In presentations at the American Society of Nephrology Kidney Week in New Orleans, some biopharmas looked to push the envelope while others sought redemption. The take-home message from abstracts and experts was that innovative leaps remain elusive in the field, foiled to an extent by challenging endpoints sought by regulators. But thanks to collaborative efforts, trial designs are starting to change and could yield breakthroughs in the years ahead.

"It's a very, very exciting time," Steven Fishbane, professor in the department of medicine at Hofstra Northwell School of Medicine, told BioWorld Insight. "We are going to see not just incremental changes in terms of treatment but, increasingly, revolutionary improvements that are going to change the way nephrology is practiced and how people with kidney disease are treated."

Fishbane was primary investigator of Astrazeneca plc's open-label, phase III ZS-005 trial assessing the long-term safety and efficacy of ZS-9 (sodium zirconium cyclosilicate) to treat hyperkalemia. Patients with hyperkalemia who achieved normokalemia – defined as mean potassium levels of 3.5 mEq/L to 5 mEq/L during the first 24 to 72 hours (99.3 percent; n=746/751) – were eligible for the extended one-year maintenance phase. Full results, presented at Kidney Week, showed that mean potassium levels of ≤5.1 mEq/L or ≤5.5 mEq/L were maintained during the extended phase in 88 percent and 99 percent of patients, respectively, from month three to month 12.

The safety profile of ZS-9 was consistent with prior studies for the patient population. Common adverse effects (AEs) reported during the extended dosing phase included hypertension, peripheral edema, urinary tract infection, nausea, constipation, anemia and upper respiratory tract infection.

Astrazeneca, of Cambridge, U.K., has received two complete response letters (CRLs) from the FDA on ZS-9, most recently in March, both related to drug manufacturing facility issues and neither requesting additional clinical data. The company has not disclosed a response to the second CRL, but in February its marketing authorization application for ZS-9 did receive a positive opinion from the EMA's Committee for Medicinal Products for Human Use for treatment of hyperkalemia. (See BioWorld Today, May 31, 2016.)

ZS-9 was the prize in Astrazeneca's 2015 acquisition of ZS Pharma Inc. for $2.7 billion. (See BioWorld Today, Nov. 15, 2015.)

Astrazeneca's initial CRL was seen as a boost for Relypsa Inc., giving its approved hyperkalemia drug, Veltassa (patiromer), a longer monopoly. Weeks later, the Redwood City, Calif.-based firm agreed to a $1.53 billion acquisition by Swiss biopharma Galenica Group to strengthen its iron replacement unit, Vifor Pharma Ltd. (See BioWorld Today, July 22, 2016.)

Opening up the possibilities in kidney disease therapies

Kidney disease has been a bit of a backwater for biopharma, but the space is getting more attention, according to Fishbane, who predicted coming advances in the treatment of transplant patients and those with primary kidney disease and its complications.

"Those are areas where we just haven't made tremendous progress over the last 10, 20 years," he admitted. "Now, for the first time, we've got the opportunity to do some great things."

New medicines have made kidney transplants easier and safer, Fishbane said, and he anticipates the field progressing to the point where "dialysis isn't necessarily the first treatment choice anymore." Although he welcomes the opportunity to make transplants more widely available, "as medications and other therapies to treat kidney disease improve, that opens up a lot of possibilities."

Another headliner during Kidney Week was Reata Pharmaceuticals Inc., which presented primary 12-week data during the late-breaking clinical trial posters from the phase II portion of its CARDINAL trial of bardoxolone methyl (bard) to treat chronic kidney disease (CKD) caused by Alport syndrome. (See BioWorld, Nov. 6, 2017.)

An Nrf2 activator, Bard blew past the primary efficacy endpoint of change from baseline in estimated glomerular filtration rate (eGFR). The mean baseline eGFR (± SD) of the 30 Alport syndrome patients in the trial was 54 ± 24 mL/min/1.73 m2. Administered orally once daily, bard increased eGFR by 13.4 mL/min/1.73 m2 (n=30, p<0.000000001, 95 percent CI 10.5 to 16.3) after 12 weeks of treatment, consistent with an interim release from CARDINAL in July that reported an increase of 12.7 mL/min/1.73 m2 for the first eight patients that reached the week 12 thresholds.

Moreover, all patients showed an increase from baseline, and 87 percent had an increase of at least 4 ml/min/1.73 m2 – the approximate annual rate of decline in kidney function in patients with Alport syndrome and similar in magnitude to those previously observed in patients with type 2 diabetes and stage 3b-4 CKD.

Overall, the increases in eGFR translated to an improvement in CKD stage for 22 of 30, or 73 percent, of patients, and none worsened during treatment.

"Our drug targets common pathways that conspire to reduce kidney function in many forms of CKD, including Alport syndrome," said Colin Meyer, Reata's chief medical officer and vice president of product development. "There's a large unmet need in Alport syndrome since there are no approved therapies and, in affected males, the median age of [end-stage renal disease] is 25. We thought this was a nice setting to demonstrate activity and safety."

'True improvements in kidney function'

In addition to promising efficacy, bard showed a favorable safety profile in the Alport syndrome patients. Blood pressure was stable, with no overt signs of fluid overload – a critical point, considering that patients with stage 4 CKD and T2D enrolled in the company's previous phase III BEACON trial did show fluid retention, which became a factor in Reata halting that trial and ending development in CKD. (See BioWorld Today, Oct. 19, 2012.)

But Reata's partner, Kyowa Hakko Kirin Co. Ltd. (KHK), picked up the CKD baton and, during Kidney Week's high impact oral abstract session, crossed the finish line with data from the stage 3 portion of its randomized, double-blind, placebo-controlled, multicenter phase II TSUBAKI study. In that trial, bard showed statistically significant and clinically meaningful increases in directly measured GFR in 124 patients with T2D and stage 3-4 CKD across 16 weeks of treatment, using the inulin clearance method to evaluate stage 3 patients.

The drug's safety profile was favorable, with no effect on blood pressure, urinary volume or sodium retention, and no evidence of overt fluid overload or cardiac toxicity.

TSUBAKI was designed to assess whether bard actually increases kidney function, determined by inulin clearance, considered the gold standard to measure kidney function empirically. The study was technically challenging, requiring KHK to hospitalize patients overnight and control for fluid intake and output.

"Inulin is not produced anywhere in the body, so when they inject it into the blood and monitor it being filtered through the kidney, there's no potential metabolic effect on inulin that can be affected by anything except the kidney's filtration rate," explained Warren Huff, Reata's founding CEO and president.

As specified in study's protocol, subsequent measurement of inulin clearance was stopped after the data monitoring committee determined that the primary endpoint was met at the interim analysis, based on findings from 40 patients that met the statistically significant bar.

"This is the first time any drug has ever been shown to improve inulin clearance," Meyer said. "The results address one of the major questions that had been raised by the community and further demonstrate that the improvements that we've seen in our CARDINAL trial in Alport syndrome patients are true improvements in kidney function."

Other analyses show momentum in the field

More momentum in the field came from Keryx Biopharmaceuticals Inc., whose hyperphosphatemia drug, Auryxia (ferric citrate), faces a PDUFA Monday on a supplemental new drug application for iron deficiency anemia in nondialysis-dependent CKD patients.

An oral presentation examining the effect of ferric citrate on the phosphate regulating hormone fibroblast growth factor 23 (FGF23) in adults with nondialysis-dependent CKD and iron deficiency anemia (IDA) showed significant reductions in those levels. Post-hoc analysis of a phase III study showed that reductions in FGF23 levels occurred regardless of a patient's baseline serum phosphorus or baseline iron levels, giving Boston-based Keryx ammunition to suggest that Auryxia may reduce FGF23 via multiple, potentially independent pathways in patients with CKD and IDA.

Alnylam Pharmaceuticals Inc. continued a week of winning data with a preliminary report during the late-breakers from its ongoing phase I/II study with lumasiran (formerly ALN-GO1), its RNAi therapeutic targeting glycolate oxidase (GO) to treat primary hyperoxaluria type 1 (PH1). The Cambridge, Mass.-based company reported initial data from part B of the single-blind, placebo-controlled study in the first of two cohorts of patients with PH1, ages 6 to 19.

Compared to one patient receiving placebo, results showed that the patients who received monthly subcutaneous doses of lumasiran at 1 mg/kg for three months experienced decreases in urinary oxalate excretion of more than 50 percent relative to baseline. The placebo patient in the first cohort was subsequently given lumasiran at 1 mg/kg monthly for three months and achieved a similar reduction in urinary oxalate. The mean maximal reduction in urinary oxalate for the four patients in the low-dose cohort was 66 percent, and all patients achieved urinary oxalate levels at or near the normal range.

Lumasiran also lowered urinary oxalate excretion below 1.1 mmol/24hrs/1.73m2 – a threshold that Alnylam said was associated with reduced progression to end-stage renal disease in clinical studies – in the three patients with baseline excretion ≥ 1.6 mmol/24hrs/1.73m2.

Individuals in the second cohort of the study continue to receive monthly doses of lumasiran at 3 mg/kg or placebo, and that cohort remains blinded.

Among the other presenters, Dimerix Ltd., of Melbourne, Australia, continued the data flow on its lead program, DMX-200, in CKD. Following up on top-line data from July showing the drug, which adds propagermanium to a stable dose of irbesartan, met the primary endpoint and secondary efficacy endpoints in a phase IIa study, the company presented a post hoc analysis of individual patients by subgroup. Five of the six patient responders had a primary diagnosis of diabetic nephropathy and one of the six responders had a primary diagnosis of IgA nephropathy, according to Dimerix, suggesting the phase IIa findings indicated particularly strong efficacy signals in the subgroups. (See BioWorld, July 14, 2017.)

Making kidney disease clinical programs 'tractable'

And in a trend that bodes well for the field, new entrants continue to emerge. Last week, Klotho Therapeutics Inc. closed a $10 million series A preferred financing round to fund manufacturing scale-up, first in-human studies and an IND application with the FDA. A scientific advisor for the San Diego-based company also presented preclinical data at Kidney Week on the role of Klotho, an enzyme encoded in humans by the KL gene, in acute kidney injury.

Despite the dearth of late-breaking oral presentations at Kidney Week – only seven were selected by meeting organizers – the field is beginning to make progress in trial design, seen as a major bugaboo for companies seeking to treat patients with various forms of kidney disease. For years, Huff said, key opinion leaders, regulators and developers wrestled with a key question in kidney disease drug development: Will these treatments delay dialysis?

"Patients typically progress relatively slowly, so even though you can demonstrate improvements in renal function, the question was always how to prove that it delays dialysis," he told BioWorld Insight. "Some great work has been done validating other endpoints that are highly predictive in answering that question, and that's opening up new development opportunities in the space."

Huff cited not just Reata's trials but also the Kidney Week late-breaker from Tokyo-based Otsuka Pharmaceutical Co. Ltd. on tolvaptan, which was shown to slows eGFR decline in later-stage autosomal dominant polycystic kidney disease. In a model worth emulating in the field, both programs featured nondialysis endpoints, "which makes the clinical programs tractable and encourages people to move forward," Huff said.

Another trend Huff expects to see play out over the next five years is the recognition of kidney disease as an inflammatory condition.

"The common pathways for injury are inflammation and immune activation," he pointed out. "A lot of the very early stage programs are targeting various aspects of these pathways, and we'll see more of that in the field."