studies as a surrogate marker. I have heard that they have now initiated. Principally it will be performed in Americans so it’s going to be North and South America and probably in most European countries.

Question: How long will it last?

Prof. Walz: 4 to 6 years that’s the estimate right now.

Question: Thank you.

Chairman: Ok thank you very much indeed Gerd for that very interesting presentation.