UKidney Blog

At the end of 2011, Novartis suspended the ALTITUDE Study, effectively ending the possibility that the direct renin inhibitor (DRI) Aliskiren will play a significant role in the management of patients with CKD already on an ACE or ARB. This development was disappointing but actually represents only part of a growing body of evidence that now casts major doubt on the use of microalbuminuria (MAU) as a treatment surrogate in patients with cardiovascular disease.

The use of MAU as a predictor of cardiovascular risk is sound and supported by a sizable evidence base. There is little doubt that patients with risks for cardiovascular disease who also have MAU are at far greater risk for adverse outcomes including death. In numerous studies, including the Heart Outcomes Prevention Evaluation (HOPE) Trial [7], MAU was the single most potent risk factor for adverse outcomes, with greater predictive power than diabetes, male gender, smoking and hypertension. The fascinating part of this observation is that even seemingly modest elevation in MAU was highly predictive of adverse events. It was very tempting then to anticipate a concomitant reduction in risk among patients whose MAU was targeted for therapeutic reduction with any of: (1) high dose ACE or ARB, (2) combination ACE and ARB, and most recently, (3) combination ACE or ARB with DRI. Unfortunately, recent prospective studies have essentially decimated this hypothesis and in all, proteinuria improved whereas patients did not or actually fared worse.

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).

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.

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

WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR and THROMBOEMBOLIC EVENTS, and TUMOR PROGRESSION

 

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.

 

Cancer:

 

-- 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 www.amgen.com.

 

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.

 

 

SOURCE Amgen

 

 

Nocturnal hemodialysis in the home has emerged as a very impressive modality when managing patients with end-stage renal failure. The added dialysis time, combined with gentle solute and water removal has led to the improvement in several important parameters in patients who undergo it. However, not all patients can manage the complexities or some of the practicalities of having dialysis in the home. In this month's issue of Clinical Journal of the ASN, Dr. Goldstein et al report on their experience with nocturnal dialysis in hospital. Several parameters were positively effected by this novel therapy where patients sleep three nights per week at St. Michael's Hospital in Toronto. The study suggests that this modality is a viable option when caring for patients with end-stage renal failure.

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The Trillium Gift of Life Program has launched a very innovative website promoting organ donation. The website is very slick and provides excellent and entertaining information on organ donation. Have a look.

 

 

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Professor Jonathan Sprent and Dr Kylie Webster from Sydney's Garvan Institute of Medical Research, in collaboration with colleagues, Dr Shane Grey and Stacey Walters reported a major breakthrough in the area of transplantation tolerance in this month's issue of the Journal of Experimental Medicine. This fascinating report describes a method of inducing tolerance of islet cell grafts transplanted into mice. The technique involves combining an antibody with IL2 in a complex that upregulated T-regulatory cells, suppressing T-Killer cells that lead to acute rejection. No immunosuppression was required by the animals and 80% enjoyed tolerance of the graft. While these results are preliminary and in an animal model, it does offer a glimpse at a potential strategy that might obviate  or significantly reduce the need for toxic medications in human transplant recipients of all kinds.

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In a stunning development, Novartis said Tuesday that it will terminate the late-stage ALTITUDE study investigating Rasilez (aliskiren) in patients with type 2 diabetes and renal impairment on the recommendation of an independent data monitoring committee. The company indicated that the committee concluded that "patients were unlikely to benefit" from the addition of Rasilez to standard anti-hypertensives and also identified higher adverse events in this group (source: FirstWord).

On a personal and professional note, these results come as a great disappointment to me. Not only does it suggest no further protection for our patients prescribed this strategy in an effort to reduce the burden of cardiorenal disease, but I was a great believer in the hypothesis and taught about it extensively throughout my career.

The long awaited ROADMAP trial was recently published in the New England Journal of Medicine. This randomized controlled trial enrolled 4,447 patients to determine whether treatment with the angiotensin receptor blocker olmesartan could delay or prevent microalbuminuria.

In the study, blood pressure was targeted at less than 130/80 mmHg, yet patients randomized to the ARB group had a lower clinic blood-pressure by 3.1/1.9 overall. The time to onset of microalbuminuria was increased by 23% in the olmesartan group [hazard ratio for the onset of microalbuminuria 0.77; 95% confidence interval, 0.632 0.94; P=0.01]. However surprisingly, there was fewer cardiovascular deaths in the placebo group [3 versus 15, P=0.01].

This fascinating video discusses the concept of organ generation as a method of bridging the enormous gap between supply and demand that exists among patients who experience organ failure.

This may well move from science fiction to the mainstream in the not-too-distant future.

Click 'Read more' below to see the video

This is a great post on chloroquine in lupus. It appears as below on Skin and Allergy News. A great and promising read:

SNOWMASS, Colo. – The past 12 months have brought a slew of studies making a persuasive case for hydroxychloroquine as a far more important drug in lupus than previously thought. Indeed, the drug could now even be considered essential.

"In 2011, all lupus patients should receive hydroxychloroquine," Dr. David Wofsy flatly declared at a symposium sponsored by the American College of Rheumatology.

"The indication for hydroxychloroquine in lupus is lupus," added Dr. Wofsy, professor of medicine and microbiology/immunology at the University of California, San Francisco.

There is now solid evidence that hydroxychloroquine (Plaquenil) prevents lupus flares, treats the skin manifestations of the disease, protects against thromboembolic events, prevents cardiac neonatal lupus, and prolongs life.

"It will be a very long time before we've proven that any biologic therapy can do all those things," Dr. Wofsy, who is also chief of rheumatology at the San Francisco Veterans Affairs Medical Center.

The Planet 1 and 2 studies are not widely publicized. However, they do provide some eye-opening information.

According to these studies, in patients with diabetes and intact renal function, there was a significant decline in renal function and failure to reduce urinary protein in patients randomized to rosuvastatin but not atorvastatin. Furthermore, there were more renal events in the rosuvastatin group (doubling of serum creatinine and episodes of acute renal failure).

These results are very surprising and difficult to rationalize at face value. Nevertheless, the design of the trials appears sound and the number of patients adequate.

Dr. Marecllo Tonelli from the University of Alberta walks us through this data in his outstanding presentation seen here on UKidney

Nephrology has become a field of medicine that is vastly expanding in knowledge and complexity. The number of students, residents considering the field of nephrology are declining every year. Lot of times the students consider nephrology as a difficult subject to grasp and hence have a "renal fear" to consider this field of medicine. To make nephrology more exciting and fun, and to add adjunctive tools of teaching, there have been attempts to develop interesting tools of teaching in nephrology. Websites like UKidney and others are one such example. E-learning can be used to enhance interest in nephrology. Other innovative tools have been tried as well ( crosswords, anagrams, role playing, concept maps) and we are hoping such tools will aid nephrology education and also enhancement of the field. Here are some links to publications that are reviewing some of these tools. Please give us your comments on these tools and how we can improve and make it more useful for all.

Refs: Link1, Link2, Link3, Link4, Link5, Link6