A serious medical condition that leads to increased mortality and morbidity if left untreated
Anemia generally exists when hemoglobin is less than 13 g/dL in men and 12 g/dL in women. Anemia has a number of potential causes, including nutritional deficiencies, iron deficiency, bone marrow disease, medications, and abnormalities in EPO production or sensitivity. Common causes of anemia due to inadequate EPO production include chronic kidney disease (CKD), age, heart failure, inflammatory diseases, cancer, and other critical illnesses.
Untreated anemia is associated with chronic fatigue, increased risk of progression of multiple diseases, and death. This morbidity and mortality risk has been clearly shown in the CKD population, where in patients age 66 and older, anemic patients with mid-stage CKD (stage 3) have a 149% increase in cardiovascular events and patients with severe CKD (stage 4 and 5) have a 24% increase in cardiovascular events versus non-anemic patients in the same group, according to a paper published in 2006 in the peer-reviewed journal Blood. Similarly, compared to non-anemic patients, anemia increases the mortality rate by 199% in mid-stage CKD, and 59% in severe CKD. Successful treatment of anemia significantly improves patients’ quality of life, especially with respect to vitality, fatigue, and physical function. In addition, patients whose anemia has been successfully treated have demonstrated lower mortality rates, less frequent hospitalization, and decreases in cardiovascular morbidity.
Chronic kidney disease (CKD), a serious and worsening global healthcare problem, will lead to growing prevalence of severe anemia
The prevalence and severity of anemia in CKD increases as renal function deteriorates. This is because a high proportion of the required EPO is produced in the kidneys. As CKD progresses, the combined effect of decreased RBC production from lower EPO signaling, increased rate of RBC destruction, and reduced iron availability to the bone marrow results in the increased prevalence and severity of anemia.
More about CKD, a common cause of anemia
CKD is a condition in which the kidneys are progressively damaged to the point that they cannot properly filter the blood circulating in the body. This damage can cause waste products to build up in the subject’s blood and can lead to other health problems, including cardiovascular disease, anemia, and bone disease. CKD patients are classified by the degree of their loss of kidney function as measured by the glomerular filtration rate, or GFR, and albuminuria, the protein levels in urine. CKD affects more than 30 million people in the United States, and the prevalence of anemia is associated with the severity of CKD in this population.
There are many causes of CKD, the most common of which are diabetes and hypertension. The prevalence and incidence of CKD is increasing in all segments of the US population, particularly in patients over 65, as shown below. Risk factors for the development of CKD include underlying disease (hypertension, diabetes, and cardiovascular disease), lifestyle factors (tobacco use and inactivity), family history, aging, and prenatal factors (maternal diabetes mellitus, low birth weight, and small-for-gestational-age status).
Beyond the United States, according to a May 2013 article from The Lancet, projected worldwide population changes suggest that the potential number of cases of kidney disease, specifically end stage, will increase disproportionately in developing countries such as China and India, where the numbers of elderly people are expanding. This effect will be enhanced further if the trends of increasing hypertension and diabetes prevalence persist, competing causes of death—such as stroke and cardiovascular diseases—are reduced, and access to treatment improves.
These global trends will continue to lead to an increase in prevalence of anemia globally.
Current treatments leave a substantial unmet need
Injectable recombinant erythropoietin stimulating agents (rESAs), including epoetin alfa, epoetin beta, and darbepoetin alfa, are currently the standard of care for treating anemia in patients with CKD and must be administered intravenously or subcutaneously with iron supplements.
Based on the reported revenues of companies that market and sell rESAs, we estimate that global sales of injectable rESAs were $7 billion in 2013, as compared to an estimated $12 billion in 2006. Of these 2013 revenues, an estimated $3.5 billion were generated in the United States, the vast majority of which were for renal indications.
In 2006, data on the risks of rESA use among these patients started to become available, forcing physicians to balance serious safety concerns against the efficacy of rESAs. The safety concerns with injectable rESA use include increased risk of cardiovascular disease as well as a potentially increased rate of tumor progression in patients with cancer. We believe that the decline in market revenue since 2007 is a direct result of these increased safety concerns, as well as reimbursement pressures.
We also believe that an opportunity exists for a safer, well-tolerated alternative to replace injectable rESAs as the standard of care for anemia.
As a result of the safety concerns related to rESA use, patients have been forced to live with lower hemoglobin levels, higher rates of transfusions, and more intravenous (IV) iron use. The percentage of patients on dialysis in the United States receiving IV iron has increased from 50% in 1999 to 71% in 2011, which is consistent with the general trend of increasing IV iron. Among US patients receiving IV iron, the mean monthly dose has also increased by 21%. Despite the increased use of iron and rate of transfusions, patients are subject to safety risks related to these alternative treatments to injectable rESAs. The risks of transfusions include the development of antibodies to foreign antigens, transmission of blood-borne pathogens, impairment of venous access in patients with CKD (nondialysis), and iron overload with chronic transfusion. The risks of IV iron include hypersensitivity reactions, such as fatal anaphylactic-type reactions.
High EPO doses, not high hemoglobin levels, appear to be correlated most strongly with adverse outcomes
While there is currently no scientific consensus regarding the adverse cardiovascular outcomes associated with the use of injectable rESAs to normalize hemoglobin levels, the results of the 4 major randomized, controlled clinical trials on the treatment of anemia secondary to CKD with rESAs and adjunctive iron supplementation (Normal Hematocrit Trial/NHCT, CREATE, CHOIR, and TREAT) all showed an increased risk of adverse cardiovascular outcomes. These results were surprising at the time and contradicted the extensive body of data from observational studies that showed reduced mortality and improved health outcomes to be associated with higher hemoglobin levels.
A number of critical post-hoc analyses of the randomized controlled trials data have shifted attention from the role of normalized hemoglobin levels to the potential of dose-related toxicity of injectable rESAs in CKD patients as a contributing factor to the reported adverse cardiovascular outcomes. The strongest correlation of adverse outcomes in the post-hoc analyses has been to the level of the rESA dose, not the hemoglobin level achieved. Learn more
History of safety concerns with injectable rESAs highlights the need for a safe therapeutic alternative
The significant safety risks associated with rESAs are outlined in a black-box warning in their prescribing information. This warning arose from numerous events highlighting the safety concerns of injectable rESAs and the responses by the FDA, as highlighted below.
In 2007, boxed warnings added to the labels of marketed injectable rESAs
As a result of concerns associated with administering injectable rESAs to target higher hemoglobin levels, the FDA required that revised warnings, including boxed warnings, be added to the labels of marketed injectable rESAs advising physicians to monitor hemoglobin levels, use the lowest dose of injectable rESA, and increase the hemoglobin concentration to the lowest level sufficient to avoid the need for RBC transfusions.
In 2007, black-box labeling added
In November 2007, the FDA found evidence that the use of injectable rESAs to increase hemoglobin to more than 12 g/dL can stimulate progression of some cancers. As a result, injectable rESAs were required to contain black-box labeling for this risk. Following this change in labeling, the use of injectable rESAs in cancer patients has declined significantly.
In 2009, clinical trial failure to show benefit regarding all-cause mortality or cardiovascular morbidity (TREAT)
In late 2009, Amgen announced the results from the Trial to Reduce Cardiovascular Endpoints with Aranesp Therapy, or TREAT, its large, randomized, double-blind, placebo-controlled phase 3 study of patients with CKD (not requiring dialysis), anemia, and type 2 diabetes. In this study, Aranesp was used to treat anemia to a target hemoglobin level of 13 g/dL, which was higher than the 10 g/dL to 12 g/dL range previously approved by the FDA in the label. Study results reportedly failed to show benefit compared to the control group with regard to composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and composite of time to all-cause mortality or chronic renal replacement. In addition, higher rates of stroke were reported among patients in the 13 g/dL target group compared with the control group. Finally, among a subgroup of patients with a history of cancer at baseline, a statistically significant increase in deaths from cancer was observed in the Aranesp-treated patients compared to placebo-treated patients.
In 2010, publication by FDA officials supporting more cautious dosing and more frequent hemoglobin monitoring with use of injectable rESAs
In January 2010, FDA officials published an editorial in the New England Journal of Medicine noting that a number of randomized trials, including TREAT, had attempted to show that using injectable rESAs to raise hemoglobin concentrations to higher targets improves clinical outcomes, but instead suggested the opposite. Accordingly, the article indicated that more conservative hemoglobin targets (well below 12 g/dL), more frequent hemoglobin monitoring, and more cautious dosing should be evaluated.
In 2010, Risk Evaluation and Mitigation Strategy (REMS) required for injectable ESAs
In February 2010, the FDA required that injectable rESAs be prescribed and used under a REMS to ensure the safe use of the drugs. As part of the REMS, a medication guide explaining the risks and benefits of injectable rESAs must be provided to all patients receiving injectable rESAs for all indications, and the FDA imposed reporting and monitoring obligations on the manufacturers to ensure compliance.
In 2011, dosing guidelines revisions with injectable ESAs
In June 2011, the FDA cited increased risks of cardiovascular events as a basis for more conservative dosing guidelines for use of injectable rESAs in CKD patients and announced related changes to injectable rESA labeling. The FDA removed the prior target hemoglobin range of 10 to 12 g/dL, and recommended that CKD patients initiate treatment when the hemoglobin level is less than 10 g/dL and reduce or interrupt dosing if the hemoglobin level approaches or exceeds 10 g/dL for nondialysis patients and 11 g/dL for dialysis patients. The FDA also required Amgen to conduct additional clinical trials to explore dosing strategies to minimize hemoglobin variability, rates of change, and excursions.
We believe there is now substantial evidence to suggest that EPO level, not hemoglobin, is the cause of the safety issues in the above trials. The collective preclinical and clinical data support a critical rethinking on the best approach to treating anemia, the appropriate and safe hemoglobin target, and the right time to initiate treatment for these patients.
Vadadustat (also known as AKB-6548) as a potential solution
We are developing our lead product candidate, vadadustat, to be a best-in-class hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor for the treatment of anemia secondary to CKD. We expect vadadustat to offer
- Predictable, meaningful, and sustained improvements in hemoglobin levels
- Once-a-day therapy delivered orally
- A dosing regimen that restores the normal diurnal EPO pattern
- Robust pharmacodynamics and substantially lower peak EPO levels than with injectable rESAs
- Reduced administration of IV or oral iron supplementation
- Differentiated safety profile