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Gout Dugout.Issue#019.Gout causing gene identified;Commitee votes to approve Krystexxa(Pegloticase)
July 03, 2009

A warm welcome to the July 2009 edition of the Gout Dugout newsletter, and to new readers who have signed up since the June edition.


Good news for genetic gout sufferers. If your gout is caused by a genetic factor - a gout gene if it's put that way - it may have been precisely identified last month. I say may because there could be other genetic causes of high uric acid (UA)levels.

But it was announced in June that at least one genetic cause has been identified. The credit goes to scientists at Johns Hopkins University School of Medicine in the U.S.

The cause is on the failure to excrete side of the equation rather than the uric acid over production side. The problem gene's name sounds like a five letter and number cipher in a spy's message - the ABCG2 gene.

How does it cause gout?

When this gene behaves normally ABCG2 produces a protein that transports urate (uric acid) from the kidneys into the urine.

But when it doesn't, the scientists' research findings were that only half the normal amount of uric acid is excreted. Hence, I guess, uric acid in the blood rises for this reason, hyperuricemia results and, as you know, this can lead to gout attacks.

Nothing to do with purines, insulin resistance, blood pressure lowering drugs, cold weather or any other cause.

What could this lead to?

Here's a few thoughts. Research scientists are going to have to find out whether dietary measures or drugs can reduce uric acid production sufficiently to negate the effect of this malfunctioning gene in raising uric acid levels.

A real solution would be to correct this malfunctioning gene - i.e. get it to produce the transporting protein correctly so that uric acid can be excreted normally. But correcting this malfunctioning gene sounds like something we are at least 30 years away from being able to do.

Or, perhaps this gene's ability to create the transporting protein can be made more reliable - to excrete sufficient uric acid so that UA levels are lowered in cases of hyperuricemia or hyperuricemia and gout. That too sounds like something for the far future.

But with this genetic cause of gout I guess you'll find it reassuring to know we are still dealing with uric acid levels. If you think you have genetic gout, lowering UA levels is still the key to a solution, as it always is.


The U.S. FDA convened a special arthritis advisory committee (AAC) meeting on June 16 to discuss Pegloticase (Krystexxa) approval.The committee voted 14-1-0 (in favour, against, abstentions)in favour of its approval. The decision should be announced in July because the FDA said they would decide before August 1.

This is a strong endorsement almost as strong as the 12-0-1 (in favour,against,abstention) vote for Febuxostat towards the end of last year. And Febuxostat was approved not long after.

Pegloticase's (Krystexaa's)developers, Savient Pharmaceuticals, have their whole future hanging on this decision because Krystexxa is just about their only product. The company even paid for a few people in its trials to attend the meeting and give their testimony to the committee. There were some strong endorsements. Krystexxa has even cleared up some cases of tophi and reduced uric acid levels by impressive amounts, such as from 9.8 mg/dL to 3.0 mg/dL in a 2 week group by month 3. 6.0 mg/dL, for those readers who don't know, is considered, roughly, the level at which gout attacks may cease, or begin to cease.

The FDA does not doubt Pegloticase's effectiveness in lowering uric acid levels. It said:

"The agency does not dispute the efficacy of both the every 2 week and every 4 week dose regimens."

But there are downsides. One is safety - there have been deaths from heart attacks in trials, but none where Pegloticase could be clearly identified as the cause.

Another is, what will Krystexxa cost? This isn't a tablet like Allopurinol or Febuxostat. This is a course of infusions into veins, in the trials every 2 or 4 weeks. And it will require specially trained nurses/clinical assistants to administer it.

So far Savient haven't announced pricing and presumably it won't unless and until it gets FDA approval. In progress presentations to Wall Street financial analysts Savient have talked about "biologic pricing" which to me sounds like premium pricing i.e. expensive. We shall see.

This means that unless tophi is or are very severe, and unless other drugs don't work which could occur in gout patients who have done nothing about their condition for years, or for whom nothing could be done, Allopurinol, or Probenecid or Febuxostat are probably going to be tried first. Krystexxa is, after all, for treatment failure gout patients.

Some other drawbacks. In trials there were double digit %'s (up to 24%) of trialists who suffered side effects. And for 30% in one trial it did not lower UA levels. Furthermore, in months 4-6 on an 8mg every 2 week group, 41% still suffered flares.

If you want to download Savient's impressive and detailed pegloticase briefing documents from the FDA site click on this link

If you want to download the FDA's briefing document to the committee click here


RDEA594 always gets mentioned at the end of this newsletter because it's still a number a years away from any possibility of approval, and I imagine, not yet of significant interest. It's one of the promising gout drugs under development - another is Arcalyst.

Perhaps I am being unfair to it. In June its developers, Ardea Biosciences, announced some results from a phase 2 trial. One interesting point is the amount of it taken - 400 mg, and 600 mg in some patients. Allopurinol is seldom prescribed at more than 300 mg daily, although in some countries this can go up to 700-800mg daily. Febuxostat was not trialed above 240 mg daily and has been approved for lower levels than this.

A second point of interest is that RDEA594 reduces uric acid levels quickly - roughly you can say 40% down in only 8 days using an immediate release capsule on up to 20 patients in the trial. 40% means that if 7 patients began at 9.5 mg/dL on average, then levels fell to 5.7 mg/dL on average for 6 of them (my projections).

If about that was the size of the reduction in detail, it's good. You will not get that sort of reduction from cherries or strawberries, or raising pH or diets, or other natural methods. And you might want to consider how that compares with your own progress in UA reduction, whether by drugs or the naturals.

The RDEA594 phase 2 results were in line with earlier phase 1 trials but study numbers were small. This drug needs a big phase 3 study which no doubt it is going to get, although there will first be another phase 2 trial later this year.

RDEA594 works by encouraging uric acid excretion. As mentioned above, patient UA levels fell quickly in this trial. (UA levels fell quickly with the first dose of Pegloticase (Krystexxa) too and by more than 40%. Despite the 400mg/600 mg doses, no one discontinued the trial due to adverse effects, or suffered serious adverrse effects. but only up to 20 patients took part.

Nevethless sharp falls in uric acid levels often cause gout attacks. The developing company didn't specifically say whether this sharp fall led to any gout attacks, but will publish more results later this year.


This has been a "drugs and gene" issue, nothing about natural remedies. But we are in the cherry season in temperate climate countries. Studies have found cherries lower uric acid levels too, albeit not by the amounts the drugs I've mentioned here do. Read more about cherries and gout on here

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Thanks for reading and all the best.

John Mepham BA (Hons)

165,Union Street, Maidstone, Kent, United Kingdom ME14 1EY

P.S. You may distribute this newsletter freely and free-of-charge, providing any links in it remain unchanged and it remains intact. Partial copying is not allowed.

NB. The contents of this newsletter contain medical information, not medical advice. Please always discuss gout remedies with a doctor or other health care professional before implementing any treatment.

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