Over the past few years much has been learned about the causes and serious long-term health implications of acute kidney injury (AKI). Physicians, however, have nothing to reach for in terms of active therapeutics.
The limited activity says much about how tough it is to make an impact on a condition that manifests in a rapid deterioration of kidney function. Two mid-stage candidates recently fell by the wayside, leaving two companies as the most advanced in this space. Both are in phase II: AM-Pharma is about to start a large trial in AKI caused by sepsis while Thrasos is focusing on susceptible patients undergoing cardiac surgery (see table).
These two settings form a majority of the cases of AKI, which is mostly a complication of another serious illness. Various studies suggest that anywhere from a third to half of AKI cases result from sepsis, while in the surgery setting it is a major risk for patients having heart operations. Thrasos estimates that 20-25% of cardiac surgery patients develop AKI, and in high-risk groups incidence can rise to 50%.
“There is no drug that has been shown to prevent or treat AKI,” says Jerome Rossert, Thrasos’s chief scientific officer. “You need proper fluid management and to avoid giving drugs that are toxic to the kidney, but in many cases there is not much you can do to prevent it.”
AKI is usually identified using changes in serum creatinine and urinary output, though a specific diagnostic is also available (NephroCheck approval could pit Astute’s backer against its partner, September 9, 2014). Patients admitted to hospital with the condition or at risk of developing it are frequently frail or elderly, and treatment can amount to just fluid and electrolyte management. However, AKI is measured on a scale that ranges from minor loss of function to complete kidney failure so serious interventions like dialysis are sometimes required.
Companies working in this space are focusing on defined patient populations where the cause of AKI is clear and where intervention with an active agent can either prevent damage in the first place or ameliorate deterioration. As well as the surgery and sepsis settings, contrast-induced nephropathy is a big focus. The increasing use of iodinated contrast media in diagnostic imaging and interventional procedures has exposed ever larger numbers of patients to these potentially damaging agents.
But for all patients who suffer AKI, from whatever cause and however severely, the long-term health implications are serious. These might be more apparent for those that suffer irreversible damage and progress to chronic kidney disease. But it is becoming increasingly recognised that even patients with mild injury that reverses are at risk of worsening health and early death.
This fact alone justifies the preventive approach Thrasos is taking with THR-184, a synthetic peptide that activates the bone morphogenetic protein (BMP) pathway. This has been shown to have protective effects in animal models of kidney disease, protecting against cell death and decreasing inflammation.
“There is not much you can do to prevent AKI after cardiac surgery,” Mr Rossert says. “But because cardiac surgery is predictable, it presents a unique situation to do a prevention study.”
The company started a phase II study last year testing three doses of the project in high-risk patients undergoing cardiac surgery; the primary endpoint is incidence of AKI at day seven, compared with placebo. Last month, on the recommendation of an independent data monitoring board, the lower two doses were dropped.
The study has an adaptive design and Thrasos will now introduce an even higher dose; at the end of the study the two active arms and the placebo arm will contain more than 100 patients each.
“We believe the interim analysis was good news, and we were encouraged they saw no safety signals of concern, so we decided to add an even higher dose,” Mr Rossert says.
The study was enriched to include those at high risk of developing AKI; a rate of around 50% is expected in the placebo arm.
|AKI therapies in recent clinical development|
|Project||Pharma class||Company||Trial||AKI setting|
|THR-184||BMP type II receptor agonist||Thrasos Therapeutics||NCT01830920 - Phase II||Cardiac surgery - prevention|
|Alkaline Phosphatase||Recombinant alkaline phosphatase||AM-Pharma||NCT02182440 - Phase II||Sepsis|
|CMX-2043||Reperfusion injury inhibitor||Ischemix||NCT02103959 - Phase IIa||Contrast induced|
|CXA-10||nitro-FA||Complexa||NCT02127190 - Phase I||Contrast induced|
|ZP1480/ABT-719||Melanocortin receptor agonist||AbbVie||NCT01777165 - Phase II||Cardiac surgery - prevention|
|AC607||Mesenchymal stem cell||AlloCure||NCT01602328 - Phase II||Cardiac surgery|
Final results from Thrasos are still some way away – expected at the end of 2015 – and these realistically represent the next big data readout for the cardiac surgery space. News could emerge from a couple of other companies but they are unlikely to detail positive studies; trials being run by both AbbVie and Allocure were terminated recently.
AbbVie’s partner Zealand Pharma confirmed last month that ABT-719 had been scrapped because of disappointing phase II results. The melanocortin (alpha-MSH) peptide analogue was being tested in a 240-patient cardiac surgery trial, also in a preventive setting.
In August, Allocure changed the recruitment status of its phase II trial of AC607 to terminated. This project comprises allogeneic adult bone marrow-derived mesenchymal stem cells that the company believes mediate anti-inflammatory and organ repair processes in injured kidneys.
AC607 was tested in cardiac surgery patients who developed AKI within 48 hours of surgery, and the company set out to prove that its agent could improve time to kidney recovery versus placebo. Allocure did not reply to emails seeking further information.
It seems likely these two therapies will join the list of other novel agents that have stalled in phase II in the past few years. These include a Novartis asset called BCT197, which is thought to be a p38 alpha inhibitor, and a p53 RNAi therapeutic developed by Quark, over which the Swiss pharma giant also had an option.
A fair amount of work is ongoing with patients exposed to the potentially damaging contrast imaging media, and progress could be seen here in the next few years.
Complexa raised $13m in June to progress its candidate, CXA-10, through the clinic. The project is a proprietary fatty acid derivative, nitro-FA; the company believes that these represent a novel class of endogenous metabolic and anti-inflammatory signalling mediators.
Ichemix is more advanced and earlier this year enrolled the first patient into a 240-patient phase IIa trial of CMX-2043, seeking to establish whether the agent can prevent AKI in acute coronary syndrome patients undergoing coronary angiography. Data are expected in mid-2015. The company describes its project as a chemically modified, naturally occurring molecule that activates the Akt pathway.
However the most expansive work in AKI is planned by AM-Pharma, which recently raised $16m to run a large phase II in sepsis patients (Interview – AM-Pharma heads back to the clinic with kidney contender, September 15, 2014).
Sepsis-associated AKI is the largest market within AKI, and is also the most severe. Patients frequently require dialysis, and around 35-45% will die.
The company plans to recruit 290 patients and test three doses of its recombinant form of human alkaline phosphatase, recAP, against placebo in an adaptive trial that will see the most effective dose progress to a second stage. The primary endpoint of the trial will measure changes in kidney function.
“It will be a real breakthrough if we can show an effect,” says its chief executive, Erik van den Berg.
Ultimately, however, the real hope for recAP, THR-184 and the other projects is that preventing kidney damage or even preserving some function can lessen the longer-term health implications of AKI.
“We know that episodes of AKI, the duration of AKI and its severity, are all associated with hard clinical outcomes like mortality, progression to end-stage renal disease or [worsening] chronic kidney disease,” Mr van den Berg says.
To get their projects to market none of these companies will be required to prove an impact on these measures. However any positive improvements on surrogate measures like kidney function will be considered a notable achievement in this very problematic setting.