New gout drugs. Pegloticase continues to progress, but has not yet been approved

This new gout drug has not yet been approved.(See below) Pegloticase, (generic name), previously called Puricase/PEG-Uricase, is a much needed, and ingeniously different, drug medication approach to the problem of reducing uric acid levels. How does this new gout drug work?

Humans, chimpanzees, gorillas and a few other animals, are the only mammals that do not possess a uric acid lowering liver enzyme called uricase (or urate oxidase) So humans have much more uric acid, an antioxidant, than most other mammals and that is perhaps one reason why we live longer.

We lost uricase at some period during evolution. Uricase converts uric acid (UA) into an unharmful substance called Allantoin. Allantoin is more soluble than uric acid and is well excreted. So Pegloticase, unlike Allopurinol or Febuxostat, does not block uric acid production, it improves its excretion by converting uric acid to a substance that's more excretable.

Gout sufferers increase uric acid solubility by drinking lots of water, perhaps with the addition of an alkalizing agent such as baking soda or alkaline water, which improves pH balance. Or by a pH balance improving diet, or by vitamins of various kinds. These are described elsewhere on this website.

Pegloticase is formulated from the substance animals use. In phase two trials it very effectively reduced serum uric acid levels among study participants. Two participants had significant tophi reduction.

It completed its phase three trials in October 2007. These trials were for symptomatic gout using participants who have failed to reduce uric acid levels in other attempts and by other methods. It is in phase two trials for other gout conditions (see below).

PEGLOTICASE(KRYSTEXXA)MAKES PROGRESS, BUT NEEDS APPROVAL

August 2 2009 The U.S. FDA decided not to approve Krystexxa. The main problem seemed to be that the FDA found what it described as 'deficiencies with the chemistry, manufacturing and controls section' of the developers' application. And the FDA thought the developers needed more safety information. Required safety information amounted to a medication guide for patients -to ensure safe and effective use. And a communication plan for healthcare providers for better information about the risks of side effects. In addition, a monitoring plan for both these information requirements would be needed.

Approval comes later? Krystexxa's developers, Savient Pharmaceuticals, said they would seek a meeting with the FDA to discuss the issues, that they believed they could reapply by early 2010, and that they would hope for an FDA decision 2-6 months after their re-application. The meeting was subsequently held, and Savient have said they will re-apply early in 2010.

June 16 2009 A special advisory commitee of the U.S. FDA voted 14-1 in favour of FDA approval for Krystexxa, the new trade name of the gout medication Pegloticase. The committee proposes but the FDA disposes. A decision about Krystexxa's approval should be made before August 1 2009.

May 7 2009 There will be a meeting of the FDA's arthritis advisory committee on June 16 2009 to review Pegloticase. It has been given a U.S.and European trade name - Krystexxa.

December 28 2008 Pegloticase's developers announced that it had been granted a priority review by the US FDA. They now expect that a decision about its approval will be made by the end of April 2009.

October 31 2008 The latest news is that the developers of pegloticase announced that it has completed all its trials, including an extension trial, and that they have applied to the FDA for approval in the United States. They hope for approval sometime during the first six months of 2009. If it is FDA approved, they will next apply to the European Medicines Agency, then to other areas of the world. The extension trial showed a good continuing performance against gout attacks, and especially for clearing up tophi.

May 7 2008 The company developing Pegloticase, Savient Pharmaceuticals Inc., made another statement about its progress, which remained upbeat. Among the points they made were:

- 70% of patients receiving pegloticase every four weeks showed normal UA levels, whereas before, many in this group had not shown statistical significance in normalisation. (Some were new joiners).

- All patients on the two week programme who had reached normal UA levels maintained their normal levels, including new joiners.

- Tophi reduction 31% of patients who had not previously shown improvement in tophi reduction had now shown improvement to what was described as a complete response, and others showed a partial response.

- Gout attacks And the result everybody really wants to know. In the two week group (41 patients) there were only 4 gout attacks after 2 months, and none after 5 months.

- A large majority of patients who started the phase 3 trials wanted to continue the treatment in the OLE extension. This popularity is an excellent sign. Many patients who had been experiencing six to eight gout flares a year, (or up to about once every six weeks, had cleared them up.

- And tophi have been cleared up in sufferers for whom other medications (usually allopurinol) have not worked.

A few simple conclusions seem clear. This drug works better when it's taken every two weeks. And that the longer it's taken the more likely it is to achieve a good outcome.

The key question is being addressed – i.e. "will gout attacks/flares cease?" Not just "has there been a reduction to normal UA levels." A reduction to normal levels of 6.0 mg/dL does not necessarily halt gout attacks.

Side effects, or what the company calls infusion reactions, (Pegloticase is taken by intravenous infusion i.e directly into a vein) were it said suffered by 21% of patients and were similar to those described above in the December 2007 update.

Savient's Open Label Extension trial continues. It hopes to apply for a Biologics License Application to the US FDA later in 2008, so Pegloticase still has to be approved. Savient hope to begin marketing it in 2009.

In December 2007 the US company developing it made an upbeat statement about the trials which ended in October 2007. The aim was to examine whether Pegloticase would have a positive effect on plasma uric acid levels and on tophi, with of course a sharp eye on any side effects, especially since the trial patients suffered other medical conditions.

The results were reasonably encouraging. Decent percentages were achieved amongst participants for the normalisation of uric acid levels. And, what the company's statement described as statistical significance in the complete elimination of at least one tophi and without new tophi being formed. But in this case, only among participants who received 8 mg Pegloticase every two weeks. Another group who received this dosage every 4 weeks did not show statistical significance.

It's not a tablet or capsule to take at home. If approved, pegloticase will be first used in the United States, where it will only be administered at infusion centres, with IV infusion sessions lasting two hours.

Side effects, or what the statement describes as infusion reactions, occurred in about one third of participants but were usually mild or moderate and usually controllable. However 11% suffered infusion reactions described as serious or severe – these were mainly chest or back pains, muscle cramping, sweating and flushes.

So, Pegloticase makes progress in an important and very difficult segment of gout treatment. This new gout drug continues to offer hope to thousands, perhaps hundreds of thousands of gout sufferers around the world who have gout plus other medical conditions, and who don’t get uric acid down from other treatments.

Other medical conditions include heart disease, high blood pressure and diabetes. This is why it is significant. i.e. it has shown success, in trials at least, where other approved and marketed drugs haven't. And among people for whom other drugs are not suitable.

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