Saxagliptin (Onglyza) fails to reach primary endpoint in a CV outcome study of type 2 diabetic patients

On June 19, 2013 Bristol-Myers Squibb (BMS) announced top-line results of the phase IV study, named SAVOR-TIMI-53. In this study of adult patients with type 2 diabetes with either a history of established cardiovascular disease or multiple risk factors, Onglyza met the primary safety objective of non-inferiority, and did not meet the primary efficacy objective of superiority, for a composite endpoint of cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke, when added to a patient’s current standard of care (with or without other anti-diabetic therapies), as compared to placebo.  The full findings will be presented September 2, 2013 at the European Society of Cardiology (ESC) 2013 Congress in Amsterdam. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor approved in the US, Canada, Europe, and elsewhere as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Non-randomized analyses had suggested that DPP-4 ihbitors might have a CV-protective effect in diabetic patients [see here].

Saxagliptin was the first new diabetes drug to receive FDA approval after the issuance of new agency guidelines in July 2009, requiring companies to perform CV-outcomes studies with new diabetes drugs [see here]. The drug’s clinical development program had been completed before the guidance, but because of the new rule, the company launched SAVOR-TIMI 53. The four-year-long trial had a target enrollment of 16 500 patients [Source: Heartwire].

Commentary.  Prior to approval of saxagliptin, BMS provided an analysis of the phase 2b/3 data, based on  4607 subjects, 3356 of whom had received saxagliptin [see here].  This retrospective analysis, using the newly issued FDA Guidance, showed no increased risk of major adverse cardiac events (MACE) or other CV events.  The upper limit of 95% CI of hazard ratio of point estimates for FDA-defined MACE or acute CV events remained at or below 1.8 for saxagliptin compared to placebo controls [see presentation here].  This information was subsequently published and the authors suggested that saxagliptin may actually lower CV risk in patients with type 2 DM [see Cobble & Frederich].  Other, non-randomized analyses had raised hopes that this class of drugs might provide protective effect on the vasculature of diabetes patients [see here and here] and also published by [Monami et al.] and by [Frederich et al.]. Based on these encouraging data, the sponsors undertook the large phase 4 study named (SAVOR-TIMI-53], a randomized, double-blind, placebo-controlled trial that involved 16,500 patients in 25 countries with type 2 diabetes who had a history of established cardiovascular disease or multiple risk factors, with or without renal impairment [see clinicaltrials.gov].  Failure to show superiority compared to standard of care, does not affect Onglyza‘s ability to remain on the market.  However, it removes the possibility of Bristol-Myers and AstraZeneca to update the label to claim an advantage in reducing CV risks in patients with type 2 diabetes. The inability to differentiate Onglyza from competitors could have financial consequences [see here].  As detailed elsewhere on this website, demonstrating cardiovascular benefit in post-approval studies has been an elusive goal for many drugs, which in non-randomized studies or retrospective analyses had shown such benefits.  Recent examples include the TREAT study, the ALTITUDE study, and the EVOLVE  study.

© Copyright M. Loghman-Adham, MD

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Results of Phase 3 clinical trial of ferric citrate (Zerenex) to be presented at the ISN World Congress of Nephrology (WCN)

According to the WCN program (see here), a poster (#SU401) entitled ” Ferric citrate is a novel efficacious phosphate binder” will be presented on June 2nd by Dr. Julia Lewis from Vanderbilt University Medical Center (view abstract) during the Annual Meeting in Hong Kong.   Top-line results of the phase 3 study were announced by Keryx Biopharmaceuticals on January 28, 2013 (see News release).  The study was a multi-center, randomized, open label trial of ferric citrate, a novel non-calcium containing phosphate binder, in 441 dialysis patients (HD and PD).  The study included a 52 week safety assessment whereby the subjects were randomized 2:1 to receive ferric citrate or an active control (either calcium acetate or sevelamer carbonate).  The safety assessment was followed by a one-month efficacy assessment period during which 192 subjects who remained on ferric citrate were randomized 1:1 to either continue on ferric citrate or switch to placebo.  The ferric citrate doses, given as 1 g capsules with meals were titrated during the study to achieve a serum phosphorus concentration between 3.5 and 5.5 mg/dL.  Oral iron was not permitted and intravenous iron was only permitted if serum ferritin was >1000 ng/ml or TSAT was >30%.  Fairly detailed results are available within the Press Release by Keryx Biopharmaceuticals (see News release) .

The primary efficacy endpoint was the change in mean serum phosphorus from week 52 to week 56.  Mean phosphorus levels were 4.9 ± 1.4 and 7.2 ± 1.5 mg/dL for Zerenex and placebo, respectively (p<0.01).  All the secondary endpoints were also met.  Of interest were the effects of ferric citrate on iron metabolism and on hemoglobin levels. The mean change in ferritin from baseline to week 52 was 302 ng/mL for Zerenex, compared to 9 ng/mL for placebo (p<0.0001). There was also a higher mean Hb concentration in the Zerenex group compared to placebo (11.4 ± 1.5 vs 11.1 ± 1.4 g/dL) at week 52.  Most importantly, Zerenex appeared to be safe and well tolerated. Excluding stool discoloration, which is a known effect of iron salts, the gastrointestinal side effects were similar between Zerenex and active control.  Full analysis of these data will be presented at the WCN and we expect that  they will be also published at about the same time (see News release).

According to Keryx, the NDA (New Drug Application) and European MAA (Marketing Authorization Application) is anticipated in the second quarter of 2013. Generally it takes about one year from the NDA submission until approval.

Commentary:  Phosphate retention and  hyperphosphatemia are common consequences of ESRD and lead to multiple complications, which include not only secondary hyperparathyroidism and renal osteodystrophy, but also vascular calcifications and increased mortality, primarily from coronary artery disease complications (see here).  The use of calcium-free phosphate binders such as sevelamer can result in stabilization and even regression of vascular calcifications (see here).  However, to be effective, all currently available phosphate binders require multiple pills that need to be taken with meals.  The large pill burden often results in gastrointestinal side effects and low patient adherence.   Ferric citrate is no exception.  Zerenex doses  are not given in the available Press Release. In the phase 2 study, patients received three 1 g capsules, which were titrated to obtain the desirable serum phosphorus levels (see Yang et al).  Being an iron compound, it is not entirely surprising to see a beneficial effect of Zerenex on iron metabolism and on Hb concentrations.  The overall effect was a reduction in cumulative intravenous iron doses and a reduction in cumulative ESA doses.  A recently published pharmacoeconomic evaluation assessed the potential cost savings from the use of  ferric citrate compared to other phosphate binders (see Mutell et al.).  The authors concluded that the use of ferric citrate  to treat hyperphosphatemia in ESRD patients may help reduce treatment costs.  The study was sponsored by Keryx Biopharmaceuticals.

Based on what is known in the public domain, the overall data package that will be submitted in support of an NDA appears to be very favorable and could lead to the approval of Zerenex for treatment of hyperphosphatemia in ESRD patients on dialysis.  Additional studies are underway to assess its effectiveness in the management of hyperphosphatemia and anemia in CKD patients not on dialysis (see here).

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Abbvie announces initiation of the phase 3 registration trial of atrasentan on renal outcomes in patients with diabetic nephropathy

Atrasentan is a selective endothelin A receptor antagonist,  which was found to have cytostatic properties in prostate cancer (reviewed here) .  Due to promising early results, atresantan was initially developed for the treatment of hormone-refractory prostate cancer (see here).  However, a phase 3 trial of atrasentan in non-metastatic HRPC, showed no statistically significant difference in time to progression between atrasentan and placebo (see ASCO abstract and Cancer 2008).  Furthermore, the incidence of peripheral edema, nasal congestion, headache, dyspnea, and heart failure was greater with atrasentan than with placebo (Cancer 2008).  However, the dose used in oncology trials was 10 mg/day compared to 0.75 mg/day for the planned phase 3 study in diabetic nephropathy (see below).  In September 2005, the Oncology Drug Advisory Committee (ODAC) of the FDA recommended against approval of atrasentan (assigned the brand name Xinlay at the time) (see here).  Another study of atrasentan added to standard chemotherapy in advanced prostate cancer also failed to show any benefit and was terminated by the DSMB for futility (see here and here).  Due to these unfavorable results, Abbott changed its focus to the use of atrasentan in the treatment of diabetic nephropathy.

In a recently completed dose ranging phase 2 study in 89 subjects with diabetic nephropathy (eGFR >20 mL/min/1.73 m2; UACR 100 to 3000 mg/g),  atresantan at doses of 0.75 or 1.75 mg/day resulted in significant reduction in UACR (see JASN article).   Following the positive outcome of the phase 2 trial (see here), Abbvie has initiated a pivotal phase 3 trial of atrasentan in patients with diabetic nephropathy (see News release from Abbvie).  If successful in reaching  the pre-defined endpoints, this study will form the basis of a New Drug Application (NDA) submission to the FDA.  The phase 3 clinical trial, called  SONAR (Study Of Diabetic Nephropathy with Atrasentan)  is a large, multinational, double-blind, placebo-controlled clinical study that is expected to enroll more than 4,000 patients with diabetic nephropathy.   The inclusion criteria include estimated GFR (eGFR) of 25 to 75 mL/min/1.73 m2 (CKD stage 2 to 4), UACR >300 and <5,000 mg/g, and systolic blood pressure within 110 and 160 mgHg (see Abbvie News release).  Based on the phase 2 study, the dose for this trial will be 0.75 mg per day.

The primary endpoint will evaluate the effect of atrasentan on time to doubling of serum creatinine or the onset of ESRD, as defined by need for chronic dialysis, transplant or death due to renal failure. Secondary endpoints will assess the effects of atrasentan on urine albumin excretion, eGFR and cardiovascular events including cardiovascular death, heart attack and stroke.  Quality of life evaluations also will be conducted.  More detailed information about the trial is available at (Abbvie News release).

Commentary:  Very few drugs have been successful in slowing the progression of renal disease.  Currently, only ACE inhibitors and ARBs are approved for this indication.  Bardoxolone methyl, co-developed by Reata Pharmaceuticals and Abbott (now Abbvie) had shown promise in a phase 2 trial in patients with diabetic nephropathy, but its phase 3 trial had to be halted due to excess mortality in the bardoxolone arm (see KDDD posting and Reata news release).  studies aimed at slowing progression of kidney disease in patients with diabetic nephropathy or other types of chronic kidney disease are expensive, requiring large numbers of patients and long treatment durations.  Unfortunately, no surrogate endpoints exist to predict the clinically relevant outcomes (need for dialysis or death), so currently only composite hard endpoints, including doubling of serum Cr or a significant (usually >25%) decrease in eGFR, combined with time to dialysis or death are used in clinical trials.  Changes in proteinuria or albuminuria are not acceptable as endpoints for registration purposes but are often included either as part of the composite endpoint or as secondary endpoints.

Another issue in performing  phase 3 trials in CKD is the need to include patients who show a decline in eGFR,  ascertained either from historical values or during a run-in period.  Inclusion of patients with early stages of CKD (e.g. stage 2) in a trial aimed at slowing the rate of CKD progression will require very long (4 or 5 years) treatment and observation and large numbers of patients, in order to see a statistically significant change in eGFR.  Patients at more advanced stage of CKD (e.g. stage 4) will progress more rapidly and require a shorter treatment and observation period, but in late stages, glomerulosclerosis, interstitial fibrosis, and other “irreversible” changes have already occurred, making it unlikely that the treatment will be effective.  So, selecting patients for such trials is a very difficult task indeed.  Some of these issues  and proposed solutions have been discussed in a recent review by Formentini et al. that was published in NDT.

Until a validated surrogate endpoint, able to predict long-term outcomes in CKD patients has been identified, clinical trials aimed at assessing progression to ESRD will require long observation periods and thousands of patients to have a chance to be successful.

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Another trial of darbepoetin alfa (Aranesp) shows disappointing results

In 2009 TREAT, a large placebo-controlled trial of darbepoetin alfa, an erythropoiesis stimulating agent (ESA) was conducted in patients with type 2 diabetes who had chronic kidney disease and anemia (see TREAT).  The rationale for the study was that CKD patients with anemia are at increased risk of developing adverse cardiovascular outcomes, so correction of anemia with darbepoetin alfa might reduce cardiovascular risk.  However, TREAT failed to reach its endpoint of composite outcomes of death or a cardiovascular event and of death or end-stage renal disease. Furthermore, stroke occurred in twice as many patients assigned to darbepoetin alfa as compared to placebo.

Now, another trial of darbepoetin alfa has been completed and again the results are not what the investigators and the sponsor had hoped for.  In  the Reduction of Events by Darbepoetin Alfa in Heart Failure (RED-HF) trial, 2278 patients with systolic heart failure and anemia were randomized to receive either darbepoetin alfa or placebo (see RED-HR).  The Hb  target in the darbepoetin arm was 13 g/dL.  The treatment duration was 60 months (5 years) during which a clear separation of Hb levels were achieved between the two groups.  The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure.  The primary outcome occurred in 50.7% of darbepoetin alfa group and in 49.5% of placebo group (p=0.87). There was also no significant difference between darbepoetin alfa and placebo in any of the secondary outcomes.  Thromboembolic adverse events were more common in the darbepoetin alfa-treated patients (13.5% versus 10.0%, p = 0.01).  The authors concluded that treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild to moderate anemia.

Commentary:  Since their introduction more than 20 years ago, ESAs have had a significant impact in the life of patients with ESRD who suffer from severe anemia.  However, some patients appear unresponsive to low dose ESA and require relatively high doses to maintain the Hb level within the recommended range.  As a result, plasma erythropoietin levels, or more precisely plasma ESA levels have to be maintained several fold above the physiologic levels of anemic subjects without renal failure such as those with iron deficiency anemia.  It is possible that these pharmacological levels of ESAs have deleterious effects, particularly on the cardiovascular system.  In fact, patients with ESA-hypo-responsive anemia who require higher doses to maintain adequate Hb levels, appear to be at much higher risk of CV complications regardless of their Hb levels [Zhang et al AJKD 2004]. Since 2007, the FDA has required a “black box warning” on ESA labels (see also  here), which was further restricted, following the availability of the TREAT data (see here).  As we learn more about the cause or causes of ESA hypo-responsiveness, new approaches could be applied to improve ESA response.

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The Costs of Clinical Trials and Drug Development

A recent report published in Pharmalot  shows that the cost of conducting clinical trials has risen to staggering figures.  Across all therapeutic areas, the average cost per patient in phase 1 trials rose from $15,023 in 2008 to 21,882 in 2011.  For phase 2 trials, the costs rose from 21,009 to $36,070 and in phase 3b trials, the costs increased from $25,707 to $47,095. If one adds the R&D costs to these, then one should not be surprised than billion dollar estimates have been proposed.  Whether costs are really this high is controversial and the debate continues.

Current estimates place the costs of developing new drugs somewhere between $1.0 billion to $1.5 billion.  A report by Pharmaceutical Research and Manufacturers of America (PhRMA) estimated that the costs for drug development were  $1.38 billion in 2005. This figure was of course much higher than the previously reported and often quoted cost of $802 million (see DiMasi et al].   The most recent estimates come from a report commissioned by an independent UK research organization called the Office of Health Economics and summarized recently in The Burrill Report .  Despite the staggering costs, the success rate for bringing a new drug from early human trials to market has declined to 1 in 10.  The issue of increasing costs of clinical trials and the causes of this increase has been studied in a recent report written by Avik S. A. Roy, a Senior Fellow, Manhattan Institute for Policy Research, entitled ” Stifling New Cures: The True Cost of Lengthy Clinical Drug Trials”.  The report can be accessed as a pdf document at the Manhattan Institute website.

The cost estimates vary depending on the methodology used, the type of therapy and the company developing the drug.  Christopher Adams and Van Brantner from the Bureau of Economics, Federal Trade Commission, used estimates similar to those of DiMasi et al. but a publicly available database to reach their cost estimates [see here].   They concluded that [estimates vary from around $500 million to more than $2 billion, depending on the therapy or the developing firm].  Recent reports are critical of the costs calculated by PhRMA and the pharmaceutical industry as a whole.  They suggest that such figures may have been inflated and that the real cost of drug development may be much lower.  This issue was recently addressed in an editorial written by Michael Hiltzik in Aug 3, 2011 in Los Angeles Times.  The editorial is based on the findings of a recent article written by Donald Light and Rebecca Warburton in BioSocieties.

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OMONTYS® (peginesatide) recalled due to fatal allergic reactions

On February 23, 2013, Affymax and Takeda announced a voluntary nationwide recall of all lots of Omontys (peginesatide), a peptide mimetic erythropoiesis stimulating agent (ESA), which was approved on March 27, 2012 by the FDA for the treatment of anemia due to chronic kidney disease in adult patients on dialysis (see here and here).  Peginesatide has the advantage over currently available ESAs on the US market that it can be administered once monthly by either intravenous or subcutaneous routes.  Additional information is available on the FDA website.

Post-marketed surveillance has shown hypersensitivity reactions in 0.2% of subjects, with serious-life threatening reactions occurring in one-third.  In a joint News Release, the Companies report that, since launch, more than 25,000 patients have received peginesatide and fatal reactions have been reported in approximately 0.02% .  A Dear Healthcare Provider letter has been posted on the Omontys website informing prescribers to cease using the drug.

The prescribing information for Omontys does carry a black box, which  is now required for all ESAs.  There were no anaphylactic reactions reported in the label, which restricts itself to those AEs with a frequency of ≤ 10%.  It does indicate the risk of immunogenicity and production of neutralizing antibodies.  Below is an excerpt from the label:

[Of the 2357 patients tested, 29 (1.2%) had detectable levels of peginesatide-specific binding antibodies. There was a higher incidence of peginesatide-specific binding antibodies in patients dosed subcutaneously (1.9%) as compared to those dosed intravenously (0.7%). Peginesatide neutralizing antibodies were detected in vitro using a cell-based functional assay in 21 of these patients (0.9%).]

Editor’s Comments: The occurrence of fatal anaphylactic reactions with the reported frequency of 0.02% or 1 in 5000 patients dosed with peginesatide has very negative consequences.  According to the Affymax and Takeda, serious, but non fatal hypersensitivity reactions were observed at a frequency of 0.2% (2 in 1000).  Such reactions were not observed during phase 2 and phase 3 trials of peginasetide where 1066 patients received the drug.  It is for this reason that post-marketing surveillance and REMS are being required by the FDA at the time of approval for many new drugs.  Whether serious anaphylactic reactions were a consequence of the known immunogenicity of the drug or due to increased immunogenicity of specific batches is not clear at this time.  We also do not know if these subjects received the drug by the subcutaneous route, known to be more immunogenic than the intravenous route.

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Targeted therapy with folate-conjugated rapamycin, a promising treatment for PKD

Autosomal dominant polycystic kidney disease(ADPKD) is a common genetic kidney disease caused by mutations in either PKD1 or PKD2 genes, resulting in the presence of multiple cysts that increase in size and lead to a number of complications, including early-onset hypertension, hematuria, pain, infection, and slowly progressive chronic kidney disease that leads to end-stage renal disease by the 6th decade of life.

Dr Thomas Weimb’s group at UC Santa Barbara had shown that mTOR pathway is involved in polycystic kidney disease and that it’s inhibition reverses cyst formation in two different mice model of polycystic kidney disease, namely the Tg737orpk/orpk;TgRsq and the bpk/bpk mice (see Shilingford et al).  This discovery led to two recently completed clinical trials of mTOR inhibitors, already approved as immunosuppressive agents in organ transplantation. These studies were published in the August 26, 2010 issue of New England Journal of Medicine.

The trial by Serra et al. included 100 ADPKD patients with relatively preserved renal function, treated with sirolimus or placebo for 18 months. Kidney volume and GFR were measuerd over time.  The authors found no difference in kidney volume change between the sirolimus and the placebo-treated subjects and no difference in GFR between the two groups.  In another study by Walz et al. published in the same issue of New England Journal of Medicine, 433 ADPKD patients were randomly assigned to receive everolimus or placebo for 24 months. In this study, everolimus resulted in a statistically non-significant slowing of the kidney volume growth compared to placebo, but no difference in GFR was observed between the two groups.  The everolimus group experienced a significantly higher rate of adverse events contributing in a higher rate of discontinuation in the everolimus group.

The issues related to the use mTOR Inhibitors in ADPKD and some of the reasons for the failure of the studies by Waltz et al. and Serra et al. have been very nicely summarized in the commentary written by Terry Watnick and Gergory Germino that accompanied the publications of these two studies in same issue of  the New England Journal of Medicine.  A major issue with mTOR inhibitors is their toxicity at high doses, making it impossible to reach therapeutic drug levels within the kidney that have been shown in rodent models to slow the growth of cysts. To be effective, these agents must be targeted to be delivered at relatively high concentrations to the cysts within  the kidney.

In a recent study published in the September 28, 2012 issue of the American Society of Nephrology, Jonathan Shillingford et al.  used a folate-conjugated form of rapamycin (FC-rapa) to target renal cells.  They first showed that normal tubules and cysts-lining epithelial cells from human patients and two murine models of PKD express folate receptors.  Treatment of the mouse PKD models with FC-rapa reduced cyst proliferation and preserved renal function. The technology to produce folate-conjugated drugs for targeted therapy comes from Endocyte, a biotech company headquartered in Lafayette Indiana.  Endocyte is developing small molecule drug conjugates for treatment of cancer, autoimmune diseases and PKD, using the folate receptor targeting technology.

A summary of this study and the collaboration with Endocyte can be found on a news release from the University of California Santa Barbara, where Dr Weimb’s laboratory is located.

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Trials and tribulations in kidney disease

On November 3, 2012 at the recent meeting of the American Society of Nephrology-Kidney Week  in San Diego, the results of three important clinical trials in nephrology were presented during  a special session on High Impact Clinical Studies.

The first report presented by Dr Hans-Henrik Parving , University of Copenhagen was the result of the ALITITUDE Trial.  This study was undertaken to determine whether the addition of aliskiren, a direct renin inhibitor to either an ACE inhibitor or an angiotensin receptor blocker (ARB) in patients with type 2 diabetes and chronic kidney disease (CKD) would lead to a reduction in cardiovascular and renal events in this high-risk population.  We reported that on December 20, 2011 the  ALTITUDE Trial was discontinued on recommendation of the Data and Safety Monitoring Board [KDDD].   Therefore, the report on the final data was anxiously awaited.  It was confirmed that, in patients with type 2 diabetes and CKD who are at  high risk of cardiovascular and renal events,  the addition of aliskiren to the standard therapy with RAS blockade does not provide additional benefit and may be harmful due to the increased risk of hyperkalemia.  The results of the trial were simultaneously published in the New England Journal of Medicine.  A summary of the trial and commentary can also be found at Heartwire.

The second report presented by Dr Vicente Torres, Mayo Clinic, Minnesota was the result of a phase 3 trial of tolvaptan, a vasopressin V2 receptor antagonist in patients with autosomal dominant polycystic kidney diseases (ADPKD).  Tolvaptan is already approved and marketed by Otsuka under the brand name Samsca for the treatment of clinically significant hypervolemic and euvolemic hyponatremia.

Previous work in animal models of ADPKD had shown that blockade of vasopressin V2 receptors slows cyst growth by down-regulating cAMP signaling (see Devuyst et al).  The TEMPO 3:4 trial was a pivotal phase 3 multicenter trial including 1445 adult patients with ADPKD and relatively preserved GFR and a total kidney volume (TKV) of 750 ml or more.  Patients with larger TKV have been shown to  have more rapid increase in kidney size, and likely more rapid progression of disease.  Over the 3 years treatment period, the decrease in TKV was lower in the tolvaptan-treated patients compared to placebo (2.8% vs 5.5% per year).  There was also a lower incidence of kidney pain and slower decline in kidney function, as measured by the reciprocal of serum creatinine, in the tolvaptan group.  Adverse events leading to discontinuation were higher in the tolvaptan group.   Not surprisingly, thirst, polyuria and nocturia were reported more frequently in the tolvaptan group with a frequency more than double that of placebo group.  The next step will be the submission of a New Drug Application (NDA) to the FDA.  Otsuka had previously obtained fast track designation for tolvaptan in ADPKD, which will allow a faster review and approval  process.   Should tolvaptan be approved for treatment of ADPKD, it will be the first drug specifically developed for this indication.  The results of TEMPO 3:4 trial were simultaneously published in New England Journal of Medicine as well.  A summary of the results can also be found at the eAJKD blog.

The third report presented by Dr Glenn Chertow, Stanford University, California was the result of a phase 4 trial of the calcimimetic agent, cinacalcet (Sensipar, Amgen) called Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events (EVOLVE) Trial.  The rationale to conduct this trial was based on reports from observational studies of patients receiving dialysis treatment that showed elevated serum phosphorus, calcium, parathyroid hormone and alkaline phosphatase were associated with increased risk of cardiovascular events and death (see here and here).   The results of the EVOLVE Trial were also published in New England Journal of Medicine.  The study enrolled 3883 hemodialysis patients with moderate hyperparathyroidism (median iPTH 693 pg/mL) to receive either cinacalcet or placebo.  The patients were followed for up to 64 months and the median treatment duration was 21.2 months.  The study results showed that cinacalcet did not significantly reduce the risk of death or major cardiovascular events in this high risk patient group.  A summary of the results of this trial is also available at Heartwire.

Commentary:  well designed randomized controlled trials (RCT) are considered  the gold standard to evaluate the effect of a therapeutic intervention.  Often epidemiological or observational studies may suggest a link between an abnormal laboratory test (e.g. phosphorus) or a biomarker (e.g. CRP)  and a clinical outcome such as mortality.  However, this does not mean that correcting the laboratory abnormality with a therapeutic intervention will necessarily alter the outcome.  Only a well-conducted RCT will be able to provide a definitive answer.  In this respect, we must congratulate the sponsors and the investigators of ALTITUDE and  EVOLVE Trials for undertaking these well conducted studies without which these questions would not have been answered.  We can now focus our attention on testing other hypotheses related to the causes of increased cardiovascular morbidity and mortality among CKD patients, especially those receiving chronic dialysis.

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Phase 3 Clinical Trial of CKD Drug Bardoxolone Halted on Safety Concerns

Reata Pharmaceuticals announced yesterday (Oct 18, 2012) that it has decided to terminate the phase 3 clinical trial of Bardoxolone methyl [BEACON] for treatment of patients with stage 4 kidney disease and type 2 diabetes.  Abbott is co-developing Bardoxolone and has  the rights to develop this drug outside the US market.  Bardoxolone has generated a lot of interest within the nephrology community, since there have been no new safe and effective treatments to slow or reverse the progression of CKD other than ACE inhibitors or angiotensin receptor blockers.  I had previously reported on the results of the phase 2 dose ranging trial of Bardoxolone that had shown some safety concerns including muscle spasms, hyperkalemia and hypomagnesemia.  But the new finding of increased mortality in the active treatment arm were unexpected.

The company announcement can be found here [Reata-Bardoxolone] and below:

Reata, in consultation with the BEACON Steering Committee, has decided to terminate the Phase 3 BEACON trial of bardoxolone methyl in patients with stage 4 chronic kidney disease and type 2 diabetes.  This decision was made based upon a recommendation of the Independent Data Monitoring Committee (IDMC) to stop the trial “for safety concerns due to excess serious adverse events and mortality in the bardoxolone methyl arm.”

Clinical trial sites have been notified, and patient participants are being instructed to stop taking study drug and return to the clinic for a final visit.  In addition, Reata and Abbott have notified the FDA and other regulatory agencies of the decision to stop the clinical trial and all ongoing clinical trials with bardoxolone methyl in CKD.

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Calcium-Free Phosphate Binders – Review

This article was originally published in abbreviated form at an Spanish on-line journal [http://www.siicsalud.com/dato/dat048/06406023a.htm].  The attached pdf link is the full version, not published previously.  The article summarizes the issues related to phosphate retention, excess calcium absorption due to the use of calcium-containing phosphate binders and some of the data related to adverse cardiovascular consequences related to the exclusive use of such binders.  This is followed by a discussion of calcium-free phosphate binders such as sevelamer and lanthanum carbonate.  For more up-to-date information, the reader is encouraged to read some of the excellent recent reviews such as the one by Malindretos, published this month in Expert Opinion in Pharmacotherapy.

Phosphate binders-Updated 10-12

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