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AstraZeneca Presents New Data Evaluating Safety and Efficacy of FARXIGA in Patients with Type 2 Diabetes and Moderate Renal Impairment

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DERIVE trial results presented as a late breaker at ENDO 2018

AstraZeneca today announced the results of DERIVE, a Phase 3 study that
evaluated the efficacy and safety of FARXIGA® (dapagliflozin
10 mg), in patients with type 2 diabetes (T2D) with moderate renal
impairment (chronic kidney disease [CKD] stage 3A with eGFR of 45-59 mL
/min /1 .73m2). The results were presented at the Endocrine
Society's 100th Annual Meeting and Expo (ENDO).

FARXIGA, an SGLT2 inhibitor, is indicated as an adjunct to diet and
exercise to improve glycemic control in adults with T2D mellitus.1
FARXIGA is not indicated for weight loss or for the treatment of CKD or
hypertension.

The DERIVE trial randomized 321 patients with T2D (hemoglobin A1C
[HbA1C] between 7-11%; mean 8.2%) and stage 3A CKD (mean estimated
glomerular filtration rate [eGFR] 53 mL/min/1.73m2) from
eight countries and treated them with either dapagliflozin 10 mg or
placebo over 24 weeks.2 The study met its primary and
secondary efficacy endpoints including:

  • Dapagliflozin 10 mg significantly decreased mean HbA1C (-0.37%) vs
    placebo (-0.03%) from baseline to week 24 (difference -0.34%, p
    < 0.001).
  • Dapagliflozin 10 mg significantly reduced mean body weight (-3.17 kg)
    vs placebo (-1.92 kg) from baseline to week 24 (difference -1.25 kg, p
    < 0.001).
  • Dapagliflozin 10 mg significantly reduced mean fasting plasma glucose
    (-21.46 mg/dL) vs placebo (-4.87 mg/dL) from baselines to week 24
    (difference -16.6 mg/dL, p = 0.001).
  • Dapagliflozin 10 mg significantly reduced mean systolic blood pressure
    (-4.8 mm Hg) vs placebo (-1.7 mm Hg) from baseline to week 24
    (difference -3.1 mm Hg, p < 0.05).

The DERIVE trial also provides the following safety information:

  • Mean eGFR was decreased at 24 weeks with dapagliflozin (-3.23
    mL/min/1.73m2) vs placebo (-0.63 mL/min/1.73m2)
    (difference [95% CI]: -2.60 mL/min/1.73m2 [−5.03 vs −0.16]).
  • Overall, adverse events (AEs) occurred in 41.9% of patients with
    dapagliflozin and 47.8% with placebo. AEs related to study treatment
    by the investigators were reported in 10.6% of patients with
    dapagliflozin and 6.2% with placebo. The most frequent AEs related to
    study treatment included urinary tract infection and pollakiuria.
  • No AEs of bone fracture or amputation were reported in the study.

FARXIGA is contraindicated in patients with severe renal impairment
(eGFR <30 mL/min/1.73 m2), end-stage renal disease, or in
patients on dialysis. FARXIGA is not recommended in patients with an
eGFR persistently between 30 and <60 mL/min/1.73 m2. The
recommended starting dose for FARXIGA is 5 mg.

Jim McDermott, PhD, Vice President, US Medical Affairs, Diabetes at
AstraZeneca, said: "We are committed to helping patients with complex
and comorbid diseases like T2D and chronic kidney disease, which is
demonstrated through the breadth of our research and our unique
cardiovascular, renal and metabolic approach. The DERIVE study will help
us learn more and provide additional data for FARXIGA in T2D."

DERIVE adds important information to previous dapagliflozin studies in
patients with T2D diabetes and moderate renal impairment. AstraZeneca is
planning to submit the results of DERIVE to the FDA to add to the
breadth of data already contained within the existing FARXIGA
Prescribing Information.

According to the Centers for Disease Control and Prevention, 30.3
million people in the US have diabetes, and T2D accounts for 90% to 95%
of all diabetes cases.3 T2D is the leading cause of CKD in
the US, affecting over 40% of patients, and sustaining control of
diabetes can help lower patients risk of developing severe kidney
disease.4, 5

Important Safety Information for FARXIGA®
(dapagliflozin)

Contraindications

  • Prior serious hypersensitivity reaction to FARXIGA
  • Severe renal impairment (eGFR <30 mL/min/1.73 m2),
    end-stage renal disease, or patients on dialysis

Warnings and Precautions

  • Hypotension: FARXIGA causes intravascular volume contraction,
    and symptomatic hypotension can occur. Assess and correct volume
    status before initiating FARXIGA in patients with impaired renal
    function, elderly patients, or patients on loop diuretics. Monitor for
    hypotension
  • Ketoacidosis has been reported in patients with type 1 and type
    2 diabetes receiving FARXIGA. Some cases were fatal. Assess patients
    who present with signs and symptoms of metabolic acidosis for
    ketoacidosis, regardless of blood glucose level. If suspected,
    discontinue FARXIGA, evaluate and treat promptly. Before initiating
    FARXIGA, consider risk factors for ketoacidosis. Patients on FARXIGA
    may require monitoring and temporary discontinuation in situations
    known to predispose to ketoacidosis
  • Acute Kidney Injury and Impairment in Renal Function: FARXIGA
    causes intravascular volume contraction and renal impairment, with
    reports of acute kidney injury requiring hospitalization and dialysis.
    Consider temporarily discontinuing in settings of reduced oral intake
    or fluid losses. If acute kidney injury occurs, discontinue and
    promptly treat.

    FARXIGA increases serum creatinine and
    decreases eGFR. Elderly patients and patients with impaired renal
    function may be more susceptible to these changes. Before initiating
    FARXIGA, evaluate renal function and monitor periodically. FARXIGA is
    not recommended in patients with an eGFR persistently between 30 and
    <60 mL/min/1.73 m2
  • Urosepsis and Pyelonephritis: SGLT2 inhibitors increase the
    risk for urinary tract infections [UTIs] and serious UTIs have been
    reported with FARXIGA. Evaluate for signs and symptoms of UTIs and
    treat promptly
  • Hypoglycemia: FARXIGA can increase the risk of hypoglycemia
    when coadministered with insulin and insulin secretagogues. Consider
    lowering the dose of these agents when coadministered with FARXIGA
  • Genital Mycotic Infections: FARXIGA increases the risk of
    genital mycotic infections, particularly in patients with prior
    genital mycotic infections. Monitor and treat appropriately
  • Increases in Low-Density Lipoprotein Cholesterol (LDL-C) occur
    with FARXIGA. Monitor LDL-C and treat per standard of care
  • Bladder cancer: An imbalance in bladder cancers was observed in
    clinical trials. There were too few cases to determine whether the
    emergence of these events is related to FARXIGA, and insufficient data
    to determine whether FARXIGA has an effect on preexisting bladder
    tumors. FARXIGA should not be used in patients with active bladder
    cancer. Use with caution in patients with a history of bladder cancer
  • Macrovascular Outcomes: There have been no clinical studies
    establishing conclusive evidence of macrovascular risk reduction with
    FARXIGA

Adverse Reactions

In a pool of 12 placebo-controlled studies, the most common adverse
reactions (≥5%) associated with FARXIGA 5 mg, 10 mg, and placebo
respectively were female genital mycotic infections (8.4% vs 6.9% vs
1.5%), nasopharyngitis (6.6% vs 6.3% vs 6.2%), and urinary tract
infections (5.7% vs 4.3% vs 3.7%).

Use in Specific Populations

  • Pregnancy: Advise females of potential risk to a fetus
    especially during the second and third trimesters.
  • Lactation: FARXIGA is not recommended when breastfeeding.

Indication and Limitations of Use for FARXIGA®
(dapagliflozin)

FARXIGA is indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.

FARXIGA is not recommended for patients with type 1 diabetes mellitus or
for the treatment of diabetic ketoacidosis.

Please see accompanying US Full
Prescribing Information
and Medication
Guide
for FARXIGA.

NOTES TO EDITORS

About AstraZeneca in Diabetes

AstraZeneca is pushing the boundaries of science with the goal of
developing life-changing medicines that aim to reduce the global burden
and complications of diabetes. As a main therapy area for the company,
we are focusing our research and development efforts on diverse
populations and patients with significant co-morbidities, such as
cardiovascular disease, obesity, non-alcoholic steatohepatitis (NASH),
and chronic kidney disease.

Our commitment to diabetes is exemplified by the depth and breadth of
our global clinical research program. This commitment is advancing the
understanding of the treatment effects of our diabetes medicines in
broad patient populations, as well as exploring combination products to
help more patients achieve treatment success earlier in their disease.

About AstraZeneca in Cardiovascular, Renal & Metabolic Diseases

Cardiovascular, renal and metabolic diseases together form one of
AstraZeneca's main therapy areas and platforms for future growth. By
following the science to understand more clearly the underlying links
between the heart, kidney and pancreas, AstraZeneca is investing in the
development of a portfolio of medicines to protect organs and improve
outcomes by slowing disease progression, reducing risks and tackling
co-morbidities. Our ambition is to modify or halt the natural course of
CVMDs and even regenerate organs and restore function, by continuing to
deliver transformative science that improves treatment practices and
CVMD health for millions of patients worldwide.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that
focuses on the discovery, development and commercialization of
prescription medicines, primarily for the treatment of diseases in three
main therapy areas - Oncology, Cardiovascular & Metabolic Diseases and
Respiratory. The Company also is selectively active in the areas of
Autoimmunity, Neuroscience and Infection. AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. For more information, please visit www.astrazeneca-us.com
and follow us on Twitter @AstraZenecaUS.

1 AstraZeneca Pharmaceuticals. Prescribing Information:
FARXIGA (dapagliflozin). Accessed 12 March 2018 http://www.azpicentral.com/farxiga/pi_farxiga.pdf#page=1
2
Fioretto P on behalf of the DERIVE Investigators and Study Team.
Efficacy and Safety of Dapagliflozin in Patients with Type 2 Diabetes
and Moderate Renal Impairment (Chronic Kidney Disease Stage 3A): The
DERIVE Study [presentation]. Presented at: Endocrine Society's 100th
Annual Meeting and Expo; March 19, 2018; Chicago, IL.
3
National Diabetes Statistics Report, 2017 Estimates of Diabetes and Its
Burden in the United States. Centers for Disease Control and Prevention.
2017. Available at: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf.
Accessed March 6, 2018.
4 Bailey RA, Wang Y, Zhu V,
Rupnow MF. Chronic kidney disease in US adults with type 2 diabetes: an
updated national estimate of prevalence based on Kidney Disease:
Improving Global Outcomes (KDIGO) staging. BMC Research Notes.
2014;7:415. doi:10.1186/1756-0500-7-415.
5 National
Kidney Foundation. Diabetes - A Major Risk Factor for Kidney Disease
Accessed March 2, 2018. https://www.kidney.org/atoz/content/diabetes.

US-18844 Last updated 3/18

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