The NIH Conference: Impact of Chronic Kidney Disease, opportunities for randomized clinical trials

On July 19 and 20, I attended a conference and workshop organized by the NIH, entitled “Reducing the Impact of Chronic Kidney Disease, opportunities for randomized clinical trials”. It was attended by over 150 people representing academic nephrologists, NIH, FDA, as well as a dozen pharmaceutical companies (Abbott, Amgen, Ardelyx, Celgene, Concert, CoreMedix, Eli Lilly, Genzyme, Kureha, Mitsubishi-Tanabe, Otsuka, Pfizer, Questcor, Reata, Sanofi-Aventis…).

There were presentations on investigator-initiated pilot studies of anti-oxidants, bicarbonate, mineralocorticoid receptor blockers, pentoxifylline, and vitamin D in the prevention or slowing of progression of CKD. There were several workshops with the goal of identifying and designing studies to prevent progression. The investigator-initiated studies were in general of small scale and the drugs used are currently approved for other indications or are generic unpatented drugs such as bicarbonate. However, they provide information on interesting targets for improvements on the existing drugs or the development of new molecular entities. The use of aldosterone receptor blockers on top of ACEI and ARBs is associated with a relatively high incidence of hyperkalemia, and this could be much higher in patients with stage 4 CKD. So their widespread use is unlikely. Pentoxifylline has beneficial effects but high doses (1800 to 2400 mg) are needed, leading to poor GI tolerance. Studies of vitamin D supplements are becoming more complicated since 25-OH-D levels in the general population is increasing as more people are taking large doses of vitamin D supplements.

The session on industry-sponsored studies included reports of the BEACON trial (patients with diabetic nephropathy with stage 3 CKD) by Reata, which is co-developing Bardoxolone with Abbott. The results of this phase 2, dose finding and efficacy trial were published last month in the NEJM (see link to press release by Reata and to the article). The safety remains an issue with 60% of patients at higher doses having muscle spasms and 14-23% having hyperkalemia. These were significantly higher than for the placebo group. The drug also has hemodynamic effects, rising GFR rapidly within the first 4-8 weeks, which then remains unchanged for 52 weeks. The presenter said that there is not an effect on the Cr measurements. Only eGFR was measured, but in preclinical studies they used inulin clearance which showed similar findings. The higher GFR seems to last for 4 weeks after stopping the drug, which suggest that there may be real improvements. Clearly they need to tease out the hemodynamic versus structural changes. Perhaps renal biopsy may be needed.

Concert pharmaceuticals use a proprietary method to replace H+ atoms on existing drugs with deuterium (D), which results in improvements in their pharmacodynamics properties. They have deuterated versions of pentoxifylline called CTP-499. More information on their website.

The presentation by Celgene was on AC-011, which is an activin receptor fusion protein. It is being co-developed with Aceleron and Celgene to improve bone metabolism and increase bone density. Although it did have effects on bone, patients suffered from thrombotic related side effects and hypertension, which were related to a rapid rise in hemoglobin. They are now focusing on the use of this drug for the treatment of chemotherapy-induced anemia. The mechanism of action is not well understood. It does result in a dose-dependent increase in Hb, up to a mean of 3.6 g/dL at the highest dose of 10 mg/kg. It is given once every 28 days. See the publications and a recent poster presentation on this drug on Aceleron website. Considering the restriction on the use of ESAs in CIA, the commercial success of this drug in this indication may not be certain, but it has revealed a new mechanism of anemia correction, which could lead to new drugs for anemia of CKD.

Abbott presented the results of their phase 2 dose ranging study on atrasentan, an endothelin-1a receptor antagonist in patients with diabetic nephropathy and overt proteinuria. The results have been published in JASN. Briefly, there was a marked reduction in urinary albumin excretion which was dose dependent. The major side effect was edema, which occurred in 18% of those on the 0.75 mg dose (optimum dose to take forward). A summary is also available at Abbott website.

Mitsubishi-Tanabe showed data on AST-120, a resin that binds uremic toxins. It has been marketed in Japan for over 10 years and has a good safety record, as it is not absorbed systemically. They are conducting a phase 3 global outcomes trial on 4000 patients in the US and Europe with the aim of obtaining approval. They also have a similar resin to be used as phosphate binder, which is also in phase phase 3 (see company website). I think that MP-146 is the same drug.

Questcor Pharmaceuticals presented data on Acthar, which is their porcine ACTH. The drug has been marketed for many years but new information has emerged on its action on melanocortin receptors and on oxidative stress, which opens the possibility of using it to alter progression of renal disease and other diseases. They are using it in diabetic nephropathy. Proteinuria was significantly reduced and serum Cr did not increased in treated patients, but it did in controls. Some preliminary data were also presented at last year’s ASN meeting (see press release). This is a very interesting concept and may lead the path to the development of NMEs affecting the melanocortin receptors in a more selective fashion. See also a recent paper in JASN.

The breakout sessions were on: pediatric studies of progression, trials with bicarbonate, trials with pentoxifylline, trials with mineralocorticoid receptor blockers, and trials with phosphate control and vitamin D. I participated at the pediatric session. The aim was for the teams to identify areas where clinical trials are needed to settle unanswered questions such as to confirm the results of observational studies. The teams were also charged to recommend high level study designs/protocols for such studies. The studies will be multi-center studies of approximately 5-years in duration and most likely funded through NIH via specific RFAs issued based on these recommendations.

Copyright © Mahmoud Loghman-Adham, MD

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