CME Slides Forum - C. Wanner

A joint Congress by ERA-EDTA and ISN

TREATMENT CHOICES FOR FABRY NEPHROPATHY

Christoph Wanner, Würzburg, Germany

Chair: Joao Paulo Oliveira, Porto, Portugal

David Warnock, Birmingham, USA

wanner

Prof C.Wanner
Bayerische-Julius-Maximilans University
Department of Medicine, Division of Nephrology
Würzburg, Germany

when you are talking about treatment choices for Fabry Nephropathy, then you have to talk about enzyme replacement therapy, a treatment option available since 2001, now for more than 8 years. There are two different forms of enzyme, the gene activated human or the recombinant α Galactosidase A called agalsidase α or agalsidase β.

It has controversially been discussed but to me the two forms are identical proteins? The aminoacid sequence is identical, there is similar glycosylation, there’s an equivalent plasmatic stability, equivalent uptake, equivalent immunogenicity. Bioavailability and pharmacokinetic profiles are also equivalent. So it really appears to be a similar treatment.

In addition to what we have already heard enzyme replacement therapy (ERT) appears to be differently effective in what stage of disease it is administered and wheather it requires adjuvant therapies. For example, ERT appears does not lower substantially proteinuria, so you add an ACE or and ARB or other renal and cardioprotective medications.

Here are further questions which clinicians ask today and the questions are: whom to treat? Males and females? When, early or late? The treatment is expensive and clinicians tend to save and treat late. Further questions are: enzyme replacement therapy at what dose? α at the dose of 0.2 mg/kg body weight or β at the dose of 1 mg/kg per body weight. I will address some of these questions.

First let me give an introduction on the Fabry disease model, the cascade of disease progression. You can easily understand from the pathogenesis of the disease that disease starts very early at birth or even during pregnancy with mild storage which is largely reversible. It goes then on to an impact on cells and tissue and this is the initiation of secondary pathologies and processes. Later in life during adolescence there is progressive build up of damage which appears to be reversible only up to a certain stage. Finally, you have end organ failure or events that are coming in.

When you are now investigating this disease, you have to recognise that there are surrogate markers which appear early on in life and later you will then have events and outcomes and clinicians always ask: does enzyme treatment really save lives, though they go automatically to events and outcome. You have a rare disease and to study a rare disease in terms of events and outcome is very difficult. It’s better to study it early on and look at some clinical markers. Demonstrate that lysosomal storage is reduced or even tissue structure and organ size is preserved. It becomes more difficult to study whether organ function tests become better during enzyme replacement therapy and it’s most difficult to reverse the disease late on and to show that major clinical events or even death is reduced.

Clinical symptoms are also difficult to investigate, but lysosomal storage and clinical symptoms were investigated in the early trials and there has been shown a reduction in neuropathic pain or a reduction of tissue burden of the storage.
Here, you see these vacuolated cells in the glomerulus which is GL-3 deposition and the early studies have focused on the reduction of this deposition. In fact, the trials were very successful. The trials also focused on electron microscopy showing heavy deposition in a podocyte in the kidney and substantial reduction and sufficient treatment by enzyme was shown to reduce this load of the cells. But if you look at later stages of disease and to this shrunken kidney, heavily fibrosed, then you can imagine that if you go in with treatment in these late stages, you may be less successful and this has already been shown. It’s only demonstrated here by me, with these pictures to be a little bit consistant.

So, enzyme replacement therapy approval was given in 2001. The two products are Fabrazyme approved worldwide, Replagal approved in Europe and some other countries. The efficacy noted here for Fabryzyme is tissue clearance and for Replagal is improved neuropathic pain. We assume that the one product at a higher dose may cause a higher percentage of antibodies than the lower dose, as this has been shown in studies. There has been approval thereafter at this given dose. The journals are prominent.

Let’s come to a recent publication and go into the various studies and publications. The one from Dominique Germain showing long term renal stabilisation after nearly 5-6 years of agalsidase β therapy in Fabry patients.

There was the initial study phase 3, called phase 3 placebo controlled and after 20 weeks after the enzyme was approved the placebo was abandoned and Fabrazyme was given for another 34 weeks.

This was the first part of the approval study and the next part was the long term extension and follow up period. As you can see from the serum creatinine (GFR gives an aequivalentl picture over time. Renal function is normal at the beginning and remains normal over very long periods of time and then creatinine starts to increase in the enzyme replacement therapy group.

This caused some concern and the group was intensively studied and the 6 patients who caused this increase were identified from the treatment group and these investigators could show that the number of sclerotic glomeruli in these 6 patients at baseline were substantial, but kidney function was good enough that patients could be included. You can see that these patients have in part stage 4 and some of them had about 40 years of age and at baseline proteinuria was prominent. It was not the case in the other remaining patients but in those 6 who deteriorated proteinuria was prominent. Over the 40-54 months of enzyme treatment and enzyme did not substantially lower proteinuria.

The serum creatinine at the beginning is shown here with one patient in the clearly pathological range. So if you eliminate these 6 patients and follow them over time, then you can clearly see that this was the reason advanced disease in this subset of patients and enzyme stabilised the kidney function.

If you look into the maintaining of renal function, in this case Fabrazyme was given in this study, then you see that baseline proteinuria below 1 did not cause a decrease in renal function. There was a slope estimated GFR the slope was -1 ml/min/year in comparison to the baseline proteinuric patients above one and this was significant and substantial loss of renal function in those advanced patients.

If you go not only to renal function but also look at significant renal sclerosis, then you can see a similar thing, renal sclerosis at baseline causing faster progression of kidney function.

There have been published some pictures where podocytes were heavily loaded at the beginning and are less loaded and you see less deposition after 5 years of treatment but if nephrologists look carefully at this one glomeruli, then you see here regions where matrix is accumulating substantially and giving the impression that there is reduction of material but matrix accumulation which may cause even progression of renal disease.

Doctor Shiffmann has already mentioned it that progression is heavily depending on proteinuria and proteinuria is predictive in developing subsequent renal events. You see baseline protein creatinine ratios plotted against risk of renal events and the higher the protein: creatinine ratio, the higher the risk of another renal event progressing to ESRD.

So this brings me to a paper which has already been mentioned by our chairman’s group and they showed that anti-proteinuric therapy in these patients is essential for Fabry nephropathy progression and there was a sustained reduction of proteinuria in patients receiving ERT when you add enzyme, when you add an ACE to enzyme replacement therapy.
This was an observational study in a small number of patients including 3 women who were affected. The mean age was 37 years and combined treatment with ACE and ERT for 30 months follow up of proteinuria caused a reduction of progression substantially and down to 0.23 ml/min per minute per year in the following 30 months of follow up.
I think the authors or we have to acknowledge that this is a fabulous inhibition or halting of progression of renal disease. The authors must admit this is a small number and maybe some selection is already there. 11 patients but it’s hypothesis generating, it’s a hope and gives us a good indication to add adjunctive therapy to ERT, bring this proteinuria down as much as you can and there’s a study underway with a larger number of patients proving this concept.
Nephrologists are very familiar with this.

Another trial was given in Annals Internal Medicine, agalsidase-β therapy for advanced Fabry disease

and there were 82 patients in this trial randomised in a 2:1 fashion. The serum creatinine was elevated above 1.2-3.0 mg/dL so advanced, far advanced patients. Duration was 18 months and you can see a separation of the curve between the enzyme and placebo over the period and this was significant mainly in the group of those patients with an estimated GFR below 55 ml/min and they had a hazard ratio of minus 15 and those with above 55, those who had a better renal function they had nearly a reduction of progression of nearly 80%. So you clearly can see the difference in stage of renal disease in terms of enzyme replacement therapy.

Agalsidase-α results here in a paper in JASN, and this is only 4 weeks old because it has been shown similar benefits in respect to kidney dysfunction in Fabry disease.

The strength of this paper in JASN is that the authors used measured GFR. So this is inulin clearance, these are two tracer technologies, chromium EDTA and technetium DTPA. The limitation of this is that the results are coming from three separate trials conducted at different times and different study sites but I think the reviewer of these prominent kidney journals felt that you can accept that 3 cohorts are combined and evaluated in respect to the rare disease. One figure in this paper shows different stages of disease with patients, 8 in the first cohort which showed a GFR above 135 ml/min, those, 33 in the range of 90-135 ml/min and in lower stages of chronic kidney disease down to 30-60 ml/min (14 patients). First of all, it’s impressive that apparently those with the best kidney function are progressing very fast or, and this is currently discussed maybe they are hyperfiltrating and they go down to normal, they are normalised. So maybe we can discuss this only 8 patients but the rest of the patients appear to be stabilised under agalsidase-α over a 30 month period of time and even in the range of 30-60 ml/min there is some drop here but over a period of time they were stabilised.

If you look at the blood progression before ERT in the so-called placebo period was 7.6 ml/min/year 18 patients and only the patients between 30-90 ml/min are shown here and after enzyme they go back to 2.5 ml/min/year. So it appears that the enzyme is slowing the progression of renal disease. Also proteinuria in some patients is not affected to a significant range.

This paper also gave a short overview of papers. Enzyme replacement therapy on the left side and a number of papers done earlier you see here the discussed paper from Branton, untreated patients plotted against the mean annualised decline of GFR or estimated GFR over time. The untreated patients appear to progress faster and the number of patients are considerable. There are at least 80 something patients there in comparison to the Germain paper I showed to you, another uncontrolled series of our group and the present study with 58 patients followed without proteinuria over time and with significant proteinuria.
You see that the groups are always taking a cut-off of 1 g/24 hours and those with small or let’s say that’s not sufficient in our view to go below 1 as low as possible but the progression of renal disease is lower in those with small proteinuria. This is consistent over all papers published so far which gives us a feeling that we are here on the right track.

So coming to the end, my previous speaker has given his view, the essence is in the kidney. We focus today mainly on the kidney also more data are now emerging for heart and stroke and I hope I have given you some insight into this rare disease.

Chairman: Thank you Christophe. I think we have time for one question. Any questions from the audience?

Question: Thank you for your presentation. I have a small question. If I see these results I’m a bit disappointed and you did not answer the question when should we treat which patient? Especially the placebo controlled study the first one that you showed does not show a negative result but the group was worse than the other group but is it really true? How was the other group? So in fact two questions that I wanted to ask you.

Prof. Wanner: Ok maybe you got a point which I maybe didn’t say explicitly. Early treatment is important when the organ damage is not advanced. When you have fibrosis and similar things are going on in the heart when you have high fibrosis, you cannot reburse this then patients are in a later stage of kidney disease and the earlier the better. There are some heavily affected young people also at every early age so you have to stage disease, look at every organ carefully and males have no enzyme, males as early as possible and females according to the damage you already see and clinical symptoms. So early treatment. The second was placebo? Excuse me.

Question: I was a bit disappointed by -----improvement but still the results are not very convincing. There’s one study that shows results but all the others are either not controls or ---

Prof. Wanner: Actually I could take out only a few papers which show you the direction of where we are going. Actually you are disappointed because you cannot stop the disease absolutely and maybe you have to take adjunctive therapies. This is the point that still in later stages there is progression and events happen. But at least you slow progression of renal disease I think this is clear in my opinion.

Question: I think one of the expectations of the clinical nephrologist regarding ERT is precisely that one that they expect that we can stop disease but unfortunately it seems the best we can do is slow progression. I’d like to ask you a question Christophe regarding the role of kidney biopsies on patients and ERT. I know that in your group you are doing protocol biopsies. Can you now defend the role of protocol biopsies as an instrument to follow up in response to therapy?

Prof. Wanner: Sometimes you are uncertain on whether you should treat or not especially in females, in women. They have no substantial damage to the heart, to the brain as sensitive your methods are and they have little proteinuria, 300 mg and some clinical symptoms. So we do a routine biopsies in women and we see very early on, as could be a logical thing, you see heavy deposition and then we go for ERT so it gives you some justification and of course we want to learn something. We add these biopsies to an international group which is now exploring the histology to learn more about stages of disease. So we do this in women routinely when we are uncertain about treatment. Maybe one other word, first this ERT came to the market with Gaucher and it cures this disease, the Gaucher disease. Then it came to the Fabry and from day 1 we did not see the same success so maybe this was a bit of a disappointment and now we see that the disease is different and progresses differently and affects other organs and I think we have come quite far in the ideas to understand what’s going on.