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UKidney Nephrology News and Insights


More positive news for Tolvaptan (Jinarc) in ADPKD: Reprise Study topline results

Topline results of the Reprise Study in ADPKD have been announced and the good news continues for ADPKD. According to top-line results released by Otsuka, the maker of Tolvaptan:

- Primary and key secondary endpoints were positive for tolvaptan vs. placebo in an additional Phase 3 clinical trial that examined the efficacy and safety of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD)- The data are intended to address the Complete Response Letter (CRL) issued by the FDA for a New Drug Application (NDA) for tolvaptan in ADPKD in 2013- Trial results will be submitted for presentation at a nephrology medical congress in the second half of 2017
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Jinarc (Tolvaptan) approved in Canada for the management of autosomal dominant polycystic kidney disease (ADPKD)

Canada becomes the first country outside Japan to approve JinarcTM (Tolvaptan) for the treatment of ADPKD. This medication, dosed twice daily, is the first of its kind to show a slowing in renal function decline as well as a slowing in kidney enlargement among patients with ADPKD.

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Cinacelcet and cardiovascular outcomes: neutral study underscores a fundamental problem in nephrology research

Top-line results for the EVOLVE study using cinacalcet (Sensipar) in patients with end-stage renal disease (ESRD) were reported last week. In this phase 3 placebo-controlled randomized trial of 3,883 patients with secondary hyperparathyroidism, those on active treatment received a titrated dose of cinacalcet starting at 30 mg/day up to 180mg and were followed for approximately 4 years. Patients were evaluated for the composite primary outcome of all-cause mortality or first non-fatal cardiovascular event, including myocardial infarction, hospitalization for unstable angina, heart failure or peripheral vascular event. Despite very promising biochemical outcomes from earlier studies with cinacalcet, the reduction in the primary outcome, while numerically positive, was not statistically significant. A more detailed analysis of this study will be completed once the paper is published.

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SGLT2 inhibitors and nephroprotection: a perspective on the renal outcome data

A long awaited analysis of the renal outcomes from the EMPA-REG study was published in the New England Journal of Medicine on June 14th [2].  As originally reported on UKidney, compared to patients taking placebo, the use of empagliflozin was associated with significant improvements in important renal end-points, namely doubling of serum creatinine and end-stage renal disease (ESRD). While these results are indeed very promising, some perspective is warranted when considering the potential nephroprotective properties of this drug, and of the SGLT2 inhibitor class in general.

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Renal outcomes with Empagliflozin: a game-changer

Data from the EMPA-REG study were unveiled in Stockholm 6 weeks ago. In more than 7,000 adults with type 2 diabetes (T2D) at high risk for CV events, EMPA-REG OUTCOME met its primary endpoint and demonstrated superiority of JARDIANCE, when added to standard of care, in CV risk reduction. The primary endpoint was defined as time to first occurrence of either CV death, or non-fatal myocardial infarction or non-fatal stroke[1].

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Are calcium-based phosphate binders obsolete?

As reported on UKidney, earlier in July 2013, Jamal et al published a systematic review comparing calcium-based phosphate binders with non-calcium-based phosphate binders in terms of their impact on cardiovascular outcomes. This pivotal work shows a small but statistically significant advantage of non-calcium-based binders over calcium vis-à-vis mortality outcomes in patients with chronic kidney disease and hyperphosphatemia.

Calcium dose has been implicated in the development of vascular calcification and in the excess cardiovascular morbidity common in patients with CKD, especially those on dialysis. The hope for non-calcium-based phosphate binders has always been that by limiting calcium intake, patients taking non-calcium-based binders would benefit from phosphate reduction without the exposure to potentially harmful dosages of calcium. While individual clinical trials have failed to show any clear advantage of non-calcium-based phosphate binders in terms of reducing cardiovascular morbidity and mortality, this latest systematic review now shows a statistically significant advantage of non-calcium-based phosphate binders over calcium in terms of limiting mortality in patients with CKD.

So where do we go from here? There will likely be discussion as to whether the finding in this systematic review is valid. Furthermore, even if the effect is indeed real, the cost of non-calcium-based binders over calcium-based binders is substantial. Nevertheless, it is likely time to consider whether calcium-based phosphate binders should be made obsolete. There are now substantial data supporting at least a modest effect of calcium dose on mortality and the rationale for using phosphate binders that are not calcium-based. An important question remains as to whether hyperphosphatemia should be treated at all – that is, with binders of any sort. It is entirely possible that non-calcium-based phosphate binders are superior to calcium simply because they limit calcium intake and that the drugs themselves do not offer any other outcome advantage - even if they lower phopshate.

And so, while this systematic review comes closer to answering a long-standing question in nephrology related to optimal phosphate binder class, it underscores an important lingering question as to whether hyperphosphatemia requires treatment at all. To answer this critical question, we require a long overdue placebo-controlled trial of hyperphosphatemia treatment. Objections to a placebo-controlled trial in this area have often centered around the ethics of withholding treatment for hyperphohsphatemia in the form of phosphate binders. However, there appears to be equipoise in this area; there is real uncertainty as to the saftey of calcium-based phosphate binders and whether hyperphosphatemia truly mediates cardiovascular illness in patients with CKD, or if it is only a disease association and nothing more.

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Calcium-based phosphate binders likely harmful in CKD

Researchers from the University of Toronto and the University of Alberta add to existing data that calcium-based phosphate binders are harmful compared to binders that do not contain calcium. An updated systematic review on this topic that appears in the July 19th online version of the Lancet shows that patients with CKD across 8 studies (5 randomized) treated with non-calcium based binders had a 22% reduction in all-cause mortality compared to those taking calcium based binders.

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SAVOR Trial Negative: No CVD advantage for Saxagliptin

Top-line results for the SAVOR trial were announced this week in which Saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) failed to demonstrate superiority over placebo in reducing a composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke when added to usual care in patients with type 2 diabetes with either a history of established CVD or multiple CVD risk factors.  While the trial did demonstrate non-inferiority from a cardiovascular safety perspective, it failed to show any efficacy advantage. As reported originally on

Princeton, NJ and Wilmington, DE - The SAVOR-TIMI 53 trial has failed to demonstrate the superiority ofsaxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) over placebo in reducing a composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke when added to usual care in patients with type 2 diabetes with either a history of established CVD or multiple CVD risk factors [1].

The trial sponsors, Bristol-Myers Squibb and AstraZeneca, announced the top-line results from the trial early this morning. The full findings will be presented September 2, 2013 at the European Society of Cardiology(ESC) 2013 Congress. The trial did meet its "primary safety objective of noninferiority" vs placebo, a joint statement from the companies reads. SAVOR-TIMI-53 is part of an ESC hot-line session dedicated to risk factors and diabetes. The full schedule of ESC 2013 hot lines was published on the ESC website earlier this week.

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. Other, nonrandomized analyses had raised hopes that this class of drugs might have a protective effect on the vasculature of diabetes patients.

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. 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, and principal investigators for the trial are Dr Itamar Raz (Hadassah Medical Organization, Jerusalem, Israel) and Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA).

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Tolvaptan in Polycystic Kidney Disease (ADPKD): the most exciting nephrology development in years

The High Impact Clinical Trials Session at this year's American Society of Nephrology Renal Week was the site of one of the most important and exciting nephrology developments to materialize in years. Researchers presented the results of a Phase 3 study using Tolvaptan (a vasopressin receptor antagonist) for the treatment of autosomal dominant polycystic kidney disease (ADPKD). Previously a disease with no medical treatment, ADPKD accounts for 10% of the dialysis population and is associated with pain, hematuria, hypertension and a number of extra-renal manifestations.

The Tempo 3:4 Study randomized 1445 patients to receive a mean dose of 95 mg of Tolvaptan versus placebo over a 3 year period of observation. Patients receiving active drug experienced a slowing of kidney volume by 50% and also a slower deterioration in GFR,  the primary and secondary outcomes of the study respectively. While there was a greater number of adverse effects related to the medication (polyuria, thirst, hyperuricemia, gout, hepatitis, hypernatremia), there were less ADPKD-related effects (pain, hemturia, urinary tract infection).

While the primary invstigator V. E Torrres was quick to temper enthusiasm until regulatory bodies such as the FDA weigh in on these findings, this study is a major breakthrough in the management of ADPKD and represents a shining example of bench to bedside research that will provide hope for a large group of patients who previously had no medical option for delaying the onset of end-stage renal disease in ADPKD. This will truly be a fascinating story to watch unfold as more study in this area continues.

Please see the New England Journal of Medicine publication here.

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Bardoxolone study terminated over excess mortality

Some very disappointing news released today, as seen on Reuters:

Oct 18 (Reuters) - Abbott Laboratories Inc said its partner Reata Pharmaceuticals was discontinuing a late-stage trial of their potential blockbuster treatment for chronic kidney disease and diabetes based on safety concerns raised by an independent safety committee. The news for bardoxolone represents a major setback for Abbott just months before the planned Jan. 1 spinoff of its branded prescription drugs into a separate publicly traded company called AbbVie. Without the high-profile drug, Wall Street concerns about AbbVie's dependence on Abbott's $8 billion-a-year rheumatoid arthritis drug Humira could intensify. An independent data monitoring committee found excess serious adverse events and mortality in patients taking the oral anti-inflammatory drug, Abbott said in a regulatory filing.

Regulators were notified of the decision, and study participants were being informed, the company said.

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Fascinating new therapy for PCKD on the horizon

While the nephrology community awaits the outcome of a much awaited study of tolvaptan on progression of polycystic kidney disease (PCKD), a new story is emerging with very intriguing possibilities.
Previously on UKidney, we reported the disappointing outcomes with mTOR-based treatments on PCKD outcomes. While in one study with everolimus, cyst volume was blunted, renal functional loss was unchanged at the expense of greater side effects. The problem with this approach in treating PCKD is one that plagues drug therapy for many other conditions, namely that one must expose all tissues to a drug in the hope that target organ, receives adequate therapeutic exposure. The result of this strategy is overdosing the bystander organs and potentially under-dosing the target organ.
A new drug is emerging that could change all of this. FC-rapa conjugates rapamycin with folate, capitalizing on the observation that PCKD cells express high levels of folate receptors. The result is that this chimeric compound delivers a greater concentration of the drug to its target while sparing a greater number of bystander tissues. According to Dr. Jonathan M. Shillingford, who is lead investigator in this work, the uptake of FC-rapa by tissues other than the kidney would be negligible and in their studies, only kidney cells were shown to take up the chimeric compunds (see commment below). Endocyte, the company behind the congujgated rapamycin specializes in this technique which is being studied increasingly in cancer treatments as well. It is very early in the life-cycle of FC-rapa, but in one study seen in the Journal of the Amercian Society of Nephrology, the drug was highly effective at limiting cyst growth in mice while side effects are much fewer than with conventional rapamycin.
Along with the possibility of using tolvaptan to treat PCKD, this resurgence in mTOR-based treatments further brightens the horizon for patients with this disorder.
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Generic drugs: a dangerous public misunderstanding?

Dr. Elizabeth Cohen, senior medical correspondent for CNN's Health, Medical and Wellness unit made a dangerously incorrect statement in her report on generic drugs in the US (Seen at approximately 1:37 of the following video).

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Bardoxolone in Chronic Kidney Disease: A major breakthrough?

In this week's New England Journal of Medicine, Pergola et al report the results of a phase 2 randomized trial of an antioxidant inflammation modulator, bardoxolone, in patients with type 2 diabetes and chronic kidney disease (CKD). Over a period of 52 weeks, 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m2 of body-surface area) were randomized in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. Primary outcome was a change from baseline in the estimated GFR with bardoxolone, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks. The results were quite surprising.

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Dilemma for Dialysis Patients, Skinny is Dangerous

SAN DIEGO—Dialysis patients with low body fat are at increased risk of death—even compared to patients at the highest level of body fat percentage, according to research being presented at the American Society of Nephrology's 42nd Annual Meeting and Scientific Exposition in San Diego.

"Our study indicates that body fat may be protective in dialysis patients," said Kamyar Kalantar-Zadeh, PhD, of LABioMed at Harbor-UCLA. "The results add to the increasing number of reports about the 'obesity paradox' or 'reverse epidemiology' in patients with chronic kidney disease and other chronic diseases."

Nephrologists have puzzled over the "obesity paradox" in dialysis patients, Kalantar-Zadeh said. "Counter-intuitively, higher body mass index is associated with greater survival in hemodialysis patients. We hypothesized that very low body fat—less than ten percent—would be a strong predictor of mortality."

Using near-infrared interactance technology, the researchers measured body fat percentage in 671 hemodialysis patients from eight California dialysis centers. They then compared five-year mortality rates for patients at different levels of body fat percentage. The mortality rate was highest for dialysis patients with less than 10 percent body fat—2.5 to 3 times higher than for those with body fat of 20 to 30 percent. The increased risk of death for patients with very low body fat remained after adjustment for age, sex, race, other illnesses, and key laboratory results. Further analyses using continuous values of body fat (rather than categories) confirmed a direct, linear relationship between body fat and mortality risk: "The higher the body fat, the greater the survival," said Kalantar-Zadeh. Although more research is needed, the results suggest that the obesity paradox may be explained by an increased risk of death for patients with very low body fat, compared to those with average—or even very high—body fat percentage.

The observational study had the same limitations as other epidemiological studies, Kalantar-Zadeh points out. "In addition, we estimated body fat by measuring the subcutaneous fat of the upper arm, which may be different from the intra-abdominal fat." 10/31/2009

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Amgen Announces Top-Line Results of Trial to Reduce Cardiovascular Events With Aranesp(R) Therapy (TREAT) in CKD Patients With Type-2 Diabetes

No Statistically Significant Difference in Cardiovascular and Renal Composite Endpoints Between Aranesp and Placebo

THOUSAND OAKS, Calif., Aug. 25 /PRNewswire-FirstCall/ -- Amgen (Nasdaq: AMGN) today announced that in a large, randomized, double-blind, placebo-controlled, Phase 3 study of patients with chronic kidney disease (CKD) (not requiring dialysis), anemia and type-2 diabetes (the Trial to Reduce CardiovascularEndpoints with Aranesp((R)) Therapy, or TREAT), treatment of anemia with Aranesp((R) )(darbepoetin alfa) to a hemoglobin target of 13 g/dL had no statistically significant effect on either of two primary endpoints compared with placebo treatment. The two primary endpoints were a composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and a composite of time to all-cause mortality or chronic renal replacement therapy. Among the elements that formed these composite endpoints, an excess of stroke events (a labeled risk of Aranesp therapy) occurred in the Aranesp-treated patients compared to those receiving placebo.


These summary results will be followed by full efficacy and safety analyses, which will be shared with global regulatory authorities and presented at an upcoming medical meeting later this year.

"TREAT was designed to answer important questions about the effects of erythropoiesis-stimulating agents (ESAs) on cardiovascular and renal outcomes in patients with renal insufficiency and type-2 diabetes. It is by any measure the most comprehensive analysis that has ever been performed to examine the impact of anemia therapy in patients who do not yet require dialysis. The trial will provide nephrologists with important information as they endeavor to improve renal care," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "In contrast to a recent, smaller study of ESAs in a similar patient population, TREAT did not show a statistically significant adverse effect on all-cause mortality or cardiovascular morbidity when patients were treated to a hemoglobin target of 13 g/dL. We continue to believe that ESAs have a favorable benefit:risk profile when used according to the approved label."

Currently, Aranesp is indicated for the treatment of anemia in patients with chronic renal failure (CRF), including patients on dialysis and patients not on dialysis. The approved label for Aranesp recommends individualizing dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL. TREAT studied uses for Aranesp in which it is not approved.

TREAT Study Design

TREAT was an international, Phase 3, randomized, double-blind, placebo-controlled study of 4,038 chronic kidney disease (CKD) patients with type-2 diabetes and anemia. It is the largest study of ESA use in CKD patients to date. Patients enrolled in the study were randomized in a one-to-one ratio to receive either treatment with Aranesp to a target hemoglobin of 13 g/dL or placebo. Due to the increased risk of negative outcomes associated with low hemoglobin levels, patients in the control arm whose hemoglobin fell below 9 g/dL were given Aranesp until their hemoglobin level was 9 g/dL. Investigators were blinded to this intervention.


TREAT had two primary endpoints. The first evaluated time to all-cause mortality or cardiovascular morbidity including heart attack (myocardial infarction), congestive heart failure, hospitalization for angina (myocardial ischemia), or stroke (cerebrovascular accident). The second primary endpoint evaluated time to all-cause mortality or chronic dialysis. TREAT was not designed to determine the appropriate hemoglobin target in this patient population.


For patients randomized to the Aranesp group, the starting dose was 0.75 mcg/kg administered subcutaneously every two weeks; subsequent doses were titrated to achieve hemoglobin target of 13.0 g/dL. Once the target hemoglobin was reached, the frequency of administration was extended to once-monthly.


Chronic Kidney Disease: Impact and Prevalence

CKD affects more than 26 million Americans and millions more worldwide. The disease is characterized by progressive kidney damage and impaired kidney function and is most often caused by type-2 diabetes or high blood pressure. When CKD progresses to kidney failure, chronic dialysis or a kidney transplant are required to sustain life. Approximately 350,000 people in the United States are on dialysis today. Anemia is a common complication of CKD that may begin in the early stages of the disease and becomes more common and severe as kidney function declines. Studies have shown that anemia is associated with an increased risk of mortality and cardiovascular morbidity in CKD patients.


About Aranesp

Aranesp was approved by the U.S. Food and Drug Administration in 2001 for the treatment of anemia associated with CRF for patients on dialysis and patients not on dialysis. The European Commissiongranted marketing authorization for the same indication in 2001 and subsequently updated it for CRF patients with symptomatic anemia in 2008.


In 2002, the FDA approved the treatment of anemia caused by concomitantly administered chemotherapy in patients with nonmyeloid malignancies. The European Commission authorized the treatment of anemia caused by concomitantly administered chemotherapy in patients with non-haemological malignancies in 2002 and extended it to include non-myeloid malignancies in patients receiving chemotherapy in 2003.


Important Aranesp Safety Information



Renal failure: Patients experienced greater risks for death and serious cardiovascular events when administered erythropoiesis-stimulating agents (ESAs) to target higher versus lower hemoglobin levels (13.5 vs. 11.3 g/dL; 14 vs. 10 g/dL) in two clinical studies. Individualize dosing to achieve and maintain hemoglobin levels within the range of 10 to 12 g/dL.




-- ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers when dosed to target a hemoglobin of greater than or equal to 12 g/dL.


-- To minimize these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.


-- Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.


-- ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. (This information is specific to the U.S. prescribing information)


-- Discontinue following the completion of a chemotherapy course.


Aranesp is contraindicated in patients with uncontrolled hypertension.


All patients, including patients with cancer or chronic kidney failure:


-- You may get serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with Aranesp to a hemoglobin level above 12 g/dL.


-- You may get blood clots at any time while taking Aranesp. If you are receiving Aranesp and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus).



About Amgen

Amgen discovers, develops, manufactures and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe and effective medicines from lab, to manufacturing plant, to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives. To learn more about our pioneering science and our vital medicines, visit


Forward-Looking Statements

This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in theSecurities and Exchange Commission (SEC) reports filed by Amgen, including Amgen's most recent annual report on Form 10-K and most recent periodic reports on Form 10-Q and Form 8-K. Please refer toAmgen's most recent Forms 10-K, 10-Q and 8-K for additional information on the uncertainties and risk factors related to our business. Unless otherwise noted, Amgen is providing this information as of Aug. 25, 2009 and expressly disclaims any duty to update information contained in this news release.


No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and products liability claims. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.


In addition, sales of our products are affected by the reimbursement policies imposed by third-party payors, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment as well as U.S. legislation affecting pharmaceutical pricing and reimbursement. Government and others' regulations and reimbursement policies may affect the development, usage and pricing of our products. In addition, we compete with other companies with respect to some of our marketed products as well as for the discovery and development of new products. We believe that some of our newer products, product candidates or new indications for existing products, may face competition when and as they are approved and marketed. Our products may compete against products that have lower prices, established reimbursement, superior performance, are easier to administer, or that are otherwise competitive with our products. In addition, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors and there can be no guarantee of our ability to obtain or maintain patent protection for our products or product candidates. We cannot guarantee that we will be able to produce commercially successful products or maintain the commercial success of our existing products. Our stock price may be affected by actual or perceived market opportunity, competitive position, and success or failure of our products or product candidates. Further, the discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations.


The scientific information discussed in this news release related to our product candidates is preliminary and investigative. Such product candidates are not approved by the U.S. Food and Drug Administration(FDA), and no conclusions can or should be drawn regarding the safety or effectiveness of the product candidates. Only the FDA can determine whether the product candidates are safe and effective for the use(s) being investigated. Further, the scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by theU.S. Food and Drug Administration (FDA) for the products. The products are not approved for the investigational use(s) discussed in this news release, and no conclusions can or should be drawn regarding the safety or effectiveness of the products for these uses. Only the FDA can determine whether the products are safe and effective for these uses. Healthcare professionals should refer to and rely upon the FDA-approved labeling for the products, and not the information discussed in this news release.






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INSPRA approved as adjunct to standard therapy to reduce risk of death

KIRKLAND, QC, June 3 /CNW/ - A new treatment option for heart failure is now available in Canada (from CNW Group)

Canada as an adjunct to standard therapy, to reduce the risk of deathfollowing a heart attack in clinically stable patients who have evidence of heart failure and left ventricular systolic dysfunction: INSPRA (eplerenonetablets) is the first aldosterone receptor blocker to be approved for thisindication in Canada. In the landmark Eplerenone Post-acute myocardial infarction Heart failureEfficacy and SUrvival Study (EPHESUS),(1) INSPRA provided significant earlyand sustained all-cause mortality benefits above and beyond standardtherapies, including angiotensin converting enzyme (ACE) inhibitors,angiotensin receptor blockers (ARBs) and beta blockers in patients with acutemyocardial infarction (AMI) complicated by heart failure. "Pfizer Canada is pleased to introduce INSPRA as part of our establishedportfolio of cardiovascular treatment options. This innovative medication willprovide Canadians afflicted by congestive heart failure after a myocardialinfarcation, with a proven and effective treatment," said Dr. Bernard Prigent,Vice President and Medical Director, Pfizer Canada Inc. "We are confident thatINSPRA will become an essential, life-saving component of standardpost-myocardial infarction care in Canada, based on the 2009 American Collegeof Cardiology and American Heart Association guidelines that recommendshort-term and long-term use of aldosterone blockade."

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Sodium bicarbonate replacement delays progression of chronic kidney disease

In the latest edition of the Journal American Association of Nephrology, investigators report that sodium bicarbonate administration delays the progression of kidney disease to end-stage renal failure. 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m2) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard care for 2 yr. With this simple intervention, patients receiving sodium bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P < 0.0001). Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88 ml/min 1.73 m2; P < 0.0001). Nutritional parameters were improved as well. This very simple intervention, practiced variably by nephrologists, shows great promise in the management of patients with chronic kidney disease.

Click here to download the PDF

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High cut-off hemodialysis for the treatment of multiple myeloma

Myeloma cast nephropathy has a very high morbidity and mortality, largely due to many of these patients' dependence on hemodialysis. Several attempts have been made to improve these outcomes with extracorporeal strategies that remove toxic light chains characteristic of this disease. In the latest issue of the Clinical Journal of the American Society of Nephrology, investigators report on an uncontrolled pilot study of high cut off hemodialysis (HCO-HD), a strategy that removes light chains in addition to traditional solutes. Although uncontrolled, 75% of patients studied became independent of dialysis compared to traditional studies where fewer than 25% come off dialysis. This promising result will be studied further in a multicenter randomized control trial, known as EuLITE (European Trial of Free Light Chain Removal by Extended Hemodialysis in Cast Nephropathy).


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ASH: Calcium Channel Blocker Benefits in ACCOMPLISH Not Explained by Ambulatory BP

By Crystal Phend, Staff Writer, MedPage Today
Published: May 12, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

SAN FRANCISCO, May 12 -- Ambulatory blood pressure monitoring didn't explain the cardiovascular advantage of calcium channel blockade found in the ACCOMPLISH trial, researchers said.

The primary findings of that trial revealed a 20% reduction in cardiovascular mortality and morbidity with the calcium channel blocker amlodipine (Norvasc) versus the diuretic hydrochlorothiazide (Microzide) as the initial antihypertensive in combination with the ACE inhibitor benazepril (Lotensin).

But in a secondary analysis of ACCOMPLISH results, 24-hour blood pressure monitoring revealed no difference in blood pressure control between the regimens, Kenneth Jamerson, M.D., of the University of Michigan in Ann Arbor, and colleagues found.

These results affirm that the calcium channel blocker combination has some "pleiotropic" benefits beyond blood pressure lowering alone, Dr. Jamerson reported at the American Society of Hypertension meeting.
Action Points  

    * Note that guidelines from the National Heart, Lung, and Blood Institute (JNC 7) recommend thiazide-type diuretics as initial therapy for most hypertensive patients, whether alone or in combination with an agent from another class.

    * Note that this study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

"It really does matter what agent you use," he said.

After the primary report of the data, concerns had arisen that lower blood pressure in the calcium channel blocker group biased the results, commented co-author George Bakris, M.D., of the University of Chicago, who moderated a press conference at which the findings were presented. (See ACC: Calcium Channel Blocker Beats Diuretic for Initial BP Combo Therapy)

Also, the trial used hydrochlorothiazide rather than the longer-acting diuretic chlorthalidone, which could have meant less blood pressure control over the full 24 hours compared with the other combination regimen.

But the ambulatory blood pressure results lay these questions to rest, Dr. Jamerson said.

"This type of data has the potential to change the paradigm to treat blood pressure from mostly being diuretic-based combination therapy to being amlodipine with benazipril type regimens," he said.

In the analysis of 573 patients in ACCOMPLISH, the in-clinic systolic blood pressure after two years of treatment averaged 0.6 mm Hg lower with amlodipine plus benazipril compared with hydrochlorothiazide plus benazipril (129.7 versus 130.3 mm Hg, P=0.621).

But the 24-hour blood pressure average actually favored the diuretic-ACE combination (122.3 versus 123.9 mm Hg, P=0.128), as did daytime and nighttime averages (P=0.097 and P=0.332).

For diastolic pressure, the diuretic combination also had a small, 0.3-mm Hg advantage over 24 hours (P=0.7).

None of these were significant differences, and both groups attained greater than 80% blood pressure control rates (81.3% with the calcium channel blocker and 84.9% with the diuretic combination, P=0.243).

Dr. Bakris said that a calcium channel blocker may have "pleiotropic" benefits for endothelial function and the atherosclerotic process that may have lowered cardiovascular risk despite similar blood pressure.

However, some at the late-breaking clinical trials session where the research was presented were skeptical.

Marvin Moser, M.D., of Yale University, who moderated the session, cautioned that the conclusions of the trial may have been overstated.

"The weight of data suggests it's the blood pressure level and not the specific drug," he said.

Guidelines from the National Heart, Lung, and Blood Institute (JNC 7) recommend thiazide-type diuretics as initial therapy for most hypertensive patients, whether alone or in combination with an agent from another class.

"Diuretics have held up as well as anything else," Dr. Moser said. "Before we abandon them we need further confirmation."

Another study presented at the same session, on which Dr. Bakris was also a co-author, suggested there was no difference between agents for left ventricular hypertrophy regression. (See ASH: Lower Blood Pressure Trumps Regimen in LV Remodeling)

Dr. Bakris noted that this surrogate endpoint may be important, but doesn't capture broader cardiovascular effects or the more important mortality endpoint.
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More evidence for mycophenolate mofetil in lupus nephritis

Many nephrologists, myself included, are eager to find alternatives to cyclophosphamide in the management of lupus nephritis. As many of these patients are young men and women of child-bearing age, the effects of cyclophosphamide on fertility, along with bone marrow and other adverse effects make alternative medications more attractive. Several studies have suggested that mycophenolate mofetil (MMF) may be superior and less toxic than cyclophosphamide in the management of lupus nephritis. In the May issue of the Journal of the American Society of Nephrology, investigators report the result of a study comparing IV cyclophsphamide with oral MMF. While a reprint is not yet available for review, preliminary reports suggest that MMF is slightly more effective and less toxic in this trial. In a 24-week open-label induction study of 370 patients with class III-V lupus, there were no differences in the primary end-point (a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine) or the secondary end-point (complete renal remission, systemic disease activity and damage, and safety).  As well, there were no differences in the rate of adverse events between the 2 groups. For the studied patients, IV cyclophosphamide and oral MMF share similar efficacy and harm. This study adds to the growing evidence base showing no difference between these 2 treatment strategies.

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