Dapagliflozin–saxagliptin ‘attractive’ options for patients with type 2 diabetes with chronic kidney disease

MedwireNews (April 16, 2019): Dapagliflozin, with or without saxagliptin, reduces albuminuria in people with type 2 diabetes and moderate-to-severe chronic kidney disease when used in combination with antihypertensive treatments, DELIGHT study data show. Furthermore, using the sodium-glucose co-transporter (SGLT)2 inhibitor and dipeptidyl peptidase-4 inhibitor together achieved “the dual objectives of effective lowering of blood glucose and reduction of urinary albumin excretion,” Hiddo Heerspink (University of Groningen, the Netherlands) and co-authors write in The Lancet Diabetes & Endocrinology.

They add: “This beneficial profile makes the combination of these drugs a potentially attractive option to slow the progression of kidney and cardiovascular disease in these patients.”

The phase III DELIGHT study included 448 patients with type 2 diabetes and moderate-to-severe chronic kidney disease who were randomly assigned to 24 weeks of once-daily treatment with dapagliflozin 10 mg (n=145), dapagliflozin 10 mg plus saxagliptin 2.5 mg (n=155), or placebo (n=148).  At baseline, median urine albumin-to-creatinine ratio (UACR) ranged from 218.4 to 270.0 mg/g, mean estimated glomerular filtration rate (eGFR) was 47.7–50.2 mL/min per 1.73 m2, and mean glycated hemoglobin (HbA1c) was 8.2–8.6% (66.0–70.0 mmol/mol).  By week 24, UACR was a significant 21% lower in the dapagliflozin group than in the placebo group, and it was  a significant 38% lower  in the dapagliflozin–saxagliptin group. The researchers note that the reductions were “largely independent” of simultaneous changes in HbA1c, systolic blood pressure, eGFR, and uric acid.

Heerspink and team also found that HbA1c was a signficant 0.58% lower in the dapagliflozin–saxagliptin group than in the placebo group at week 24, and was a non-significant 0.16% lower in the dapagliflozin-only group.

They say: “The reduction in HbA1c when saxagliptin is added to dapagliflozin is clinically relevant in patients with kidney impairment because the glycaemic effects of SGLT2 inhibitors are attenuated when kidney function declines.” Both drugs were well tolerated by patients with no new safety signals observed.

In accompanying commentary, Katherine Tuttle (University of Washington, Spokane, USA) stresses the importance of the finding “that dapagliflozin and saxagliptin can be used together safely for glycaemic control in patients with type 2 diabetes and moderate- to severe chronic kidney disease.”

She writes: “Because there are few drugs available to treat hyperglycaemia without increasing risk of hypoglycaemia (and other adverse events) for this population, the current data provide reassurance about combining SGLT2 inhibition with an incretin mimetic.”

Heerspink et al conclude that the DELIGHT data “support the importance of SGLT2 inhibitors in reducing albuminuria in patients with type 2 diabetes and chronic kidney disease when used in addition to guideline­recommended treatment.”  However, they add: “Whether or not this effect translates into improved kidney outcomes remains uncertain and requires dedicated outcome trials with longer follow-up.”

Written by Laura Cowen and reproduced from MedwireNews

medwireNews is an independent medical news service provided by Springer Healthcare. © 2019 Springer Healthcare part of the Springer Nature group

References:

Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30086-5
Lancet Diabetes Endocrinol 2019; doi:10.1016/S2213-8587(19)30116-0

Additional information on diabetic nephropathy can be found here.

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Proton pump inhibitors linked to increased risk of renal toxicity

February 19, 2019 | By Heather Buschman, PhD

Source:  UC San Diego News Center

Proton pump inhibitors (PPIs), which include well-known brand names Prilosec, Nexium and Prevacid, are among the most commonly prescribed medications in the world. Approximately 10 percent of adults in the United States take these drugs for frequent heartburn, acid reflux and gastroesophageal reflux disease. Given their prevalence, researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego mined the FDA Adverse Effect Reporting System (FAERS) database for unexpected consequences of PPI consumption.

In the study, published February 19, 2019 by Scientific Reports, the team found that patients who took PPIs were more likely to experience kidney disease than people who took histamine-2 receptor antagonists, another form of antacid that treats the same conditions and includes the brands Pepcid and Zantac.

“Post-marketing data collected by the FDA and deposited in the FAERS database allows us to look for potential adverse effects beyond what was found in a clinical trial, which may not have lasted as long or included as much diversity as the FAERS does,” said senior author Ruben Abagyan, PhD, professor of pharmacy.

Abagyan led the study with pharmacy students Tigran Makunts and Isaac Cohen, and Linda Awdishu, PharmD, associate clinical professor and chair of the Division of Clinical Pharmacy, all at Skaggs School of Pharmacy.

The FAERS database contains more than 10 million patient records — all voluntary reports of adverse effects while taking a medication. The research team focused on patients who took PPIs and no other medications, narrowing their study population down to approximately 43,000 patients. They applied a mathematical algorithm to look for statistically significant differences in reported kidney-related complications between patients who took PPIs and the control group, approximately 8,000 patients who took histamine-2 receptor blockers, such as Zantac or Pepcid, and no other medications.

Here’s what they found: Patients who took only PPIs reported a kidney-related adverse reaction at a frequency of 5.6 percent, compared to 0.7 percent for patients who took only histamine-2 receptor antagonists.

Drilling down, the team found that, compared to the control group, patients who took only PPIs were 28.4 times more likely to report chronic kidney disease, as well as acute kidney injury (4.2 times more likely), end-stage renal disease (35.5 times more likely) and unspecified kidney impairment (8 times more likely). Patients who took PPIs were also more likely to experience electrolyte abnormalities, but this varied more by individual PPI, while the kidney-specific effects held true for all five PPIs examined.

Abagyan cautioned that this study does not reveal the absolute frequency of these kidney-related complaints for all people taking PPIs, since reporting in the FAERS is voluntary. He also says it’s possible, though unlikely, the effect could be due to unidentified confounding factors. A large, randomized, controlled clinical trial would be needed to definitively show causality between PPI usage and absolute risk of kidney disease in humans.

As the World Health Organization notes, PPIs are essential medicines for many people, helping them to control symptoms that are often painful and disruptive to daily life. But Abagyan hopes this initial data will prompt health care providers to provide the appropriate warnings, education and monitoring for patients who require PPIs, particularly if they are already at elevated risk for kidney disease and electrolyte abnormalities. Researchers made similar recommendations following a 2017 UC San Diego School of Medicine study that found evidence in mice and humans that PPIs promote chronic liver disease.

PPIs are relatively inexpensive medications, retailing for approximately $7 for a recommended two-week course of generic, over-the-counter Prilosec (omeprazole). But the frequency of use adds up — one study estimated Americans spend $11 billion on PPIs each year. There are inexpensive and readily available alternatives to PPIs. However, non-PPI-based antacids (e.g., Pepto-Bismol, Tums, histamine-2 receptor antagonists) may not be as effective.

This research was funded, in part, by the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego.

Commentary:

The three phases of clinical trials generate important safety information for new drugs, but they can miss adverse effects that are very infrequent and those that only occur after prolonged use.  Post-authorization studies and post-marketing safety surveillance allow for the detection of these rare events, which cumulatively can affect many patients, if a drug is prescribed for a common medical problem such as acid reflux or as an analgesic.

The study by Makunts et al. as well as the earlier study by Llorente et al. shed light on the potential kidney and liver and toxicity of proton pump inhibitors (PPIs) as a class, when used on a chronic basis.  The implications of these findings, as the authors suggest, are the increased awareness of the safety issues of PPIs and the consequent need for close monitoring of patients during long-term treatment courses.

M. Loghman-Adham, MD

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Disappointing Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)

FOSTER CITY, Calif.–(BUSINESS WIRE)–Feb. 11, 2019– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that STELLAR-4, a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib, an investigational, once-daily, oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), in patients with compensated cirrhosis (F4) due to nonalcoholic steatohepatitis (NASH), did not meet the pre-specified week 48 primary endpoint of a ≥ 1-stage histologic improvement in fibrosis without worsening of NASH.

In the study of 877 enrolled patients who received study drug, 14.4 percent of patients treated with selonsertib 18 mg (p=0.56 vs. placebo) and 12.5 percent of patients treated with selonsertib 6 mg (p=1.00) achieved a ≥ 1-stage improvement in fibrosis according to the NASH Clinical Research Network (CRN) classification without worsening of NASH after 48 weeks of treatment, compared with 12.8 percent of patients who received placebo. Selonsertib was generally well-tolerated and safety results were consistent with prior studies.

“While we are disappointed that the STELLAR-4 study did not achieve its primary endpoint, we remain committed to advancing therapies for patients with advanced fibrosis due to NASH, where there is a significant unmet need for effective and well-tolerated treatments. Gilead has a long-term commitment and proven track record of addressing significant challenges in the field of liver diseases. Data from this large study of patients with compensated cirrhosis due to NASH, including the extensive set of biomarkers collected, will further advance our understanding of the disease and inform our broader NASH development programs,” said John McHutchison, AO, MD, Chief Scientific Officer, Head of Research and Development, Gilead. “We are grateful to the patients and investigators who participated in the STELLAR-4 study, and we now await the upcoming results from the Phase 3 STELLAR-3 trial of selonsertib in patients with bridging fibrosis (F3) due to NASH and the Phase 2 ATLAS combination trial of selonsertib, cilofexor (GS-9674) and firsocostat (GS-0976) in patients with advanced fibrosis due to NASH later this year.”

Further in-depth analysis of the findings is ongoing and the data will be submitted to an upcoming scientific conference. Gilead will work with the Data Monitoring Committee and investigators to conclude the STELLAR-4 study in a manner consistent with the best interests of each patient.

Selonsertib, cilofexor and firsocostat, alone or in combination, are investigational compounds and are not approved by the U.S. Food & Drug Administration (FDA) or any other regulatory authority. Safety and efficacy have not been established for these agents.

About Selonsertib and the STELLAR-4 Study

Selonsertib is an investigational small molecule inhibitor of ASK1, a protein that promotes inflammation, apoptosis (cell death) and fibrosis in settings of oxidative stress. Oxidative stress can be increased in many pathological conditions including liver diseases such as NASH.

The STELLAR-4 study is a Phase 3, randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of selonsertib in patients with compensated cirrhosis (F4) due to NASH. Eligible adults ages 18 to 70 years were randomized and received selonsertib 18 mg (n=354), selonsertib 6 mg (n=351) or placebo (n=172) for up to 240 weeks. Either selonsertib or placebo is being administered orally once daily. The primary endpoints of the study are a composite of the proportion of patients who achieve a ≥ 1-stage improvement in fibrosis according to the NASH CRN classification without worsening of NASH at week 48 and event-free survival at week 240 as assessed by time to the first clinical event. Further information about the clinical study can be found at www.clinicaltrials.gov.

Commentary:

Non-alcoholic steatohepatitis (NASH) is a progressive disease that affects about 3% of adults. It can progress to fibrosis, cirrhosis and hepatocellular carcinoma.  Many patients have features of metabolic syndrome and insulin resistance.  There are no drugs approved specifically for NASH but, many pharmaceutical companies are developing drugs for this indication.  Selonsertib had shown promise in phase 2 studies, but as is often the case with new therapies, positive results cannot always be replicated in larger Phase 3 studies with more heterogeneous populations.  Last year, Intercept pharmaceuticals announced the start of the phase 3 study of obeticholic acid (Oaliva), a farsenoid X receptor agonist in patients with NASH.  Ocaliva is already approved for the treatment of primary biliary c h o l a n g i t i s (PBC) in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA (see Prescribing Information).  Ocaliva remains the forerunner in the race for NASH treatment and analysts have high expectations that it could succeed. It remains to be seen which pharma company will win the race to develop an effective treatment for NASH.

Update (29-February-2019). Today, Inercept Pharmaceuticals announced positive topline results from their Ph3 REGENERATE study of Obeticholic acid in the treatment of patients with liver fibrosis due to NASH (see here). The data from this trial will form the basis of FDA submission for approval.

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Alexion Announces Positive Top-Line Results From Phase 3 Study Of ULTOMIRIS™ (Ravulizumab-Cwvz) In Complement Inhibitor-Naïve Patients With Atypical Hemolytic Uremic Syndrome (AHUS)

Monday, January 28, 2019 6:30 am EST

BOSTON–(BUSINESS WIRE)–Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) today announced that the Phase 3 study of ULTOMIRIS™ (ravulizumab-cwvz), the company’s long-acting C5 complement inhibitor, met its primary objective in complement inhibitor-naïve patients with atypical hemolytic uremic syndrome (aHUS). In the initial 26 week treatment period, 53.6 percent of patients (95% CI [39.6%, 67.5%]) demonstrated complete thrombotic microangiopathy (TMA) response. ULTOMIRIS provided immediate and complete inhibition of the complement C5 protein that was sustained over the entire eight-week dosing interval.

The primary endpoint of complete TMA response was defined by hematologic normalization and improved kidney function. Treatment with ULTOMIRIS resulted in:

  • reduced thrombocytopenia, as measured by normalization in platelet count, in 83.9 percent of patients (95% CI [73.4%, 94.4%]),
  • reduced hemolysis (the destruction of red blood cells), as measured by normalization in lactate dehydrogenase (LDH) level, in 76.8 percent of patients (95% CI [64.8%, 88.7%]) and
  • improved kidney function, as measured by ≥ 25 percent improvement in serum creatinine level from baseline, in 58.9 percent of patients (95% CI [45.2%, 72.7%]). For patients on dialysis at enrollment, baseline was established after they had come off dialysis.

To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days.

The safety profile was consistent with that observed in two large Phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH).1,2

“We are very pleased with these data, which demonstrate that ULTOMIRIS can provide clinically meaningful benefits to patients with aHUS,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “The results met the high bar of complete TMA response, defined by hematologic normalization and improved kidney function, and provide confidence that ULTOMIRIS has the potential to become the new standard of care for patients with aHUS. We are preparing regulatory submissions for ULTOMIRIS in aHUS in the U.S., European Union and Japan as quickly as possible.”

Atypical HUS is a severe and chronic ultra-rare disease that can cause progressive damage to vital organs, predominantly the kidneys, leading to kidney failure and premature death. The disease is characterized by TMA (inflammation and blood clotting in small blood vessels throughout the body) that is mediated by chronic, uncontrolled activation of the complement system.3,4,5,6,7

“If left untreated, many patients progress to end-stage renal disease or die during the first clinical manifestations of aHUS or in the first year following these manifestations despite supportive care,” said Spero Cataland, M.D., hematologist at Ohio State University Wexner Medical Center and an investigator in the study. “I am very excited about these data and the potential for an effective new treatment option that can provide hematologic normalization and improved kidney function, including the potential to stop dialysis, when administered every eight weeks.”

The most frequently observed adverse events in this study were headache, diarrhea and vomiting. The most frequently observed serious adverse events were pneumonia and hypertension. In these critically ill patients, there were four patient deaths, none of which were considered related to treatment with ULTOMIRIS. No case of meningococcal infection was observed. Meningococcal infections are a known risk with terminal complement inhibition. To minimize the risk for patients, specific risk-mitigation plans have been established for ULTOMIRIS, based on plans that have been in place for more than 11 years for SOLIRIS® (eculizumab).

Detailed results from this Phase 3 study will be presented at a future medical congress. A Phase 3 study of ULTOMIRIS in children and adolescents with aHUS is currently ongoing.

About the ULTOMIRIS aHUS-311 Study 
This global, multicenter, single arm, Phase 3 study evaluated the safety and efficacy of ULTOMIRIS administered by intravenous infusion in 56 adults (≥ 18 years of age) who hadn’t been treated with a complement inhibitor before. The study consists of an up to seven-day screening period, a 26-week initial evaluation period and an extension period of up to two years, which is still ongoing. Patients received a weight-based loading dose (≥ 40 to < 60 kg = 2,400 mg; ≥ 60 to < 100 kg = 2,700 mg; ≥ 100 kg = 3,000 mg) on Day 1, followed by weight-based maintenance doses (≥ 40 to < 60 kg = 3,000 mg; ≥ 60 to < 100 kg = 3,300 mg; ≥ 100 kg = 3,600 mg) on Day 15 and once every eight weeks thereafter. The primary endpoint was defined as complete TMA response during the 26-week initial evaluation period, as evidenced by normalization of platelet count and lactate dehydrogenase (LDH) level and an improvement in serum creatinine of ≥ 25 percent from baseline. For patients on dialysis at enrollment, baseline was established after they had come off dialysis. To achieve complete TMA response, patients had to meet all three criteria at the same time at least once. In addition, each of the criteria had to be met for at least 28 consecutive days. Complete C5 inhibition was defined as free C5 levels of <0.5 µg/mL.

About atypical Hemolytic Uremic Syndrome (aHUS) 
Atypical hemolytic uremic syndrome (aHUS) is a chronic, progressive and debilitating ultra-rare disease that affects both children and adults and can lead to potentially irreversible damage to kidneys and other vital organs, sudden or progressive kidney failure (requiring dialysis or transplant) and premature death.3,4,7,8 aHUS is characterized by inflammation and the formation of blood clots in small blood vessels throughout the body (thrombotic microangiopathy [TMA]) mediated by chronic, uncontrolled activation of the complement system, which is part of the body’s immune system.3,4,5,6,7 TMA consists of reduced platelet count (thrombocytopenia), hemolytic anemia (as a result of hemolysis [destruction of red blood cells]) and acute kidney injury (AKI).5,7,9,10 If left untreated, significant proportions of adults (46 percent) and children (16 percent) can progress to end-stage renal disease (ESRD) or die during first clinical manifestations of aHUS despite supportive care, including plasma exchange or plasma infusion (PE/PI). One year following clinical manifestations, 56 percent of adults and 29 percent of children can progress to ESRD or die, if left untreated.11 Early and careful diagnosis of aHUS is critical as many coexisting diseases and events are known or suspected to activate the complement cascade, and as patients may not necessarily present with the classic TMA triad of thrombocytopenia, hemolytic anemia and renal impairment12 or may have less severe renal involvement.13 Available tests can help distinguish aHUS from other hemolytic diseases with similar symptoms such as HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS) and thrombotic thrombocytopenic purpura (TTP).7

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Tricida Announces Positive Pivotal Phase 3 Clinical Trial Results for TRC101 in CKD Patients With Metabolic Acidosis

SOUTH SAN FRANCISCO, Calif.–(BUSINESS WIRE)–Tricida, Inc., a late-stage pharmaceutical company, announced results from its pivotal Phase 3 double-blind, randomized, placebo-controlled, multi-center Phase 3 clinical trial, TRCA-301, in 217 chronic kidney disease (CKD) patients with metabolic acidosis. TRC101 represents a first-in-class candidate for the treatment of metabolic acidosis, a common complication of CKD that can accelerate progression of kidney disease, increase the risk of muscle wasting and cause the loss of bone density.

Based on the initial topline analyses, the TRCA-301 trial met both its primary and secondary endpoints in a highly statistically significant manner (p < 0.0001 for all primary and secondary endpoints). TRC101 was well tolerated in the TRCA-301 trial. Both active (124 subjects) and placebo groups (93 subjects) had low discontinuation rates and low rates of treatment-related adverse events.

For the primary endpoint, after 12 weeks of treatment, 59.2% of subjects in the TRC101 treatment group exhibited an increase in blood bicarbonate level of at least 4 milliequivalents per liter (mEq/L) or achieved a blood bicarbonate level in the normal range of 22 to 29 mEq/L, compared with 22.5% of subjects in the placebo group (p< 0.0001). For the secondary endpoint, the mean change in blood bicarbonate from baseline to week 12, subjects in the TRC101 treatment group exhibited a mean increase in blood bicarbonate of 4.49 mEq/L, compared with 1.66 mEq/L in the placebo group (p<0.0001).

In addition, two pre-specified exploratory endpoints of the pivotal Phase 3 TRCA-301 trial assessed patient quality of life and improvement in muscle function. The first exploratory endpoint examined the effect of treatment with TRC101 on self-reported responses to the physical functioning subpart of the Kidney Disease and Quality of Life Short Form survey (KDQOL-SF survey). The second exploratory endpoint objectively measured physical function, assessed using a repeated chair stand test, involving a timed measurement of five repetitions of moving from a seated to standing position. Initial topline analyses of the results of the physical functioning KDQOL-SF survey showed a statistically significant positive difference in the TRC101-treated subjects compared with the placebo group after 12 weeks of treatment (p=0.0122) and the repeated chair stand test showed a trend toward significance in the positive difference in the TRC101-treated subjects compared with the placebo group (p=0.0630).

The overall safety profile of TRC101 observed in the trial was consistent with that expected for the general population of patients with Stage 3 to 5 CKD and with similar non-absorbed polymer drugs with a site of action in the gastrointestinal tract. The incidence of serious adverse events was low and balanced in the two treatment groups and none were assessed to be related to TRC101 by the clinical investigator, Medical Monitor or Drug Safety and Pharmacovigilance Team. There were two deaths in the study and both occurred in the placebo group. Overall treatment-related adverse events occurred in 9.7% of subjects in the placebo group and 13.7% of the TRC101-treated subjects. Treatment-related gastrointestinal adverse events that occurred in more than one subject include diarrhea, flatulence, nausea and constipation. Over 95% of the subjects in each group completed the trial.

TRCA-301 Clinical Trial Design

The TRCA-301 double-blind, randomized, placebo-controlled Phase 3 trial was conducted at 47 sites in the United States and Europe and enrolled 217 Stage 3b or 4 CKD patients with baseline blood bicarbonate levels between 12 mEq/L and 20 mEq/L. Subjects were randomized in a 4:3 ratio to receive TRC101 or placebo. The study drug dosing (TRC101 or placebo) continued for 12 weeks once daily. The primary outcome measure was change from baseline in blood bicarbonate (Time Frame: Week 12) and included comparison of TRC101 and placebo with regard to the proportions of subjects with change from baseline in blood bicarbonate ≥ 4 mEq/L or with blood bicarbonate in the normal range (22 to 29 mEq/L). Eligible subjects that completed the TRCA-301 trial were invited to participate in a 40-week safety extension trial, TRCA-301E. Of the 208 subjects who completed the TRCA-301 trial, 196 were enrolled in the TRCA-301E safety extension trial.

The principal investigator for the trial was Dr. Donald E. Wesson, MD, MBA, Professor of Medicine at Texas A&M Health Sciences Center College of Medicine in Dallas, Texas, President of the Baylor Scott & White Health and Wellness Center (BSW HWC), Senior Vice President of Baylor Scott & White Weight Management Services and a board-certified internist and nephrologist.

About TRC101

TRC101 represents a first-in-class candidate for the treatment of metabolic acidosis, a common complication of CKD that can result in accelerated progression of kidney disease. It is a novel, non-absorbed polymer drug that is designed to bind hydrochloric acid in the gastrointestinal tract, removing it from the body with high capacity and specificity, with the objective to treat chronic metabolic acidosis associated with CKD as measured by an increase in blood bicarbonate levels.

Additional information:

Tricida presentation at the 37th annual JP Morgan Healthcare Conference Jan 9, 2019

Published Phase 2 results of TRC101

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AstraZeneca Reports Full Results from DECLARE-TIMI 58 Cardiovascular Outcomes Trial for FARXIGA (dapagliflozin)

November 12, 2018;  Reproduced from StreetInsider

AstraZeneca today announced positive full results from the DECLARE-TIMI 58 cardiovascular (CV) outcomes trial (CVOT) for FARXIGA (dapagliflozin). The data were presented as a late-breaking abstract (#19485) at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago, IL, and simultaneously published in the New England Journal of Medicine (NEJM).

Results from DECLARE-TIMI 58, the largest SGLT-2 inhibitor (SGLT-2i) CVOT conducted to date, including more than 17,000 patients across 33 countries, showed that FARXIGA significantly reduced the risk of hospitalization for heart failure (hHF) or CV death composite vs. placebo by 17% (4.9% vs. 5.8%; HR 0.83 [95% CI 0.73-0.95], p=0.005), one of the two primary efficacy endpoints. The reduction in hHF or CV death was consistent across the entire patient population, which included those with CV risk factors and those with established CV disease.1 FARXIGA is not indicated to reduce the risk of CV events or hHF.

Additionally, there were fewer major adverse cardiovascular events (MACE) observed with FARXIGA for the other primary efficacy endpoint, however this did not reach statistical significance (8.8% for FARXIGA vs. 9.4% for placebo; HR 0.93 [95% CI 0.84-1.03], p=0.17).1

DECLARE-TIMI 58 also confirmed the well-established safety profile for FARXIGA, which met the primary safety endpoint of non-inferiority vs. placebo, demonstrating no increase in the composite of MACE, defined as CV death, heart attack (myocardial infarction), or stroke.

Further, on other relevant safety measures, the trial showed no imbalance with FARXIGA vs. placebo in amputations (1.4% vs. 1.3%), fractures (5.3% vs. 5.1%), bladder cancer (0.3% vs. 0.5%) or Fournier’s gangrene (1 case vs. 5 cases). The respective incidences of diabetic ketoacidosis (0.3% vs. 0.1%) and genital infections (0.9% vs. 0.1%) were rare.1

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development, said: “These positive results are clinically relevant to the 425 million people worldwide living with diabetes, of whom those with type 2 diabetes have a two-to-five times greater risk of heart failure along with an increased risk of a heart attack or stroke. Heart failure survival rates are only 50% after five years from diagnosis, which is why these new findings are so important in broadening our understanding of how to go beyond blood glucose, so we may better address this serious and often overlooked cardiovascular complication.”2-6

Although secondary endpoints were only nominally significant, the renal composite endpoint showed that FARXIGA reduced the rate of new or worsening nephropathy by 24% vs. placebo across the broad patient population studied (4.3% vs. 5.6%; HR 0.76 [95% CI 0.67-0.87]), and there were fewer all-cause mortality events with FARXIGA vs. placebo (6.2% vs. 6.6%; HR 0.93 [95% CI 0.82-1.04]).1 FARXIGA is not indicated to reduce the risk of HF, other CV outcomes, nephropathy or all-cause mortality.

References:

Zinman, Bernard, et al. “Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.” New England Journal of Medicine 373.22 (2015): 2117-2128.

Wanner, Christoph, et al. “Empagliflozin and progression of kidney disease in type 2 diabetes.” New England Journal of Medicine 375.4 (2016): 323-334.

Neal, Bruce, et al. “Canagliflozin and cardiovascular and renal events in type 2 diabetes.” New England Journal of Medicine 377.7 (2017): 644-657.

Wiviott SD et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine Nov 12, 2018 DOI: 10.1056/NEJMoa1812389

Commentary:

Dapagliflozin is the third SGLT2 inhibitor that has completed a cardiovascular outcome trial (CVOT), as required for all new drugs approved for treatment of type 2 diabetes (see FDA Guidance).  Previous CVOT studies include EMPA-REG Outcome trial  for empagliflozin and the CANVAS study for canagliflozin.  The results for dapagliflozin are not as compelling since it did not reduce MACE compared to placebo. Another interesting finding with SGLT2 inhibitors is their ability to slow the progression of renal disease in type 2 diabetes and perhaps even in non-diabetic chronic kidney disease. The renal outcome trial of canagliflozin (CREDENCE trial) was recently stopped earlier than planned due to meeting the pre-specified primary composite endpoint.  The empagliflozin renal outcome trial is also ongoing and is based on encouraging secondary reno-protection data from the EMPA-REG Outcome trial (see here). These encouraging results open new therapeutic options to slow the progression of CKD not only in patients with type 2 diabetes and cardiovascular disease but in patients with CKD due to other causes. The result of the CANVAS trial are awaited with great enthusiasm from the renal community.

Copyright © M. Loghman-Adham, MD

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Lokelma approved in the US for the treatment of adults with hyperkalemia

On May 18, 2018 AstraZeneca announced the FDA approval of their new drug Lokelma, for the treatment of hyperkalemia.  The full new release is reproduced below:

The US Food and Drug Administration (FDA) has approved Lokelma (sodium zirconium cyclosilicate), formerly ZS-9, for the treatment of adults with hyperkalaemia,1 a serious condition characterized by elevated potassium levels in the blood associated with cardiovascular, renal and metabolic diseases.2

The risk of hyperkalemia increases significantly for patients with chronic kidney disease (CKD) and for those who take common medications for heart failure (HF), such as renin-angiotensin-aldosterone system (RAAS) inhibitors, which can increase potassium in the blood.2,3 To help prevent the recurrence of hyperkalemia, RAAS-inhibitor therapy is often modified or discontinued, which can compromise cardio-renal outcomes and increase the risk of death.3,4

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “We are pleased by today’s FDA approval of Lokelma as it enables us to help address a long-standing clinical need with a new medicine that offers rapid and sustained treatment for adults with hyperkalemia. The consequences of hyperkalemia can be very serious and it’s reassuring for treating physicians that Lokelma has demonstrated lowering of potassium levels in patients with chronic kidney disease, heart failure, diabetes and those taking RAAS inhibitors.”

Lokelma is a highly-selective, oral potassium-removing agent.The FDA approval is supported by data from three double-blind, placebo-controlled trials and two open-label trials, which showed that for patients receiving Lokelma the onset of action was at 1.0 hour and the median time to achieving normal potassium levels in the blood was 2.2 hours, with 92% of patients achieving normal potassium levels within 48 hours from baseline.1,8 The treatment effect was maintained for up to 12 months.1,5,6,7,8

Steven Fishbane, MD, Professor, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, New York, said: “This FDA approval represents an exciting milestone, as it stands to deliver a rapid, effective and generally well-tolerated treatment option to patients suffering from hyperkalemia in the US.”

The European Commission granted marketing authorization for Lokelma in the European Union on 22 March 2018.

About Hyperkalemia

The risk of hyperkalemia increases significantly for patients with CKD and for those who take common medications for HF, such as RAAS inhibitors, which can increase potassium in the blood. Hyperkalemia occurs in 23% to 47% of patients with CKD and/or HF, with an estimated 200 million and 38 million people, respectively, living with each condition worldwide. Hyperkaliemia may lead to cardiac arrest and death, with mortality being up to 30% in patients with severe hyperkalaemia, if not treated rapidly.

About Lokelma

Lokelma is an insoluble, non-absorbed sodium zirconium silicate, formulated as a powder for oral suspension, that acts as a highly-selective potassium-removing agent. It is administered orally, is odorless, tasteless and stable at room temperature. It has been studied in three double-blind, placebo-controlled trials and in two 12-month open label clinical trials in adult patients with hyperkalemia.

About AstraZeneca in Cardiovascular, Renal & Metabolism

Cardiovascular and metabolic diseases are a main therapy area and a key growth platform for AstraZeneca, which is now called Cardiovascular, Renal & Metabolism (CVRM), following the addition of Lokelma to our portfolio of medicines.

By following the science to understand more clearly the underlying links between the heart, kidney and pancreas, AstraZeneca is investing in a portfolio of medicines to protect organs and improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. Our ambition is to modify or halt the natural course of these diseases and even regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and CVRM health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. The Company also is selectively active in the areas of autoimmunity, neuroscience and infection. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information, please visit www.astrazeneca.com and follow us on Twitter @AstraZeneca.

Commentary: hyperkalemia is a common complication in patients with chronic kidney disease, particularly those who require treatment with renin-angiotensin aldosterone (RAAS) inhibitors. Until recently, the only available oral treatment for hyperkalemia was sodium polystyrene sulfonate (Kayexalate).  In 2015 another drug, patiromer (Valtessa), was approved for this indication and provided a new treatment option. The recent approval of sodium zirconium cyclosilicate (Lokelma) provides an addition treatment choice for hyperkalemia. With the availability of oral therapies, patients should be able to take their RAAS inhibitors without the fear of hyperkalemia and without the need for frequent blood tests. It remains to be seen if these new treatments will have a favorable impact on long-term patient outcomes.

© M Loghman-Adham, MD

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Otsuka Announces Phase 3 Results for Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

November 04, 2017 12:03 PM Eastern Daylight Time

TOKYO–(BUSINESS WIRE)–Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced detailed results from the Phase 3 REPRISE trial of tolvaptan, which is under investigation in the United States in patients with autosomal dominant polycystic kidney disease (ADPKD).

According to trial results, tolvaptan showed greater reduction on the primary endpoint, the rate of change in estimated glomerular filtration rate (eGFR) compared to placebo. Estimated GFR, the primary endpoint of the trial, is a key measure of kidney function. Change in estimated eGFR from pre-treatment baseline to post-treatment follow-up, adjusted by the duration of the trial for each patient and expressed per year was -2.34 mL/min/1.73 m2-year with tolvaptan versus -3.61 mL/min/1.73 m2-year with placebo, representing a 35% reduction of 1.27 mL/min/1.73 m2-year (95% CI 0.86 to 1.68; P<0.001). These data were presented today as a late breaking oral abstract at the American Society of Nephrology (ASN) 2017 Kidney Week in New Orleans,2 and were simultaneously published online in the New England Journal of Medicine.

Polycystic kidney disease (PKD) is a progressive genetic disorder affecting the kidneys, in which fluid-filled cysts develop in the kidneys over time, enlarging these organs and inhibiting their ability to function normally, leading to kidney failure in most patients (see here). Autosomal dominant PKD, known as ADPKD, is the most common type, and is the fourth leading cause of kidney failure.4 By age 57, more than half of people with ADPKD will need dialysis or a kidney transplant (see here and here)

Vicente Torres, MD, PhD, Director of the Mayo Clinic Translational Polycystic Kidney Disease Center, and lead investigator on the REPRISE trial, commented, “Tolvaptan slowed the rate of kidney function decline in this trial. These data represent a significant milestone in the investigation of this condition, for which there are currently no approved treatments in the U.S.”

“It is gratifying to see the significance of findings from the REPRISE trial, which further support the utility of tolvaptan in patients with ADPKD,” said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “These robust findings provide evidence that tolvaptan, if approved in the U.S., may be an important new treatment option with the potential to help patients with this debilitating disease, and we look forward to discussing these data with regulatory agencies.”

Along with results from previous pivotal studies, findings from the REPRISE trial have formed the basis of a response to the Complete Response Letter (CRL) that FDA issued in August 2013, which Otsuka has submitted to the U.S. Food and Drug Administration (FDA) for tolvaptan as a treatment for patients with ADPKD.

About the Phase 3 REPRISE Trial

REPRISE was a Phase 3, multi-center, randomized withdrawal, placebo-controlled, double-blind trial in adult patients with late-stage 2 to early-stage 4 chronic kidney disease due to ADPKD. After an 8-week pre-randomization period including sequential placebo and tolvaptan treatments, 1,370 ADPKD patients were randomized 1:1 to tolvaptan (90 or 120 mg per day) or placebo and treated for 12 months. The primary endpoint measured change in estimated GFR from pre-treatment baseline to post-treatment follow-up adjusted by the duration of the trial for each patient. The key secondary endpoint was the estimated GFR slope derived from the individual slopes in each patient adjusted for the duration of the observations and expressed per year. This analysis used all serum creatinine values from placebo run-in, tolvaptan run-in (not including tolvaptan titration), 12-month double-blind treatment, and posttreatment follow-up measurements. In the trial, tolvaptan patients had a significantly smaller decline, of 3.16mL/min/1.73m2/year compared with 4.17 mL/min/1.73m2/year for placebo treated patients (p<0.0001).

Key safety findings (collected monthly) were generally consistent with previous pivotal data with the majority of events across the study. Following randomization, patients who received tolvaptan experienced more frequent polyuria, nocturia, thirst, polydipsia, dry mouth, fatigue and diarrhea, whereas those who received placebo experienced more frequent peripheral edema, renal pain, and urinary tract infection; most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. In the double-blind treatment period, 5.6 percent of patients taking tolvaptan had significantly abnormal liver blood tests (greater than 3 times the upper limit of normal), compared with 1.2 percent of those taking placebo. Transaminase elevations were reversible after stopping tolvaptan and no patients showed concomitant bilirubin elevations greater than 2 times the upper limit of normal. In the study, risk minimization measures consisting of monthly monitoring of liver parameters helped minimize the risk of serious liver toxicity.

Otsuka collaborated on the development of the protocol for this clinical trial with the FDA through the special protocol assessment process in order to address a CRL issued by the agency for a New Drug Application (NDA) for tolvaptan in ADPKD in 2013. In the coming weeks the FDA will acknowledge whether the company’s response is complete and whether their regulatory review can proceed.

 

Commentary and opinion

As discussed in this forum in November 2012 (see here), following the publication of the data for TEMPO 3:4 trial (see here), the investigators of this study (sponsored by Otsuka Pharmaceuticals) showed moderate slowing in the rate of increase in total kidney volume (TKV) and reduced kidney pain, but this was negated by higher discontinuation rate (23% for Tolvaptan versus 14% in the placebo group), as well as by hepatic adverse events.

Due to the increased risk of hepatic toxicity, the FDA issued a Drug Safety Communication for tolvaptan (Samsca®) and convened an Advisory Committee to review the data from TEMPO 3:4 trial.  The Advisory Committee voted 9 to 6 against approval of Tolvaptan for the treatment of ADPKD (see here).  The panel cited excessive dropouts and limited efficacy in slowing progression of renal disease, despite reductions in kidney volume and pain.  The overall risk was assessed to be higher than the benefit observed, despite a high unmet medical need in this patient population.  The FDA issued a Complete Response Letter, requiring submission of additional data before considering evaluating tolvaptan for this indication. Now, armed with the data from REPRISE trial, the Sponsor is seeking approval of tolvaptan for the treatment of ADPKD.  Since FDA provided advice through Special Protocol Assessment, and since the Sponsors are bound to follow this advice, it is likely that the new data, supported by TEMPO 4:4 extension trial, will provide sufficient evidence of efficacy and a manageable safety profile, to grant approval of tolvaptan for the new indication of treatment of ADPKD if certain severity criteria are met.  This would represent a deviation from the FDA standards that require demonstration of a significant difference in time to doubling of serum Cr or time to 50% decline in eGFR.  However, given that the results of TEMPO 3:4 and REPRISE trials complement each other and both show slowing of the slope of decline in renal function (measured either by reciprocal of serum Cr or by eGFR), and given a high unmet medical need, it is likely that a full approval or a conditional approval will be granted.  In case of conditional approval, there will be a post-approval requirement to continue to follow the subjects to ascertain that the beneficial effects on GFR and other clinically relevant parameters are sustained as well as a REMS requirement, given the hepatotoxicity seen in TEMPO 3:4 trial.

The study design of REPRISE and the overall clinical program for the development of tolvaptan will now set a precedence to guide the development of other drugs for the treatment of ADPKD as well as for other types of slowly progressive chronic kidney disease (CKD).

Tolvaptan is currently approved for the treatment of adult patients with ADPKD in Japan, the EU, Canada, South Korea, Switzerland, Hong Kong and Australia (see EPAR).  However, it has multiple side effects, including aquaresis accompanied by thirst, nocturia and polyuria. It also can result in hepatotoxicity, which can be managed with monthly monitoring of liver function tests.  As a condition of approval, the European Medicines Agency (EMA) has required a non-interventional post-authorization safety study (PASS) to investigate the risks of hepatotoxicity, basal cell carcinoma and glaucoma associated with the use of tolvaptan (marketed under the brand names Smsca and Jinrac)

While we do not know what label restrictions will be imposed by the FDA, due to the above safety issues, tolvaptan may only be suitable for ADPKD patients who have shown rapid progression or who are likely to progress rapidly.  This subset of ADPKD patients are most likely to benefit from long-term therapy with tolvaptan. It is hoped that another V2 receptor antagonist could be developed that would be devoid of organ toxicity. However, the aquaretic effect is an integral part of the mechanism of action of all V2 antagonists and will have to be managed by increased fluid intake and administration of the second dose in the afternoon instead of in the evening (Ron Perrone, MD personal communication).  Drugs targeting other pathways in the pathogenesis of ADPKD are currently in early stage development [see here and here], but it remains to be seen if they will be successful in clinical trials and whether their safety profile will be better than tolvaptan.

Update April 24, 2018

TOKYO–(BUSINESS WIRE)-Otsuka Pharmaceutical Co., Ltd. (Otsuka) announced that the U.S. Food and Drug Administration (FDA) has approved JYNARQUE (tolvaptan) as the first drug treatment to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease (ADPKD).  As was discussed in the previous post above, due to the risk of serious liver injury, Jynraque label will contain a box warning and the drug will be available only through a REMS (Risk Evaluation and Mitigation Strategy) program, which requires frequent monitoring of liver function as well as certification of providers that prescribe it for the treatment of ADPKD.  The wholesale price of Jynarque has been set to $13,041.10 for a 28-day treatment pack, so reimbursement hurdles could emerge until additional health evaluation and outcome research data become available showing a clear cost/benefit ratio of Jynarque over current standard of care.

Copyright © M. Loghman-Adham, MD

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U.S. FDA APPROVES AURYXIA® (FERRIC CITRATE) TABLETS AS A TREATMENT FOR PEOPLE WITH IRON DEFICIENCY ANEMIA AND CHRONIC KIDNEY DISEASE, NOT ON DIALYSIS

BOSTON, Nov. 07, 2017 (GLOBE NEWSWIRE) — Keryx Biopharmaceuticals, Inc. (Nasdaq:KERX), a company focused on bringing innovative medicines to people with kidney disease, today announced that the U.S. Food and Drug Administration (FDA) has approved Auryxia for an additional indication. The approval is for the treatment of iron deficiency anemia in adults with chronic kidney disease (CKD), not on dialysis. Auryxia was originally approved in September 2014 for the control of serum phosphorus levels in people with chronic kidney disease who require dialysis.

With the new indication, millions of people living with chronic kidney disease have the potential to benefit from treatment with Auryxia. This medication is available today in pharmacies and covered broadly by Medicare Part D and commercial insurance providers in the United States.

“More than half of the approximate 30 million people in the United States living with chronic kidney disease are iron deficient, and yet, this is the only tablet that has been developed and approved specifically to address iron deficiency anemia in these patients, who are not on dialysis,” said Steven Fishbane, M.D., chief, division of kidney diseases and hypertension, department of medicine, Northwell Health in Great Neck, New York. “Starting today, physicians can prescribe an oral iron medicine to help people living with this condition, the majority of whom are not being optimally treated.”

“We are pleased with the broad indication permitted by the FDA, as a first-line treatment option for adults with iron deficiency anemia and chronic kidney disease, not on dialysis,” said John Neylan, M.D., senior vice president and chief medical officer of Keryx Biopharmaceuticals. “Physicians and their patients now have a new treatment option to help manage a serious complication of this complex disease.”

Auryxia’s supplemental new drug application (sNDA) approval was based on results from a 24-week placebo controlled Phase 3 clinical trial in 234 adults with stage 3-5 non-dialysis dependent chronic kidney disease. Patients enrolled in the trial had hemoglobin levels between 9.0 g/dL and 11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements. The starting dose in the study was three tablets per day taken with meals; the mean dose was five tablets per day. Importantly, during the study, patients were not allowed to receive any intravenous (IV) or oral iron, or erythropoiesis-stimulating agents (ESAs). In the study, treatment with Auryxia demonstrated significant increases in hemoglobin levels of >1 g/dL at any point during the 16-week efficacy period for the majority of patients (52.1 percent, n=61/117 compared to 19.1 percent, n=22/115 in the placebo group), a clinically meaningful result. In the trial, ferric citrate was generally well tolerated and adverse events were consistent with its known safety profile. The most commonly reported adverse events in the Phase 3 study were diarrhea (21%), constipation (19%), discolored feces (15%), nausea (11%), abdominal pain (6%) and hyperkalemia (7%). Results were published January 2017 in the online issue of the Journal of the American Society of Nephrology (JASN).

Commentary:

Patients with chronic kidney disease (CKD) suffer from multiple metabolic abnormalities, chief among them are disorders of mineral metabolism, including hyperphosphatemia, and disorders of iron metabolism, which can lead to both iron deficiency anemia and iron refractory anemia.  The latter is in part, due to the inflammatory nature of CKD and dialysis and in part, due to erythropoietin deficiency, leading to chronic renal anemia.  While erythropoiesis stimulating agents (ESA) can replace the deficiency of erythropoietin, optimal ESA response requires the concomitant administration of intravenous iron [see here].  Orally administered iron supplements are not effective in restoring iron stores in ESRD patients and are associated with gastrointestinal symptoms.

Ferric citrate [Auryxia®], initially developed as a phosphate binder, was found to also improve iron deficiency anemia in CKD patients, due to the absorption of iron from the GI tract.  Previously marketed phosphate binders have included aluminum hydroxide, which was shown to result in aluminum deposition in bone and in brain in ESRD.  The former can lead to osteomalacia, while the latter is associated with encephalopathy.  For these reasons, the use of aluminum hydroxide as a phosphate binder has been abandoned.  Calcium carbonate, although an effective phosphate binder, was shown to result in hypercalcemia, over-suppression of parathyroid hormone and adynamic bone disease as well as coronary artery and cardiac calcifications [see here]. These side effects led to the development of aluminum-free and calcium-free phosphate binders such as Sevelamer (Renagel®, Renvela®) and lanthanum carbonate (Fosrenol®].  Lanthanum carbonate does not result in any significant lanthanum absorption and has not been shown to have any untoward consequences [see here].  Sevelamer is a non-absorbable resin, so its action is limited to binding phosphate and bile acids in the gut.

The development of ferric citrate as a phosphate binder was a departure from the previous strategies of developing non-absorbable phosphate binding compounds.  This new approach has paid off in that, iron deficiency, a common problem in pre-dialysis CKD patients, was shown to improve with ferric citrate, while it was primarily prescribed as a phosphate binder [Block 20015; Fishbane 2017].  The approval of the supplemental application for the use of ferric citrate [Auryxia®] to treat iron-deficiency anemia in pre-dialysis CKD patients, should now allow patients to obtain re-imbursement for this indication.  Of course, ferric citrate will continue to be used for its primary indication as a phosphate binder in ESRD patients on dialysis.  In this indication, the additional benefit of ferric citrate is the reduced need for intravenous iron and to also the reduction in the ESA dose [see here]and [here].  Considering the high costs of these treatments, reduced doses is likely to reduce the overall cost of anemia treatment, which is currently bundled under the CMS rules [see here].

Copyright © M. Loghman-Adham, MD

 

References:

Besarab, Anatole, et al. “Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients.” Journal of the American Society of Nephrology 11.3 (2000): 530-538.

Fishbane S1, Block GA, Loram L, Neylan J, Pergola PE, Uhlig K, Chertow GM. Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.  J Am Soc Nephrol. 2017 Jun;28(6):1851-1858. doi: 10.1681/ASN.2016101053. Epub 2017 Jan 12. (see here)

Block, Geoffrey A., et al. “A 12-week, double-blind, placebo-controlled trial of ferric citrate for the treatment of iron deficiency anemia and reduction of serum phosphate in patients with CKD stages 3-5.” American Journal of Kidney Diseases 65.5 (2015): 728-736.

Umanath K, Jalal DI, Greco BA, Umeukeje EM, Reisin E, Manley J, Zeig S, Negoi DG, Hiremath AN, Blumenthal SS, Sika M, Niecestro R, Koury MJ, Ma KN, Greene T, Lewis JB, Dwyer JP; Collaborative Study Group. Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD. J Am Soc Nephrol. 2015 Oct;26(10):2578-87

Lewis JB, Sika M, Koury MJ, Chuang P, Schulman G, Smith MT, Whittier FC, Linfert DR, Galphin CM, Athreya BP, Nossuli AK, Chang IJ, Blumenthal SS, Manley J, Zeig S, Kant KS, Olivero JJ, Greene T, Dwyer JP; Collaborative Study Group. Ferric citrate controls phosphorus and delivers iron in patients on dialysis. J Am Soc Nephrol. 2015 Feb;26(2):493-503

How ‘Bundling’ Changed Dialysis Care.  Renal & Urology News March 02, 2017  (see here)

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Pharmalink AB announces the publication in Lancet of Phase 2b trial of Nefecon in primary IgA nephropathy. The data were also presented at the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) conference (Madrid, Spain)

 

Stockholm, Sweden – June 4, 2017 (see press release). The Phase 2b trial (known as the NEFIGAN trial), was presented in a special session co-hosted by The Lancet by lead author Bengt Fellström, MD, PhD, Professor of Nephrology at Uppsala University Hospital and Principal Investigator of the NEFIGAN Trial.

Nefecon® is an investigational treatment for patients with primary IgAN at risk of developing ESRD. Nefecon®  has successfully completed a randomized, placebo-controlled Phase 2b study in 149 primary IgAN patients (full analysis set) at risk of developing ESRD, under standardized rigorous blood pressure control with an angiotensin-converting enzyme inhibitor (ACEI) and/or angiotensin II receptor blocker (ARB).  Nefecon®  is an oral, targeted-release and locally acting formulation of the potent corticosteroid, budesonide, that down-regulates the disease process in the kidney through suppression of the gastrointestinal immune system thus exploiting the pivotal role the gastrointestinal tract plays in the overall immune response. These promising results indicate that treatment with Nefecon® may provide clinical benefits to primary IgAN patients at risk of progressing to ESRD, and provide an alternative to dialysis and transplantation. Nefecon® has received orphan drug designation in primary IgAN by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

The NEFIGAN trial was randomized, double-blinded, and placebo-controlled in male and female patients (aged >18 years) with primary IgAN and overt proteinuria considered at risk of progressing to end-stage renal disease (ESRD)1. The trial was conducted at 62 sites across 10 European countries between November 2012 and June 2015. Data from 149 patients constituted the final analysis set, from a total of 249 patients screened.  Following a 6-month run-in phase (to optimize RAS blockade treatment), patients underwent a 9-month treatment phase in which they were randomized in a 1:1:1 ratio to receive Nefecon at 16 mg/day, 8 mg/day or placebo.  The primary outcome of the Phase 2b clinical trial was assessed on the full analysis set (n=149), defined as all randomized patients who took at least one dose of trial medication and had at least one post-dose efficacy measurement (modified intention-to-treat analysis). At nine months, mean urine protein to creatinine ratio (UPCR) decreased by -26.4% with Nefecon [p=0.0066] (-29.3% with 16 mg/day [p=0.009; p=NS], -23.7% with 8 mg/day [p=0.029]), vs. placebo. The effect was sustained throughout the follow-up; mean UPCR decreased by -32% from baseline at 12 months for 16 mg/day vs. a 0.5% increase for placebo. Over nine months, eGFR was stable with Nefecon but decreased 9.8% with placebo (Nefecon vs. placebo: p=0.001). Nefecon was well tolerated and the total incidence of treatment-emergent adverse events was similar across all treatment groups.

Commentary:

Immunoglobulin A (IgA) nephropathy (IgAN) is a chronic glomerular disease characterized histologically by the presence of mesangial deposits of IgA, which are often accompanied by IgG or IgM deposits and often by complement deposits. It is a slowly progressive disease, leading to end-stage renal disease (ESRD) in 20% to 40% of patients over 20 years.  IgA nephropathy IgA Nephropathy is the most common primary glomerulonephritis worldwide2,3.

The presence of hypertension and low GFR at the onset are associated with more rapid progression and worse outcomes.2,3  Multiple studies have shown that proteinuria is a risk factor for progression of renal disease in patients with IgAN and other glomerular diseases. Furthermore, higher levels of proteinuria are associated with a more rapid decline in renal function and reduction in proteinuria with treatment, may lead to slowing of the rate of progression of kidney dysfunction.4

Several studies have shown the benefit of treatment with corticosteroids, given either as 6 monthly pulses of methylprednisolone or orally for 8 weeks. Inhibition of the renin-angiotensin system (RAS) pathway is also recommended 5,6.  In addition to lowering blood pressure, it reduces proteinuria.  Treatment recommendations for IgAN have recently been summarized in the Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines.6 Treatment of hypertension targeting a blood pressure (BP) <130/80 mmHg should slow the rate of progression of disease. Additionally, the guidelines recommend treatment using RAS blockade (as tolerated, with either an ACE inhibitor or an angiotensin receptor blocker [ARB]) to achieve a maximal reduction in proteinuria, when proteinuria is >1 g/24 h.6 Other supportive therapy, such as fish oil and statins, should be considered and have been associated with clinical benefits.

The novelty of the targeted release budesonide (Nefecon)® is the ability to target the distal ileum and block the immune mechanisms responsible for the development of circulating immune complexes, while reducing the adverse effects seen with systemic steroid treatment.  The reduction in proteinuria is an acceptable endpoint for Phase 2 proof-of-concept studies in IgAN and other forms of GN.  However, for Phase 3 registration studies, both the FDA and the EMA require assessment of time to doubling of serum creatinine or 50% reduction in eGFR or time to ESRD.  To reach these endpoints, long treatment and follow-up times (24-36 months) are needed7.  Recent studies suggest that reductions in eGFR less than 50% may be acceptable, but agreement of the agency is required before finalizing the design of the clinical trial.

References:

  1. Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tsars V, Del Vecchio L; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomized, placebo-controlled phase 2b trial.  2017 May 27;389(10084):2117-2127. doi: 10.1016/S0140-6736(17)30550-0. Epub 2017 Mar 28.(link)
  2. Canetta PA, Kiryluk K, Appel GB. Glomerular diseases: emerging tests and therapies for IgA nephropathy. Clin J Am Soc Nephrol 2014; 9: 617-25 (link).
  3. Rodrigues JC1, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017 Apr 3;12(4):677-686. doi: 10.2215/CJN.07420716. Epub 2017 Feb 3 (link).
  4. Reich HN, Troyanov S, Scholey JW, Cattran DC, for the Toronto Glomerulonephritis Registry. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol 2007; 18:3177-83 (link). doi:10.1681/ASN.2007050526.
  5. Lv J, Zhang H, Chen Y, et al. Combination therapy of prednisone and ACE inhibitor versus ACE-inhibitor therapy alone in patients with IgA nephropathy: a randomized controlled trial. Am J Kidney Dis 2009; 53:26-32 (link).
  6. KDIGO Clinical Practice Guideline for Glomerulonephritis. June 2012; 2(2). http://www.kidney-international.org (link).
  7. Formentini I, Bobadilla M, Haefliger C, Hartmann G, Loghman-Adham M, Mizrahi J, Pomposiello S, Prunotto M, Meier M. Current drug development challenges in chronic kidney disease (CKD)—identification of individualized determinants of renal progression and premature cardiovascular disease (CVD). Nephrol Dial Transplant; 27 (suppl 3), 2012, iii81–iii88, https://doi.org/10.1093/ndt/gfs270 (link)

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